Combined Linkage and Association Analyses of the 124-bp Allele of Marker D2S2944 with Anxiety, Depression, Neuroticism and Major Depression

A central issue in psychiatric genetics is whether positive findings replicate. Zubenko et al. (2002b, Mol. Psychiatry 7:460-467) reported an association of the 124-bp allele of D2S2944 with recurrent early-onset major depression for females. We tested for association of this allele to continuous measures of anxiety, depression and neuroticism in a Dutch sample of 347 males and 448 females, and to DSM-IV major depression in a subsample of 210 males and 295 females. The association of the 124-bp allele to depression in females was not replicated, but there were significant associations (not significant after correction for multiple testing) with anxiety and anxious depression in males. However, the association occurred in the absence of evidence for linkage in this region on chromosome 2. © 2006 Springer Science+Business Media, Inc

Complete genome sequences of gram-negative opportunistic pathogens isolated in hospitals in Almaty, Kazakhstan

The problem of nosocomial infections is growing due to the introduction of new treatment regimens involving immunosuppressive drugs. The genomes of seven Gram-negative clinical isolates of Escherichia, Klebsiella, and Pseudomonas were sequenced and analyzed in this study to serve as model microorganisms to study drug-induced antibiotic resistance reversion.Sequencing was funded by grant BR09458960 of the program “Study of reversion of antibiotic resistance of pathogenic microorganisms,” provided by the Industrial Development Committee of the Ministry of Industry and Infrastructure Development of the Republic of Kazakhstan.https://mra.asm.orgam2022BiochemistryGeneticsMicrobiology and Plant Patholog

Genetic Linkage and Association Analysis for Loneliness in Dutch Twin and Sibling Pairs Points to a Region on Chromosome 12q23–24

We obtained evidence from a large study in Dutch twins (N = 8387) and siblings (N = 2295) that variation in loneliness has a genetic component. The heritability estimate for loneliness, which was assessed as an ordinal trait, was 40% and did not differ between males and females. There were 682 sibling pairs with genotypic (around 400 microsatellite markers) data. We combined phenotypic and genotypic data to carry out a genome scan to localize QTLs for loneliness. One region on chromosome 12q23.3-24.3, showed near suggestive linkage. Genetic association tests within this region revealed significant association (p-value 0.009) with one of the alleles of marker D12S79 and with one of the alleles of neighbouring marker D12S395 (p-value 0.043). We review evidence for linkage in this region for psychiatric disorders and discuss our findings within this context. © 2006 Springer Science+Business Media, Inc

Analysis of SEC9 Suppression Reveals a Relationship of SNARE Function to Cell Physiology

BACKGROUND:Growth and division of Saccharomyces cerevisiae is dependent on the action of SNARE proteins that are required for membrane fusion. SNAREs are regulated, through a poorly understood mechanism, to ensure membrane fusion at the correct time and place within a cell. Although fusion of secretory vesicles with the plasma membrane is important for yeast cell growth, the relationship between exocytic SNAREs and cell physiology has not been established. METHODOLOGY/PRINCIPAL FINDINGS:Using genetic analysis, we identified several influences on the function of exocytic SNAREs. Genetic disruption of the V-ATPase, but not vacuolar proteolysis, can suppress two different temperature-sensitive mutations in SEC9. Suppression is unlikely due to increased SNARE complex formation because increasing SNARE complex formation, through overexpression of SRO7, does not result in suppression. We also observed suppression of sec9 mutations by growth on alkaline media or on a non-fermentable carbon source, conditions associated with a reduced growth rate of wild-type cells and decreased SNARE complex formation. CONCLUSIONS/SIGNIFICANCE:Three main conclusions arise from our results. First, there is a genetic interaction between SEC9 and the V-ATPase, although it is unlikely that this interaction has functional significance with respect to membrane fusion or SNAREs. Second, Sro7p acts to promote SNARE complex formation. Finally, Sec9p function and SNARE complex formation are tightly coupled to the physiological state of the cell

ТРАНСПЛАНТАЦИЯ ПЕЧЕНИ ОТ ДОНОРОВ СТАРШЕ 60 ЛЕТ

Donor organs shortage leads to extending criteria for deceased liver donation in the whole world.Aim: to compare results of deceased donor liver transplantation (DDLT) depending of donor age over 60 years old.Materials and methods: the study includes 390 DDLT from January 2010 to November 2017. All liver donors separated by age for two groups: I – 60 years and older (n = 26); II – younger than 60 years (n = 364). All donors were standardized by demographic, laboratory fi ndings and inotropic drug requirement. Results: no difference between both groups in severity of ischemia-reperfusion injury, ICU or in-hospital staying (median 2 and 7,5 days respectively) was found. There is also no difference between biliary or vascular complication rate. 5-year actuarial survival rate found no difference between both groups (I: 70%: II: 76%, p = 0,54).Conclusion. Using grafts from donors older than 60 years don’t worsen early and late results of DDLT. Care should be taken to avoid other risk factors (cold ischemia time, warm ischemia time).Дефицит донорских органов во всем мире способствует постепенному расширению донорских критериев для трансплантации.Цель: провести анализ результатов трансплантации печени от доноров 60 лет и старше в сравнении с донорами более молодого возраста.Материалы и методы: в исследование включено 390 трансплантаций печени: группа I – возраст донора 60 и более лет (n = 26); группа II – возраст донора менее 60 лет (n = 364), выполненных за период с 2010-го по ноябрь 2017 г. Доноры обеих групп стандартизованы по демографическим характеристикам, лабораторным показателям, а также объему инотропной поддержки.Результаты: статистически значимых различий тяжести ишемически-реперфузионного повреждения трансплантата, длительности пребывания в отделении реанимации, продолжительности пребывания в стационаре не выявлено.Также не выявлено различий в частоте развития билиарных или сосудистых осложнений. Сравнение 5-летней актуриальной выживаемости не показало достоверной разницы (группа I – 70%; группа II – 76%, р = 0,54).Выводы. По нашему опыту, использование трансплантатов печени от доноров старше 60 лет при условии минимизации факторов риска (холодовая ишемия, вторичная тепловая ишемия) не ухудшает результаты трансплантации печени в раннем и отдаленном сроке и может быть одним из путей увеличения числа трансплантаций печени от посмертного донора. Длительность наблюдения за реципиентами 8 лет

Hyperphosphorylated tau in young and middle-aged subjects

The brain tissue obtained from ninety-five cognitively unimpaired subjects, with ages ranging from 22 to 50 years upon death, were immunohistochemically assessed for neurodegenerative changes, i.e., hyperphosphorylated tau (HPτ) and β-amyloid (Aβ) pathology in predilection neuroanatomical areas. HPτ pathology was observed in the transentorhinal cortex and/or the locus coeruleus (LC) in 33% of the subjects, without any obvious risk factors known to alter the microtubule-associated protein. HPτ pathology was noted in the LC in 25 out of 83 subjects (30%), lacking concomitant cortical Aβ or transentorhinal HPτ pathology. This observation was present even when assessing only one routine section of 7 μm thickness. The recent suggestion of prion-like propagation of neurodegeneration and the finding of neurodegeneration being quite common in middle-aged persons is alarming. It is noteworthy, however, that a substantial number of neurologically unimpaired subjects even at a very old age display only sparse to modest extent of neurodegenerative pathology. Thus, only a subset of subjects with neurodegenerative changes early in life seem to progress to a symptomatic disease with ageing. This observation brings forth the notion that other, yet unknown modifying factors influence the progression of degeneration that leads to a symptomatic disorder. The known association between alterations in the LC and mood disorders, and the finding of the LC being frequently affected with HPτ pathology suggest that clinicopathological studies on young subjects both with or without mood disorders are warranted

Трансплантация печени от посмертного донора 73 лет

Orthotopic liver transplantation is the only way to cure chronic liver failure and certain liver tumors. Deceased donor organs are the prevailing source in most transplantation centers. However, there is an organ shortage because of the increasing number of patients in need of transplantation. Using expanded criteria deceased donors is a routine way to overcome organ shortage. The majority of transplantation centers take older donors depending on the local rules. Successful liver transplantation from 73-year-old deceased donor. Recipient suffered from liver neuroendocrine tumor without signs of extrahepatic spread. Liver function is adequate during 90-day follow-up. Liver transplantation from older deceased donors has good outcome according to world experience. Careful donor-recipient selection is the key to success. The first positive trial in our center enlightens the way for further practice.Расширение критериев изъятия печени при трансплантации от доноров со смертью мозга представляет собой наиболее распространенную практику преодоления дефицита органов для трансплантации. В зависимости от принятых правил большинство центров трансплантации не считают возраст противопоказанием к донорству органов при прочих удовлетворительных параметрах, а правильный подбор пары «донор–реципиент» позволяет получить удовлетворительный результат. Приводится клиническое наблюдение трансплантации печени от донора 73 лет реципиенту с метастазами нейроэндокринной опухоли в печень. Функция трансплантата удовлетворительная в течение 3 месяцев на момент публикации. Положительный исход, обзор опыта большого количества центров трансплантации печени позволяют надеяться на дальнейшее расширение подобной практики

Assessing the presence of shared genetic architecture between Alzheimer's disease and major depressive disorder using genome-wide association data

We are grateful to the families and individuals who took part in the GS:SFHS and UKB studies, and to all those involved in participant recruitment, data collection, sample processing and QC, including academic researchers, clinical staff, laboratory technicians, clerical workers, IT staff, statisticians and research managers. This work is supported by the Wellcome Trust through a Strategic Award, reference 104036/Z/ 14/Z. We acknowledge with gratitude the financial support received from the Dr Mortimer and Theresa Sackler Foundation. This research has been conducted using the GS:SFHS and UK Biobank (project #4844) resources. GS:SFHS received core funding from the Chief Scientist Office of the Scottish Government Health Directorates [CZD/16/6] and the Scottish Funding Council [HR03006]. UKB was established using funding from the Wellcome Trust, Medical Research Council, the Scottish Government Department of Health, and the Northwest Regional Development Agency. DJP, IJD, TCR and AMM are members of the University of Edinburgh Centre for Cognitive Ageing and Cognitive Epidemiology, part of the cross council Lifelong Health and Wellbeing Initiative (MR/K026992/1). TCR is supported by Alzheimer's Scotland, through the Marjorie MacBeath bequest. Funding from the Biotechnology and Biological Sciences Research Council and Medical Research Council is gratefully acknowledged. We are grateful for the use of summary data from the International Genomics of Alzheimer's Project and the Major Depressive Disorder working group of the Psychiatric Genomics Consortium.Peer reviewedPublisher PD

The Impact of Phenocopy on the Genetic Analysis of Complex Traits

A consistent debate is ongoing on genome-wide association studies (GWAs). A key point is the capability to identify low-penetrance variations across the human genome. Among the phenomena reducing the power of these analyses, phenocopy level (PE) hampers very seriously the investigation of complex diseases, as well known in neurological disorders, cancer, and likely of primary importance in human ageing. PE seems to be the norm, rather than the exception, especially when considering the role of epigenetics and environmental factors towards phenotype. Despite some attempts, no recognized solution has been proposed, particularly to estimate the effects of phenocopies on the study planning or its analysis design. We present a simulation, where we attempt to define more precisely how phenocopy impacts on different analytical methods under different scenarios. With our approach the critical role of phenocopy emerges, and the more the PE level increases the more the initial difficulty in detecting gene-gene interactions is amplified. In particular, our results show that strong main effects are not hampered by the presence of an increasing amount of phenocopy in the study sample, despite progressively reducing the significance of the association, if the study is sufficiently powered. On the opposite, when purely epistatic effects are simulated, the capability of identifying the association depends on several parameters, such as the strength of the interaction between the polymorphic variants, the penetrance of the polymorphism and the alleles (minor or major) which produce the combined effect and their frequency in the population. We conclude that the neglect of the possible presence of phenocopies in complex traits heavily affects the analysis of their genetic data