Two regulatory T cell populations in the visceral adipose tissue shape systemic metabolism.

Visceral adipose tissue (VAT) is an energy store and endocrine organ critical for metabolic homeostasis. Regulatory T (Treg) cells restrain inflammation to preserve VAT homeostasis and glucose tolerance. Here, we show that the VAT harbors two distinct Treg cell populations: prototypical serum stimulation 2-positive (ST2+) Treg cells that are enriched in males and a previously uncharacterized population of C-X-C motif chemokine receptor 3-positive (CXCR3+) Treg cells that are enriched in females. We show that the transcription factors GATA-binding protein 3 and peroxisome proliferator-activated receptor-γ, together with the cytokine interleukin-33, promote the differentiation of ST2+ VAT Treg cells but repress CXCR3+ Treg cells. Conversely, the differentiation of CXCR3+ Treg cells is mediated by the cytokine interferon-γ and the transcription factor T-bet, which also antagonize ST2+ Treg cells. Finally, we demonstrate that ST2+ Treg cells preserve glucose homeostasis, whereas CXCR3+ Treg cells restrain inflammation in lean VAT and prevent glucose intolerance under high-fat diet conditions. Overall, this study defines two molecularly and developmentally distinct VAT Treg cell types with unique context- and sex-specific functions.

MYB orchestrates T cell exhaustion and response to checkpoint inhibition.

CD8+ T cells that respond to chronic viral infections or cancer are characterized by the expression of inhibitory receptors such as programmed cell death protein 1 (PD-1) and by the impaired production of cytokines. This state of restrained functionality-which is referred to as T cell exhaustion1,2-is maintained by precursors of exhausted T (TPEX) cells that express the transcription factor T cell factor 1 (TCF1), self-renew and give rise to TCF1- exhausted effector T cells3-6. Here we show that the long-term proliferative potential, multipotency and repopulation capacity of exhausted T cells during chronic infection are selectively preserved in a small population of transcriptionally distinct CD62L+ TPEX cells. The transcription factor MYB is not only essential for the development of CD62L+ TPEX cells and maintenance of the antiviral CD8+ T cell response, but also induces functional exhaustion and thereby prevents lethal immunopathology. Furthermore, the proliferative burst in response to PD-1 checkpoint inhibition originates exclusively from CD62L+ TPEX cells and depends on MYB. Our findings identify CD62L+ TPEX cells as a stem-like population that is central to the maintenance of long-term antiviral immunity and responsiveness to immunotherapy. Moreover, they show that MYB is a transcriptional orchestrator of two fundamental aspects of exhausted T cell responses: the downregulation of effector function and the long-term preservation of self-renewal capacity.

Sex-specific adipose tissue imprinting of regulatory T cells.

Adipose tissue is an energy store and a dynamic endocrine organ1,2. In particular, visceral adipose tissue (VAT) is critical for the regulation of systemic metabolism3,4. Impaired VAT function-for example, in obesity-is associated with insulin resistance and type 2 diabetes5,6. Regulatory T (Treg) cells that express the transcription factor FOXP3 are critical for limiting immune responses and suppressing tissue inflammation, including in the VAT7-9. Here we uncover pronounced sexual dimorphism in Treg cells in the VAT. Male VAT was enriched for Treg cells compared with female VAT, and Treg cells from male VAT were markedly different from their female counterparts in phenotype, transcriptional landscape and chromatin accessibility. Heightened inflammation in the male VAT facilitated the recruitment of Treg cells via the CCL2-CCR2 axis. Androgen regulated the differentiation of a unique IL-33-producing stromal cell population specific to the male VAT, which paralleled the local expansion of Treg cells. Sex hormones also regulated VAT inflammation, which shaped the transcriptional landscape of VAT-resident Treg cells in a BLIMP1 transcription factor-dependent manner. Overall, we find that sex-specific differences in Treg cells from VAT are determined by the tissue niche in a sex-hormone-dependent manner to limit adipose tissue inflammation.

Genetic analyses point to alterations in immune-related pathways underpinning the association between psychiatric disorders and COVID-19.

Current literature suggests that people with psychiatric disorders have a higher risk of COVID-19 infection and a worse prognosis of the disease. We aimed to study the genetic contribution to these associations across seven psychiatric disorders as well as a general psychopathology factor (P-factor) and determine whether these are unique or shared across psychiatric disorders using statistical genetic techniques. Using the largest available genome-wide association studies (GWAS), we found a significant genetic overlap between depression, ADHD, PTSD, and the P-factor with both COVID-19 infection and hospitalization, and between anxiety and COVID-19 hospitalization. We used pairwise GWAS to examine this overlap on a fine-grained scale and identified specific regions of the genome shared between several psychiatric disorders, the P-factor, and COVID-19. Gene-based analysis in these genomic regions suggested possible links with immune-related pathways such as thyroid homeostasis, inflammation, and stress response. Finally, we show preliminary evidence for causal associations between depression, ADHD, PTSD, and the P-factor, and higher COVID-19 infection and hospitalization using Mendelian Randomization and Latent Causal Variable methods. Our results support the hypothesis that the relationship between psychiatric disorders and COVID-19 risk is likely due to shared alterations in immune-related pathways and is not a result of environmental factors alone, shedding light on potentially viable therapeutic targets.

Genetic overlap between cortical brain morphometry and frontotemporal dementia risk.

Frontotemporal dementia (FTD) has a complex genetic etiology, where the precise mechanisms underlying the selective vulnerability of brain regions remain unknown. We leveraged summary-based data from genome-wide association studies (GWAS) and performed LD score regression to estimate pairwise genetic correlations between FTD risk and cortical brain imaging. Then, we isolated specific genomic loci with a shared etiology between FTD and brain structure. We also performed functional annotation, summary-data-based Mendelian randomization for eQTL using human peripheral blood and brain tissue data, and evaluated the gene expression in mice targeted brain regions to better understand the dynamics of the FTD candidate genes. Pairwise genetic correlation estimates between FTD and brain morphology measures were high but not statistically significant. We identified 5 brain regions with a strong genetic correlation (rg > 0.45) with FTD risk. Functional annotation identified 8 protein-coding genes. Building upon these findings, we show in a mouse model of FTD that cortical N-ethylmaleimide sensitive factor (NSF) expression decreases with age. Our results highlight the molecular and genetic overlap between brain morphology and higher risk for FTD, specifically for the right inferior parietal surface area and right medial orbitofrontal cortical thickness. In addition, our findings implicate NSF gene expression in the etiology of FTD.

Expansion of Sinotaia quadrata (Mollusca: Gastropoda: Architaenioglossa: Viviparidae) in two major rivers from Argentina.

Invasive non-native freshwater mollusks are a growing concern in South America, with 16 species already recorded in the region. Among them, Sinotaia quadrata has only been documented in Argentina, for the first time in the Punilla Valley, Córdoba (2009) and La Plata, Buenos Aires (since 2015). In this study, we report the presence of S. quadrata in two additional areas, the Río de la Plata River and a stream (unnamed) in the Paraná River basin, two of the most significant rivers in South America, located in the provinces of Buenos Aires and Entre Ríos, respectively. These new records confirm the invasive nature of this species, which has also been identified in Europe, the United States, and Africa in recent years. The findings of this study highlight the need for continued monitoring and management of invasive species in South America's freshwater ecosystems.

Freshwater mussel conservation: A global horizon scan of emerging threats and opportunities.

We identified 14 emerging and poorly understood threats and opportunities for addressing the global conservation of freshwater mussels over the next decade. A panel of 17 researchers and stakeholders from six continents submitted a total of 56 topics that were ranked and prioritized using a consensus-building Delphi technique. Our 14 priority topics fell into five broad themes (autecology, population dynamics, global stressors, global diversity, and ecosystem services) and included understanding diets throughout mussel life history; identifying the drivers of population declines; defining metrics for quantifying mussel health; assessing the role of predators, parasites, and disease; informed guidance on the risks and opportunities for captive breeding and translocations; the loss of mussel-fish co-evolutionary relationships; assessing the effects of increasing surface water changes; understanding the effects of sand and aggregate mining; understanding the effects of drug pollution and other emerging contaminants such as nanomaterials; appreciating the threats and opportunities arising from river restoration; conserving understudied hotspots by building local capacity through the principles of decolonization; identifying appropriate taxonomic units for conservation; improved quantification of the ecosystem services provided by mussels; and understanding how many mussels are enough to provide these services. Solutions for addressing the topics ranged from ecological studies to technological advances and socio-political engagement. Prioritization of our topics can help to drive a proactive approach to the conservation of this declining group which provides a multitude of important ecosystem services.

Elucidating the relationship between migraine risk and brain structure using genetic data.

Migraine is a highly common and debilitating disorder that often affects individuals in their most productive years of life. Previous studies have identified both genetic variants and brain morphometry differences associated with migraine risk. However, the relationship between migraine and brain morphometry has not been examined on a genetic level, and the causal nature of the association between brain structure and migraine risk has not been determined. Using the largest available genome-wide association studies to date, we examined the genome-wide genetic overlap between migraine and intracranial volume, as well as the regional volumes of nine subcortical brain structures. We further focused the identification and biological annotation of genetic overlap between migraine and each brain structure on specific regions of the genome shared between migraine and brain structure. Finally, we examined whether the size of any of the examined brain regions causally increased migraine risk using a Mendelian randomization approach. We observed a significant genome-wide negative genetic correlation between migraine risk and intracranial volume (rG = -0.11, P = 1 × 10-3) but not with any subcortical region. However, we identified jointly associated regional genomic overlap between migraine and every brain structure. Gene enrichment in these shared genomic regions pointed to possible links with neuronal signalling and vascular regulation. Finally, we provide evidence of a possible causal relationship between smaller total brain, hippocampal and ventral diencephalon volume and increased migraine risk, as well as a causal relationship between increased risk of migraine and a larger volume of the amygdala. We leveraged the power of large genome-wide association studies to show evidence of shared genetic pathways that jointly influence migraine risk and several brain structures, suggesting that altered brain morphometry in individuals with high migraine risk may be genetically mediated. Further interrogation of these results showed support for the neurovascular hypothesis of migraine aetiology and shed light on potentially viable therapeutic targets.

Phenotypic and genetic factors associated with donation of DNA and consent to record linkage for prescription history in the Australian Genetics of Depression Study.

Samples can be prone to ascertainment and attrition biases. The Australian Genetics of Depression Study is a large publicly recruited cohort (n = 20,689) established to increase the understanding of depression and antidepressant treatment response. This study investigates differences between participants who donated a saliva sample or agreed to linkage of their records compared to those who did not. We observed that older, male participants with higher education were more likely to donate a saliva sample. Self-reported bipolar disorder, ADHD, panic disorder, PTSD, substance use disorder, and social anxiety disorder were associated with lower odds of donating a saliva sample, whereas anorexia was associated with higher odds of donation. Male and younger participants showed higher odds of agreeing to record linkage. Participants with higher neuroticism scores and those with a history of bipolar disorder were also more likely to agree to record linkage whereas participants with a diagnosis of anorexia were less likely to agree. Increased likelihood of consent was associated with increased genetic susceptibility to anorexia and reduced genetic risk for depression, and schizophrenia. Overall, our results show moderate differences among these subsamples. Most current epidemiological studies do not search for attrition biases at the genetic level. The possibility to do so is a strength of samples such as the AGDS. Our results suggest that analyses can be made more robust by identifying attrition biases both on the phenotypic and genetic level, and either contextualising them as a potential limitation or performing sensitivity analyses adjusting for them.

The Effect of Genetic Predisposition to Alzheimer's Disease and Related Traits on Recruitment Bias in a Study of Cognitive Aging.

The recruitment of participants for research studies may be subject to bias. The Prospective Imaging Study of Ageing (PISA) aims to characterize the phenotype and natural history of healthy adult Australians at high future risk of Alzheimer's disease (AD). Participants approached to take part in PISA were selected from existing cohort studies with available genomewide genetic data for both successfully and unsuccessfully recruited participants, allowing us to investigate the genetic contribution to voluntary recruitment, including the genetic predisposition to AD. We use a polygenic risk score (PRS) approach to test to what extent the genetic risk for AD, and related risk factors predict participation in PISA. We did not identify a significant association of genetic risk for AD with study participation, but we did identify significant associations with PRS for key causal risk factors for AD, IQ, household income and years of education. We also found that older and female participants were more likely to take part in the study. Our findings highlight the importance of considering bias in key risk factors for AD in the recruitment of individuals for cohort studies.

Estimating the Genetic Contribution to Astigmatism and Myopia in the Mexican Population.

Astigmatism and myopia are two common ocular refractive errors that can impact daily life, including learning and productivity. Current knowledge suggests that the etiology of these conditions is the result of a complex interplay between genetic and environmental factors. Studies in populations of European ancestry have demonstrated a higher concordance of refractive errors in monozygotic (MZ) twins compared to dizygotic (DZ) twins. However, there is a lack of studies on genetically informative samples of multi-ethnic ancestry. This study aimed to estimate the genetic contribution to astigmatism and myopia in the Mexican population. A sample of 1399 families, including 243 twin pairs and 1156 single twins, completed a medical questionnaire about their own and their co-twin's diagnosis of astigmatism and myopia. Concordance rates for astigmatism and myopia were estimated, and heritability and genetic correlations were determined using a bivariate ACE Cholesky decomposition method, decomposed into A (additive genetic), C (shared environmental) and E (unique environmental) components. The results showed a higher concordance rate for astigmatism and myopia for MZ twins (.74 and .74, respectively) than for DZ twins (.50 and .55). The AE model, instead of the ACE model, best fitted the data. Based on this, heritability estimates were .81 for astigmatism and .81 for myopia, with a cross-trait genetic correlation of rA = .80, nonshared environmental correlation rE = .89, and a phenotypic correlation of rP = .80. These results are consistent with previous findings in other populations, providing evidence for a similar genetic architecture of these conditions in the multi-ethnic Mexican population.

The role of anthropogenic habitats in freshwater mussel conservation.

Anthropogenic freshwater habitats may provide undervalued prospects for long-term conservation as part of species conservation planning. This fundamental, but overlooked, issue requires attention considering the pace that humans have been altering natural freshwater ecosystems and the accelerated levels of biodiversity decline in recent decades. We compiled 709 records of freshwater mussels (Bivalvia, Unionida) inhabiting a broad variety of anthropogenic habitat types (from small ponds to large reservoirs and canals) and reviewed their importance as refuges for this faunal group. Most records came from Europe and North America, with a clear dominance of canals and reservoirs. The dataset covered 228 species, including 34 threatened species on the IUCN Red List. We discuss the conservation importance and provide guidance on how these anthropogenic habitats could be managed to provide optimal conservation value to freshwater mussels. This review also shows that some of these habitats may function as ecological traps owing to conflicting management practices or because they act as a sink for some populations. Therefore, anthropogenic habitats should not be seen as a panacea to resolve conservation problems. More information is necessary to better understand the trade-offs between human use and the conservation of freshwater mussels (and other biota) within anthropogenic habitats, given the low number of quantitative studies and the strong biogeographic knowledge bias that persists.

Massive mortality of the giant freshwater mussel Anodontites trapesialis (Lamarck, 1819) (Bivalvia: Mycetopodidae) during a severe drought in a Neotropical reservoir.

In 2012, a severe drought struck the southeastern of Brazil compromising the Paraná River Basin reservoirs. Here, we described how this climatic event promoted a massive mortality of the giant freshwater mussel Anodontites trapesialis in Furnas reservoir and reported the consequences of this phenomenon. In November 2012, three quarters of 100 m2 were sampled in this reservoir, where 812 dead shells of A. trapesialis were analyzed and measured (33 Ë« 133 mm). The species showed an aggregated distribution with high density ( X ¯ : 1.0 - 5.5 ind/m2). Despite the massive mortality detected in field, it was possible to find living specimens in a small channel in the studied area, allowing the species to survive the water level fluctuations. Large adult individuals (100 Ë« 124 mm) were more affected by drought than juveniles, accounting for about 90% of the dead mussels analyzed. Two years after the massive mortality event, water level was not reestablished and a terrestrial succession (with elevations in the concentration of organic matter and calcium in sediment) was observed in the studied area. We verified that the damming associated with extreme climatic events affect negatively the populations of A. trapesialis and should be faced as a conservationist problem.

Stroke target identification guided by astrocyte transcriptome analysis.

Astrocytes support normal brain function, but may also contribute to neurodegeneration when they become reactive under pathological conditions such as stroke. However, the molecular underpinnings of this context-dependent interplay between beneficial and detrimental properties in reactive astrogliosis have remained incompletely understood. Therefore, using the RiboTag technique, we immunopurified translating mRNAs specifically from astrocytes 72 hr after transient middle cerebral artery occlusion in mice (tMCAO), thereby generating a stroke-specific astroglial translatome database. We found that compared to control brains, reactive astrocytes after tMCAO show an enrichment of transcripts linked to the A2 phenotype, which has been associated with neuroprotection. However, we found that astrocytes also upregulate a large number of potentially neurotoxic genes. In total, we identified the differential expression of 1,003 genes and 38 transcription factors, of which Stat3, Sp1, and Spi1 were the most prominent. To further explore the effects of Stat3-mediated pathways on stroke pathogenesis, we subjected mice with an astrocyte-specific conditional deletion of Stat3 to tMCAO, and found that these mice have reduced stroke volume and improved motor outcome 72 hr after focal ischemia. Taken together, our study extends the emerging database of novel astrocyte-specific targets for stroke therapy, and supports the role of astrocytes as critical safeguards of brain function in health and disease.

Impact of route of administration on genotoxic oestrogens concentrations using oral vs transdermal oestradiol in girls with Turner syndrome.

OBJECTIVE: The established link between oestrogen and breast cancer occurs via both oestrogen receptor (ER)-mediated and non ER-mediated mechanisms. The term genotoxic estrogens describes mutagenic metabolites, including oestrogen catechols and quinones, which have been linked to breast carcinogenesis in post-menopausal women. We aimed to assess whether the route of administration of 17ß oestradiol (E2 ) affects the accumulation of genotoxic oestrogen metabolites in a model of ovarian failure in young girls with Turner syndrome. METHODS: Stored plasma samples obtained at 0 and 12 months were used from 40 adolescents with Turner syndrome who participated in a 12 months randomized controlled trial of the metabolic impact of E2 orally (2 mg/d) vs transdermally (100 µg/d); dose escalation allowed matching of unconjugated E2 levels in the parent study. We measured 12 oestrogen metabolites (total concentrations = conjugated and unconjugated) using a highly sensitive LCMSMS assay. Results from 48 normally menstruating adolescents were used for comparison. RESULTS: After treatment, least square mean (SE) total E2 concentrations were higher in the oral vs transdermal group (6784 pmol/L vs 1123 [1614], P < 0.0001), as was oestrone (E1 ) (91 060 pmol/L vs 19 278 [16 534], P < 0.0001). Also, higher after oral treatment were catechol-oestrogens 4-hydroxy-E2 (149 vs 28 [±49] pmol/L), 2-hydroxy-E2 (300 vs 76 [±52]), 4-hydroxy-E1 (450 vs 105 [±113]), 2-hydroxy-E1 (3094 vs 740 [±684]) and 16α-hydroxy-E1 (3,007 vs 157 [±534]) (<0.001 between groups). Levels were much closer to controls in the transdermal group. CONCLUSIONS: Common feminizing doses of oral oestradiol for 12 months result in substantial accumulation of unphysiologic, genotoxic oestrogens compared to transdermal oestradiol, expanding concerns about oral oestrogens' first hepatic passage. Further studies assessing long-term risks of these metabolites in women taking different forms of oestrogen are needed.

Glutamine and type 1 diabetes mellitus: is there a role in glycemic control?

PURPOSE OF REVIEW: Recent literature suggests dietary glutamine supplementation may lower blood glucose in patients with type 1 diabetes (T1D), who have no residual insulin secretion. The mechanisms and potential relevance to the care of T1D remain unclear. RECENT FINDINGS: Glutamine is involved in multiple pathways including gluconeogenesis, lipolysis, antioxidant defense, the production of nitric oxide, the secretion of peptides (e.g., glucagon-like peptide 1, GLP-1), or neuromediators (e.g., [Latin Small Letter Gamma]-aminobutyric acid), all processes that may impact insulin sensitivity and/or glucose homeostasis. The article reviews potential mechanisms and literature evidence suggesting a role in improving glucose tolerance in patients with illness associated with insulin resistance, as well as the preliminary evidence for the increased incidence of postexercise hypoglycemia in T1D after oral glutamine. SUMMARY: Further studies are warranted to determine whether the lowering effect of glutamine on blood glucose is sustained over time. If so, long-term randomized trials would be warranted to determine whether there is a role for glutamine as an adjunct dietary supplement to improve glucose control in patients with T1D.

Is There a Difference between Ultrasonographic (US) Uterine Changes of Oral Versus Transdermal (TD) 17ß Estradiol (17ß E2) in Girls with Turner Syndrome (TS)? Own Experience and Literature Review.

BACKGROUND: Among patients with Turner Syndrome (TS), premature ovarian failure is a main feature. Recently published consensus guidelines recommend that transdermal (TD) estradiol is the preferred route for estrogen replacement. Studies related to ultrasound (US) measurements during estrogen replacement in TS patients using estradiol (17ß E2) and correlating uterine growth with estrogen metabolites are limited. OBJECTIVES: To compare uterine morphology and hormonal changes depending on route of administration of 17ß E2 (oral vs. TD) in a small population of girls with TS. SUBJECTS: 11 hypogonadal girls with TS (mean (SE) age 14.5 ± 1.4 years; BMI -0.98 ± -1.0 SDS) who participated in a larger study on the effects of oral versus TD 17ß E2 agreed to do a sub-study on the effect of the form of 17ß E2 treatment on uterine size. METHODS: 17ß E2 was given orally or TD for 12 months, titrated to doses up to 2 mg orally or 100 µg TD to achieve normal estradiol levels. Subjects received monthly progesterone for 1 week for withdrawal bleeding. At baseline, 6 and 12 months, a pelvic ultrasound was performed while on estradiol only. RESULTS: Uterine morphology and endometrial thickness increased comparably in both groups. E2 concentrations were comparable at 12 months between both groups but E1 and E1S were lower in TD group at 12 months. CONCLUSIONS: According to our experience, in a group of TS patients randomized to oral vs TD 17ß E2 and monitored with trans-abdominal US, both groups achieved similar increases in uterine size comparable to normal women. To confirm our observation a larger sample and a longer evaluation period is needed.

A white dwarf cooling age of 8 Gyr for NGC 6791 from physical separation processes.

NGC 6791 is a well studied open cluster that it is so close to us that can be imaged down to very faint luminosities. The main-sequence turn-off age ( approximately 8 Gyr) and the age derived from the termination of the white dwarf cooling sequence ( approximately 6 Gyr) are very different. One possible explanation is that as white dwarfs cool, one of the ashes of helium burning, (22)Ne, sinks in the deep interior of these stars. At lower temperatures, white dwarfs are expected to crystallize and phase separation of the main constituents of the core of a typical white dwarf ((12)C and (16)O) is expected to occur. This sequence of events is expected to introduce long delays in the cooling times, but has not hitherto been proven. Here we report that, as theoretically anticipated, physical separation processes occur in the cores of white dwarfs, resolving the age discrepancy for NGC 6791.

Approach to the Peripubertal Patient With Short Stature.

CONTEXT: The assessment and treatment of children with growth retardation is increasingly complex, and due to availability of targeted genetic sequencing, an ever-expanding number of conditions impeding growth are being identified. Among endocrine-related etiologies of short stature amenable to hormonal treatment, defects in the growth hormone (GH)-insulin-like growth factor I axis remain pre-eminent, with a multiplicity of disorders causing decreased secretion or insensitivity to GH action. Sex steroids in puberty increase epiphyseal senescence and eventual growth plate closure. This is mediated mostly via estrogen receptor (ER)α in males and females, effects that can greatly limit time available for growth. EVIDENCE ACQUISITION: Extensive literature review through PubMed and other search engines. EVIDENCE SYNTHESIS: Therapeutic strategies to be considered in peripubertal and pubertal children with disordered growth are here discussed, including daily and weekly GH, low-dose sex steroids, gonadotropin hormone releasing hormone (GnRH) analogues in combination with GH, aromatase inhibitors (AIs) alone and in combination with GH in boys. When used for at least 2 to 3 years, GnRH analogues combined with GH can result in meaningful increases in height. AIs used with GH permit puberty to progress in boys without hindrance, selectively decreasing estrogen, and resulting in taller height. With more than 20 years of cumulative experience in clinical use of these medications, we discuss the safety profile of these treatments. CONCLUSION: The approach of growth retardation in the peripubertal and pubertal years must consider the sex steroid milieu and the tempo of bone acceleration. Treatment of affected children in this period must be individualized.