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  • 1.
    Abu Hamdeh, Sami
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Enblad: Neurosurgery.
    Ciuculete, Diana-Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Sarkisyan, Daniil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Bakalkin, Georgy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Ingelsson, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. Institute for Translational Medicine and Biotechnology, Sechenov First Moscow State Medical University, Moscow, Russia..
    Marklund, Niklas
    Department of Clinical Sciences Lund, Neurosurgery, Skåne University Hospital Lund University, Lund, Sweden .
    Differential DNA methylation of the genes for amyloid precursor protein, tau and neurofilaments in human traumatic brain injury2021In: Journal of Neurotrauma, ISSN 0897-7151, E-ISSN 1557-9042, Vol. 38, no 12, p. 1679-1688Article in journal (Refereed)
    Abstract [en]

    Traumatic brain injury (TBI) is an established risk factor for neurodegenerative disorders and dementias. Epigenetic modifications, such as DNA methylation, may alter the expression of genes without altering the DNA sequence in response to environmental factors. We hypothesized that DNA methylation changes may occur in the injured human brain and be implicated in the neurodegenerative aftermath of TBI. The DNA methylation status of genes related to neurodegeneration, e.g. amyloid beta precursor protein (APP), microtubule associated protein tau (MAPT), neurofilament heavy (NEFH), neurofilament medium (NEFM) and neurofilament light (NEFL), was analyzed in fresh, surgically resected human brain tissue from 17 severe TBI patients and compared with brain biopsy samples from 19 patients with idiopathic normal pressure hydrocephalus (iNPH). We also performed an epigenome-wide association study (EWAS) comparing TBI patients to iNPH controls. Thirty-eight CpG sites in the APP, MAPT, NEFH and NEFL genes were differentially methylated by TBI. Among the top 20 differentially methylated CpG sites, 11 were in the APP gene. In addition, the EWAS evaluating 828 888 CpG sites revealed 308 differentially methylated CpG sites in genes related to cellular/anatomical structure development, cell differentiation and anatomical morphogenesis. These preliminary findings provide the first evidence of an altered DNA methylome in the injured human brain and may have implications for the neurodegenerative disorders associated at long-term with TBI. 

  • 2.
    Affatato, Oreste
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. Uppsala University, WoMHeR (Centre for Women’s Mental Health during the Reproductive Lifespan).
    Miguet, Maud
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. IM Sechenov First Moscow State Med Univ, Inst Translat Med & Biothechnol, Moscow, Russia..
    Mwinyi, Jessica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. Uppsala University, WoMHeR (Centre for Women’s Mental Health during the Reproductive Lifespan).
    Major sex differences in migraine prevalence among occupational categories: a cross-sectional study using UK Biobank2021In: Journal of Headache and Pain, ISSN 1129-2369, E-ISSN 1129-2377, Vol. 22, no 1, article id 145Article in journal (Refereed)
    Abstract [en]

    Background Migraine represents one of the most prevalent neurological conditions worldwide. It is a disabling condition with high impact on the working situation of migraineurs. Interestingly, gender-related differences regarding an association of migraine with important occupational characteristics has been hardly studied. Methods The current study scrutinizes gender-specific differences in the prevalence of migraine across a broad spectrum of occupational categories, shedding also light on associations with important job-related features such as shift work, job satisfaction, and physical activity. The study included data from 415 712 participants from the UK Biobank cohort, using the official ICD10 diagnosis of migraine and other health conditions as selection criteria. Prevalence ratios of migraineurs compared to healthy controls among different occupational categories and job-related variables were estimated using log-binomial regression analyses. Statistical models were adjusted for important sociodemographic features such as age, BMI, ethnicity, education and neuroticism. To better highlight specific differences between men and women we stratified by sex. Results We detected a differential prevalence pattern of migraine in relation to different job categories between men and women. Especially in men, migraine appears to be more prevalent in highly physically demanding occupations (PR 1.38, 95% CI [0.93, 2.04]). Furthermore, migraine is also more prevalent in jobs that frequently involve shift or night shift work compared to healthy controls. Interestingly, this prevalence is especially high in women (shift work PR 1.45, 95% CI [1.14, 1.83], night shift work PR 1.46, 95% CI [0.93, 2.31]). Conclusion Our results show that migraine is genderdependently associated with physically demanding jobs and shift working.

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  • 3.
    Affatato, Oreste
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Moulin, Thiago
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Pisanu, Claudia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. Univ Cagliari, Dept Biomed Sci, Cagliari, Italy..
    Babasieva, Victoria S.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. IM Sechenov First Moscow State Med Univ, Inst Pharm, Dept Pharmacol, Moscow, Russia..
    Russo, Marco
    Azienda USL IRCCS Reggio Emilia, Neuromotor & Rehabil Dept, Neurol Unit, Reggio Emilia, Italy..
    Aydinlar, Elif I.
    Acibadem Univ, Dept Neurol, Sch Med, Istanbul, Turkey..
    Torelli, Paola
    Univ Parma, Dept Med & Surg, Headache Ctr, Parma, Italy..
    Chubarev, Vladimir N.
    IM Sechenov First Moscow State Med Univ, Inst Pharm, Dept Pharmacol, Moscow, Russia..
    Tarasov, Vadim V.
    IM Sechenov First Moscow State Med Univ, Inst Pharm, Dept Pharmacol, Moscow, Russia.;IM Sechenov First Moscow State Med Univ, Inst Translat Med & Biothechnol, Moscow, Russia..
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. IM Sechenov First Moscow State Med Univ, Inst Translat Med & Biothechnol, Moscow, Russia..
    Mwinyi, Jessica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    High efficacy of onabotulinumtoxinA treatment in patients with comorbid migraine and depression: a meta-analysis2021In: Journal of Translational Medicine, ISSN 1479-5876, E-ISSN 1479-5876, Vol. 19, no 1, article id 133Article, review/survey (Refereed)
    Abstract [en]

    Background: Migraine and depression are highly prevalent and partly overlapping disorders that cause strong limitations in daily life. Patients tend to respond poorly to the therapies available for these diseases. OnabotulinumtoxinA has been proven to be an effective treatment for both migraine and depression. While many studies have addressed the effect of onabotulinumtoxinA in migraine or depression separately, a growing body of evidence suggests beneficial effects also for patients comorbid with migraine and depression. The current meta-analysis systematically investigates to what extent onabotulinumtoxinA is efficient in migraineurs with depression.

    Methods: A systematic literature search was performed based on PubMed, Scopus and Web of Science from the earliest date till October 30th, 2020. Mean, standard deviation (SD) and sample size have been used to evaluate improvement in depressive symptoms and migraine using random- effects empirical Bayes model.

    Results: Our search retrieved 259 studies, eight of which met the inclusion criteria. OnabotulinumtoxinA injections administered to patients with both chronic migraine and major depressive disorder led to mean reduction of - 8.94 points (CI [ - 10.04,- 7.84], p < 0.01) in the BDI scale, of - 5.90 points (CI [ - 9.92,- 1.88], p < 0.01) in the BDI-II scale and of - 6.19 points (CI [ - 9.52,- 2.86], p < 0.01) in the PHQ-9 scale, when evaluating depressive symptoms. In the case of the migraine-related symptoms, we found mean reductions of - 4.10 (CI [ - 7.31,- 0.89], p = 0.01) points in the HIT6 scale, - 32.05 (CI [ - 55.96,- 8.14], p = 0.01) in the MIDAS scale, - 1.7 (CI [ - 3.27,- 0.13], p = 0.03) points in the VAS scale and of - 6.27 (CI [ - 8.48,- 4.07], p < 0.01) migraine episodes per month. Comorbid patients showed slightly better improvements in BDI, HIT6 scores and migraine frequency compared to monomorbid patients. The latter group manifested better results in MIDAS and VAS scores.

    Conclusion: Treatment with onabotulinumtoxinA leads to a significant reduction of disease severity of both chronic migraine and major depressive disorder in patients comorbid with both diseases. Comparative analyses suggest an equivalent strong effect in monomorbid and comorbid patients, with beneficial effects specifically seen for certain migraine features.

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  • 4.
    Ai, Sizhi
    et al.
    Chinese Univ Hong Kong, Fac Med, Sha Tin Dist,Dept Psychiat, Li Chiu Kong Family Sleep Assessment Unit, 33 A Kung Kok St, Hong Kong 000000, Peoples R China.;Guangdong Prov Peoples Hosp, Guangdong Acad Med Sci, Guangdong Mental Hlth Ctr, Yuexiu Dist, 123 Huifu West Rd, Guangzhou 510000, Peoples R China.;Xinxiang Med Univ, Heart Ctr, Dept Cardiol, Affiliated Hosp 1, 88 Jiankang Rd, Weihui 453100, Peoples R China..
    Zhang, Jihui
    Chinese Univ Hong Kong, Fac Med, Sha Tin Dist,Dept Psychiat, Li Chiu Kong Family Sleep Assessment Unit, 33 A Kung Kok St, Hong Kong 000000, Peoples R China.;Guangdong Prov Peoples Hosp, Guangdong Acad Med Sci, Guangdong Mental Hlth Ctr, Yuexiu Dist, 123 Huifu West Rd, Guangzhou 510000, Peoples R China.;Southern Med Univ, Sch Clin Med 2, 253 Ind Ave Middle, Guangzhou 510280, Peoples R China..
    Zhao, Guoan
    Xinxiang Med Univ, Heart Ctr, Dept Cardiol, Affiliated Hosp 1, 88 Jiankang Rd, Weihui 453100, Peoples R China..
    Wang, Ningjian
    Shanghai Jiao Tong Univ, Shanghai Peoples Hosp 9, Inst & Dept Endocrinol & Metab, Sch Med, 639 Mfg Bur Rd, Shanghai 200011, Peoples R China..
    Li, Guohua
    Xinxiang Med Univ, Heart Ctr, Dept Cardiol, Affiliated Hosp 1, 88 Jiankang Rd, Weihui 453100, Peoples R China..
    So, Hon-Cheong
    Chinese Univ Hong Kong, Fac Med,Sch Biomed Sci,Sha Tin Dist, Horse Mat Water,Cheung Res Ctr Management Parkins, Dept Psychiat,KIZ CUHK Joint Lab Bioresources & M, Da Xue Rd, Hong Kong 000000, Peoples R China..
    Liu, Yaping
    Chinese Univ Hong Kong, Fac Med, Sha Tin Dist,Dept Psychiat, Li Chiu Kong Family Sleep Assessment Unit, 33 A Kung Kok St, Hong Kong 000000, Peoples R China..
    Chau, Steven Wai-Ho
    Chinese Univ Hong Kong, Fac Med, Sha Tin Dist,Dept Psychiat, Li Chiu Kong Family Sleep Assessment Unit, 33 A Kung Kok St, Hong Kong 000000, Peoples R China..
    Chen, Jie
    Chinese Univ Hong Kong, Fac Med, Sha Tin Dist,Dept Psychiat, Li Chiu Kong Family Sleep Assessment Unit, 33 A Kung Kok St, Hong Kong 000000, Peoples R China..
    Tan, Xiao
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Jia, Fujun
    Guangdong Prov Peoples Hosp, Guangdong Acad Med Sci, Guangdong Mental Hlth Ctr, Yuexiu Dist, 123 Huifu West Rd, Guangzhou 510000, Peoples R China..
    Tang, Xiangdong
    Sichuan Univ, State Key Lab Biotherapy,West China Hosp, Sleep Med Ctr,Mental Hlth Ctr, Translat Neurosci Ctr,Dept Resp & Crit Care Med, 37 Guoxue Alley, Chengdu 610041, Peoples R China..
    Shi, Jie
    Peking Univ, Peking Univ Hosp 6, Natl Inst Drug Dependence, 38 Xueyuan Rd, Beijing 100191, Peoples R China..
    Lu, Lin
    Peking Univ, Peking Univ Hosp 6, Natl Inst Drug Dependence, 38 Xueyuan Rd, Beijing 100191, Peoples R China..
    Wing, Yun-Kwok
    Chinese Univ Hong Kong, Fac Med, Sha Tin Dist,Dept Psychiat, Li Chiu Kong Family Sleep Assessment Unit, 33 A Kung Kok St, Hong Kong 000000, Peoples R China..
    Causal associations of short and long sleep durations with 12 cardiovascular diseases: linear and nonlinear Mendelian randomization analyses in UK Biobank2021In: European Heart Journal, ISSN 0195-668X, E-ISSN 1522-9645, Vol. 42, no 34, p. 3349-3357Article in journal (Refereed)
    Abstract [en]

    Aims Observational studies have suggested strong associations between sleep duration and many cardiovascular diseases (CVDs), but causal inferences have not been confirmed. We aimed to determine the causal associations between genetically predicted sleep duration and 12 CVDs using both linear and nonlinear Mendelian randomization (MR) designs. Methods and results Genetic variants associated with continuous, short (<= 6 h) and long (>= 9 h) sleep durations were used to examine the causal associations with 12 CVDs among 404 044 UK Biobank participants of White British ancestry. Linear MR analyses showed that genetically predicted sleep duration was negatively associated with arterial hypertension, atrial fibrillation, pulmonary embolism, and chronic ischaemic heart disease after correcting for multiple tests (P <0.001). Nonlinear MR analyses demonstrated nonlinearity (L-shaped associations) between genetically predicted sleep duration and four CVDs, including arterial hypertension, chronic ischaemic heart disease, coronary artery disease, and myocardial infarction. Complementary analyses provided confirmative evidence of the adverse effects of genetically predicted short sleep duration on the risks of 5 out of the 12 CVDs, including arterial hypertension, pulmonary embolism, coronary artery disease, myocardial infarction, and chronic ischaemic heart disease (P< 0.001), and suggestive evidence for atrial fibrillation (P < 0.05). However, genetically predicted long sleep duration was not associated with any CVD. Conclusion This study suggests that genetically predicted short sleep duration is a potential causal risk factor of several CVDs, while genetically predicted long steep duration is unlikely to be a causal risk factor for most CVDs. [GRAPHICS] .

  • 5.
    Alsehli, Ahmed
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    The role of HMG-coenzyme A reductase (HMGCR) and statin medication in the Central Nervous System: Cognitive Functions, Metabolism, Feeding and Sleep Behaviour2021Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Millions of people are currently on statin medications (HMGCR inhibitors) to prevent cardiovascular diseases. Despite considerable central nervous system expression, little is known about HMGCR function in the brain. In Paper I, we used Drosophila and rodent models and found that inhibiting Hmgcr expression in the insulin-producing cells of the Drosophila hypothalamus equivalent, known as the pars intercerebralis (PI), throughout development, significantly reduces the expression of Insulin–like peptides 2 and 3 (ILP2 and ILP3), severely decreasing insulin signalling. This reduction causes decreased body size, hyperglycemia, increased lipid storage, and hyperphagia. We also discovered that Farnesyl pyrophosphate synthase (Fpps), an enzyme downstream of Hmgcr in the mevalonate pathway, is required for ILP2 expression in the PI. In rodents, acute inhibition of hypothalamic Hmgcr stimulates food intake as well. Furthermore, in rats, we found two regions within the hypothalamus that had significantly increased neural activity, the paraventricular nucleus and arcuate nucleus, which are known to regulate food intake. In Paper II, we explored the effects of statins on cognition and performed an observational study on a population-based sample from the UK Biobank. Cognitive performance in terms of reaction time, working memory and fluid intelligence was analysed at baseline and two follow-ups. Subjects were classified depending on age (up to 65 and over 65 years). The effect of statin use differed between the two age groups, with a beneficial effect on reaction time in older persons and fluid intelligence in both age groups, and a negative effect on working memory in younger subjects. In Paper III, we examined association of single nucleotide polymorphisms within the HMGCR gene, rs17238484 and rs12916, with self-reported insomnia symptoms. We found that statin users are associated with a higher risk for self-reported insomnia. The HMGCR genetic variants were also associated with self-reported insomnia, but in different manner. Carriers the rs12916-T risk allele had a protective effect from insomnia symptoms. No associations were found for either statin takers or carriers of these HGCMR risk alleles and late evening chronotype. The increased risk of insomnia noted with statins is partially explained by a mechanism that might be independent of HMGCR inhibition. In Paper IV, we discovered a novel role for Hmgcr in sleep regulation in Drosophila, where lacking of pan-neuronal Hmgcr expression causes sleep-promoting effects. We also found that loss of Hmgcr expression specifically in the PI insulin-producing cells, recapitulates the effect of pan-neuronal Hmgcr inhibition. Conversely, inhibiting Hmgcr in only six PI DH44 expressing neurons has the opposite effect on sleep, increasing sleep latency and decreasing sleep duration. This bi-functional property of Hmgcr in the fly brain underlies its importance in sleep regulation. Furthermore, loss of Hmgcr showed no effect on circadian rhythm, suggesting that Hmgcr regulates sleep by pathways distinct from the circadian clock.

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  • 6.
    Alsehli, Ahmed M.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Clemensson, Laura Emily
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Rukh, Gull
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Ciuculete, Diana-Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Tan, Xiao
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Al-Sabri, Mohamed H.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Williams, Michael J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Benedict, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Differential associations of statin treatment and polymorphism in genes coding for HMGCR and PCSK9 to risk for insomnia2021In: Frontiers in Bioscience-Landmark, Vol. 26, no 12, p. 1453-1463Article in journal (Refereed)
    Abstract [en]

    Importance: Statins have been linked to an increased risk for insomnia, but the literature is controversial. Moreover, it is unknown, if the potential effects are directly related to the inhibition of the statin target HMGCR, the subsequently lowered cholesterol levels, or other off-target effects of statins. Aims: To investigate the association of statin treatment and genetic proxies of cholesterol lowering drugs with the risk for insomnia and chronotype in a large population-based cohort. Methods: A cross-sectional cohort study based on baseline data collected between 2006–2010 in UK biobank cohort was conducted. European participants without any history of psychiatric/neurological disorders or of stroke and with available genetic data as well as information on statin use were included in the present study. Self-reported measures of insomnia and chronotype were analysed (a) in statin users versus control subjects, (b) subjects carrying single nucleotide polymorphisms (SNPs) in the HMGCR gene, which are associated with reduced enzymatic function and lower cholesterol levels (rs17238484 and rs12916) and (c) subjects carrying a SNP in the PCSK9 gene (rs1159147), which leads to lower cholesterol levels independent of HMGCR. The main analysis were performed using multivariable regression models. Statin treatment and SNPs in HMGCR and PCSK9 genes were used as exposures and main outcomes were insomnia and chronotype. Results: A total of 206,801participants (mean [SD] age, 57.5 [7.9] years; 56% women; 20% statin users) were included in the present study. Statin users had an increased risk of insomnia compared to controls (odds ratio [95% CI], 1.07 [1.03 to 1.11]; p = 1.42 × 10−4). A similar effect was observed for PCSK9 rs11591147-T allele (1.07 [1.01–1.14]; 0.014), while the two gene variants of HMGCR were associated with a reduced risk for insomnia (rs17238484-G: 0.97 [0.95 to 0.99]; 0.014 and rs12916-T: 0.97 [0.96 to 0.99]; 0.002). In regard to chronotype, there was no effect of either statin treatment or HMGCR SNPs, but the PCSK9 rs11591147-T allele was associated with a higher evening preference (1.17 [1.06 to 1.29]; 0.001). Conclusion: Our data suggests that statin treatment can pose an increased risk for insomnia in in the European population. Interestingly, there was no agreement between the effects of statins and the effects of reduced HMGCR activity based on genetic variants, suggesting that the observed unfavourable effect of statins on sleep is conveyed through other targets. This further explains why the literature on statin effects on sleep is not conclusive. Finally our data encourage further investigations into the molecular processes linking statins, HMGCR and PCSK9 to sleep behaviour.

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  • 7.
    Alsehli, Ahmed M.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Schiöth: Functional Pharmacology. King Abdulaziz Univ & Hosp, Fac Med, Al Ehtifalat St, Jeddah 21589, Saudi Arabia..
    Liao, Sifang
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Schiöth: Functional Pharmacology.
    Al-Sabri, Mohamed H.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Schiöth: Functional Pharmacology.
    Vasionis, Lukas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Schiöth: Functional Pharmacology.
    Purohit, Archana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Schiöth: Functional Pharmacology.
    Behare, Neha
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Schiöth: Functional Pharmacology.
    Clemensson, Laura Emily
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Schiöth: Functional Pharmacology.
    Williams, Michael J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Schiöth: Functional Pharmacology.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Schiöth: Functional Pharmacology. Sechenov First Moscow State Med Univ, Sechenov Biomed Sci & Technol Pk, Inst Translat Med & Biotechnol, Trubetskay Str 8, Moscow 119991, Russia..
    The Statin Target HMG-Coenzyme a Reductase (Hmgcr) Regulates Sleep Homeostasis in Drosophila2022In: Pharmaceuticals, E-ISSN 1424-8247, Vol. 15, no 1, article id 79Article in journal (Refereed)
    Abstract [en]

    Statins, HMG Coenzyme A Reductase (HMGCR) inhibitors, are a first-line therapy, used to reduce hypercholesterolemia and the risk for cardiovascular events. While sleep disturbances are recognized as a side-effect of statin treatment, the impact of statins on sleep is under debate. Using Drosophila, we discovered a novel role for Hmgcr in sleep modulation. Loss of pan-neuronal Hmgcr expression affects fly sleep behavior, causing a decrease in sleep latency and an increase in sleep episode duration. We localized the pars intercerebralis (PI), equivalent to the mammalian hypothalamus, as the region within the fly brain requiring Hmgcr activity for proper sleep maintenance. Lack of Hmgcr expression in the PI insulin-producing cells recapitulates the sleep effects of pan-neuronal Hmgcr knockdown. Conversely, loss of Hmgcr in a different PI subpopulation, the corticotropin releasing factor (CRF) homologue-expressing neurons (DH44 neurons), increases sleep latency and decreases sleep duration. The requirement for Hmgcr activity in different neurons signifies its importance in sleep regulation. Interestingly, loss of Hmgcr in the PI does not affect circadian rhythm, suggesting that Hmgcr regulates sleep by pathways distinct from the circadian clock. Taken together, these findings suggest that Hmgcr activity in the PI is essential for proper sleep homeostasis in flies.

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  • 8.
    Alsehli, Ahmed M.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. King Abdulaziz Univ, Dept Physiol, Fac Med, Al Ehtifalat St, Jeddah 21589, Saudi Arabia..
    Olivo, Gaia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Clemensson, Laura Emily
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Williams, Michael J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. Sechenov First Moscow State Med Univ, Inst Translat Med & Biotechnol, Sechenov Biomed Sci & Technol Pk,Trubetskay Str 8, Moscow 119991, Russia..
    The Cognitive Effects of Statins are Modified by Age2020In: Scientific Reports, E-ISSN 2045-2322, Vol. 10, no 1, article id 6187Article in journal (Refereed)
    Abstract [en]

    To reveal new insights into statin cognitive effects, we performed an observational study on a population-based sample of 245,731 control and 55,114 statin-taking individuals from the UK Biobank. Cognitive performance in terms of reaction time, working memory and fluid intelligence was analysed at baseline and two follow-ups (within 5-10 years). Subjects were classified depending on age (up to 65 and over 65 years) and treatment duration (1-4 years, 5-10 years and over 10 years). Data were adjusted for health- and cognition-related covariates. Subjects generally improved in test performance with repeated assessment and middle-aged persons performed better than older persons. The effect of statin use differed considerably between the two age groups, with a beneficial effect on reaction time in older persons and fluid intelligence in both age groups, and a negative effect on working memory in younger subjects. Our analysis suggests a modulatory impact of age on the cognitive side effects of statins, revealing a possible reason for profoundly inconsistent findings on statin-related cognitive effects in the literature. The study highlights the importance of characterising modifiers of statin effects to improve knowledge and shape guidelines for clinicians when prescribing statins and evaluating their side effects in patients.

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  • 9.
    Amorim, Felippe E.
    et al.
    Univ Fed Rio de Janeiro, Inst Med Biochem Leopoldo de Meis, BR-21941902 Rio De Janeiro, Brazil..
    Chapot, Renata L.
    Univ Fed Rio de Janeiro, Inst Med Biochem Leopoldo de Meis, BR-21941902 Rio De Janeiro, Brazil..
    Moulin, Thiago
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Lee, Jonathan L. C.
    Univ Birmingham, Sch Psychol, Birmingham B15 2TT, W Midlands, England..
    Amaral, Olavo B.
    Univ Fed Rio de Janeiro, Inst Med Biochem Leopoldo de Meis, BR-21941902 Rio De Janeiro, Brazil..
    Memory destabilization during reconsolidation: a consequence of homeostatic plasticity?2021In: Learning & memory (Cold Spring Harbor, N.Y.), ISSN 1072-0502, E-ISSN 1549-5485, Vol. 28, no 10, p. 371-389Article in journal (Refereed)
    Abstract [en]

    Remembering is not a static process: When retrieved, a memory can be destabilized and become prone to modifications. This phenomenon has been demonstrated in a number of brain regions, but the neuronal mechanisms that rule memory destabilization and its boundary conditions remain elusive. Using two distinct computational models that combine Hebbian plasticity and synaptic downscaling, we show that homeostatic plasticity can function as a destabilization mechanism, accounting for behavioral results of protein synthesis inhibition upon reactivation with different re-exposure times. Furthermore, by performing systematic reviews, we identify a series of overlapping molecular mechanisms between memory destabilization and synaptic downscaling, although direct experimental links between both phenomena remain scarce. In light of these results, we propose a theoretical framework where memory destabilization can emerge as an epiphenomenon of homeostatic adaptations prompted by memory retrieval.

  • 10.
    Andreoli, María F
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and Neuroscience. Instituto de Desarrollo e Investigaciones Pediátricas (IDIP), HIAEP Sor María Ludovica de la Plata, Comisión de Investigaciones Científicas de la Provincia de Buenos Aires (CIC-PBA), Calle 63 # 1069, La Plata, Buenos Aires, Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), La Plata, Argentina. mfandreoli@fbcb.unl.edu.ar..
    Fittipaldi, Antonela S
    Castrogiovanni, Daniel
    De Francesco, Pablo N
    Valdivia, Spring
    Heredia, Florencia
    Ribet-Travers, Carole
    Mendez, Ignacio
    Fasano, María V
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Doi, Suhail A
    Habib, Abdella M
    Perello, Mario
    Pre-prandial plasma liver-expressed antimicrobial peptide 2 (LEAP2) concentration in humans is inversely associated with hunger sensation in a ghrelin independent manner.2023In: European Journal of Nutrition, ISSN 1436-6207, E-ISSN 1436-6215Article in journal (Refereed)
    Abstract [en]

    PURPOSE: The liver-expressed antimicrobial peptide 2 (LEAP2) is a newly recognized peptide hormone that acts via the growth hormone secretagogue receptor (GHSR) blunting the effects of ghrelin and displaying ghrelin-independent actions. Since the implications of LEAP2 are beginning to be elucidated, we investigated if plasma LEAP2 concentration varies with feeding status or sex and whether it is associated with glucose metabolism and appetite sensations.

    METHODS: We performed a single test meal study, in which plasma concentrations of LEAP2, ghrelin, insulin and glucose as well as visual analogue scales for hunger, desire to eat, prospective food consumption, fullness were assessed before and 60 min after breakfast in 44 participants (n = 21 females) with normal weight (NW) or overweight/obesity (OW/OB).

    RESULTS: Pre-prandial plasma LEAP2 concentration was ~ 1.6-fold higher whereas ghrelin was ~ 2.0-fold lower in individuals with OW/OB (p < 0.001) independently of sex. After adjusting for body mass index (BMI) and sex, pre-prandial plasma LEAP2 concentration displayed a direct relationship with BMI (β: 0.09; 95%CI: 0.05, 0.13; p < 0.001), fat mass (β: 0.05; 95%CI: 0.01, 0.09; p = 0.010) and glycemia (β: 0.24; 95%CI: 0.05, 0.43; p = 0.021), whereas plasma ghrelin concentration displayed an inverse relationship with BMI and fat mass but not with glycemia. Postprandial plasma LEAP2 concentration increased ~ 58% in females with OW/OB (p = 0.045) but not in females with NW or in males. Pre-prandial plasma LEAP2 concentration displayed an inverse relationship with hunger score (β: - 11.16; 95% CI: - 18.52, - 3.79; p = 0.004), in a BMI-, sex- and ghrelin-independent manner.

    CONCLUSIONS: LEAP2 emerges as a key hormone implicated in the regulation of metabolism and appetite in humans.

    TRIAL REGISTRATION: The study was retrospectively registered in clinicaltrials.gov (April 2023).

    CLINICALTRIALS: gov Identifier: NCT05815641.

  • 11.
    Ashworth, Emma
    et al.
    Liverpool John Moores Univ, Fac Hlth, Sch Psychol, Liverpool, Merseyside, England..
    Brooks, Samantha
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. Liverpool John Moores Univ, Fac Hlth, Sch Psychol, Liverpool, Merseyside, England.;Univ Witwatersrand, Sch Human & Community Dev, Dept Psychol, Johannesburg, South Africa..
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. Sechenov First Moscow State Med Univ, Inst Translat Med & Biotechnol, Moscow, Russia..
    Neural activation of anxiety and depression in children and young people: A systematic meta-analysis of fMRI studies2021In: Psychiatry Research: Neuroimaging, ISSN 0925-4927, E-ISSN 1872-7506, Vol. 311, article id 111272Article in journal (Refereed)
    Abstract [en]

    Functional magnetic resonance imaging (fMRI) studies consistently demonstrate altered neural activation in youth experiencing anxiety and depression in a way that is distinct from adult-onset disorders. However, there is a paucity of research systematically reviewing this, and no meta-analyses have been conducted using Activation Likelihood Estimation (ALE). The present study conducted a systematic literature search to identify fMRI studies in youth (age 4?18) with depression or anxiety disorders. 48 studies with over 2000 participants were identified that met the inclusion criteria. Significant foci were extracted. Five ALE meta-analyses were conducted: a) activation for both anxiety disorders and depression; b) activation for anxiety disorders only; c) activation for depression only; d) deactivation for both anxiety disorders and depression; e) deactivation for depression. Results indicated significant clusters of increased activation in the bilateral amygdala for youth with internalising disorders, and specifically for those with anxiety disorders. Significant increased activation extended into the dorsal anterior cingulate, entorhinal cortex, the putamen, and the medial and lateral globus pallidus in youth with anxiety disorders. These findings help to detail the nature of anxiety being an amygdala hyperactivity disorder, whilst also defining the distinction between neural activation patterns in anxiety and depression.

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  • 12.
    Attwood, Misty M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Membrane-bound proteins: Characterization, evolution, and functional analysis2020Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Alpha-helical transmembrane proteins are important components of many essential cell processes including signal transduction, transport of molecules across membranes, protein and membrane trafficking, and structural and adhesion activities, amongst others. Their involvement in critical networks makes them the focus of interest in investigating disease pathways, as candidate drug targets, and in evolutionary analyses to identify homologous protein families and possible functional activities. Transmembrane (TM) proteins can be categorized into major groups based the same gross structure, i.e., the number of transmembrane helices, which are often correlated with specific functional activities, for example as receptors or transporters. The focus of this thesis was to analyze the evolution of the membrane proteome from the last holozoan common ancestor (LHCA) through metazoans to garner insight into the fundamental functional clusters that underlie metazoan diversity and innovation. Twenty-four eukaryotic proteomes were analyzed, with results showing more than 70% of metazoan transmembrane protein families have a pre-metazoan origin. In concert with that, we characterized the previously unstudied groups of human proteins with three, four, and five membrane-spanning regions (3TM, 4TM, and 5TM) and analyzed their functional activities, involvement in disease pathways, and unique characteristics. Combined, we manually curated and classified nearly 11% of the human transmembrane proteome with these three studies. The 3TM data set included 152 proteins, with nearly 45% that localize specifically to the endoplasmic reticulum (ER), and are involved in membrane biosynthesis and lipid biogenesis, proteins trafficking, catabolic processes, and signal transduction due to the large ionotropic glutamate receptor family. The 373 proteins identified in the 4TM data set are predominantly involved in transport activities, as well as cell communication and adhesion, and function as structural elements. The compact 5TM data set includes 58 proteins that engage in localization and transport activities, such as protein targeting, membrane trafficking, and vesicle transport. Notably, ~60% are identified as cancer prognostic markers that are associated with clinical outcomes of different tumour types. This thesis investigates the evolutionary origins of the human transmembrane proteome, characterizes formerly dark areas of the membrane proteome, and extends the fundamental knowledge of transmembrane proteins.

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  • 13.
    Attwood, Misty M.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Fabbro, Doriano
    Sokolov, Aleksandr V.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Knapp, Stefan
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. Institute for Translational Medicine and Biotechnology, Sechenov First Moscow State Medical University, Moscow, Russia.
    Trends in kinase drug discovery: targets, indications and inhibitor design2021In: Nature reviews. Drug discovery, ISSN 1474-1776, E-ISSN 1474-1784, Vol. 20, no 11, p. 839-861Article in journal (Refereed)
    Abstract [en]

    The FDA approval of imatinib in 2001 was a breakthrough in molecularly targeted cancer therapy and heralded the emergence of kinase inhibitors as a key drug class in the oncology area and beyond. Twenty years on, this article analyses the landscape of approved and investigational therapies that target kinases and trends within it, including the most popular targets of kinase inhibitors and their expanding range of indications. There are currently 71 small-molecule kinase inhibitors (SMKIs) approved by the FDA and an additional 16 SMKIs approved by other regulatory agencies. Although oncology is still the predominant area for their application, there have been important approvals for indications such as rheumatoid arthritis, and one-third of the SMKIs in clinical development address disorders beyond oncology. Information on clinical trials of SMKIs reveals that approximately 110 novel kinases are currently being explored as targets, which together with the approximately 45 targets of approved kinase inhibitors represent only about 30% of the human kinome, indicating that there are still substantial unexplored opportunities for this drug class. We also discuss trends in kinase inhibitor design, including the development of allosteric and covalent inhibitors, bifunctional inhibitors and chemical degraders.

  • 14.
    Attwood, Misty M.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Jonsson, Jörgen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Rask-Andersen, Mathias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. Sechenov First Moscow State Med Univ, Inst Translat Med & Biotechnol, Moscow, Russia..
    Soluble ligands as drug targets2020In: Nature reviews. Drug discovery, ISSN 1474-1776, E-ISSN 1474-1784, Vol. 19, no 10, p. 695-710Article, review/survey (Refereed)
    Abstract [en]

    Historically, the main classes of drug targets have been receptors, enzymes, ion channels and transporters. However, owing largely to the rise of antibody-based therapies in the past two decades, soluble protein ligands such as inflammatory cytokines have become an increasingly important class of drug targets. In this Review, we analyse drugs targeting ligands that have reached clinical development at some point since 1992. We identify 291 drugs that target 99 unique ligands, and we discuss trends in the characteristics of the ligands, drugs and indications for which they have been tested. In the last 5 years, the number of ligand-targeting drugs approved by the FDA has doubled to 34, while the number of clinically validated ligand targets has doubled to 22. Cytokines and growth factors are the predominant types of targeted ligands (70%), and inflammation and autoimmune disorders, cancer and ophthalmological diseases are the top therapeutic areas for both approved agents and agents in clinical studies, reflecting the central role of cytokine and/or growth factor pathways in such diseases. With the rise of antibody-based therapies in the past two decades, soluble protein ligands such as inflammatory cytokines have become an increasingly important class of drug targets. This Review analyses drugs targeting ligands that have reached clinical development in the past three decades and discusses strategic issues such as the pros and cons of different ligand-targeting therapeutic modalities.

  • 15.
    Attwood, Misty M.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. Sechenov First Moscow State Med Univ, Inst Translat Med & Biotechnol, Moscow, Russia..
    Characterization of five transmembrane proteins: With focus on the Tweety, Sidoreflexin, and YIP1 domain families2021In: Frontiers in Cell and Developmental Biology, E-ISSN 2296-634X, Vol. 9, article id 708754Article in journal (Refereed)
    Abstract [en]

    Transmembrane proteins are involved in many essential cell processes such as signal transduction, transport, and protein trafficking, and hence many are implicated in different disease pathways. Further, as the structure and function of proteins are correlated, investigating a group of proteins with the same tertiary structure, i.e. the same number of transmembrane regions, may give understanding about their functional roles and potential as therapeutic targets. This analysis investigates the previously unstudied group of proteins with five transmembrane-spanning regions (5TM). More than half of the 58 proteins identified with the 5TM architecture belong to twelve families with two or more members, with ten complete families that do not have any other homologous human proteins identified. Interestingly, more than half the proteins in the dataset function in localization activities through movement or tethering of cell components and more than one-third are involved in transport activities, particularly in the mitochondria. Surprisingly, no receptor activity was identified within this family in large contrast with other TM families. The three major 5TM families include the Tweety family, which are pore-forming subunits of the swelling-dependent volume regulated anion channel in astrocytes; the sidoreflexin family that act as mitochondrial amino acid transporters; and the Yip1 domain family engaged in vesicle budding and intra-Golgi transport.  About 30% of the 5TM proteins have enhanced expression in the brain, liver, or testis. Importantly, 60% of these proteins are identified as cancer prognostic markers, where they are associated with clinical outcomes of various tumour types, indicating further investigation into the function and expression of these proteins is important. This study provides the first comprehensive analysis of proteins with 5TM providing details of the unique characteristics

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  • 16.
    Attwood, Misty M.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. Institute for Translational Medicine and Biotechnology, Sechenov First Moscow State Medical University, Moscow, Russia.
    Classification of Trispanins: A Diverse Group of Proteins That Function in Membrane Synthesis and Transport Mechanisms2020In: Frontiers in Cell and Developmental Biology, E-ISSN 2296-634X, Vol. 7, article id 386Article in journal (Refereed)
    Abstract [en]

    As the structure and functions of proteins are correlated, investigating groups of proteins with the same gross structure may provide important insights about their functional roles. Trispanins, proteins that contain three alpha-helical transmembrane (3TM) regions, have not been previously studied considering their transmembrane features. Our comprehensive identification and classification using bioinformatic methods describe 152 3TM proteins. These proteins are frequently involved in membrane biosynthesis and lipid biogenesis, protein trafficking, catabolic processes, and in particular signal transduction due to the large ionotropic glutamate receptor family. Proteins that localize to intracellular compartments are overrepresented in the dataset in comparison to the entire human transmembrane proteome, and nearly 45% localize specifically to the endoplasmic reticulum (ER). Furthermore, nearly 20% of the trispanins function in lipid metabolic processes and transport, which are also overrepresented. Nearly one-third of trispanins are identified as being targeted by drugs and/or being associated with diseases. A high number of 3TMs have unknown functions and based on this analysis we speculate on the functional involvement of uncharacterized trispanins in relationship to disease or important cellular activities. This first overall study of trispanins provides a unique analysis of a diverse group of membrane proteins.

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  • 17.
    Babenko, Vladislav V.
    et al.
    Fed Med Biol Agcy, Fed Res & Clin Ctr Phys Chem Med, 1a Malaya Pirogovskaya Str, Moscow 119435, Russia..
    Podgorny, Oleg, V
    Fed Med Biol Agcy, Fed Res & Clin Ctr Phys Chem Med, 1a Malaya Pirogovskaya Str, Moscow 119435, Russia.;Russian Acad Sci, Koltzov Inst Dev Biol, 26 Vavilov Str, Moscow 119334, Russia..
    Manuvera, Valentin A.
    Fed Med Biol Agcy, Fed Res & Clin Ctr Phys Chem Med, 1a Malaya Pirogovskaya Str, Moscow 119435, Russia.;Moscow Inst Phys & Technol, 9 Inst Skiy Per, Dolgoprudnyi 141700, Moscow Region, Russia..
    Kasianov, Artem S.
    Moscow Inst Phys & Technol, 9 Inst Skiy Per, Dolgoprudnyi 141700, Moscow Region, Russia.;Russian Acad Sci, Vavilov Inst Gen Genet, 3 Gubkina Str, Moscow 119991, Russia..
    Manolov, Alexander, I
    Fed Med Biol Agcy, Fed Res & Clin Ctr Phys Chem Med, 1a Malaya Pirogovskaya Str, Moscow 119435, Russia..
    Grafskaia, Ekaterina N.
    Fed Med Biol Agcy, Fed Res & Clin Ctr Phys Chem Med, 1a Malaya Pirogovskaya Str, Moscow 119435, Russia.;Moscow Inst Phys & Technol, 9 Inst Skiy Per, Dolgoprudnyi 141700, Moscow Region, Russia..
    Shirokov, Dmitriy A.
    Fed Med Biol Agcy, Fed Res & Clin Ctr Phys Chem Med, 1a Malaya Pirogovskaya Str, Moscow 119435, Russia..
    Kurdyumov, Alexey S.
    Fed Med Biol Agcy, Fed Res & Clin Ctr Phys Chem Med, 1a Malaya Pirogovskaya Str, Moscow 119435, Russia..
    Vinogradov, Dmitriy V.
    Russian Acad Sci, AA Kharkevich Inst Informat Transmiss Problems, 19 Bolshoi Karetnyi Per, Moscow 127051, Russia.;Skolkovo Inst Sci & Technol, 3 Nobelya Ulitsa Str, Moscow 121205, Russia..
    Nikitina, Anastasia S.
    Fed Med Biol Agcy, Fed Res & Clin Ctr Phys Chem Med, 1a Malaya Pirogovskaya Str, Moscow 119435, Russia.;Moscow Inst Phys & Technol, 9 Inst Skiy Per, Dolgoprudnyi 141700, Moscow Region, Russia..
    Kovalchuk, Sergey, I
    Fed Med Biol Agcy, Fed Res & Clin Ctr Phys Chem Med, 1a Malaya Pirogovskaya Str, Moscow 119435, Russia.;Russian Acad Sci, Shemyakin Ovchinnikov Inst Bioorgan Chem, 16-10 Miklukho Maklaya Str, Moscow 117997, Russia..
    Anikanov, Nickolay A.
    Fed Med Biol Agcy, Fed Res & Clin Ctr Phys Chem Med, 1a Malaya Pirogovskaya Str, Moscow 119435, Russia.;Russian Acad Sci, Shemyakin Ovchinnikov Inst Bioorgan Chem, 16-10 Miklukho Maklaya Str, Moscow 117997, Russia..
    Butenko, Ivan O.
    Fed Med Biol Agcy, Fed Res & Clin Ctr Phys Chem Med, 1a Malaya Pirogovskaya Str, Moscow 119435, Russia..
    Pobeguts, Olga, V
    Fed Med Biol Agcy, Fed Res & Clin Ctr Phys Chem Med, 1a Malaya Pirogovskaya Str, Moscow 119435, Russia..
    Matyushkina, Daria S.
    Fed Med Biol Agcy, Fed Res & Clin Ctr Phys Chem Med, 1a Malaya Pirogovskaya Str, Moscow 119435, Russia..
    Rakitina, Daria, V
    Fed Med Biol Agcy, Fed Res & Clin Ctr Phys Chem Med, 1a Malaya Pirogovskaya Str, Moscow 119435, Russia..
    Kostryukova, Elena S.
    Fed Med Biol Agcy, Fed Res & Clin Ctr Phys Chem Med, 1a Malaya Pirogovskaya Str, Moscow 119435, Russia..
    Zgoda, Victor G.
    Russian Acad Med Sci, VN Orekhovich Res Inst Biomed Chem, 10 Pogodinskaja Str, Moscow 119832, Russia..
    Baskova, Isolda P.
    Lomonosov Moscow State Univ, Fac Biol, 1-12 Leninskie Gory, Moscow 119991, Russia..
    Trukhan, Vladimir M.
    IM Sechenov First Moscow State Med Univ, Minist Healthcare Russian Federat, Sechenovskiy Univ, Trubetskaya Str 8-2, Moscow 119991, Russia..
    Gelfand, Mikhail S.
    Russian Acad Sci, AA Kharkevich Inst Informat Transmiss Problems, 19 Bolshoi Karetnyi Per, Moscow 127051, Russia.;Skolkovo Inst Sci & Technol, 3 Nobelya Ulitsa Str, Moscow 121205, Russia.;Natl Res Univ Higher Sch Econ, Fac Comp Sci, 20 Myasnitskaya Str, Moscow 101000, Russia.;Lomonosov Moscow State Univ, Fac Bioengn & Bioinformat, 1-73 Leninskie Gory, Moscow 119991, Russia..
    Govorun, Vadim M.
    Fed Med Biol Agcy, Fed Res & Clin Ctr Phys Chem Med, 1a Malaya Pirogovskaya Str, Moscow 119435, Russia.;Moscow Inst Phys & Technol, 9 Inst Skiy Per, Dolgoprudnyi 141700, Moscow Region, Russia..
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. IM Sechenov First Moscow State Med Univ, Minist Healthcare Russian Federat, Sechenovskiy Univ, Trubetskaya Str 8-2, Moscow 119991, Russia.
    Lazarev, Vassili N.
    Fed Med Biol Agcy, Fed Res & Clin Ctr Phys Chem Med, 1a Malaya Pirogovskaya Str, Moscow 119435, Russia.;Moscow Inst Phys & Technol, 9 Inst Skiy Per, Dolgoprudnyi 141700, Moscow Region, Russia..
    Draft genome sequences of Hirudo medicinalis and salivary transcriptome of three closely related medicinal leeches2020In: BMC Genomics, E-ISSN 1471-2164, Vol. 21, no 1Article in journal (Refereed)
    Abstract [en]

    Background

    Salivary cell secretion (SCS) plays a critical role in blood feeding by medicinal leeches, making them of use for certain medical purposes even today.

    Results

    We annotated the Hirudo medicinalis genome and performed RNA-seq on salivary cells isolated from three closely related leech species, H. medicinalis, Hirudo orientalis, and Hirudo verbana. Differential expression analysis verified by proteomics identified salivary cell-specific gene expression, many of which encode previously unknown salivary components. However, the genes encoding known anticoagulants have been found to be expressed not only in salivary cells. The function-related analysis of the unique salivary cell genes enabled an update of the concept of interactions between salivary proteins and components of haemostasis.

    Conclusions

    Here we report a genome draft of Hirudo medicinalis and describe identification of novel salivary proteins and new homologs of genes encoding known anticoagulants in transcriptomes of three medicinal leech species. Our data provide new insights in genetics of blood-feeding lifestyle in leeches.

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  • 18.
    Bagchi, Sonchita
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Perland, Emelie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Hosseini, Kimia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Lundgren, Johanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Al-Walai, Noura
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Kheder, Sania
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Fredriksson, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Probable role for major facilitator superfamily domain containing 6 (MFSD6) in the brain during variable energy consumption2020In: International Journal of Neuroscience, ISSN 0020-7454, E-ISSN 1563-5279, Vol. 130, no 5, p. 476-489Article in journal (Refereed)
    Abstract [en]

    Purpose: The major facilitator superfamily (MFS) is known as the largest and most diverse superfamily containing human transporters, and these transporters are essential as they sustain the homeostasis within cellular compartments by moving substances over lipid membranes.

    Methods: We have identified a novel MFS protein, named Major facilitator superfamily domain containing 6 (MFSD6), and confirmed that it is phylogenetically related to the human Solute Carrier (SLC) transporter family. A homology model of MFSD6 revealed 12 predicted transmembrane segments (TMS) with the classical MFS fold between TMS 6 and 7.

    Results: Immunohistological analyses showed specific MFSD6 staining in neurons of wildtype mouse brain tissue, but no expression in astrocytes. Furthermore, we explored expression and probable function(s) of MFSD6 in relation to its phylogenetically related proteins, major facilitator superfamily domain containing 8 (MFSD8) and 10 (MFSD10), which is of interest as both these proteins are involved in diseases.

    Conclusions: We showed that expression levels of Mfsd6 and Mfsd10 were decreased with elevated or depleted energy consumption, while that of Mfsd8 remained unaffected.

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  • 19.
    Barnekow, Elin
    et al.
    Karolinska Inst, Dept Clin Sci & Educ, Sodersjukhuset, Stockholm, Sweden.;Soder Sjukhuset, Dept Oncol, Stockholm, Sweden..
    Liu, Wen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Schiöth: Functional Pharmacology. Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden..
    Helgadottir, Hafdis T.
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden.;Karolinska Univ Hosp, Dept Clin Genet, Stockholm, Sweden..
    Michailidou, Kyriaki
    Cyprus Sch Mol Med, Cyprus Inst Neurol & Genet, Nicosia, Cyprus..
    Dennis, Joe
    Univ Cambridge, Ctr Canc Genet Epidemiol, Cambridge, England..
    Bryant, Patrick
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden.;Stockholm Univ, Dept Biochem & Biophys, Stockholm, Sweden.;Sci Life Lab, Stockholm, Sweden..
    Thutkawkorapin, Jessada
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden.;Chulalongkorn Univ, Fac Engn, Dept Comp Engn, Bangkok, Thailand..
    Wendt, Camilla
    Karolinska Inst, Dept Clin Sci & Educ, Sodersjukhuset, Stockholm, Sweden.;Soder Sjukhuset, Dept Oncol, Stockholm, Sweden..
    Czene, Kamila
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden..
    Hall, Per
    Soder Sjukhuset, Dept Oncol, Stockholm, Sweden.;Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden..
    Margolin, Sara
    Karolinska Inst, Dept Clin Sci & Educ, Sodersjukhuset, Stockholm, Sweden.;Soder Sjukhuset, Dept Oncol, Stockholm, Sweden..
    Lindblom, Annika
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden.;Karolinska Univ Hosp, Dept Clin Genet, Stockholm, Sweden..
    A Swedish Genome-Wide Haplotype Association Analysis Identifies a Novel Breast Cancer Susceptibility Locus in 8p21.2 and Characterizes Three Loci on Chromosomes 10, 11 and 162022In: Cancers, ISSN 2072-6694, Vol. 14, no 5, article id 1206Article in journal (Refereed)
    Abstract [en]

    Background: The heritability of breast cancer is partly explained but much of the genetic contribution remains to be identified. Haplotypes are often used as markers of ethnicity as they are preserved through generations. We have previously demonstrated that haplotype analysis, in addition to standard SNP association studies, could give novel and more detailed information on genetic cancer susceptibility.

    Methods: In order to examine the association of a SNP or a haplotype to breast cancer risk, we performed a genome wide haplotype association study, using sliding window analysis of window sizes 1-25 and 50 SNPs, in 3200 Swedish breast cancer cases and 5021 controls.

    Results: We identified a novel breast cancer susceptibility locus in 8p21.1 (OR 2.08; p 3.92 x 10(-8)), confirmed three known loci in 10q26.13, 11q13.3, 16q12.1-2 and further identified novel subloci within these three loci. Altogether 76 risk SNPs, 3302 risk haplotypes of window size 2-25 and 113 risk haplotypes of window size 50 at p < 5 x 10(-8) on chromosomes 8, 10, 11 and 16 were identified. In the known loci haplotype analysis reached an OR of 1.48 in overall breast cancer and in familial cases OR 1.68.

    Conclusions: Analyzing haplotypes, rather than single variants, could detect novel susceptibility loci even in small study populations but the method requires a fairly homogenous study population.

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  • 20.
    Belyaeva, Irina I.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and neuroscience. IM Sechenov First Moscow State Med Univ, Inst Pharm, Dept Pharmacol, Moscow, Russia..
    Subbotina, Anna G.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and neuroscience. IM Sechenov First Moscow State Med Univ, Inst Pharm, Dept Pharmacol, Moscow, Russia..
    Eremenko, Ivan I.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and neuroscience. IM Sechenov First Moscow State Med Univ, Inst Pharm, Dept Pharmacol, Moscow, Russia..
    Tarasov, Vadim V.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. IM Sechenov First Moscow State Med Univ, Inst Pharm, Dept Pharmacol, Moscow, Russia.;IM Sechenov First Moscow State Med Univ, Inst Translat Med & Biotechnol, Moscow, Russia..
    Chubarev, Vladimir N.
    IM Sechenov First Moscow State Med Univ, Inst Pharm, Dept Pharmacol, Moscow, Russia..
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and neuroscience. IM Sechenov First Moscow State Med Univ, Inst Translat Med & Biotechnol, Moscow, Russia..
    Mwinyi, Jessica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and neuroscience.
    Pharmacogenetics in Primary Headache Disorders2022In: Frontiers in Pharmacology, E-ISSN 1663-9812, Vol. 12, article id 820214Article, review/survey (Refereed)
    Abstract [en]

    Primary headache disorders, such as migraine, tension-type headache (TTH), and cluster headache, belong to the most common neurological disorders affecting a high percentage of people worldwide. Headache induces a high burden for the affected individuals on the personal level, with a strong impact on life quality, daily life management, and causes immense costs for the healthcare systems. Although a relatively broad spectrum of different pharmacological classes for the treatment of headache disorders are available, treatment effectiveness is often limited by high variances in therapy responses. Genetic variants can influence the individual treatment success by influencing pharmacokinetics or pharmacodynamics of the therapeutic as investigated in the research field of pharmacogenetics. This review summarizes the current knowledge on important primary headache disorders, including migraine, TTH, and cluster headache. We also summarize current acute and preventive treatment options for the three headache disorders based on drug classes and compounds taking important therapy guidelines into consideration. Importantly, the work summarizes and discusses the role of genetic polymorphisms regarding their impact on metabolism safety and the effect of therapeutics that are used to treat migraine, cluster headache, and TTH exploring drug classes such as nonsteroidal anti-inflammatory drugs, triptans, antidepressants, anticonvulsants, calcium channel blockers, drugs with effect on the renin-angiotensin system, and novel headache therapeutics such as ditans, anti-calcitonin-gene-related peptide antibodies, and gepants. Genetic variants in important phase I-, II-, and III-associated genes such as cytochrome P450 genes, UGT genes, and different transporter genes are scrutinized as well as variants in genes important for pharmacodynamics and several functions outside the pharmacokinetic and pharmacodynamic spectrum. Finally, the article evaluates the potential and limitations of pharmacogenetic approaches for individual therapy adjustments in headache disorders.

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  • 21.
    Benedict, Christian
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Blennow, Kaj
    Sahlgrens Univ Hosp, Clin Neurochem Lab, Gothenburg, Sweden.;Univ Gothenburg, Sahlgrenska Acad, Inst Neurosci & Physiol, Dept Psychiat & Neurochem, Molndal, Sweden..
    Zetterberg, Henrik
    Sahlgrens Univ Hosp, Clin Neurochem Lab, Gothenburg, Sweden.;Univ Gothenburg, Sahlgrenska Acad, Inst Neurosci & Physiol, Dept Psychiat & Neurochem, Molndal, Sweden.;UCL Inst Neurol, Dept Neurodegenerat Dis, London, England.;UCL, UK Dementia Res Inst, London, England..
    Cedernaes, Jonathan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Transplantation and regenerative medicine.
    Effects of acute sleep loss on diurnal plasma dynamics of CNS health biomarkers in young men2020In: Neurology, ISSN 0028-3878, E-ISSN 1526-632X, Vol. 94, no 11, p. E1181-E1189Article in journal (Refereed)
    Abstract [en]

    Objective: Disrupted sleep increases CSF levels of tau and beta -amyloid (A beta) and is associated with an increased risk of Alzheimer disease (AD). Our aim was to determine whether acute sleep loss alters diurnal profiles of plasma-based AD-associated biomarkers.

    Methods: In a 2-condition crossover study, 15 healthy young men participated in 2 standardized sedentary in-laboratory conditions in randomized order: normal sleep vs overnight sleep loss. Plasma levels of total tau (t-tau), A beta 40, A beta 42, neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP) were assessed using ultrasensitive single molecule array assays or ELISAs, in the fasted state in the evening prior to, and in the morning after, each intervention.

    Results: In response to sleep loss (+17.2%), compared with normal sleep (+1.8%), the evening to morning ratio was increased for t-tau (p = 0.035). No changes between the sleep conditions were seen for levels of A beta 40, A beta 42, NfL, or GFAP (all p > 0.10). The AD risk genotype rs4420638 did not significantly interact with sleep loss-related diurnal changes in plasma levels of A beta 40 or A beta 42 (p > 0.10). Plasma levels of A beta 42 (-17.1%) and GFAP (-12.1%) exhibited an evening to morning decrease across conditions (p < 0.05).

    Conclusions: Our exploratory study suggests that acute sleep loss results in increased blood levels of t-tau. These changes provide further evidence that sleep loss may have detrimental effects on brain health even in younger individuals. Larger cohorts are warranted to delineate sleep vs circadian mechanisms, implications for long-term recurrent conditions (e.g., in shift workers), as well as interactions with other lifestyle and genetic factors.

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  • 22.
    Benedict, Christian
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Cedernaes, Jonathan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Transplantation and regenerative medicine.
    Could a good night's sleep improve COVID-19 vaccine efficacy?2021In: The Lancet Respiratory Medicine, ISSN 2213-2600, E-ISSN 2213-2619, Vol. 9, no 5, p. 447-448Article in journal (Other academic)
  • 23.
    Benedict, Christian
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Franklin, Karl A
    Department of Surgical and Perioperative Sciences, Surgery, Umeå University, Sweden.
    Bukhari, Shervin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Ljunggren, Mirjam
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Lung- allergy- and sleep research.
    Lindberg, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Lung- allergy- and sleep research.
    Sex-specific association of the lunar cycle with sleep2022In: Science of the Total Environment, ISSN 0048-9697, E-ISSN 1879-1026, Vol. 804, article id 150222Article in journal (Refereed)
    Abstract [en]

    Using one-night sleep recordings from 852 subjects all living in Uppsala, Sweden, the present study represents one of the largest polysomnography investigations into the association of the 29.53-day long lunar cycle with sleep among men and women and across a wide age range (22-81 years). Following the day after the new moon until the day of the full moon (also named the waxing period), the moon's illumination increases, and the timing of the meridian of the moon is gradually shifted from noontime toward midnight. In contrast, from the day after the full moon until the day of the new moon (also named the waning period), the moon's illumination decreases, and the timing of the meridian of the moon is gradually shifted from early night hours toward noontime. Thus, we focused on the contrast between the waxing and waning periods. Sleep duration was shorter on nights during the waxing period as compared to waning period (P < 0.001). In addition, a significant interaction effect of participants' sex with the lunar period on sleep was noted (P < 0.05). Men, but not women, exhibited lower sleep efficiency (P < 0.001 and P = 0.748, respectively) and were longer awake after sleep onset (P = 0.010 and P = 0.890, respectively) on nights during the waxing period. All associations were robust to adjustment for confounders (including regular sleep disturbances). Our findings suggest that the effects of the lunar cycle on human sleep are more pronounced among men. Based on the cross-sectional design of the study, no firm conclusions can be drawn on the causality of the relations.

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  • 24.
    Benedict, Christian
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Mateus Brandao, Luiz Eduardo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Transplantation and regenerative medicine.
    Merikanto, Ilona
    Department of Public Health Solutions, Finnish Institute for Health and Welfare, 00271 Helsinki, Finland; Department of Psychology and Logopedics, Faculty of Medicine, University of Helsinki, 00100 Helsinki, Finland; Orton Orthopaedics Hospital, 00280 Helsinki, Finland.
    Partinen, Markku
    Helsinki Sleep Clinic, Vitalmed Research Center, 00420 Helsinki, Finland; Department of Neurosciences, Clinicum, University of Helsinki, 00100 Helsinki, Finland.
    Bjorvatn, Bjørn
    Department of Global Public Health and Primary Care, University of Bergen, 5009 Bergen, Norway; Norwegian Competence Center for Sleep Disorders, Haukeland University Hospital, 5021 Bergen, Norway.
    Cedernaes, Jonathan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Transplantation and regenerative medicine. Department of Medicine, Division of Endocrinology, Metabolism, and Molecular Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
    Meal and Sleep Timing before and during the COVID-19 Pandemic: A Cross-Sectional Anonymous Survey Study from Sweden2021In: Clocks & Sleep, E-ISSN 2624-5175, Vol. 3, no 2, p. 251-258Article in journal (Refereed)
    Abstract [en]

    The COVID-19 pandemic and related restrictions, such as stay-at-home-orders, have significantly altered daily routines and lifestyles. Given their importance for metabolic health, we herein compared sleep and meal timing parameters during vs. before the COVID-19 pandemic based on subjective recall, in an anonymous Swedish survey. Among 191 adults (mean age: 47 years; 77.5% females), we show that social jetlag, i.e., the mismatch in sleep midpoint between work and free days, was reduced by about 17 min during the pandemic compared with the pre-pandemic state (p < 0.001). Concomitantly, respondents' sleep midpoint was shifted toward morning hours during workdays (p < 0.001). A later daily eating midpoint accompanied the shift in sleep timing (p = 0.001). This effect was mainly driven by a later scheduled first meal (p < 0.001). No difference in the timing of the day's last meal was found (p = 0.814). Although our survey was limited in terms of sample size and by being cross-sectional, our results suggest that the delay in sleep timing due to the COVID-19 pandemic was accompanied by a corresponding shift in the timing of early but not late meals.

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  • 25.
    Benedict, Christian
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Partinen, Markku
    University of Helsinki, Helsinki, Finland.
    Bjorvatn, Bjørn
    University of Bergen, Bergen, Norway; Haukeland University Hospital, Bergen, Norway.
    Cedernaes, Jonathan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. Northwestern University, Chicago, Illinois.
    Sleep in Female Healthcare Workers during COVID-19: A Cross-sectional Survey Study in Sweden during the Flattening of the First Wave of the Pandemic2021In: Annals of the American Thoracic Society, ISSN 2329-6933, E-ISSN 2325-6621, Vol. 18, no 8, p. 1418-1420Article in journal (Other academic)
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  • 26.
    Benjamins, Jeroen S.
    et al.
    Univ Utrecht, Social Hlth & Org Psychol, Utrecht, Netherlands.;Univ Utrecht, Helmholtz Inst, Expt Psychol, Utrecht, Netherlands..
    Hooge, Ignace T. C.
    Univ Utrecht, Helmholtz Inst, Expt Psychol, Utrecht, Netherlands..
    Benedict, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Smeets, Paul A. M.
    Univ Utrecht, UMC Utrecht Brain Ctr, Utrecht, Netherlands.;Wageningen Univ, Div Human Nutr & Hlth, Wageningen, Netherlands.;Univ Med Ctr, Image Sci Inst, Utrecht, Netherlands..
    van der Laan, Laura N.
    Tilburg Univ, Tilburg Sch Humanities & Digital Sci, Dept Commun & Cognit, POB 90153, NL-5000 LE Tilburg, Netherlands..
    The influence of acute partial sleep deprivation on liking, choosing and consuming high- and low-energy foods2021In: Food Quality and Preference, ISSN 0950-3293, E-ISSN 1873-6343, Vol. 88, article id 104074Article in journal (Refereed)
    Abstract [en]

    A wealth of cross-sectional studies found a link between sleep deprivation and food-related outcomes like energy intake and BMI. Recent experimental studies suggest that this link is causal. However, the mechanisms through which sleep deprivation influences intake remain unclear. Here, we tested two prevailing hypotheses: that sleep deprivation leads to 1) increased food reward sensitivity and 2) decreased food-related self-control. In a within-subject study (n = 60 normal-weight females), we compared outcome measures under normal sleep and partial sleep deprivation conditions. Our outcome measures were 1) proxies for food reward sensitivity - liking of high and low energy foods, 2) binary food choices ranging in level of self-control conflict, and 3) intake of high and low energy foods. Eye-movements during food choice were measured with an eye-tracker to gain insights in implicit food choice processes. Food reward sensitivity outcomes showed a lower liking of low energy foods after partial sleep deprivation. More high energy foods were chosen after partial sleep deprivation independent of the level of self-control conflict. Intake of high energy foods was higher in the partial sleep deprivation condition. Lastly, the number of gaze switches between high and low energy foods, an implicit measure of conflict in choice, was lower in the high-conflict trials after sleep deprivation than after a normal night sleep. To conclude, the increased intake of high energy foods after sleep deprivation may be driven by a decreased liking of low energy foods, rather than an increased liking of high energy foods. Further, sleep deprivation may affect self-control conflict detection as indicated by a lower number of gaze switches between food options.

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  • 27.
    Berkins, Samuel
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. Sechenov First Moscow State Med Univ, Inst Translat Med & Biotechnol, Moscow 119991, Russia..
    Rukh, Gull
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Depression and Vegetarians: Association between Dietary Vitamin B6, B12 and Folate Intake and Global and Subcortical Brain Volumes2021In: Nutrients, E-ISSN 2072-6643, Vol. 13, no 6, article id 1790Article in journal (Refereed)
    Abstract [en]

    Deficiency of vitamin B6 and vitamin B12, mostly in vegetarians, is found to be associated with depression and adverse neurological function. We investigated whether vitamin B6, B12, and folate have an effect on brain structure, especially among depressed people who follow a specific diet. The study sample comprised 9426 participants from the UK Biobank cohort with a mean age of 62.4 years. A generalized linear model controlling for age, sex, body mass index, ethnicity, town send deprivation index, educational qualification, smoking, and alcohol intake was used to test the association between study groups and structural brain volumes. Depression was more prevalent, and intake of vitamin B6 and B12 was lower among vegetarians, while non-vegetarians had a lower intake of folate. Overall, no significant association was observed between vitamin B6, B12, and folate intakes and both global and subcortical brain volumes among participants with depression. However, vitamin B12 intake was positively associated with right pallidum among non-depressed participants, and a significant interaction between vitamin B12 intake and depression status on the right pallidum was observed. Also, a significant interaction between folate intake and depression status on grey matter (GM) volume and left thalamus was observed. Upon diet stratification, folate intake is associated with total brain volume and GM volume among vegetarians with depression. Furthermore, no significant associations were observed for subcortical regions. Our findings suggest that dietary intake of vitamin B6 and B12 might have an effect on brain structure. Vegetarians, particularly those who suffer from depression may benefit from supplementing their diets with vitamins B6, B12, and folate to ensure brain health. Further studies, especially with a larger sample size and longitudinal design, are needed to confirm these findings.

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  • 28.
    Bianconi, Santiago
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. Univ Nacl Cordoba, CONICET, Inst Invest Ciencias Salud INICSA, Inst Fisiol Humana, Santa Rosa 1085, X5000ESU, Cordoba, Argentina.
    Poretti, María Belén
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. Univ Nacl Cordoba, CONICET, Inst Invest Ciencias Salud INICSA, Inst Fisiol Humana, Santa Rosa 1085, X5000ESU, Cordoba, Argentina; Univ Nacl Cordoba, Fac Ciencias Med, Santa Rosa 1085, X5000ESU, Cordoba, Argentina.
    Rodriguez, Paula
    Univ Nacl Cordoba, Fac Ciencias Quim, IFEC, Dept Farmacol, CONICET, Av Haya Torre & Medina Allende, Cordoba, Argentina.
    Maestri, Giulia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Rodríguez, Pamela Elizabeth
    Univ Nacl Cordoba, Fac Ciencias Med, Inst Virol Dr JM Vanella, Av Haya Torre S-N, Cordoba, Argentina.
    Rubiales de Barioglio, Susana
    Univ Nacl Cordoba, Fac Ciencias Quim, IFEC, Dept Farmacol,CONICET, Av Haya Torre & Medina Allende, Cordoba, Argentina.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. Sechenov First Moscow State Med Univ, Inst Translat Med & Biotechnol, Moscow, Russia.
    Carlini, Valeria Paola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. Univ Nacl Cordoba, CONICET, Inst Invest Ciencias Salud INICSA, Inst Fisiol Humana, Santa Rosa 1085, X5000ESU, Cordoba, Argentina; Univ Nacl Cordoba, Fac Ciencias Med, Santa Rosa 1085, X5000ESU, Cordoba, Argentina.
    Ghrelin restores memory impairment following olfactory bulbectomy in mice by activating hippocampal NMDA1 and MAPK1 gene expression2021In: Behavioural Brain Research, ISSN 0166-4328, E-ISSN 1872-7549, Vol. 410, article id 113341Article in journal (Refereed)
    Abstract [en]

    Ghrelin (Ghrl) is an orexigenic peptide with potential roles in the modulation of anxiety- and depressive-like symptoms induced by bilateral olfactory bulbectomy (OB) in rodents. In the present work, we assessed whether intrahippocampal Ghrl could reverse OB-induced depressive-like and amnesic effects by regulating molecular mechanisms related to neuroplasticity. Adult female albino Swiss mice were divided into sham and OB groups, and infused with saline (S) or Ghrl 0.03 nmol/μl, 0.3 nmol/μl, or 3 nmol/μl into the hippocampus before exposition to open-field test (OFT) and tail suspension test (TST) or immediately after training in the object recognition test (ORT). After test phase in ORT, animals were euthanized and their hippocampi were dissected to study the expression of genes related to memory. The OB-S animals presented hyperlocomotion in OFT, increased immobility in TST and memory impairment compared to sham-S (p < 0.05), but acute intrahippocampal infusion of Ghrl 0.3 nmol/μl produced an improvement on these parameters in OB animals (p < 0.05). In addition, this dose of Ghrl reversed OB-induced low expression of NMDA1 and MAPK1 iso1 and up-regulated the expression of CaMKIIa iso1 and iso2, and MAPK1 iso2 (p < 0.05). These results extend the existing literature regarding OB-induced behavioral and neurochemical changes, and provide mechanisms that could underlie the antidepressant effect of Ghrl in this model.

  • 29.
    Bondarev, Andrey D.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. IM Sechenov First Moscow State Med Univ, Inst Pharm, Dept Pharmacol, Moscow, Russia..
    Attwood, Misty M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Jonsson, Jörgen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Chubarev, Vladimir N.
    IM Sechenov First Moscow State Med Univ, Inst Pharm, Dept Pharmacol, Moscow, Russia..
    Tarasov, Vadim V.
    IM Sechenov First Moscow State Med Univ, Inst Pharm, Dept Pharmacol, Moscow, Russia.;IM Sechenov First Moscow State Med Univ, Inst Translat Med & Biotechnol, Moscow, Russia..
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. IM Sechenov First Moscow State Med Univ, Inst Translat Med & Biotechnol, Moscow, Russia..
    Opportunities and challenges for drug discovery in modulating Adhesion G protein-coupled receptor (GPCR) functions2020In: Expert Opinion on Drug Discovery, ISSN 1746-0441, E-ISSN 1746-045X, Vol. 15, no 11, p. 1291-1307Article, review/survey (Refereed)
    Abstract [en]

    Introduction: The G protein-coupled receptors (GPCR) superfamily is among the most widely exploited targets for therapeutics, with drugs mainly targeting the Rhodopsin, Glutamate and Secretin family receptors. The receptors of the Adhesion family, however, remain comparatively unexplored in this aspect. This review aims to discuss the druggability of Adhesion GPCRs (aGPCR), highlighting the relevant opportunities and challenges.

    Areas Covered: In this review, the authors provide a disease-oriented summary of aGPCR involvement in humans and discuss the current status of characterizing therapeutic agents with a focus on new opportunities using low molecular weight substances.

    Expert opinion: The small molecule antagonist dihydromunduletone and partial agonist 3-alpha-acetoxydihydrodeoxygedunin, along with the endogenous natural ligand synaptamide currently comprise some of the most important discoveries made in an attempt to characterize aGPCR druggability. The small molecule modulators provide important insights regarding the structure-activity relationship and suggest that targeting the tethered peptide agonist results in a nonselective pharmacological action, while synaptamide may be considered a potentially attractive tool to achieve a higher degree of selectivity.

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  • 30.
    Bondarev, Andrey D
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. Department of Pharmacology, Institute of Pharmacy, I. M. Sechenov First Moscow State Medical University, Moscow, Russia..
    Attwood, Misty M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Jonsson, Jörgen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Chubarev, Vladimir N
    Tarasov, Vadim V
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. Institute of Translational Medicine and Biotechnology, I. M. Sechenov First Moscow State Medical University, Moscow, Russia..
    Recent developments of HDAC inhibitors: Emerging indications and novel molecules2021In: British Journal of Clinical Pharmacology, ISSN 0306-5251, E-ISSN 1365-2125, Vol. 87, no 12, p. 4577-4597Article in journal (Refereed)
    Abstract [en]

    The histone deacetylase (HDAC) enzymes, a class of epigenetic regulators, are historically well established as attractive therapeutic targets. During investigation of trends within clinical trials, we have identified a high number of clinical trials involving HDAC inhibitors, prompting us to further evaluate the current status of this class of therapeutic agents. In total, we have identified 32 agents with HDAC-inhibiting properties, of which 29 were found to interact with the HDAC enzymes as their primary therapeutic target. In this review, we provide an overview of the clinical drug development highlighting the recent advances and provide analysis of specific trials and, where applicable, chemical structures. We found haematologic neoplasms continue to represent the majority of clinical indications for this class of drugs; however, it is clear that there is an ongoing trend towards diversification. Therapies for non-oncology indications including HIV infection, muscular dystrophies, inflammatory diseases as well as neurodegenerative diseases such as Alzheimer's disease, frontotemporal dementia and Friedreich's ataxia are achieving promising clinical progress. Combinatory regimens are proving to be useful to improve responsiveness among FDA-approved agents; however, it often results in increased treatment-related toxicities. This analysis suggests that the indication field is broadening through a high number of clinical trials while several fields of preclinical development are also promising.

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  • 31.
    Boström, Adrian
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Chatzittofis, Andreas
    Umeå Univ, Dept Clin Sci Psychiat, Umeå, Sweden.
    Ciuculete, Diana-Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Flanagan, John N.
    Karolinska Inst, Dept Med, Androl Sexual Med Grp ANOVA, Stockholm, Sweden.
    Krattinger, Regina
    Univ Zurich, Univ Hosp Zurich, Dept Clin Pharmacol & Toxicol, Zurich, Switzerland.
    Bandstein, Marcus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Mwinyi, Jessica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Kullak-Ublick, Gerd A.
    Univ Zurich, Univ Hosp Zurich, Dept Clin Pharmacol & Toxicol, Zurich, Switzerland.
    Oberg, Katarina Gorts
    Karolinska Inst, Dept Med, Androl Sexual Med Grp ANOVA, Stockholm, Sweden.
    Arver, Stefan
    Karolinska Inst, Dept Med, Androl Sexual Med Grp ANOVA, Stockholm, Sweden.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. Sechenov First Moscow State Med Univ, Inst Translat Med & Biotechnol, Moscow, Russia.
    Jokinen, Jussi
    Umeå Univ, Dept Clin Sci Psychiat, Umeå, Sweden;Karolinska Inst, Dept Clin Neurosci Psychiat, Stockholm, Sweden.
    Hypermethylation-associated downregulation of microRNA-4456 in hypersexual disorder with putative influence on oxytocin signalling: A DNA methylation analysis of miRNA genes2020In: Epigenetics, ISSN 1559-2294, E-ISSN 1559-2308, Vol. 15, no 1-2, p. 145-160Article in journal (Refereed)
    Abstract [en]

    Hypersexual disorder (HD) was proposed as a diagnosis in the DSM-5 and the classification ?Compulsive Sexual Behavior Disorder? is now presented as an impulse-control disorder in ICD-11. HD incorporates several pathophysiological mechanisms; including impulsivity, compulsivity, sexual desire dysregulation and sexual addiction. No previous study investigated HD in a methylation analysis limited to microRNA (miRNA) associated CpG-sites. The genome wide methylation pattern was measured in whole blood from 60 subjects with HD and 33 healthy volunteers using the Illumina EPIC BeadChip. 8,852 miRNA associated CpG-sites were investigated in multiple linear regression analyses of methylation M-values to a binary independent variable of disease state (HD or healthy volunteer), adjusting for optimally determined covariates. Expression levels of candidate miRNAs were investigated in the same individuals for differential expression analysis. Candidate methylation loci were further studied for an association with alcohol dependence in an independent cohort of 107 subjects. Two CpG-sites were borderline significant in HD ? cg18222192 (MIR708)(p < 10E-05,p(FDR) = 5.81E-02) and cg01299774 (MIR4456)(p < 10E-06, p(FDR) = 5.81E-02). MIR4456 was significantly lower expressed in HD in both univariate (p < 0.0001) and multivariate (p < 0.05) analyses. Cg01299774 methylation levels were inversely correlated with expression levels of MIR4456 (p < 0.01) and were also differentially methylated in alcohol dependence (p = 0.026). Gene target prediction and pathway analysis revealed that MIR4456 putatively targets genes preferentially expressed in brain and that are involved in major neuronal molecular mechanisms thought to be relevant for HD, e.g., the oxytocin signalling pathway. In summary, our study implicates a potential contribution of MIR4456 in the pathophysiology of HD by putatively influencing oxytocin signalling.

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  • 32.
    Bozhko, Dmitrii V.
    et al.
    Space Off Ctr, JetBrains Res Dept, St Petersburg, Russia..
    Galumov, Georgii K.
    Space Off Ctr, JetBrains Res Dept, St Petersburg, Russia..
    Polovian, Aleksandr I.
    Space Off Ctr, JetBrains Res Dept, St Petersburg, Russia..
    Kolchanova, Sofiia M.
    Space Off Ctr, JetBrains Res Dept, St Petersburg, Russia.;Univ Puerto Rico, Dept Biol, Mayaguez, PR USA.;St Petersburg State Univ, Theodosius Dobzhansky Ctr Genome Bioinformat, St Petersburg, Russia..
    Myrov, Vladislav O.
    Univ Helsinki, Helsinki Inst Life Sci, Neurosci Ctr, Helsinki, Finland.;Aalto Univ, Dept Neurosci & Biomed Engn, Espoo, Finland..
    Stelmakh, Viktoriia A.
    Space Off Ctr, JetBrains Res Dept, St Petersburg, Russia.;Ctr Life Sci, Skolkovo Inst Sci & Technol, Moscow, Russia..
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. Sechenov First Moscow State Med Univ, Inst Translat Med & Biotechnol, Moscow, Russia..
    BCNNM: A Framework for in silico Neural Tissue Development Modeling2021In: Frontiers in Computational Neuroscience, E-ISSN 1662-5188, Vol. 14, article id 588224Article in journal (Refereed)
    Abstract [en]

    Cerebral ("brain") organoids are high-fidelity in vitro cellular models of the developing brain, which makes them one of the go-to methods to study isolated processes of tissue organization and its electrophysiological properties, allowing to collect invaluable data for in silico modeling neurodevelopmental processes. Complex computer models of biological systems supplement in vivo and in vitro experimentation and allow researchers to look at things that no laboratory study has access to, due to either technological or ethical limitations. In this paper, we present the Biological Cellular Neural Network Modeling (BCNNM) framework designed for building dynamic spatial models of neural tissue organization and basic stimulus dynamics. The BCNNM uses a convenient predicate description of sequences of biochemical reactions and can be used to run complex models of multi-layer neural network formation from a single initial stem cell. It involves processes such as proliferation of precursor cells and their differentiation into mature cell types, cell migration, axon and dendritic tree formation, axon pathfinding and synaptogenesis. The experiment described in this article demonstrates a creation of an in silico cerebral organoid-like structure, constituted of up to 1 million cells, which differentiate and self-organize into an interconnected system with four layers, where the spatial arrangement of layers and cells are consistent with the values of analogous parameters obtained from research on living tissues. Our in silico organoid contains axons and millions of synapses within and between the layers, and it comprises neurons with high density of connections (more than 10). In sum, the BCNNM is an easy-to-use and powerful framework for simulations of neural tissue development that provides a convenient way to design a variety of tractable in silico experiments.

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  • 33.
    Brandao, Luiz Eduardo M.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Transplantation and regenerative medicine.
    Espes, Daniel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Transplantation and regenerative medicine. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Westholm, Jakub Orzechowski
    Martikainen, Teemu
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Transplantation and regenerative medicine. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Westerlund, Nestori
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Lampola, Lauri
    Popa, Alexandru
    Vogel, Heike
    Schürmann, Annette
    Dickson, Suzanne L
    Benedict, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Cedernaes, Jonathan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Transplantation and regenerative medicine.
    Acute sleep loss alters circulating fibroblast growth factor 21 levels in humans: A randomised crossover trial.2022In: Journal of Sleep Research, ISSN 0962-1105, E-ISSN 1365-2869, Vol. 31, no 2, article id e13472Article in journal (Refereed)
    Abstract [en]

    The hormone fibroblast growth factor 21 (FGF21) modulates tissue metabolism and circulates at higher levels in metabolic conditions associated with chronic sleep-wake disruption, such as type 2 diabetes and obesity. In the present study, we investigated whether acute sleep loss impacts circulating levels of FGF21 and tissue-specific production, and response pathways linked to FGF21. A total of 15 healthy normal-weight young men participated in a randomised crossover study with two conditions, sleep loss versus an 8.5-hr sleep window. The evening before each intervention, fasting blood was collected. Fasting, post-intervention morning skeletal muscle and adipose tissue samples underwent quantitative polymerase chain reaction and DNA methylation analyses, and serum FGF21 levels were measured before and after an oral glucose tolerance test. Serum levels of FGF21 were higher after sleep loss compared with sleep, both under fasting conditions and following glucose intake (~27%-30%, p = 0.023). Fasting circulating levels of fibroblast activation protein, a protein which can degrade circulating FGF21, were not altered by sleep loss, whereas DNA methylation in the FGF21 promoter region increased only in adipose tissue. However, even though specifically the muscle exhibited transcriptional changes indicating adverse alterations to redox and metabolic homeostasis, no tissue-based changes were observed in expression of FGF21, its receptors, or selected signalling targets, in response to sleep loss. In summary, we found that acute sleep loss resulted in increased circulating levels of FGF21 in healthy young men, which may occur independent of a tissue-based stress response in metabolic peripheral tissues. Further studies may decipher whether changes in FGF21 signalling after sleep loss modulate metabolic outcomes associated with sleep or circadian disruption.

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  • 34.
    Brandao, Luiz Eduardo M.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Transplantation and regenerative medicine.
    Martikainen, Teemu
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Transplantation and regenerative medicine.
    Merikanto, Ilona
    Holzinger, Brigitte
    Morin, Charles M
    Espie, Colin A
    Bolstad, Courtney J
    Leger, Damien
    Chung, Frances
    Plazzi, Giuseppe
    Dauvilliers, Yves
    Matsui, Kentaro
    De Gennaro, Luigi
    Sieminski, Mariusz
    Nadorff, Michael R
    Chan, Ngan Yin
    Wing, Yun Kwok
    Mota-Rolim, Sérgio Arthuro
    Inoue, Yuichi
    Partinen, Markku
    Benedict, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Bjorvatn, Bjorn
    Cedernaes, Jonathan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Transplantation and regenerative medicine. Department of Medicine, Division of Endocrinology, Metabolism, and Molecular Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
    Social Jetlag Changes During the COVID-19 Pandemic as a Predictor of Insomnia - A Multi-National Survey Study2021In: Nature and Science of Sleep, ISSN 1179-1608, Vol. 13, p. 1711-1722Article in journal (Refereed)
    Abstract [en]

    Purpose: Lifestyle and work habits have been drastically altered by restrictions due to the COVID-19 pandemic. Whether the associated changes in sleep timing modulate the risk of suffering from symptoms of insomnia, the most prevalent sleep disorder, is however incompletely understood. Here, we evaluate the association between the early pandemic-associated change in 1) the magnitude of social jetlag (SJL) - ie, the difference between sleep timing on working vs free days - and 2) symptoms of insomnia.

    Patients and Methods: A total of 14,968 anonymous participants (mean age: 40 years; 64% females) responded to a standardized internet-based survey distributed across 14 countries. Using logistic multivariate regression, we examined the association between the degree of social jetlag and symptoms of insomnia, controlling for important confounders like social restriction extension, country specific COVID-19 severity and psychological distress, for example.

    Results: In response to the pandemic, participants reported later sleep timing, especially during workdays. Most participants (46%) exhibited a reduction in their SJL, whereas 20% increased it; and 34% reported no change in SJL. Notably, we found that both increased and decreased SJL, as a result of the COVID-19 pandemic, were associated with later sleep midpoint (indicating a later chronotype) as well as more recurrent and moderate-to-severe symptoms of insomnia (about 23-54% higher odds ratio than subjects with unchanged SJL). Primarily those with reduced SJL shifted their bedtimes to a later timepoint, compared with those without changes in SJL.

    Conclusion: Our findings offer important insights into how self-reported changes to the stability of sleep/wake timing, as reflected by changes in SJL, can be a critical marker of the risk of experiencing insomnia-related symptoms - even when individuals manage to reduce their social jetlag. These findings emphasize the clinical importance of analyzing sleep-wake regularity.

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  • 35.
    Brooks, Samantha J.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience. Liverpool John Moores Univ, Fac Hlth, Sch Psychol, Liverpool 5E3 3AF, Merseyside, England.;Univ Witwatersrand, Sch Human & Community Dev, Dept Psychol, Neurosci Res Lab NeuRL, Johannesburg, South Africa..
    Feldman, Inna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Social medicine/CHAP. Uppsala Cty Council, Uppsala, Sweden..
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. Sechenov First Moscow State Med Univ, Inst Translat Med & Biotechnol, Moscow, Russia..
    Titova, Olga E
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Medical epidemiology.
    Important gender differences in psychosomatic and school-related complaints in relation to adolescent weight status2021In: Scientific Reports, E-ISSN 2045-2322, Vol. 11, article id 14147Article in journal (Refereed)
    Abstract [en]

    Underweight or overweight in adolescence is linked to several adverse health outcomes. Less evidence exists about the association between weight status and school-related psychosocial characteristics in high income countries. We sought to investigate the relationship between weight status and psychosomatic and school-related complaints with a focus on gender differences. The study is a cohort of 18,462 adolescents (12-19 years; 51% girls) conducted in Sweden. The associations between weight status and psychosomatic and school-related complaints were estimated by binary logistic regression adjusted for several potential confounders. After correction for multiple testing, being underweight or overweight/obese was adversely associated with several psychosomatic and school-related complaints with significant differences between boys and girls. Specifically, underweight boys had higher odds to have psychosomatic complaints than normal-weight boys, while no such associations were observed among underweight girls. Overweight/obese (vs. normal-weight) boys had higher odds to complain about headache, pain in the back/hips, and feeling low. Overweight/obese (vs. normal-weight) girls were more likely to complain about feeling low, anxious/worried and having difficulty in falling asleep (P <= 0.01). In relation to school-related complaints (e.g., being bullied at school and academic failure), greater associations were observed for overweight/obese girls and boys than for underweight adolescents compared with normal-weight peers.

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  • 36.
    Brooks, Samantha J.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. Liverpool John Moores Univ, Sch Psychol, Fac Hlth, Liverpool, Merseyside, England.;UppsalUniv Witwatersrand, Neurosci Res Lab NeuRL, Dept Psychol, Sch Human & Community Dev, Johannesburg, South Africa..
    Mackenzie-Phelan, Rhiannon
    Liverpool John Moores Univ, Sch Psychol, Fac Hlth, Liverpool, Merseyside, England..
    Tully, Jamie
    Liverpool John Moores Univ, Sch Psychol, Fac Hlth, Liverpool, Merseyside, England..
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. Uppsala Univ,Sechenov First Moscow State Med Univ, Inst Translat Med & Biotechnol, Moscow, Russia..
    Review of the Neural Processes of Working Memory Training: Controlling the Impulse to Throw the Baby Out With the Bathwater2020In: Frontiers in Psychiatry, E-ISSN 1664-0640, Vol. 11, article id 512761Article, review/survey (Refereed)
    Abstract [en]

    Background Smartphone technology has enabled the creation of many working memory training (WMT) Apps, with those peer-reviewed described in a recent review. WMT claims to improve working memory, attention deficits, hyperactivity and fluid intelligence, in line with plasticity brain changes. Critics argue that WMT is unable to achieve "far-transfer"-the attainment of benefits to cognition from one taught context to another dissimilar context-associated with improved quality of life. However, brain changes after a course of WMT in frontoparietal and striatal circuits-that often occur prior to behavioral changes-may be a better indicator of far-transfer efficacy, especially to improve impulse control commonly dysregulated in those with addictive disorders, yet not commonly examined in WMT studies. Method In contrast to previous reviews, the aim here is to focus on the findings of brain imaging WMT training studies across various imaging modalities that use various paradigms, publishedviaPubMed, Scopus, Medline, and Google Scholar. Results 35 brain imaging studies utilized fMRI, structural imaging (MRI, DTI), functional connectivity, EEG, transcranial direct current stimulation (tDCS), cerebral perfusion, and neurogenetic analyses with tasks based on visuospatial and auditory working memory, dual and standard n-back. Discussion Evidence suggests that repeated WMT reduces brain activation in frontoparietal and striatal networks reflective of increased neural circuitry efficiencyviamyelination and functional connectivity changes. Neural effects of WMT may persist months after training has ended, lead to non-trained task transfer, be strengthened by auxiliary methods such as tDCS and be related to COMT polymorphisms. WMT could be utilized as an effective, non-invasive intervention for working memory deficits to treat impulse and affective control problems in people with addictive disorders.

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  • 37. Cable, Jennifer
    et al.
    Schernhammer, Eva
    Hanlon, Erin C
    Vetter, Céline
    Cedernaes, Jonathan
    Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
    Makarem, Nour
    Dashti, Hassan S
    Shechter, Ari
    Depner, Christopher
    Ingiosi, Ashley
    Blume, Christine
    Tan, Xiao
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Gottlieb, Elie
    Benedict, Christian
    Van Cauter, Eve
    St-Onge, Marie-Pierre
    Sleep and circadian rhythms: pillars of health-a Keystone Symposia report2021In: Annals of the New York Academy of Sciences, ISSN 0077-8923, E-ISSN 1749-6632, Vol. 1506, no 1, p. 18-34Article in journal (Refereed)
    Abstract [en]

    The human circadian system consists of the master clock in the suprachiasmatic nuclei of the hypothalamus as well as in peripheral molecular clocks located in organs throughout the body. This system plays a major role in the temporal organization of biological and physiological processes, such as body temperature, blood pressure, hormone secretion, gene expression, and immune functions, which all manifest consistent diurnal patterns. Many facets of modern life, such as work schedules, travel, and social activities, can lead to sleep/wake and eating schedules that are misaligned relative to the biological clock. This misalignment can disrupt and impair physiological and psychological parameters that may ultimately put people at higher risk for chronic diseases like cancer, cardiovascular disease, and other metabolic disorders. Understanding the mechanisms that regulate sleep circadian rhythms may ultimately lead to insights on behavioral interventions that can lower the risk of these diseases. On February 25, 2021, experts in sleep, circadian rhythms, and chronobiology met virtually for the Keystone eSymposium "Sleep & Circadian Rhythms: Pillars of Health" to discuss the latest research for understanding the bidirectional relationships between sleep, circadian rhythms, and health and disease.

  • 38.
    Carneiro, Clarissa F. D.
    et al.
    Univ Fed Rio de Janeiro, Inst Med Biochem Leopoldo de Meis, BR-21941902 Rio De Janeiro, RJ, Brazil..
    Queiroz, Victor G. S.
    Univ Fed Rio de Janeiro, Inst Med Biochem Leopoldo de Meis, BR-21941902 Rio De Janeiro, RJ, Brazil..
    Moulin, Thiago C.
    Univ Fed Rio de Janeiro, Inst Med Biochem Leopoldo de Meis, BR-21941902 Rio De Janeiro, RJ, Brazil..
    Carvalho, Carlos A. M.
    Inst Evandro Chagas, Secao Arbovirol & Febres Hemorrag, Ananindeua, Para, Brazil.;Univ Estado Para, Dept Patol, Belem, Para, Brazil.;Ctr Univ Metropolitano Amazonia, Inst Euro Amer Educ Ciencia & Tecnol, Belem, Para, Brazil..
    Haas, Clarissa B.
    Univ Fed Rio Grande do Sul, Inst Ciencias Basicas Saude, Dept Bioquim, Porto Alegre, RS, Brazil..
    Rayee, Danielle
    Univ Fed Rio de Janeiro, Biomed Sci Inst, Rio De Janeiro, Brazil..
    Henshall, David E.
    Univ Edinburgh, Med Sch, Edinburgh, Midlothian, Scotland..
    De-Souza, Evandro A.
    Univ Fed Rio de Janeiro, Inst Med Biochem Leopoldo de Meis, BR-21941902 Rio De Janeiro, RJ, Brazil..
    Amorim, Felippe E.
    Univ Fed Rio de Janeiro, Inst Med Biochem Leopoldo de Meis, BR-21941902 Rio De Janeiro, RJ, Brazil..
    Boos, Flavia Z.
    Univ Fed Sao Paulo, Programa Posgrad Psicobiol, Sao Paulo, Brazil..
    Guercio, Gerson D.
    Univ Minnesota, Dept Psychiat, Minneapolis, MN 55455 USA..
    Costa, Igor R.
    Univ Fed Rio de Janeiro, Inst Med Biochem Leopoldo de Meis, BR-21941902 Rio De Janeiro, RJ, Brazil..
    Hajdu, Karina L.
    Univ Fed Rio de Janeiro, Biomed Sci Inst, Rio De Janeiro, Brazil..
    van Egmond, Lieve
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Modrak, Martin
    Czech Acad Sci, Inst Microbiol, Prague, Czech Republic..
    Tan, Pedro B.
    Univ Fed Rio de Janeiro, Biomed Sci Inst, Rio De Janeiro, Brazil..
    Abdill, Richard J.
    Univ Minnesota, Dept Genet Cell Biol & Dev, Minneapolis, MN USA..
    Burgess, Steven J.
    Univ Illinois, Carl R Woese Inst Genom Biol, Champaign, IL USA..
    Guerra, Sylvia F. S.
    Ctr Univ Metropolitano Amazonia, Inst Euro Amer Educ Ciencia & Tecnol, Belem, Para, Brazil.;Inst Evandro Chagas, Secao Virol, Ananindeua, Para, Brazil.;Univ Estado Para, Dept Morfol & Ciencias Fisiol, Belem, Para, Brazil..
    Bortoluzzi, Vanessa T.
    Univ Fed Rio Grande do Sul, Inst Ciencias Basicas Saude, Dept Bioquim, Porto Alegre, RS, Brazil..
    Amaral, Olavo B.
    Univ Fed Rio de Janeiro, Inst Med Biochem Leopoldo de Meis, BR-21941902 Rio De Janeiro, RJ, Brazil..
    Comparing quality of reporting between preprints and peer-reviewed articles in the biomedical literature2020In: RESEARCH INTEGRITY AND PEER REVIEW, ISSN 2058-8615, Vol. 5, no 1, article id 16Article in journal (Refereed)
    Abstract [en]

    Background Preprint usage is growing rapidly in the life sciences; however, questions remain on the relative quality of preprints when compared to published articles. An objective dimension of quality that is readily measurable is completeness of reporting, as transparency can improve the reader's ability to independently interpret data and reproduce findings. Methods In this observational study, we initially compared independent samples of articles published in bioRxiv and in PubMed-indexed journals in 2016 using a quality of reporting questionnaire. After that, we performed paired comparisons between preprints from bioRxiv to their own peer-reviewed versions in journals. Results Peer-reviewed articles had, on average, higher quality of reporting than preprints, although the difference was small, with absolute differences of 5.0% [95% CI 1.4, 8.6] and 4.7% [95% CI 2.4, 7.0] of reported items in the independent samples and paired sample comparison, respectively. There were larger differences favoring peer-reviewed articles in subjective ratings of how clearly titles and abstracts presented the main findings and how easy it was to locate relevant reporting information. Changes in reporting from preprints to peer-reviewed versions did not correlate with the impact factor of the publication venue or with the time lag from bioRxiv to journal publication. Conclusions Our results suggest that, on average, publication in a peer-reviewed journal is associated with improvement in quality of reporting. They also show that quality of reporting in preprints in the life sciences is within a similar range as that of peer-reviewed articles, albeit slightly lower on average, supporting the idea that preprints should be considered valid scientific contributions.

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  • 39.
    Ceder, Mikaela M.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Aggarwal, Tanya
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Hosseini, Kimia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Maturi, Varun
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Patil, Sourabh
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Perland, Emelie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Williams, Michael J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Fredriksson, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    CG4928 is vital for renal function in fruit flies and membrane potential in cells: A first in-depth characterization of the putative Solute Carrier UNC93A2020In: Frontiers in Cell and Developmental Biology, E-ISSN 2296-634X, Vol. 8, article id 580291Article in journal (Refereed)
    Abstract [en]

    The number of transporter proteins that are not fully characterized is immense. Here, we used Drosophila melanogaster and human cell lines to perform a first in-depth characterization of CG4928, an ortholog to the human UNC93A, of which little is known. Solute carriers regulate and maintain biochemical pathways important for the body, and malfunctioning transport is associated with multiple diseases. Based on phylogenetic analysis, CG4928 is closely related to human UNC93A and has a secondary and a tertiary protein structure and folding similar to major facilitator superfamily transporters. Ubiquitous knockdown of CG4928 causes flies to have a reduced secretion rate from the Malpighian tubules; altering potassium content in the body and in the Malpighian tubules, homologous to the renal system; and results in the development of edema. The edema could be rescued by using amiloride, a common diuretic, and by maintaining the flies on ion-free diets. CG4928-overexpressing cells did not facilitate the transport of sugars and amino acids; however, proximity ligation assay revealed that CG4928 co-localized with TASK(1) channels. Overexpression of CG4928 resulted in induced apoptosis and cytotoxicity, which could be restored when cells were kept in high-sodium media. Furthermore, the basal membrane potential was observed to be disrupted. Taken together, the results indicate that CG4928 is of importance for generating the cellular membrane potential by an unknown manner. However, we speculate that it most likely acts as a regulator or transporter of potassium flows over the membrane.

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  • 40.
    Ceder, Mikaela M.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Lindberg, Frida A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Perland, Emelie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Williams, Michael J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Fredriksson, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    The Fly Homologue of MFSD11 Is Possibly Linked to Nutrient Homeostasis and Has a Potential Role in Locomotion: A First Characterization of the Atypical Solute Carrier CG18549 in Drosophila Melanogaster2021In: Insects, E-ISSN 2075-4450, Vol. 12, no 11, article id 1024Article in journal (Refereed)
    Abstract [en]

    Cellular transport and function are dependent on substrate influx and efflux of various compounds. In humans, the largest superfamily of transporters is the SoLute Carriers (SLCs). Many transporters are orphans and little to nothing is known about their expression and/or function, yet they have been assigned to a cluster called atypical SLCs. One of these atypical SLCs is MFSD11. Here we present a first in-depth characterization of the MFSD11, CG18549. By gene expression and behavior analysis on ubiquitous and brain-specific knockdown flies. CG18549 knockdown flies were found to have altered adipokinetic hormone and adipokinteic hormone receptor expression as well as reduced vesicular monoamine transporter expression; to exhibit an altered locomotor behavior, and to have an altered reaction to stress stimuli. Furthermore, the gene expression of CG18549 in the brain was visualized and abundant expression in both the larvae and adult brain was observed, a result that is coherent with the FlyAtlas Anatomy microarray. The exact mechanism behind the observed behaviors is not fully understood, but this study provides new insights into the expression and function of CG18549. Clearly, these results provide a strong example as to why it is vital to fully characterize orphan transporters and through that gain knowledge about the body during normal condition and disease.

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  • 41.
    Chang, Baorui
    et al.
    Guangxi Normal Univ, Dept Psychol, Fac Educ, Guilin, Peoples R China..
    Cheng, Jiaxin
    Guangxi Normal Univ, Dept Psychol, Fac Educ, Guilin, Peoples R China..
    Fang, Jiandong
    Guangxi Normal Univ, Dept Psychol, Fac Educ, Guilin, Peoples R China..
    Dang, Junhua
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    The Indirect Effect of Death Anxiety on Experienced Meaning in Life via Search for Meaning and Prosocial Behavior2021In: Frontiers in Psychology, E-ISSN 1664-1078, Vol. 12, article id 673460Article in journal (Refereed)
    Abstract [en]

    This study investigated the relationship between death anxiety and experienced meaning in life. Six hundred and forty-eight Chinese college students were surveyed using the Death Anxiety Scale, the Prosocial Behavior Scale, and the Meaning in Life Scale. The results showed that death anxiety predicted experienced meaning through three pathways: the first one was through search for meaning singly; the second one was through prosocial behavior singly; and the third one was through search for meaning and prosocial behavior serially, which accounted for the highest proportion of the total effect. This study highlights the positive side of death anxiety.

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  • 42.
    Chatzittofis, Andreas
    et al.
    Univ Cyprus, Med Sch, CY-1678 Nicosia, Cyprus.;Umeå Univ, Dept Clin Sci Psychiat, Umeå, Sweden..
    Bostrom, Adrian Desai E.
    Umeå Univ, Dept Clin Sci Psychiat, Umeå, Sweden.;Karolinska Inst, Dept Womens & Childrens Hlth, Neuropaediat Unit, Stockholm, Sweden..
    Ciuculete, Diana-Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Oberg, Katarina Gorts
    Karolinska Univ Hosp, Karolinska Inst, Dept Med, Stockholm, Sweden..
    Arver, Stefan
    Karolinska Univ Hosp, Karolinska Inst, Dept Med, Stockholm, Sweden..
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. Sechenov First Moscow State Med Univ, Inst Translat Med & Biotechnol, Moscow, Russia..
    Jokinen, Jussi
    Umeå Univ, Dept Clin Sci Psychiat, Umeå, Sweden.;Karolinska Inst, Dept Clin Neurosci Psychiat, Stockholm, Sweden..
    HPA axis dysregulation is associated with differential methylation of CpG-sites in related genes2021In: Scientific Reports, E-ISSN 2045-2322, Vol. 11, no 1, article id 20134Article in journal (Refereed)
    Abstract [en]

    DNA methylation shifts in Hypothalamic-pituitary-adrenal (HPA) axis related genes is reported in psychiatric disorders including hypersexual disorder. This study, comprising 20 dexamethasone suppression test (DST) non-suppressors and 73 controls, examined the association between the HPA axis dysregulation, shifts in DNA methylation of HPA axis related genes and importantly, gene expression. Individuals with cortisol level >= 138 nmol/l, after the low dose (0.5 mg) dexamethasone suppression test (DST) were classified as non-suppressors. Genome-wide methylation pattern, measured in whole blood using the EPIC BeadChip, investigated CpG sites located within 2000 bp of the transcriptional start site of key HPA axis genes, i.e.: CRH, CRHBP, CRHR-1, CRHR-2, FKBP5 and NR3C1. Regression models including DNA methylation M-values and the binary outcome (DST non-suppression status) were performed. Gene transcripts with an abundance of differentially methylated CpG sites were identified with binomial tests. Pearson correlations and robust linear regressions were performed between CpG methylation and gene expression in two independent cohorts. Six of 76 CpG sites were significantly hypermethylated in DST non-suppressors (nominal P < 0.05), associated with genes CRH, CRHR1, CRHR2, FKBP5 and NR3C1. NR3C1 transcript AJ877169 showed statistically significant abundance of probes differentially methylated by DST non-suppression status and correlated with DST cortisol levels. Further, methylation levels of cg07733851 and cg27122725 were positively correlated with gene expression levels of the NR3C1 gene. Methylation levels of cg08636224 (FKBP5) correlated with baseline cortisol and gene expression. Our findings revealed that DNA methylation shifts are involved in the altered mechanism of the HPA axis suggesting that new epigenetic targets should be considered behind psychiatric disorders.

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  • 43.
    Chatzittofis, Andreas
    et al.
    Umeå Univ, Dept Clin Sci Psychiat, Umeå, Sweden; Univ Cyprus, Med Sch, Nicosia, Cyprus.
    Boström, Adrian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Görts Öberg, Katarina
    Karolinska Univ Hosp, Karolinska Inst, Dept Med, Stockholm, Sweden.
    Flanagan, John N.
    Karolinska Univ Hosp, Karolinska Inst, Dept Med, Stockholm, Sweden.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. Sechenov First Moscow State Med Univ, Inst Translat Med & Biotechnol, Moscow, Russia.
    Arver, Stefan
    Karolinska Univ Hosp, Karolinska Inst, Dept Med, Stockholm, Sweden..
    Jokinen, Jussi
    Umeå Univ, Dept Clin Sci Psychiat, Umeå, Sweden; Karolinska Univ Hosp, Karolinska Inst, Dept Clin Neurosci Psychiat, Stockholm, Sweden.
    Normal Testosterone but Higher Luteinizing Hormone Plasma Levels in Men With Hypersexual Disorder2020In: Sexual Medicine, E-ISSN 2050-1161, Vol. 8, no 2, p. 243-250Article in journal (Refereed)
    Abstract [en]

    Introduction: Hypersexual disorder as suggested to be included in the Diagnostic and Statistical Manual of Mental Disorders-5 integrates aspects of sexual desire deregulation, impulsivity, and compulsivity. However, it is unknown how it affects gonadal activity and the function of the hypothalamus-pituitary-gonadal (HPG) axis.

    Aim: The aim of this study was to investigate testosterone and luteinizing hormone (LH) levels in hypersexual men compared with healthy controls. Furthermore, we investigated associations between epigenetic markers and hormone levels.

    Methods: Basal morning plasma levels of testosterone, LH, and sex hormone-binding globulin (SHBG) were assessed in 67 hypersexual men (mean age: 39.2 years) compared with 39 age-matched healthy controls (mean age: 37.5 years). The Sexual Compulsivity Scale and the Hypersexual Disorder: Current Assessment Scale were used for assessing hypersexual behavior, the Montgomery-Asberg Depression Scale-self rating was used for depression severity, and the Childhood Trauma Questionnaire (CTQ) was used for assessing history of childhood adversity. The genome-wide methylation pattern of more than 850 K CpG sites was measured in whole blood using the Illumina Infinium Methylation EPIC BeadChip. CpG sites located within 2,000 bp of the transcriptional start site of hypothalamus pituitary adrenal (HPA) and HPG axis-coupled genes were included.

    Main Outcome Measures: Testosterone and LH plasma levels in association with clinical rating and a secondary outcome was the epigenetic profile of HPA and HPG axis-coupled CpG sites with testosterone and LH levels.

    Results: LH plasma levels were significantly higher in patients with hypersexual disorder than in healthy volunteers. No significant differences in plasma testosterone, follicle stimulating hormone, prolactin, and SHBG levels were found between the groups. There were no significant associations between DNA methylation of HPA and HPG axis-coupled genes and plasma testosterone or LH levels after multiple testing corrections.

    Conclusions: Subtle dysregulation of the HPG axis, with increased LH plasma levels but no difference in testosterone levels may be present in hypersexual men.

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  • 44.
    Chen, Jie
    et al.
    Chinese Univ Hong Kong, Fac Med, Dept Psychiat, Li Chiu Kong Family Sleep Assessment Unit, Hong Kong, Peoples R China..
    Zhang, Jihui
    Chinese Univ Hong Kong, Fac Med, Dept Psychiat, Li Chiu Kong Family Sleep Assessment Unit, Hong Kong, Peoples R China.;Guangdong Acad Med Sci, Guangdong Prov Peoples Hosp, Guangdong Mental Hlth Ctr, Guangzhou, Guangdong, Peoples R China.;Southern Med Univ, Sch Clin Med 2, 253 Ind Ave Middle, Guangzhou, Peoples R China..
    So, Hon Cheong
    Chinese Univ Hong Kong, Fac Med, Cheung Res Ctr Management Parkinsonism, Sch Biomed Sci,Dept Psychiat,KIZ CUHK Joint Lab B, Hong Kong, Peoples R China..
    Ai, Sizhi
    Chinese Univ Hong Kong, Fac Med, Dept Psychiat, Li Chiu Kong Family Sleep Assessment Unit, Hong Kong, Peoples R China..
    Wang, Ningjian
    Shanghai Jiao Tong Univ, Shanghai Peoples Hosp 9, Inst & Dept Endocrinol & Metab, Sch Med, Shanghai, Peoples R China..
    Tan, Xiao
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden..
    Wing, Yun Kwok
    Chinese Univ Hong Kong, Fac Med, Dept Psychiat, Li Chiu Kong Family Sleep Assessment Unit, Hong Kong, Peoples R China..
    Association of Sleep Traits and Heel Bone Mineral Density: Observational and Mendelian Randomization Studies2021In: Journal of Bone and Mineral Research, ISSN 0884-0431, E-ISSN 1523-4681, Vol. 36, no 11, p. 2184-2192Article in journal (Refereed)
    Abstract [en]

    Observational studies have suggested that sleep and circadian disturbances are potentially modifiable risk factors for low bone mineral density (BMD), but the causal relationship is unclear. This study aimed to (i) replicate the findings by examining observational association of sleep traits with low estimated BMD); (ii) examine whether these associations were causal by using Mendelian randomization (MR) analyses; and (iii) investigate potential modulation effects of sex and menopause. A total of 398,137 White British subjects (aged 39 to 73 years) with valid BMD estimated by quantitative ultrasound of the heel (eBMD) at baseline were included. Linear regression analyses and inverse-variance weighted method were used as main methods for observational and one-sample MR analyses, respectively, to investigate the associations between self-reported sleep traits (sleep duration, chronotype, daytime sleepiness, and insomnia) and low eBMD. Furthermore, sensitivity analyses were performed in subgroups based on sex and menopause in both observational and MR analyses. In observational analyses, short/long sleep, insomnia, and definite eveningness were associated with low eBMD (short sleep: beta = -0.045, effect in standard deviation change of rank-based inverse normally transformed eBMD; long sleep: beta = -0.028; sometimes insomnia: beta = -0.012; usually insomnia: beta = -0.021; definite eveningness: beta = -0.047), whereas definite morningness was associated with decreased risk of low eBMD (beta = 0.011). Subgroup analyses suggested associations of short/long sleep and definite eveningness with low eBMD among men, short sleep with low eBMD among premenopausal women, and short sleep, eveningness, and daytime sleepiness among postmenopausal women. In bidirectional MR analyses, there was no causal relationship between sleep traits and eBMD in either overall sample or subgroup analyses. In summary, although observational analysis showed a robust association of low eBMD with sleep duration, chronotype, and insomnia, there was no evidence of causal relationship as suggested by MR analysis.

  • 45.
    Chung, Frances
    et al.
    Department of Anesthesia and Pain Medicine, Toronto Western Hospital, University Health Network, University of Toronto, Toronto, ON, M5T2S8, Canada; Institute of Medical Science, Temerty Faculty of Medicine, University of Toronto, Ontario, Canada.
    Waseem, Rida
    Department of Anesthesia and Pain Medicine, Toronto Western Hospital, University Health Network, University of Toronto, Toronto, ON, M5T2S8, Canada.
    Pham, Chi
    Department of Anesthesia and Pain Medicine, Toronto Western Hospital, University Health Network, University of Toronto, Toronto, ON, M5T2S8, Canada; Institute of Medical Science, Temerty Faculty of Medicine, University of Toronto, Ontario, Canada.
    Penzel, Thomas
    Sleep Medicine Center, Charite Universitätsmedizin Berlin, Berlin, Germany.
    Han, Fang
    Department of Respiratory Medicine, Peking University People’s Hospital, Beijing, China.
    Bjorvatn, Bjørn
    Department of Global Public Health and Primary Care, University of Bergen, Bergen, Norway; Norwegian Competence Center for Sleep Disorders, Haukeland University Hospital, Bergen, Norway.
    Morin, Charles M
    École de Psychologie, Centre d’étude des troubles du sommeil, Centre de recherche CERVO/Brain Research Center, Université Laval, Québec, Canada.
    Holzinger, Brigitte
    Institute for Dream and Consciousness Research, Medical University of Vienna, Vienna, Austria.
    Espie, Colin A
    Sleep and Circadian Neuroscience Institute, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.
    Benedict, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Cedernaes, Jonathan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Transplantation and regenerative medicine. Division of Endocrinology, Metabolism, and Molecular Medicine, Department of Medicine, Northwestern University, Chicago, IL, USA.
    Saaresranta, Tarja
    Division of Medicine, Department of Pulmonary Diseases, Turku University Hospital, Turku, Finland.
    Wing, Yun Kwok
    Li Chiu Kong Family Sleep Assessment Unit, Departments of Psychiatry, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong, SAR, China.
    Nadorff, Michael R
    Department of Psychology, Mississippi State University, Starkville, USA; Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, Houston, USA.
    Dauvilliers, Yves
    Sleep-Wake Disorders Center, Department of Neurology, Gui-de-Chauliac Hospital, Institute for Neurosciences of Montpellier INM, INSERM, University of Montpellier, Montpellier, France.
    De Gennaro, Luigi
    Department of Psychology, Sapienza University of Rome, Rome, Italy; IRCCS Fondazione Santa Lucia, Rome, Italy.
    Plazzi, Guiseppe
    IRCCS, Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy; Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy.
    Merikanto, Ilona
    Department of Psychology and Logopedics and SleepWell Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
    Matsui, Kentaro
    Department of Clinical Laboratory and Department of Sleep-Wake Disorders, National Center of Neurology and Psychiatry National Institute of Mental Health, Kodaira, Japan; Department of Psychiatry, Tokyo Women’s Medical University, Tokyo, Japan.
    Leger, Damien
    Sleep and Vigilance Center, Hopital Hotel-Dieu de Paris, Paris, France; Universite de Paris, VIFASOM (EA 7331 Vigilance Fatigue Sommeil et Santé Publique), Paris, France.
    Sieminski, Mariusz
    Department of Emergency Medicine, Medical University of Gdansk, Gdansk, Poland.
    Mota-Rolim, Sergio
    Brain Institute, Onofre Lopes University Hospital, Natal, Brazil; Physiology and Behavior Department, Federal University of Rio Grande do Norte, Natal, Brazil.
    Inoue, Yuichi
    Department of Somnology, Tokyo Medical University, Tokyo, Japan; Japan Somnology Center, Neuropsychiatric Research Institute, Tokyo, Japan.
    Partinen, Markku
    Helsinki Sleep Clinic, Vitalmed Research Center, and Department of Neurosciences, Clinicum, University of Helsinki, Helsinki, Finland.
    The association between high risk of sleep apnea, comorbidities, and risk of COVID-19: a population-based international harmonized study2021In: Sleep and Breathing, ISSN 1520-9512, E-ISSN 1522-1709, Vol. 25, no 2, p. 849-860Article in journal (Refereed)
    Abstract [en]

    PURPOSE: Obstructive sleep apnea (OSA) may increase the risk of severe COVID-19; however, the level of potential modulation has not yet been established. The objective of the study was to determine the association between high risk of OSA, comorbidities, and increased risk for COVID-19, hospitalization, and intensive care unit (ICU) treatment.

    METHODS: We conducted a cross-sectional population-based web survey in adults in 14 countries/regions. The survey included sociodemographic variables and comorbidities. Participants were asked questions about COVID-19, hospitalization, and ICU treatment. Standardized questionnaire (STOP questionnaire for high risk of OSA) was included. Multivariable logistic regression was conducted adjusting for various factors.

    RESULTS: Out of 26,539 respondents, 20,598 (35.4% male) completed the survey. Mean age and BMI of participants were 41.5 ± 16.0 years and 24.0 ± 5.0 kg/m2, respectively. The prevalence of physician-diagnosed OSA was 4.1% and high risk of OSA was 9.5%. We found that high risk of OSA (adjusted odds ratio (aOR) 1.72, 95% confidence interval (CI): 1.20, 2.47) and diabetes (aOR 2.07, 95% CI: 1.23, 3.48) were associated with reporting of a COVID-19 diagnosis. High risk for OSA (aOR 2.11, 95% CI: 1.10-4.01), being male (aOR: 2.82, 95% CI: 1.55-5.12), having diabetes (aOR: 3.93, 95% CI: 1.70-9.12), and having depression (aOR: 2.33, 95% CI: 1.15-4.77) were associated with increased risk of hospitalization or ICU treatment.

    CONCLUSIONS: Participants at high risk of OSA had increased odds of having COVID-19 and were two times more likely to be hospitalized or treated in ICU.

  • 46.
    Chye, Yann
    et al.
    Monash Univ, Turner Inst Brain & Mental Hlth, Sch Psychol Sci, Clayton, Vic, Australia..
    Mackey, Scott
    Univ Vermont, Dept Psychiat, Burlington, VT 05405 USA..
    Gutman, Boris A.
    IIT, Biomed Engn, Chicago, IL 60616 USA..
    Ching, Christopher R. K.
    Univ Southern Calif, Mark & Mary Stevens Neuroimaging & Informat Inst, Imaging Genet Ctr, Dept Neurol,Keck Sch Med, Los Angeles, CA USA..
    Batalla, Albert
    Univ Utrecht, Dept Psychiat, Univ Med Ctr Utrecht, Brain Ctr, Utrecht, Netherlands.;Univ Barcelona, Dept Psychiat & Psychol, Hosp Clin, IDIBAPS,CIBERSAM,Inst Neurosci, Barcelona, Spain..
    Blaine, Sara
    Yale Univ, Sch Med, Dept Psychiat, New Haven, CT 06520 USA.;Yale Univ, Sch Med, Dept Neurosci, New Haven, CT 06520 USA..
    Brooks, Samantha
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. Liverpool John Moores Univ, Sch Psychol, Fac Hlth, Liverpool L3 3AF, Merseyside, England..
    Caparelli, Elisabeth C.
    NIDA, Neuroimaging Res Branch, Intramural Res Program, Baltimore, MD USA..
    Cousijn, Janna
    Univ Amsterdam, Dept Dev Psychol, Amsterdam, Netherlands..
    Dagher, Alain
    McGill Univ, McConnell Brain Imaging Ctr, Montreal Neurol Inst, Montreal, PQ, Canada..
    Foxe, John J.
    Univ Rochester, Sch Med & Dent, Dept Neurosci, Rochester, NY USA.;Univ Rochester, Sch Med & Dent, Ernest J Del Monte Inst Neurosci, Rochester, NY USA..
    Goudriaan, Anna E.
    Univ Amsterdam, Amsterdam UMC, Dept Psychiat, Amsterdam Inst Addict Res, Amsterdam, Netherlands.;Arkin Mental Hlth Care, Dept Res & Qual Care, Amsterdam, Netherlands..
    Hester, Robert
    Univ Melbourne, Melbourne Sch Psychol Sci, Melbourne, Vic, Australia..
    Hutchison, Kent
    Univ Colorado, Dept Psychol & Neurosci, Boulder, CO 80309 USA..
    Jahanshad, Neda
    Univ Southern Calif, Mark & Mary Stevens Neuroimaging & Informat Inst, Imaging Genet Ctr, Dept Neurol,Keck Sch Med, Los Angeles, CA USA..
    Kaag, Anne M.
    Univ Amsterdam, Dept Dev Psychol, Amsterdam, Netherlands..
    Korucuoglu, Ozlem
    Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63110 USA..
    Li, Chiang-Shan R.
    Yale Univ, Sch Med, Dept Psychiat, New Haven, CT 06520 USA.;Yale Univ, Sch Med, Dept Neurosci, New Haven, CT 06520 USA..
    London, Edythe D.
    Univ Calif Los Angeles, David Geffen Sch Med, Jane & Terry Semel Inst Neurosci & Human Behav, Los Angeles, CA 90095 USA..
    Lorenzetti, Valentina
    Monash Univ, Turner Inst Brain & Mental Hlth, Sch Psychol Sci, Clayton, Vic, Australia.;Australian Catholic Univ, Sch Psychol, Fac Hlth Sci, Melbourne, Vic, Australia..
    Luijten, Maartje
    Radboud Univ Nijmegen, Inst Behav Sci, Nijmegen, Netherlands..
    Martin-Santos, Rocio
    Univ Barcelona, Dept Psychiat & Psychol, Hosp Clin, IDIBAPS,CIBERSAM,Inst Neurosci, Barcelona, Spain..
    Meda, Shashwath A.
    Hartford Hosp IOL, Olin Neuropsychiat Res Ctr, Hartford, CT USA..
    Momenan, Reza
    NIAAA, Clin NeuroImaging Res Core, Div Intramural Clin & Biol Res, Bethesda, MD USA..
    Morales, Angelica
    Univ Calif Los Angeles, David Geffen Sch Med, Jane & Terry Semel Inst Neurosci & Human Behav, Los Angeles, CA 90095 USA..
    Orr, Catherine
    Univ Vermont, Dept Psychiat, Burlington, VT 05405 USA..
    Paulus, Martin P.
    VA San Diego Healthcare Syst, San Diego, CA USA.;Univ Calif San Diego, Dept Psychiat, La Jolla, CA 92093 USA.;Laureate Inst Brain Res, Tulsa, OK USA..
    Pearlson, Godfrey
    Yale Univ, Sch Med, Dept Psychiat, New Haven, CT 06520 USA.;Yale Univ, Sch Med, Dept Neurosci, New Haven, CT 06520 USA..
    Reneman, Liesbeth
    Locat AMC, Amsterdam UMC, Dept Radiol & Nucl Med, Amsterdam, Netherlands..
    Schmaal, Lianne
    Orygen, Natl Ctr Excellence Youth Mental Hlth, Parkville, Vic, Australia.;Univ Melbourne, Ctr Youth Mental Hlth, Parkville, Vic, Australia..
    Sinha, Rajita
    Yale Univ, Sch Med, Dept Psychiat, New Haven, CT 06520 USA.;Yale Univ, Sch Med, Dept Neurosci, New Haven, CT 06520 USA..
    Solowij, Nadia
    Univ Wollongong, Sch Psychol, Wollongong, NSW, Australia.;Univ Wollongong, Illawarra Hlth & Med Res Inst, Wollongong, NSW, Australia.;Australian Ctr Cannabinoid Clin & Res Excellence, New Lambton Hts, NSW, Australia..
    Stein, Dan J.
    Univ Cape Town, SA MRC Unit Risk & Resilience Mental Disorders, Dept Psychiat, Cape Town, South Africa.;Univ Cape Town, Inst Neurosci, Cape Town, South Africa..
    Stein, Elliot A.
    NIDA, Neuroimaging Res Branch, Intramural Res Program, Baltimore, MD USA..
    Tang, Deborah
    McGill Univ, McConnell Brain Imaging Ctr, Montreal Neurol Inst, Montreal, PQ, Canada..
    Uhlmann, Anne
    Univ Cape Town, Fac Hlth Sci, Dept Psychiat & Mental Hlth, Cape Town, South Africa..
    van Holst, Ruth
    Univ Amsterdam, Dept Psychiat, Amsterdam, Netherlands..
    Veltman, Dick J.
    Vrije Univ Amsterdam Med Ctr, Dept Psychiat, Amsterdam, Netherlands..
    Verdejo-Garcia, Antonio
    Monash Univ, Turner Inst Brain & Mental Hlth, Sch Psychol Sci, Clayton, Vic, Australia..
    Wiers, Reinout W.
    Univ Amsterdam, Addict Dev & Psychopathol ADAPT Lab, Amsterdam, Netherlands..
    Yuecel, Murat
    Monash Univ, Turner Inst Brain & Mental Hlth, Sch Psychol Sci, Clayton, Vic, Australia..
    Thompson, Paul M.
    Univ Southern Calif, Mark & Mary Stevens Neuroimaging & Informat Inst, Imaging Genet Ctr, Dept Neurol,Keck Sch Med, Los Angeles, CA USA..
    Conrod, Patricia
    Univ Montreal, Dept Psychiat, CHU Ste Justine Hosp, Montreal, PQ, Canada..
    Garavan, Hugh
    Univ Vermont, Dept Psychiat, Burlington, VT 05405 USA..
    Subcortical surface morphometry in substance dependence: An ENIGMA addiction working group study2020In: Addiction Biology, ISSN 1355-6215, E-ISSN 1369-1600, Vol. 25, no 6, article id e12830Article in journal (Refereed)
    Abstract [en]

    While imaging studies have demonstrated volumetric differences in subcortical structures associated with dependence on various abused substances, findings to date have not been wholly consistent. Moreover, most studies have not compared brain morphology across those dependent on different substances of abuse to identify substance-specific and substance-general dependence effects. By pooling large multinational datasets from 33 imaging sites, this study examined subcortical surface morphology in 1628 nondependent controls and 2277 individuals with dependence on alcohol, nicotine, cocaine, methamphetamine, and/or cannabis. Subcortical structures were defined by FreeSurfer segmentation and converted to a mesh surface to extract two vertex-level metrics-the radial distance (RD) of the structure surface from a medial curve and the log of the Jacobian determinant (JD)-that, respectively, describe local thickness and surface area dilation/contraction. Mega-analyses were performed on measures of RD and JD to test for the main effect of substance dependence, controlling for age, sex, intracranial volume, and imaging site. Widespread differences between dependent users and nondependent controls were found across subcortical structures, driven primarily by users dependent on alcohol. Alcohol dependence was associated with localized lower RD and JD across most structures, with the strongest effects in the hippocampus, thalamus, putamen, and amygdala. Meanwhile, nicotine use was associated with greater RD and JD relative to nonsmokers in multiple regions, with the strongest effects in the bilateral hippocampus and right nucleus accumbens. By demonstrating subcortical morphological differences unique to alcohol and nicotine use, rather than dependence across all substances, results suggest substance-specific relationships with subcortical brain structures.

  • 47.
    Ciuculete, Diana Maria
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Voisin, Sarah
    Victoria Univ, Inst Hlth & Sport iHeS, Footscray, Vic, Australia.
    Kular, Lara
    Karolinska Inst, Ctr Mol Med, Dept Clin Neurosci, Stockholm, Sweden.
    Welihinda, Nipuni
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Jonsson, Jörgen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Jagodic, Maja
    Karolinska Inst, Ctr Mol Med, Dept Clin Neurosci, Stockholm, Sweden.
    Mwinyi, Jessica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. Sechenov First Moscow State Med Univ, Inst Translat Med & Biotechnol, Moscow, Russia.
    Longitudinal DNA methylation changes at MET may alter HGF/c-MET signalling in adolescents at risk for depression2020In: Epigenetics, ISSN 1559-2294, E-ISSN 1559-2308, Vol. 15, no 6-7, p. 646-663Article in journal (Refereed)
    Abstract [en]

    Unrecognized depression during adolescence can result in adult suicidal behaviour. The aim of this study was to identify, replicate and characterize DNA methylation (DNAm) shifts in depression aetiology, using a longitudinal, multi-tissue (blood and brain) and multi-layered (genetics, epigenetics, transcriptomics) approach. We measured genome-wide blood DNAm data at baseline and one-year follow-up, and imputed genetic variants, in 59 healthy adolescents comprising the discovery cohort. Depression and suicidal symptoms were determined using the Development and Well-Being Assessment (DAWBA) depression band, Montgomery-Åsberg Depression Rating Scale-Self (MADRS-S) and SUicide Assessment Scale (SUAS). DNAm levels at follow-up were regressed against depression scores, adjusting for sex, age and the DNAm residuals at baseline. Higher methylation levels of 5% and 13% at cg24627299 within the MET gene were associated with higher depression scores (praw<1e-4) and susceptibility for suicidal symptoms (padj.<0.005). The nearby rs39748 was discovered to be a methylation and expression quantitative trait locus in blood cells. mRNA levels of hepatocyte growth factor (HGF) expression, known to strongly interact with MET, were inversely associated with methylation levels at cg24627299, in an independent cohort of 1180 CD14+ samples. In an open-access dataset of brain tissue, lower methylation at cg24627299 was found in 45 adults diagnosed with major depressive disorder compared with matched controls (padj.<0.05). Furthermore, lower MET expression was identified in the hippocampus of depressed individuals compared with controls in a fourth, independent cohort. Our findings reveal methylation changes at MET in the pathology of depression, possibly involved in downregulation of HGF/c-MET signalling the hippocampal region.

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  • 48.
    Ciuculete, Diana-Maria
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Voisin, Sarah
    Victoria Univ, Inst Hlth & Sport iHeS, Footscray, Vic 3011, Australia..
    Kular, Lara
    Karolinska Inst, Ctr Mol Med, Dept Clin Neurosci, S-17176 Stockholm, Sweden..
    Jonsson, Jörgen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Rask-Andersen, Mathias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Mwinyi, Jessica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. Sechenov First Moscow State Med Univ, Inst Translat Med & Biotechnol, Moscow, Russia..
    meQTL and ncRNA functional analyses of 102 GWAS-SNPs associated with depression implicate HACE1 and SHANK2 genes2020In: Clinical Epigenetics, E-ISSN 1868-7083, Vol. 12, no 1, article id 99Article in journal (Refereed)
    Abstract [en]

    Background Little is known about how genetics and epigenetics interplay in depression. Evidence suggests that genetic variants may change vulnerability to depression by modulating DNA methylation (DNAm) and non-coding RNA (ncRNA) levels. Therefore, the aim of the study was to investigate the effect of the genetic variation, previously identified in the largest genome-wide association study for depression, on proximal DNAm and ncRNA levels. Results We performed DNAm quantitative trait locus (meQTL) analysis in two independent cohorts (totaln= 435 healthy individuals), testing associations between 102 single-nucleotide polymorphisms (SNPs) and DNAm levels in whole blood. We identified and replicated 64 SNP-CpG pairs (p(adj.)< 0.05) with meQTL effect. Lower DNAm at cg02098413 located in theHACE1promoter conferred by the risk allele (C allele) at rs1933802 was associated with higher risk for depression (p(raw)= 0.014, DNAm = 2.3%). In 1202 CD14+ cells sorted from blood, DNAm at cg02088412 positively correlated withHACE1mRNA expression. Investigation in postmortem brain tissue of adults diagnosed with major depressive disorder (MDD) indicated 1% higher DNAm at cg02098413 in neurons and lowerHACE1mRNA expression in CA1 hippocampus of MDD patients compared with healthy controls (p= 0.008 and 0.012, respectively). Expression QTL analysis in blood of 74 adolescent revealed that hsa-miR-3664-5p was associated with rs7117514 (SHANK2) (p(adj.)= 0.015, mRNA difference = 5.2%). Gene ontology analysis of the miRNA target genes highlighted implication in neuronal processes. Conclusions Collectively, our findings from a multi-tissue (blood and brain) and multi-layered (genetic, epigenetic, transcriptomic) approach suggest that genetic factors may influence depression by modulating DNAm and miRNA levels. Alterations atHACE1andSHANK2loci imply potential mechanisms, such as oxidative stress in the brain, underlying depression. Our results deepened the knowledge of molecular mechanisms in depression and suggest new epigenetic targets that should be further evaluated.

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  • 49.
    Dahlén, Amelia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Dashi, Giovanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Maslov, Ivan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. Lomonosov Moscow State Univ, Dept Biol, Moscow, Russia..
    Attwood, Misty M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Jonsson, Jörgen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology.
    Trukhan, Vladimir
    IM Sechenov First Moscow State Med Univ, Russia Inst Translat Med & Biotechnol, Moscow, Russia..
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. IM Sechenov First Moscow State Med Univ, Russia Inst Translat Med & Biotechnol, Moscow, Russia..
    Trends in Antidiabetic Drug Discovery: FDA Approved Drugs, New Drugs in Clinical Trials and Global Sales2022In: Frontiers in Pharmacology, E-ISSN 1663-9812, Vol. 12, article id 807548Article, review/survey (Refereed)
    Abstract [en]

    Type 2 diabetes mellitus (T2DM) continues to be a substantial medical problem due to its increasing global prevalence and because chronic hyperglycemic states are closely linked with obesity, liver disease and several cardiovascular diseases. Since the early discovery of insulin, numerous antihyperglycemic drug therapies to treat diabetes have been approved, and also discontinued, by the United States Food and Drug Administration (FDA). To provide an up-to-date account of the current trends of antidiabetic pharmaceuticals, this review offers a comprehensive analysis of the main classes of antihyperglycemic compounds and their mechanisms: insulin types, biguanides, sulfonylureas, meglitinides (glinides), alpha-glucosidase inhibitors (AGIs), thiazolidinediones (TZD), incretin-dependent therapies, sodium-glucose cotransporter type 2 (SGLT2) inhibitors and combinations thereof. The number of therapeutic alternatives to treat T2DM are increasing and now there are nearly 60 drugs approved by the FDA. Beyond this there are nearly 100 additional antidiabetic agents being evaluated in clinical trials. In addition to the standard treatments of insulin therapy and metformin, there are new drug combinations, e.g., containing metformin, SGLT2 inhibitors and dipeptidyl peptidase-4 (DPP4) inhibitors, that have gained substantial use during the last decade. Furthermore, there are several interesting alternatives, such as lobeglitazone, efpeglenatide and tirzepatide, in ongoing clinical trials. Modern drugs, such as glucagon-like peptide-1 (GLP-1) receptor agonists, DPP4 inhibitors and SGLT2 inhibitors have gained popularity on the pharmaceutical market, while less expensive over the counter alternatives are increasing in developing economies. The large heterogeneity of T2DM is also creating a push towards more personalized and accessible treatments. We describe several interesting alternatives in ongoing clinical trials, which may help to achieve this in the near future.

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  • 50.
    Dahlén, Amelia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Schiöth: Functional Pharmacology.
    Miguet, Maud
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Schiöth: Functional Pharmacology.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Schiöth: Functional Pharmacology.
    Rukh, Gull
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Schiöth: Functional Pharmacology.
    The influence of personality on the risk of myocardial infarction in UK Biobank cohort2022In: Scientific Reports, E-ISSN 2045-2322, Vol. 12, article id 6706Article in journal (Refereed)
    Abstract [en]

    Personality is a strong determinant for several health-related behaviours and has been linked to the development of cardiovascular diseases. However, the reports of personality's mediating role have been inconsistent with no data available from large population-based cohorts. The study aimed to create proxies for the Big Five personality traits, extraversion, agreeableness, conscientiousness, openness and neuroticism, to examine the longitudinal relationship between personality and myocardial infarction in the UK Biobank. The study sample comprised of 484,205 participants (55% female, 45% male, mean age 56.4 +/- 8.1 years) from UK Biobank cohort with a mean follow-up of 7 years. The personality proxies sociability, warmth, diligence, curiosity and nervousness were created using self-reported data on psychological factors, mental health and social support, to match the facets of the Big Five traits. As neuroticism is the only Big Five personality trait available in the UK Biobank, it was included to validate the personality proxies. Myocardial infarction outcome information was collected from hospital records, death registries or was self-reported. Logistic regression and Cox proportional hazard regression were used to estimate odds ratio (OR) and hazard ratios (HR), respectively with 95% confidence intervals (CI) adjusted for demographics (age, sex, socioeconomic status, ethnicity), health-related factors (BMI, diabetes, systolic and diastolic blood pressure) and lifestyle factors (alcohol intake, smoking, and moderate-to-vigorous physical activity). Diligence was found to be significantly associated with lower prevalent myocardial infarction [OR: 0.87; (CI 0.84-0.89)] and lower incident myocardial infarction [HR: 0.88; (CI 0.85-0.92)]. Sociability was also protective against prevalent [OR: 0.89; (CI 0.87-0.92)] and incident [HR: 0.90; (CI 0.87-0.93)] myocardial infarction. Conversely, nervousness inferred a higher risk for both prevalent [OR: 1.10; (CI 1.08-1.12)] and incident [HR: 1.07; (CI 1.04-1.09)] myocardial infarction during follow-up. Sex-stratified analyses revealed that nervousness significantly increases the risk for incident myocardial infarction among women [HR: 1.13; (CI 1.08-1.19)] compared to men [HR: 1.05; (CI 1.02-1.08)]. By using our created proxies, we were able to investigate the impact of personality on the development of myocardial infarction. Persons with higher levels of diligence and sociability mimicking predominantly conscientiousness and extraversion personalities respectively are less likely to experience myocardial infarction, while personalities predominantly characterised by nervousness pose higher risk for developing myocardial infarction. These initial findings invite further validation of the use of the personality proxies in UK Biobank cohort.

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