Miracle-dz/UniFAR-FTUs huggingface dataset:
Pericyte dysfunction and loss of interpericyte tunneling nanotubes promote neurovascular deficits in glaucoma

Significance The current lack of understanding of the mechanisms leading to neurovascular deficits in glaucoma is a major knowledge gap in the field. Retinal pericytes regulate microcirculatory blood flow and coordinate neurovascular coupling through interpericyte tunneling nanotubes (IP-TNTs). We demonstrate that pericytes constrict capillaries in a calcium-dependent manner during glaucomatous stress, decreasing blood supply and compromising neuronal function. Moreover, ocular hypertension damages IP-TNTs and impairs light-evoked neurovascular responses. The reestablishment of calcium homeostasis in pericytes restores vascular and neuronal function, and prevents retinal ganglion cell death in glaucomatous eyes. This study provides important insights into the therapeutic potential of pericytes to counter vascular dysregulation in glaucoma. Reduced blood flow and impaired neurovascular coupling are recognized features of glaucoma, the leading cause of irreversible blindness worldwide, but the mechanisms underlying these defects are unknown. Retinal pericytes regulate microcirculatory blood flow and coordinate neurovascular coupling through interpericyte tunneling nanotubes (IP-TNTs). Using two-photon microscope live imaging of the mouse retina, we found reduced capillary diameter and impaired blood flow at pericyte locations in eyes with high intraocular pressure, the most important risk factor to develop glaucoma. We show that IP-TNTs are structurally and functionally damaged by ocular hypertension, a response that disrupted light-evoked neurovascular coupling. Pericyte-specific inhibition of excessive Ca2+ influx rescued hemodynamic responses, protected IP-TNTs and neurovascular coupling, and enhanced retinal neuronal function as well as survival in glaucomatous retinas. Our study identifies pericytes and IP-TNTs as potential therapeutic targets to counter ocular pressure-related microvascular deficits, and provides preclinical proof of concept that strategies aimed to restore intrapericyte calcium homeostasis rescue autoregulatory blood flow and prevent neuronal dysfunction.
Transcriptomic Analysis Reveals the Messenger RNAs Responsible for the Progression of Alcoholic Cirrhosis

Alcohol‐associated liver disease is the leading cause of chronic liver disease. We hypothesized that the expression of specific coding genes is critical for the progression of alcoholic cirrhosis (AC) from compensated to decompensated states. For the discovery phase, we performed RNA sequencing analysis of 16 peripheral blood RNA samples, 4 healthy controls (HCs) and 12 patients with AC. The DEGs from the discovery cohort were validated by quantitative polymerase chain reaction in a separate cohort of 17 HCs and 48 patients with AC (17 Child‐Pugh A, 16 Child‐Pugh B, and 15 Child‐Pugh C). We observed that the numbers of differentially expressed messenger RNAs (mRNAs) were more pronounced with worsening disease severity. Pathway analysis for differentially expressed genes for patients with Child‐Pugh A demonstrated genes involved innate immune responses; those in Child‐Pugh B belonged to genes related to oxidation and alternative splicing; those in Child‐Pugh C related to methylation, acetylation, and alternative splicing. We found significant differences in the expression of heme oxygenase 1 (HMOX1) and ribonucleoprotein, PTB binding 1 (RAVER1) in peripheral blood of those who died during the follow‐up when compared to those who survived. Conclusion: Unique mRNAs that may implicate disease progression in patients with AC were identified by using a transcriptomic approach. Future studies to confirm our results are needed, and comprehensive mechanistic studies on the implications of these genes in AC pathogenesis and progression should be further explored.
GLP-1 agonist liraglutide improves ouabain-induced mania and depressive state via GSK-3β pathway

Abstract Bipolar disorder (BD) is a severe mental illness characterized by aberrant mood changes between hypomania and mania or mixed states and depression. Metabolic changes also accompany disease progression and cause significant morbidity. Symptomatic treatment options are available, but asymptomatic patients and poor drug responders are significant problems. Based on the most common pharmacological agent that is used in the treatment, lithium and its main mechanisms of action, oxidative stress, and glycogen synthase kinase-3β (GSK-3β) signaling are extensively investigated. However, knowledge about the effects of compounds that positively affect oxidative stress and GSK-3β signaling, such as glucagon-like peptide-1 (GLP-1) mimetics, liraglutide, is still missing. Therefore, in this study, we aimed to investigate the effects of liraglutide on the ouabain-induced bipolar disease model in rats. After intracerebroventricular single dose ouabain administration, animals were treated with 100, 200, and 400 µg/kg liraglutide (s.c.) and valproic acid (200 mg/kg, i.p.) for 10 d. The locomotion and depressive states of animals were assessed by an open field, forced swimming test, and sucrose preference tests. Serum total antioxidant (TAS) and oxidant states (TOS) and glutathione, malonyl dialdehyde (MDA) levels in the brain tissue were determined. GSK-3β phosphorylation was evaluated by western blotting. Our results demonstrated that liraglutide attenuated ouabain-induced hyperlocomotion and depressive state. Additionally, liraglutide prevented oxidative stress after ouabain administration. Decreased GSK-3β phosphorylation due to the ouabain insult was alleviated by liraglutide treatment. These findings indicate that the manic and depressive-like behaviors are ameliorated by liraglutide, which exerted antioxidant action, possibly improving GSK-3β phosphorylation.
Word and pseudoword reading in young adults: an eye-tracking study

ABSTRACT Purpose To evaluate and characterize the oculomotor behavior during the reading of words and pseudowords in Brazilian Portuguese organized by frequency, length and regularity and verify its association with performance on neuropsychological tests. Methods 21 university students, with a mean age of 20.9 years, were submitted to a word and pseudoword reading task (TLPP) from the Anele Battery, in addition to verbal fluency and phonological working memory tests. The patterns of first fixation duration, gaze duration and rate of refixation were studied. Results The first fixation duration and the gaze duration were significantly lower for words if compared to pseudowords and the gaze duration was also lower for high-frequency and short words. Significant interactions were also found between verbal fluency performance and the first fixation duration. Conclusion Our results demonstrate the applicability of eye tracking to study reading patterns at the word-level in Brazilian Portuguese. The eye tracker can be an additional tool in the investigation of acquired and developmental reading disorders and can assist in the detection of reading difficulties based on comparisons of the oculomotor behavior between fluent and non-fluent readers.
Gut Microbiome-Targeted Modulations Regulate Metabolic Profiles and Alleviate Altitude-Related Cardiac Hypertrophy in Rats

Evidence suggests that gut microbiome changes upon hypobaric hypoxia exposure; however, it remains elusive whether this microbiome change is a merely derivational reflection of host physiological alteration, or it synergizes to exacerbate high-altitude diseases. We intervened gut microbiome in the rat model of prolonged hypobaric hypoxia challenge and found that the intervention could alleviate the symptoms of pathological cardiac hypertrophy, gut microbial dysbiosis, and metabolic disruptions of certain metabolites in gut and plasma induced by hypobaric hypoxia. ABSTRACT It is well known that humans physiologically or pathologically respond to high altitude, with these responses accompanied by alterations in the gut microbiome. To investigate whether gut microbiota modulation can alleviate high-altitude-related diseases, we administered probiotics, prebiotics, and synbiotics in rat model with altitude-related cardiac impairment after hypobaric hypoxia challenge and observed that all three treatments alleviated cardiac hypertrophy as measured by heart weight-to-body weight ratio and gene expression levels of biomarkers in heart tissue. The disruption of gut microbiota induced by hypobaric hypoxia was also ameliorated, especially for microbes of Ruminococcaceae and Lachnospiraceae families. Metabolome revealed that hypobaric hypoxia significantly altered the plasma short-chain fatty acids (SCFAs), bile acids (BAs), amino acids, neurotransmitters, and free fatty acids, but not the overall fecal SCFAs and BAs. The treatments were able to restore homeostasis of plasma amino acids and neurotransmitters to a certain degree, but not for the other measured metabolites. This study paves the way to further investigate the underlying mechanisms of gut microbiome in high-altitude related diseases and opens opportunity to target gut microbiome for therapeutic purpose. IMPORTANCE Evidence suggests that gut microbiome changes upon hypobaric hypoxia exposure; however, it remains elusive whether this microbiome change is a merely derivational reflection of host physiological alteration, or it synergizes to exacerbate high-altitude diseases. We intervened gut microbiome in the rat model of prolonged hypobaric hypoxia challenge and found that the intervention could alleviate the symptoms of pathological cardiac hypertrophy, gut microbial dysbiosis, and metabolic disruptions of certain metabolites in gut and plasma induced by hypobaric hypoxia. Our study suggests that gut microbiome may be a causative factor for high-altitude-related pathogenesis and a target for therapeutic intervention.
Deciphering the etiology and role in oncogenic transformation of the CpG island methylator phenotype: a pan-cancer analysis

Abstract Numerous cancer types have shown to present hypermethylation of CpG islands, also known as a CpG island methylator phenotype (CIMP), often associated with survival variation. Despite extensive research on CIMP, the etiology of this variability remains elusive, possibly due to lack of consistency in defining CIMP. In this work, we utilize a pan-cancer approach to further explore CIMP, focusing on 26 cancer types profiled in the Cancer Genome Atlas (TCGA). We defined CIMP systematically and agnostically, discarding any effects associated with age, gender or tumor purity. We then clustered samples based on their most variable DNA methylation values and analyzed resulting patient groups. Our results confirmed the existence of CIMP in 19 cancers, including gliomas and colorectal cancer. We further showed that CIMP was associated with survival differences in eight cancer types and, in five, represented a prognostic biomarker independent of clinical factors. By analyzing genetic and transcriptomic data, we further uncovered potential drivers of CIMP and classified them in four categories: mutations in genes directly involved in DNA demethylation; mutations in histone methyltransferases; mutations in genes not involved in methylation turnover, such as KRAS and BRAF; and microsatellite instability. Among the 19 CIMP-positive cancers, very few shared potential driver events, and those drivers were only IDH1 and SETD2 mutations. Finally, we found that CIMP was strongly correlated with tumor microenvironment characteristics, such as lymphocyte infiltration. Overall, our results indicate that CIMP does not exhibit a pan-cancer manifestation; rather, general dysregulation of CpG DNA methylation is caused by heterogeneous mechanisms.
Racial/ethnic differences in social support and health among Asian American and non-Hispanic White midlife women: Results from the Study of Women’s Health Across the Nation (SWAN)

ABSTRACT Objective: Although prior research suggests Asian Americans experience physical health advantages relative to other racial/ethnic groups, increasing evidence points to health inequalities within Asian American subgroups. Disparities are especially pronounced among middle-aged Asian American women, who remain an understudied population, despite studies showing that midlife corresponds with distinct social stressors and changes in the availability of protective resources, such as social support. Thus, the purpose of the study was to examine racial/ethnic differences in social support and self-rated health (SRH) among middle-aged women. Design: With data from the Study of Women’s Health Across the Nation (SWAN; N = 1258), we used modified Poisson regression models to estimate incidence rate ratios (IRR), examining how social support shaped the risk of fair-to-poor SRH by race/ethnicity. We tested interactions between perceived stress, social support and race/ethnicity to determine whether the stress-buffering role of social support varies by group. Results: Results demonstrate racial/ethnic differences in SRH. Higher levels of social support were linked to higher fair-to-poor SRH among Chinese American women (IRR = 1.24; 95% CI [1.02, 1.52]); while greater social support conferred lower risk among White women. Interaction analyses revealed additional nuances in the stress-buffering effects of social support among Chinese American women, such that the health benefits of social support depended on levels of perceived stress (IRR = 0.75; 95% CI [0.57, 1.00]). Conclusions: These findings highlight important distinctions in the ways that psychosocial factors shape health across racial/ethnic groups. In particular, this study helps advance our understanding of important subgroup differences in the stress-buffering role of social support for Asian American midlife women. Interventions should focus on identifying sources of social strain among Asian American women that can increase the risk for poor health and identify alternative sources of support that mitigate stressors to improve health.
Avian Hepatitis E Virus ORF2 Protein Interacts with Rap1b to Induce Cytoskeleton Rearrangement That Facilitates Virus Internalization

Rap1b is a multifunctional protein that is responsible for cell adhesion, growth, and differentiation. The inactive form of Rap1b is phosphorylated and distributed in the cytoplasm, while active Rap1b is prenylated and loaded with GTP to the cell membrane. ABSTRACT Avian hepatitis E virus (HEV) causes liver diseases and multiple extrahepatic disorders in chickens. However, the mechanisms involved in avian HEV entry remain elusive. Herein, we identified the RAS-related protein 1b (Rap1b) as a potential HEV-ORF2 protein interacting candidate. Experimental infection of chickens and cells with an avian HEV isolate from China (CaHEV) led to upregulated expression and activation of Rap1b both in vivo and in vitro. By using CaHEV capsid as mimic of virion to treat cell in vitro, it appears that the interaction between the viral capsid and Rap1b promoted cell membrane recruitment of the downstream effector Rap1-interacting molecule (RIAM). In turn, RIAM further enhanced Talin-1 membrane recruitment and retention, which led to the activation of integrin α5/β1, as well as integrin-associated membrane protein kinases, including focal adhesion kinase (FAK). Meanwhile, FAK activation triggered activation of downstream signaling molecules, such as Ras-related C3 botulinum toxin substrate 1 RAC1 cell division cycle 42 (CDC42), p21-activated kinase 1 (PAK1), and LIM domain kinase 1 (LIMK1). Finally, F-actin rearrangement induced by Cofilin led to the formation of lamellipodia, filopodia, and stress fibers, contributes to plasma membrane remodeling, and might enhance CaHEV virion internalization. In conclusion, our data suggested that Rap1b activation was triggered during CaHEV infection and appeared to require interaction between CaHEV-ORF2 and Rap1b, thereby further inducing membrane recruitment of Talin-1. Membrane-bound Talin-1 then activates key Integrin-FAK-Cofilin cascades involved in modulation of actin kinetics, and finally leads to F-actin rearrangement and membrane remodeling to potentially facilitate internalization of CaHEV virions into permissive cells. IMPORTANCE Rap1b is a multifunctional protein that is responsible for cell adhesion, growth, and differentiation. The inactive form of Rap1b is phosphorylated and distributed in the cytoplasm, while active Rap1b is prenylated and loaded with GTP to the cell membrane. In this study, the activation of Rap1b was induced during the early stage of avian HEV infection under the regulation of PKA and SmgGDS. Continuously activated Rap1b recruited its effector RIAM to the membrane, thereby inducing the membrane recruitment of Talin-1 that led to the activation of membrane α5/β1 integrins. The triggering of the signaling pathway-associated Integrin α5/β1-FAK-CDC42&RAC1-PAK1-LIMK1-Cofilin culminated in F-actin polymerization and membrane remodeling that might promote avian HEV virion internalization. These findings suggested a novel mechanism that is potentially utilized by avian HEV to invade susceptible cells.
Ploidy and local environment drive intraspecific variation in endoreduplication in Arabidopsis arenosa.

PREMISE Endoreduplication, nonheritable duplication of a nuclear genome, is widespread in plants and plays a role in developmental processes related to cell differentiation. However, neither ecological nor cytological factors influencing intraspecific variation in endoreduplication are fully understood. METHODS We cultivated plants covering the range-wide natural diversity of diploid and tetraploid populations of Arabidopsis arenosa in common conditions to investigate the effect of original ploidy level on endoreduplication. We also raised plants from several foothill and alpine populations from different lineages and of both ploidies to test for the effect of elevation. We determined the endoreduplication level in leaves of young plants by flow cytometry. Using RNA-seq data available for our populations, we analyzed gene expression analysis in individuals that differed in endoreduplication level. RESULTS We found intraspecific variation in endoreduplication that was mainly driven by the original ploidy level of populations, with significantly higher endoreduplication in diploids. An effect of elevation was also found within each ploidy, yet its direction exhibited rather regional-specific patterns. Transcriptomic analysis comparing individuals with high vs. low endopolyploidy revealed a majority of differentially expressed genes related to the stress and hormone response and to modifications especially in the cell wall and in chloroplasts. CONCLUSIONS Our results support the general assumption of higher potential of low-ploidy organisms to undergo endoreduplication and suggest that endoreduplication is further integrated within the stress response pathways for a fine-tune adjustment of the endoreduplication process to their local environment.
Use of unprescribed hormones in the body modification of travestis and transsexual women in Salvador/Bahia, Brazil

This article aims to analyze the use of non-prescribed hormones among travestis and transgender women (TrTGW) in Salvador, Bahia, Brazil. This cross-sectional study used the Respondent Driven Sampling (RDS) methodology to recruit TrTGW from 2014 to 2016 in Salvador and the Metropolitan Region. A comparative analysis was carried out between sociodemographic, behavioral, and gender declaration conditions using hormones. The RDS-II estimator weighted the data. Stata version 14 was used for statistical analyses. One hundred twenty-seven TrTGW were recruited. From the studied sample, 69.1% of participants used non-prescribed hormones, which was associated with industrial liquid silicone use and body satisfaction. The TrTGW who were comfortable with the penis and felt pleasure with the penis used hormone less. The seropositive participants reported a higher proportion of hormone use. The non-prescribed use of hormones was used by most TrTGW. This use is likely associated with better satisfaction with self-image and body among TrTGW. Elevated and exacerbated use of these hormones was identified, probably due to the rare access to public health services.
Effectiveness of interleukin‐4 administration or zinc supplementation in improving zinc deficiency–associated thymic atrophy and fatty degeneration and in normalizing T cell maturation process

Nutritional zinc deficiency induces thymic atrophy, but the underlying mechanisms remain unknown. In this study, we investigated the mechanism of thymic atrophy and fatty degeneration associated with zinc deficiency and its effect on T cell maturation. Building on previous research demonstrating the beneficial effect of IL‐4 administration or zinc supplementation on the spleen in zinc‐deficient rats, we further examined whether these supplements also improve thymic atrophy. Five‐week‐old male Sprague‐Dawley rats were fed a standard diet, zinc‐deficient diet (n = 16 each) with either saline or IL‐4, or a zinc‐deficient diet for 6 weeks followed by a standard diet for 4 weeks. Relative thymus weights, serum thymulin concentrations, and the number of cytokeratin‐8‐positive cells, AIRE‐positive cells, IL‐7‐positive cells, CD8+ T cells, CD4+ T cells, pre‐T cells, and CD25+ CD44+ (DN3) cells in the thymus of zinc‐deficient rats significantly decreased compared with those in all other groups. Conversely, PPAR‐γ–positive cells, oil red O‐positive areas, pro T cells, CD25− CD44+ cells, TUNEL‐positive cells, Viobility 405/452 Fixable Dye–positive cells, CD68‐, CD163‐ or CD169‐ macrophages, and IL‐1β concentrations were significantly increased in the thymus of zinc‐deficient rats as compared to those in the other groups. After IL‐4 administration or zinc supplementation for zinc deficiency, all the measurement indices were recovered to levels in standard rats. It was demonstrated that zinc deficiency caused thymic atrophy, accompanied by fatty degeneration in the cortical regions and affected T cell maturation. IL‐4 administration or zinc supplementation for zinc deficiency ameliorated thymic fatty degeneration.