IL-21 and IL-21 Receptor Expression in Lymphocytes and Neurons in Multiple Sclerosis Brain

IL-17–producing CD4+ T cells (Th-17) contribute to the pathogenesis of experimental autoimmune encephalomyelitis and are associated with active disease in multiple sclerosis (MS). In addition to IL-17, Th-17 cells can also express IL-21, IL-22, and IL-6 under Th-17–polarizing conditions (IL-6 and transforming growth factor-β). In this study we investigated IL-21 and IL-21 receptor (IL-21R) expression in MS lesions by in situ hybridization and immunohistochemistry. We detected strongly IL-21+ infiltrating cells predominantly in acute but also in chronic active white matter MS lesions in which IL-21 expression was restricted to CD4+ cells. In contrast, IL-21R was much more broadly distributed on CD4+, CD19+, and CD8+ lymphocytes but not major histocompatibility complex class-II+ macrophages/microglia. Interestingly, in cortical areas we detected both IL-21 and IL-21R expression by neurons. These findings suggest role(s) for IL-21 in both the acute and chronic stages of MS via direct effects on T and B lymphocytes and, demonstrated for the first time, also on neurons

Seasonality in Major Depressive Disorder: Effect of Sex and Age

Background: Aside from the concept of seasonal affective disorder, the evidence for a seasonal pattern (SP) of major depressive disorder (MDD) is controversial. Furthermore, the effect of sex and age is still unclear. Methods: This is a nationwide, registry-based study assessing all inpatient admissions in mental health hospitals due to MDD episodes according to ICD-10 (moderate (F32/33.1), severe (F32/33.2) and severe with psychotic features (F32/33.3)) in Austria across 14 years. Calculations were based on deviations from expected monthly admissions. Results: The sample comprised 231,824 hospitalisations (36.8% men) for MDD. A significant SP (p=0.001) in moderate and severe depressive episodes in both women and men with decreased admission rates in the summer months and December was detected. In psychotic depression a significant SP was only evidenced in women (p = 0.002, men: p = 0.291). Patients older than 55 years had a reduced SP compared to those being younger. Limitations: Only anonymised admission data of inpatient treatments were available. Hospitalization rates cannot fully be equated to the occurrence of MDD. Conclusions: The current study indicates a seasonal variation in MDD symptoms that may go beyond seasonal affective disorder. Knowledge about the predictability of depressive symptoms in patients should encourage preventive strategies

Clinical Correlates and Outcome of Major Depressive Disorder and Comorbid Migraine: A Report of the European Group for the Study of Resistant Depression

Background: The present multicenter study aimed at defining the clinical profile of patients with major depressive disorder (MDD) and comorbid migraine. Methods: Demographic and clinical information for 1410 MDD patients with vs without concurrent migraine were compared by descriptive statistics, analyses of covariance, and binary logistic regression analyses. Results: The point prevalence rate for comorbid migraine was 13.5% for female and 6.2% for male patients. MDD + migraine patients were significantly younger, heavier, more likely female, of non-Caucasian origin, outpatient, and suffering from asthma. The presence of MDD + migraine resulted in a significantly higher functional disability. First-line antidepressant treatment strategy revealed a trend towards agomelatine. Second-generation antipsychotics were significantly less often administered for augmentation treatment in migraineurs. Overall, MDD + migraine patients tended to respond worse to their pharmacotherapy. Conclusion: Treatment guidelines for comorbid depression and migraine are warranted to ensure optimal efficacy and avoid possible pitfalls in psychopharmacotherapy, including serotonin syndrome

Supraglacial debris thickness and supply rate in High-Mountain Asia

Supraglacial debris strongly modulates glacier melt rates and can be decisive for ice dynamics and mountain hydrology. It is ubiquitous in High-Mountain Asia, yet because its thickness and supply rate from local topography are poorly known, our ability to forecast regional glacier change and streamflow is limited. Here we combined remote sensing and numerical modelling to resolve supraglacial debris thickness by altitude for 4689 glaciers in High-Mountain Asia, and debris-supply rate to 4141 of those glaciers. Our results reveal extensively thin supraglacial debris and high spatial variability in both debris thickness and supply rate. Debris-supply rate increases with the temperature and slope of debris-supply slopes regionally, and debris thickness increases as ice flow decreases locally. Our centennial-scale estimates of debris-supply rate are typically an order of magnitude or more lower than millennial-scale estimates of headwall-erosion rate from Beryllium-10 cosmogenic nuclides, potentially reflecting episodic debris supply to the region’s glaciers

Interannual Dynamics of Ice Cliff Populations on Debris‐Covered Glaciers from Remote Sensing Observations and Stochastic Modeling

Ice cliffs are common on debris-covered glaciers and have relatively high melt rates due to their direct exposure to incoming radiation. Previous studies have shown that their number and relative area can change considerably from year to year, but this variability has not been explored, in part because available cliff observations are irregular. Here, we systematically mapped and tracked ice cliffs across four debris-covered glaciers in High Mountain Asia for every late ablation season from 2009 to 2019 using high-resolution multi-spectral satellite imagery. We then quantified the processes occurring at the feature scale to train a stochastic birth-death model to represent the cliff population dynamics. Our results show that while the cliff relative area can change by up to 20% from year to year, the natural long-term variability is constrained, thus defining a glacier-specific cliff carrying capacity. In a subsequent step, the inclusion of external drivers related to climate, glacier dynamics and hydrology highlights the influence of these variables on the cliff population dynamics, which is usually not a direct one due to the complexity and interdependence of the processes taking place at the glacier surface. In some extreme cases (here, a glacier surge), these external drivers may lead to a reorganization of the cliffs at the glacier surface and a change in the natural variability. These results have implications for the melt of debris-covered glaciers, in addition to showing the high rate of changes at their surface and highlighting some of the links between cliff population and glacier state

Sex-related effects in major depressive disorder: Results of the European Group for the Study of Resistant Depression

Background: Sex-related effects on the evolution and phenotype of major depressive disorder (MDD) were reported previously. Methods: This European multicenter cross-sectional study compared sociodemographic, clinical, and treatment patterns between males and females in a real-world sample of 1410 in- and outpatients with current MDD. Results: Male MDD patients (33.1%) were rather inpatients, suffered from moderate to high suicidality levels, received noradrenergic and specific serotonergic antidepressants (ADs) as first-line AD treatment, generally higher mean AD daily doses, and showed a trend towards a more frequent administration of add-on treatments. Female MDD patients (66.9%) were rather outpatients, experienced lower suicidality levels, comorbid thyroid dysfunction, migraine, asthma, and a trend towards earlier disease onset. Conclusions: The identified divergencies may contribute to the concept of male and female depressive syndromes and serve as predictors of disease severity and course, as they reflect phenomena that were repeatedly related to treatment-resistant depression (TRD). Especially the greater necessity of inpatient treatment and more complex psychopharmacotherapy in men may reflect increased therapeutic efforts undertaken to treat suicidality and to avoid TRD. Hence, considering sex may guide the diagnostic and treatment processes towards targeting challenging clinical manifestations including comorbidities and suicidality, and prevention of TRD and chronicity

Multi-decadal monsoon characteristics and glacier response in High Mountain Asia

Glacier health across High Mountain Asia (HMA) is highly heterogeneous and strongly governed by regional climate, which is variably influenced by monsoon dynamics and the westerlies. We explore four decades of glacier energy and mass balance at three climatically distinct sites across HMA by utilising a detailed land surface model driven by bias-corrected Weather Research and Forecasting meteorological forcing. All three glaciers have experienced long-term mass losses (ranging from −0.04 ± 0.09 to −0.59 ± 0.20 m w.e. a−1) consistent with widespread warming across the region. However, complex and contrasting responses of glacier energy and mass balance to the patterns of the Indian Summer Monsoon were evident, largely driven by the role snowfall timing, amount and phase. A later monsoon onset generates less total snowfall to the glacier in the southeastern Tibetan Plateau during May–June, augmenting net shortwave radiation and affecting annual mass balance (−0.5 m w.e. on average compared to early onset years). Conversely, timing of the monsoon’s arrival has limited impact for the Nepalese Himalaya which is more strongly governed by the temperature and snowfall amount during the core monsoon season. In the arid central Tibetan Plateau, a later monsoon arrival results in a 40 mm (58%) increase of May–June snowfall on average compared to early onset years, likely driven by the greater interaction of westerly storm events. Meanwhile, a late monsoon cessation at this site sees an average 200 mm (192%) increase in late summer precipitation due to monsoonal storms. A trend towards weaker intensity monsoon conditions in recent decades, combined with long-term warming patterns, has produced predominantly negative glacier mass balances for all sites (up to 1 m w.e. more mass loss in the Nepalese Himalaya compared to strong monsoon intensity years) but sub-regional variability in monsoon timing can additionally complicate this response

ATAD5 promotes replication restart by regulating RAD51 and PCNA in response to replication stress

Maintaining stability of replication forks is important for genomic integrity. However, it is not clear how replisome proteins contribute to fork stability under replication stress. Here, we report that ATAD5, a PCNA unloader, plays multiple functions at stalled forks including promoting its restart. ATAD5 depletion increases genomic instability upon hydroxyurea treatment in cultured cells and mice. ATAD5 recruits RAD51 to stalled forks in an ATR kinase-dependent manner by hydroxyurea-enhanced protein-protein interactions and timely removes PCNA from stalled forks for RAD51 recruitment. Consistent with the role of RAD51 in fork regression, ATAD5 depletion inhibits slowdown of fork progression and native 5-bromo-2??-deoxyuridine signal induced by hydroxyurea. Single-molecule FRET showed that PCNA itself acts as a mechanical barrier to fork regression. Consequently, DNA breaks required for fork restart are reduced by ATAD5 depletion. Collectively, our results suggest an important role of ATAD5 in maintaining genome integrity during replication stress