Loss of GTF2I promotes neuronal apoptosis and synaptic reduction in human cellular models of neurodevelopment.

Individuals with Williams syndrome (WS), a neurodevelopmental disorder caused by hemizygous loss of 26-28 genes at 7q11.23, characteristically portray a hypersocial phenotype. Copy-number variations and mutations in one of these genes, GTF2I, are associated with altered sociality and are proposed to underlie hypersociality in WS. However, the contribution of GTF2I to human neurodevelopment remains poorly understood. Here, human cellular models of neurodevelopment, including neural progenitors, neurons, and three-dimensional cortical organoids, are differentiated from CRISPR-Cas9-edited GTF2I-knockout (GTF2I-KO) pluripotent stem cells to investigate the role of GTF2I in human neurodevelopment. GTF2I-KO progenitors exhibit increased proliferation and cell-cycle alterations. Cortical organoids and neurons demonstrate increased cell death and synaptic dysregulation, including synaptic structural dysfunction and decreased electrophysiological activity on a multielectrode array. Our findings suggest that changes in synaptic circuit integrity may be a prominent mediator of the link between alterations in GTF2I and variation in the phenotypic expression of human sociality.

Impact of alcohol exposure on neural development and network formation in human cortical organoids.

Prenatal alcohol exposure is the foremost preventable etiology of intellectual disability and leads to a collection of diagnoses known as Fetal Alcohol Spectrum Disorders (FASD). Alcohol (EtOH) impacts diverse neural cell types and activity, but the precise functional pathophysiological effects on the human fetal cerebral cortex are unclear. Here, we used human cortical organoids to study the effects of EtOH on neurogenesis and validated our findings in primary human fetal neurons. EtOH exposure produced temporally dependent cellular effects on proliferation, cell cycle, and apoptosis. In addition, we identified EtOH-induced alterations in post-translational histone modifications and chromatin accessibility, leading to impairment of cAMP and calcium signaling, glutamatergic synaptic development, and astrocytic function. Proteomic spatial profiling of cortical organoids showed region-specific, EtOH-induced alterations linked to changes in cytoskeleton, gliogenesis, and impaired synaptogenesis. Finally, multi-electrode array electrophysiology recordings confirmed the deleterious impact of EtOH on neural network formation and activity in cortical organoids, which was validated in primary human fetal tissues. Our findings demonstrate progress in defining the human molecular and cellular phenotypic signatures of prenatal alcohol exposure on functional neurodevelopment, increasing our knowledge for potential therapeutic interventions targeting FASD symptoms.

Appearance of a population of the mangrove rail Rallus longirostris (Rallidae) in salt marshes invaded by the exotic tanner grass Urochloa arrecta (Poaceae) and its disappearance after plant management.

Biological invasions cause species extinction but can also provide benefits. Wetlands, such as salt marshes, include little-known but important ecosystems that are sometimes severely invaded by exotic plants. Salt marshes in eastern South America are increasingly impacted by invasions of the African grass Urochloa arrecta. This study investigated the appearance of a population of the mangrove rail Rallus longirostris in areas dominated by U. arrecta and its disappearance with the eradication of this plant. We monitored four areas (54.47 ha) in the Guaratuba Bay estuary in southern Brazil, from 2006 to 2022, two of which contained four patches of U. arrecta as the dominant species. In 2012, we started to eradicate U. arrecta with mechanical management, and in 2020, it was eradicated locally. We recorded R. longirostris for the first time within a patch of U. arrecta in 2007. In subsequent years we saw the species in two other patches of the exotic plant. Rallus longirostris was no longer observed once U. arrecta was eradicated. Differences in patch occupancy between invaded and uninvaded habitats observed for R. longirostris and Pardirallus nigricans, and the disappearance of R. longirostris following the exotic plant management suggest competitive advantage and/or differential habitat preference and population density as hypotheses to explain observed patterns. The invasion of U. arrecta can increase the local populations of R. longirostris. Since this bird is not endangered, we encourage the management of U. arrecta because of its impact on salt marshes, including an endemic endangered bird. Supplementary information: The online version contains supplementary material available at 10.1007/s13157-022-01642-7.

Long-term Effect of Lifestyle Interventions on the Cardiovascular and All-Cause Mortality of Subjects With Prediabetes and Type 2 Diabetes: A Systematic Review and Meta-analysis.

BACKGROUND: Lifestyle interventions improve the metabolic control of individuals with hyperglycemia. PURPOSE: We aimed to determine the effect of lifestyle interventions on cardiovascular and all-cause mortality in this population. DATA SOURCES: Searches were made through MEDLINE, Cochrane CENTRAL, Embase, and Web of Science (no date/language restriction, until 15 May 2022). STUDY SELECTION: We included randomized clinical trials (RCTs) of subjects with prediabetes and type 2 diabetes, comparing intensive lifestyle interventions with usual care, with a minimum of 2 years of active intervention. DATA EXTRACTION: Data from the 11 RCTs selected were extracted in duplicate. A frequentist and arm-based meta-analysis was performed with random-effects models to estimate relative risk (RR) for mortality, and heterogeneity was assessed through I2 metrics. A generalized linear mixed model (GLMM) was used to confirm the findings. DATA SYNTHESIS: Lifestyle interventions were not superior to usual care in reducing cardiovascular (RR 0.99; 95% CI 0.79-1.23) or all-cause (RR 0.93; 95% CI 0.85-1.03) mortality. Subgroup, sensitivity, and meta-regression analyses showed no influence of type of intervention, mean follow-up, age, glycemic status, geographical location, risk of bias, or weight change. All of these results were confirmed with the GLMM. Most studies had a low risk of bias according to the RoB 2.0 tool and the certainty of evidence was moderate for both outcomes. LIMITATIONS: Most studies had a low risk of bias according to the RoB 2.0 tool, and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach resulted in moderate certainty of evidence for both outcomes. Differences in lifestyle programs and in usual care between the studies should be considered in the interpretation of our results. CONCLUSIONS: Intensive lifestyle interventions implemented so far did not show superiority to usual care in reducing cardiovascular or all-cause mortality for subjects with prediabetes and type 2 diabetes.

Markers of respiratory function response to high-carbohydrate and high-fat intake in patients with lung diseases: a systematic review with meta-analysis of randomized clinical trials.

BACKGROUND: Macronutrients can differently affect respiratory function markers such as VO2 , VCO2 , PaO2 , PaCO2 , and respiratory quotients (RQs), but systematic appraisal of the evidence on randomized clinical trials (RCTs) is lacking. OBJECTIVE: The objective of this work is to compare the response of respiratory function markers with high-carbohydrate and high-fat intake in patients with lung diseases. METHODS: Systematic review conducted according to Cochrane Collaboration recommendations, reported following Preferred Reporting Items for Systematic Reviews and Meta-Analysis for pairwise systematic reviews of interventions 2020. PubMed, EMBASE, Scopus, and Cochrane CENTRAL were searched up to July 2021. Two reviewers selected the RCTs and extracted the data. Risk of bias and the certainty of evidence were assessed by RoB 2 and Grading of Recommendations Assessment, Development, and Evaluation System criteria, respectively. Statistical and graphical data guided the publication bias investigation. Meta-analyses were conducted. RESULTS: We included 14 RCTs (362 participants), four of which were parallel. Most studies included patients with chronic obstructive pulmonary disease. High-fat intake decreased VCO2 (mean difference [MD] = -35.89 ml/min [95% confidence interval (CI), -45.24 to -26.21]); I² = 0%), VO2 (MD = -29.30 ml/min [95% CI, -40.94 to -17.66]; I² = 0%), PaCO2 mm Hg (MD = -4.62 [95% CI, -7.67 to -1.58]; I² = 84%), and RQ (MD = -0.08 [95% CI, -0.09 to -0.06]; I² = 0%) in the subset of parallel RCTs. In crossover RCTs, there was generally no evidence of effect except for a greater decrease in RQ (MD = -0.09 [95% CI, -0.12 to -0.02]; I² = 96%) in favor of high-fat intake. CONCLUSION: High-fat intake resulted in greater reductions of VCO2 , VO2 , PaCO2 , and RQ in adult patients with lung diseases. The certainty of the evidence is very low/low, and it precludes a specific recommendation on macronutrients contribution to energy intake of these patients.

An estimate of the area of occupancy and population size of Brachycephalus tridactylus (Anura: Brachycephalidae) to reassess its conservation status, with a proposal for conservation measures.

BACKGROUND: We are experiencing a global crisis in conservation, which has led to the prioritization of targets, such as nations, regions, and animal groups, which are necessary while resources are disputed. Brazil is a priority not only because of its megadiversity, high rates of endemism, and frequent descriptions of new species but also because of its high levels of deforestation. Among the species groups prioritized for conservation is the anurans (Amphibia: Anura), the population of which is severely declining. One group of anurans is the genus Brachycephalus, which includes 37 endemic species in the Brazilian Atlantic Rainforest. Some of these species have highly restricted distributions (<100 ha). Thirty new species have been described since 2000, and 55.3% of all species are threatened with extinction. Brachycephalus tridactylus was only recently described and remains restricted to its type locality. Because of its reduced geographical distribution (0.41 km2), it has been proposed to be considered as Vulnerable. The objective of this study is to reevaluate the conservation status of Brachycephalus tridactylus and propose conservation measures. METHODS: We searched for new populations during 2016-2020, evaluated in loco impacts and potential impacts on the species' population, and performed an analysis of the density of this population and estimated its size. International Union for Conservation of Nature (IUCN) criteria were used to assess the conservation status of the species. RESULTS: We recorded the species in seven new localities (from 715-1,140 m above sea level) in the state of São Paulo up to 33 km from the type locality of the species (in state of Paraná). We estimated the area of occupancy as 148.44 km2, densities as one calling male per 4.05 m2 and 130.00 m2, and a total population size of 4,429,722 adult individuals. Based on our finding, we proposed three lines of management: (1) formation of fire brigades, (2) management of residents' mules in the conservation unit and surrounding areas, and (3) management of degraded areas. We recommend changing the species' conservation status from Vulnerable to Endangered because of its fragmented distribution and decline in the area of occupancy and in the quality of its habitat. Our results have expanded the species previous geographic distribution and delimited areas without previous records. Our estimates of population density and size are in accordance with those verified for congeners. The conservation of this species benefits the environments and other species that inhabit them, being, therefore, strategic for receiving conservation actions that will spread throughout the ecosystem.

Correlation of enthesitis indices with disease activity and function in axial and peripheral spondyloarthritis: a cross-sectional study comparing MASES, SPARCC and LEI.

BACKGROUND: The presence of enthesitis is associated with higher disease activity, more disability and incapacity to work and a poorer quality of life in spondyloarthritis (SpA). There is currently no consensus on which clinical score should be used to assess enthesitis in SpA. The objective of the present work was to compare the correlation of three enthesitis indices (MASES, SPARCC and LEI) with measures of disease activity and function in a heterogeneous population of patients with axial and peripheral SpA. METHODS: A cross-sectional study was conducted in three Brazilian public university hospitals; patients fulfilling ASAS classification criteria for peripheral or axial SpA were recruited and measures of disease activity and function were collected and correlated to three enthesitis indices: MASES, SPARCC and LEI using Spearman's Correlation index. ROC curves were used to determine if the the enthesitis indices were useful to discriminate patients with active disease from those with inactive disease. RESULTS: Two hundred four patients were included, 71.1% (N = 145) fulfilled ASAS criteria for axial SpA and 28.9% (N = 59) for peripheral SpA. In axial SpA, MASES performed better than LEI (p = 0.018) and equal to SPARCC (p = 0.212) regarding correlation with disease activity (BASDAI) and function (BASFI). In peripheral SpA, only MASES had a weak but statistical significant correlation with DAS28-ESR (rs 0.310 p = 0.05) and MASES had better correlation with functional measures (HAQ) than SPARCC (p = 0.034). CONCLUSION: In this sample composed of SpA patients with high coexistence of axial and peripheral features, MASES showed statistical significant correlation with measures of disease activity and function in both axial and peripheral SpA.

Correlation of enthesitis indices with disease activity and function in axial and peripheral spondyloarthritis: a crosssectional study comparing MASES, SPARCC and LEI

Abstract Background: The presence of enthesitis is associated with higher disease activity, more disability and incapacity to work and a poorer quality of life in spondyloarthritis (SpA). There is currently no consensus on which clinical score should be used to assess enthesitis in SpA. The objective of the present work was to compare the correlation of three enthesitis indices (MASES, SPARCC and LEI) with measures of disease activity and function in a heterogeneous population of patients with axial and peripheral SpA. Methods: A cross-sectional study was conducted in three Brazilian public university hospitals; patients fulfilling ASAS classification criteria for peripheral or axial SpA were recruited and measures of disease activity and function were collected and correlated to three enthesitis indices: MASES, SPARCC and LEI using Spearman's Correlation index. ROC curves were used to determine if the the enthesitis indices were useful to discriminate patients with active disease from those with inactive disease. Results: Two hundred four patients were included, 71.1% (N = 145) fulfilled ASAS criteria for axial SpA and 28.9% (N = 59) for peripheral SpA. In axial SpA, MASES performed better than LEI (p = 0.018) and equal to SPARCC (p = 0.212) regarding correlation with disease activity (BASDAI) and function (BASFI). In peripheral SpA, only MASES had a weak but statistical significant correlation with DAS28-ESR (rs 0.310 p = 0.05) and MASES had better correlation with functional measures (HAQ) than SPARCC (p = 0.034). Conclusion: In this sample composed of SpA patients with high coexistence of axial and peripheral features, MASES showed statistical significant correlation with measures of disease activity and function in both axial and peripheral SpA.(AU)

Proposed design for the PGAA facility at the TRIGA IPR-R1 research reactor.

BACKGROUND: This work presents an initial proposed design of a Prompt Gamma Activation Analysis (PGAA) facility to be installed at the TRIGA IPR-R1, a 60 years old research reactor of the Centre of Development of Nuclear Technology (CDTN) in Brazil. The basic characteristics of the facility and the results of the neutron flux are presented and discussed. FINDINGS: The proposed design is based on a quasi vertical tube as a neutron guide from the reactor core, inside the reactor pool, 6 m below the room's level where shall be located the rack containing the set sample/detector/shielding. The evaluation of the thermal and epithermal neutron flux in the sample position was done considering the experimental data obtained from a vertical neutron guide, already existent in the reactor, and the simulated model for the facility. METHODS: The experimental determination of the neutron flux was obtained through the standard procedure of using Au monitors in different positions of the vertical tube. In order to validate both, this experiment and calculations of the simulated model, the flux was also determined in different positions in the core used for sample irradiation. The model of the system was developed using the Monte Carlo code MCNP5. CONCLUSION: The preliminary results suggest the possibility of obtaining a beam with minimum thermal flux of magnitude 10(6) cm(-2) s(-1), which confirm the technical feasibility of the installation of PGAA at the TRIGA IPR-R1 reactor. This beam would open new possibilities for enhancing the applications using the reactor.