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By adulthood, most males with fragile X syndrome (FXS) require support to navigate day-to-day settings. The present study cross-sectionally: (1) characterized the profile of daily living skills in males with FXS and (2) examined associated participant characteristics (i.e., fragile X mental retardation protein [FMRP] expression, nonverbal cognition, language, autism symptomatology, and anxiety symptomatology) using the Waisman-Activities of Daily Living questionnaire. Males with FXS (n = 57, ages 15-23 years) needed more help/support in the areas of domestic and community daily livings skills, than in the area of personal daily living skills. Significant associations were observed between reduced daily living skills and lower nonverbal cognition, receptive language, expressive language, and increased autism symptomatology. Receptive language emerged as the strongest unique predictor of daily living skill performance.

Atmospheric nitrous oxide contributes directly to global warming, yet models of the nitrogen cycle do not account for bedrock, the largest pool of terrestrial nitrogen, as a source of nitrous oxide. Although it is known that release rates of nitrogen from bedrock are large, there is an incomplete understanding of the connection between bedrock-hosted nitrogen and atmospheric nitrous oxide. Here, we quantify nitrogen fluxes and mass balances at a hillslope underlain by marine shale. We found that, at this site, bedrock weathering contributes 78% of the subsurface reactive nitrogen, while atmospheric sources (commonly regarded as the sole sources of reactive nitrogen in pristine environments) account for only the remaining 22%. About 56% of the total subsurface reactive nitrogen denitrifies, including 14% emitted as nitrous oxide. The remaining reactive nitrogen discharges in porewaters to a floodplain where additional denitrification probably occurs. We also found that the release of bedrock nitrogen occurs primarily within the zone of the seasonally fluctuating water table and suggest that the accumulation of nitrate in the vadose zone, often attributed to fertilization and soil leaching, may also include contributions from weathered nitrogen-rich bedrock. Our hillslope study suggests that, under oxygenated and moisture-rich conditions, weathering of deep, nitrogen-rich bedrock makes an important contribution to the nitrogen cycle.

Medically important flaviviruses cause diverse disease pathologies and collectively are responsible for a major global disease burden. A contributing factor to pathogenesis is secreted flavivirus nonstructural protein 1 (NS1). Despite demonstrated protection by NS1-specific antibodies against lethal flavivirus challenge, the structural and mechanistic basis remains unknown. Here, we present three crystal structures of full-length dengue virus NS1 complexed with a flavivirus-cross-reactive, NS1-specific monoclonal antibody, 2B7, at resolutions between 2.89 and 3.96 angstroms. These structures reveal a protective mechanism by which two domains of NS1 are antagonized simultaneously. The NS1 wing domain mediates cell binding, whereas the β-ladder triggers downstream events, both of which are required for dengue, Zika, and West Nile virus NS1-mediated endothelial dysfunction. These observations provide a mechanistic explanation for 2B7 protection against NS1-induced pathology and demonstrate the potential of one antibody to treat infections by multiple flaviviruses.

Anna Bokszczanin,1 Marek Palace,2 William Brown,3 Olga Gladysh,4 Rakhi Tripathi,5 Divya Shree6 1Institute of Psychology, University of Opole, Opole, Poland; 2School of Psychology, Liverpool John Moores University, Liverpool, UK; 3School of Psychology, University of Bedfordshire, Luton, UK; 4Institute of Psychology, Polish Academy of Sciences, Warsaw, Poland; 5Information Technology Area, FORE School of Management, New Delhi, India; 6School of Criminology and Behavioural Sciences, Rashtriya Raksha University Lavad, Dahegam, IndiaCorrespondence: Anna Bokszczanin, University of Opole, Institute of Psychology, 45-052 Opole, Plac Staszica 1, Opole, Poland, Email abok@uni.opole.plBackground: The study examines the prevalence of depression among university students in Poland, the UK and India in the face of the second pandemic wave of COVID-19. The paper also examines the protective role of perceived social support, the hypothesis being that social support from friends would reduce depression.&#x00A0Methods: The data from university students (N=732) in Poland (N=335), UK (N= 198), and India (N=199) were collected online during of the fall/winter 2021. Participants completed measures of depression (CES-D), COVID-19 risk perception index, loneliness (DJGLS), and perceived social support (MSPSS).Results: Almost 52% of all participants (58.5% in Poland, 62.6% in the UK, and 29.1% in India) met the criteria for major depression. The higher levels of depression symptoms were associated with a higher perceived risk of COVID-19, greater loneliness, female gender, younger students’ age, and the lower levels of perceived social support. The greater family support predicted lower levels of depression symptoms in the Polish and Indian samples. Structural equation analyses (SEM) revealed the indirect effect of perceived social support from friends on the association between social loneliness and depression and between age and depression. This result shows that the support from friends significantly reduced depression, regardless of age, the level of social loneliness, and the perceived risk of COVID-19.Conclusion: Our conclusions link to university specialists’ enhancement of psychological help for students with depression. We also recommend information campaigns on depression and treatment options.Keywords: depression, perceived risk of COVID-19, loneliness, perceived social support, university students

Prenylated indole alkaloids such as the calmodulin-inhibitory malbrancheamides and anthelmintic paraherquamides possess great structural diversity and pharmaceutical utility. Here, we report complete elucidation of the malbrancheamide biosynthetic pathway accomplished through complementary approaches. These include a biomimetic total synthesis to access the natural alkaloid and biosynthetic intermediates in racemic form and in vitro enzymatic reconstitution to provide access to the natural antipode (+)-malbrancheamide. Reductive cleavage of an L-Pro-L-Trp dipeptide from the MalG non-ribosomal peptide synthetase (NRPS) followed by reverse prenylation and a cascade of post-NRPS reactions culminates in an intramolecular [4+2] hetero-Diels-Alder (IMDA) cyclization to furnish the bicyclo[2.2.2]diazaoctane scaffold. Enzymatic assembly of optically pure (+)-premalbrancheamide involves an unexpected zwitterionic intermediate where MalC catalyses enantioselective cycloaddition as a bifunctional NADPH-dependent reductase/Diels-Alderase. The crystal structures of substrate and product complexes together with site-directed mutagenesis and molecular dynamics simulations demonstrate how MalC and PhqE (its homologue from the paraherquamide pathway) catalyse diastereo- and enantioselective cyclization in the construction of this important class of secondary metabolites.

Major components of hydrologic and elemental cycles reside underground, where their complex dynamics and linkages to surface waters are obscure. We delineated seasonal subsurface flow and transport dynamics along a hillslope in the Rocky Mountains (USA), where precipitation occurs primarily as winter snow and drainage discharges into the East River, a tributary of the Gunnison River. Hydraulic and geochemical measurements down to 10 m below ground surface supported application of transmissivity feedback of snowmelt to describe subsurface flow and transport through three zones: soil, weathering shale, and saturated fractured shale. Groundwater flow is predicted to depths of at least 176 m, although a shallower limit exists if hillslope-scale hydraulic conductivities are higher than our local measurements. Snowmelt during the high snowpack water year 2017 sustained flow along the weathering zone and downslope within the soil, while negligible downslope flow occurred along the soil during the low snowpack water year 2018. We introduce subsurface concentration-discharge (C-Q) relations for explaining hillslope contributions to C-Q observed in rivers and demonstrate their calculations based on transmissivity fluxes and measured pore water specific conductance and dissolved organic carbon. The specific conductance data show that major ions in the hillslope pore waters, primarily from the weathering and fractured shale, are about six times more concentrated than in the river, indicating hillslope solute loads are disproportionately high, while flow from this site and similar regions are relatively smaller. This methodology is applicable in different representative environments within snow-dominated watersheds for linking their subsurface exports to surface waters.

Understanding concentration-discharge (C-Q) relationships are essential for predicting chemical weathering and biogeochemical cycling under changing climate and anthropogenic conditions. Contrasting C-Q relationships have been observed widely, yet a mechanistic framework that can interpret diverse patterns remains elusive. This work hypothesizes that seemingly disparate C-Q patterns are driven by switching dominance of end-member source waters and their chemical contrasts arising from subsurface biogeochemical heterogeneity. We use data from Coal Creek, a high-elevation mountainous catchment in Colorado, and a recently developed watershed reactive transport model (BioRT-Flux-PIHM). Sensitivity analysis and Monte-Carlo simulations (500 cases) show that reaction kinetics and thermodynamics and distribution of source materials across depths govern the chemistry gradients of shallow soil water and deeper groundwater entering the stream. The alternating dominance of organic-poor yet geo-solute-rich groundwater under dry conditions and organic-rich yet geo-solute-poor soil water during spring melt leads to the flushing pattern of dissolved organic carbon and the dilution pattern of geogenic solutes (e.g., Na, Ca, and Mg). In addition, the extent of concentration contrasts regulates the power law slopes (b) of C-Q patterns via a general equation (Formula presented.). At low ratios of soil water versus groundwater concentrations (Cratio = Csw/Cgw  1.8), flushing arises; chemostasis occurs in between. This equation quantitatively interprets b values of 11 solutes (dissolved organic carbon, dissolved P, NO3−, K, Si, Ca, Mg, Na, Al, Mn, and Fe) from three catchments (Coal Creek, Shale Hills, and Plynlimon) of differing climate, geologic, and land cover conditions. This indicates potentially broad regulation of subsurface biogeochemical heterogeneity in determining C-Q patterns and wide applications of this equation in quantifying b values, which can have broad implications for predicting chemical weathering and biogeochemical transformation at the watershed scale.

Many males with FXS meet criteria for ASD. This study was designed to (1) describe ASD symptoms in adolescent and young adult males with FXS (n = 44) and (2) evaluate the contributions to ASD severity of cognitive, language, and psychiatric factors, as well as FMRP (the protein deficient in FXS). A few ASD symptoms on the ADOS-2 were universal in the sample. There was less impairment in restricted and repetitive behaviors (RRB) than in the social affective (SA) domain. The best predictor of overall ASD severity and SA severity was expressive syntactic ability. RRB severity was best predicted by the psychiatric factors. Implications for clinical practice and for understanding the ASD comorbidity in FXS are discussed.

The U.S. Department of Energy's Watershed Function Scientific Focus Area (SFA), centered in the East River, Colorado, generates diverse datasets including hydrological, geological, geochemical, geophysical, ecological, microbiological and remote sensing data. The project has deployed extensive field infrastructure involving hundreds of sensors that measure highly diverse phenomena (e.g. stream and groundwater hydrology, water quality, soil moisture, weather) across the watershed. Data from the sensor network are telemetered and automatically ingested into a queryable database. The data are subsequently quality checked, integrated with the United States Geological Survey's stream monitoring network using a custom data integration broker, and published to a portal with interactive visualizations. The resulting data products are used in a variety of scientific modeling and analytical efforts. This paper describes the SFA's end-to-end infrastructure and services that support the generation of integrated datasets from a watershed sensor network. The development and maintenance of this infrastructure, presents a suite of challenges from practical field logistics to complex data processing, which are addressed through various solutions. In particular, the SFA adopts a holistic view for data collection, assessment and integration, which dramatically improves the products generated, and enables a co-design approach wherein data collection is informed by model results and vice-versa.

Background: The objective of this study is to identify patient and EMS agency factors associated with timely reperfusion of patients with ST-elevation myocardial infarction (STEMI). Methods: We conducted a cohort study of adult patients (≥18 years old) with STEMI activations from 2016 to 2020. Data was obtained from a regional STEMI registry, which included eight rural county EMS agencies and three North Carolina percutaneous coronary intervention (PCI) centers. On each patient, prehospital and in-hospital time intervals were abstracted. The primary outcome was the ability to achieve the 90-minute EMS FMC to PCI time goal (yes vs. no). We used generalized estimating equations accounting for within-agency clustering to evaluate the association between patient and agency factors and meeting first medical contact (FMC) to PCI time goal while accounting for clustering within the agency. Results: Among 365 rural STEMI patients 30.1% were female (110/365) with a mean age of 62.5 ± 12.7 years. PCI was performed within the time goal in 60.5% (221/365) of encounters. The FMC to PCI time goal was met in 45.5% (50/110) of women vs 69.8% (178/255) of men (p < 0.001). The median PCI center activation time was 12 min (IQR 7–19) in the group that received PCI within the time goal compared to 21 min (IQR 10–37) in the cohort that did not. After adjusting for loaded mileage and other clinical variables (e.g., pulse rate, hypertension etc.), the male sex was associated with an improved chance of meeting the goal of FMC to PCI (aOR: 2.94; 95% CI 2.11–4.10) compared to the female sex. Conclusion: Nearly 40% of rural STEMI patients transported by EMS failed to receive FMC to PCI within 90 min. Women were less likely than men to receive reperfusion within the time goal, which represents an important health care disparity. [ABSTRACT FROM AUTHOR]

BackgroundFragile X syndrome (FXS) is caused by a mutation in the FMR1 gene on the X chromosome, leading to decreased levels of FMR1 protein (FMRP), which causes the array of neuropsychological impairments that define FXS. Because FXS is an X-linked condition, fewer females display FXS and females with FXS are more mildly affected than males, on average. However, there is a considerable variability in terms of severity of affectedness among females with FXS. The current study was designed to investigate potential genetic (FMRP level and ratio of affected to total chromosomes) and environmental factors (maternal psychological distress and closeness in the mother-child relationship) influencing the cognitive (fluid and crystallized intelligence) and behavioral (anxiety and withdrawal) phenotype of females with FXS.MethodsWe conducted a prospective 3-year longitudinal study of 16 females with FXS (with up to four assessments, each separated by a year) using an accelerated longitudinal design so that we had coverage of the age range of 10-15 years at study start and 13-18 at study end. We focused on both the level of functioning related to chronological age expectations (standard scores) and absolute change in skill (raw scores) over the 3-year period.ResultsAt a cross-sectional level, fluid intelligence and crystallized intelligence were both predicted by a closer mother-child relationship and lower maternal psychological distress. However, only fluid intelligence was predicted by a lower ratio of affected to total chromosomes. Anxiety and withdrawal were predicted by a higher ratio of affected to total chromosomes. Withdrawal was also predicted by lower closeness in the mother-child relationship and higher maternal distress. In terms of longitudinal change, gains were observed in fluid and crystallized intelligence, whereas anxious and withdrawn behaviors remained stable over visits. Gains in fluid intelligence were solely predicted by FXS biomarkers (higher FMRP level and lower ratio of affected to total chromosomes), while gains in crystallized intelligence were not predicted by any of the biological and environmental variables.ConclusionsOur results show that FXS biomarkers and maternal variables contribute differentially to the cognitive and behavioral features of the adolescent female with FXS. These findings can help in the design of treatment studies aimed at enhancing cognitive and behavioral abilities in the FXS population.

The structural diversity and complexity of marine natural products have made them a rich and productive source of new bioactive molecules for drug development. The identification of these new compounds has led to extensive study of the protein constituents of the biosynthetic pathways from the producing microbes. Essential processes in the dissection of biosynthesis have been the elucidation of catalytic functions and the determination of 3D structures for enzymes of the polyketide synthases and nonribosomal peptide synthetases that carry out individual reactions. The size and complexity of these proteins present numerous difficulties in the process of going from gene to structure. Here, we review the problems that may be encountered at the various steps of this process and discuss some of the solutions devised in our and other labs for the cloning, production, purification, and structure solution of complex proteins using Escherichia coli as a heterologous host.

BackgroundAutonomic dysfunction is implicated in a range of psychological conditions, including depression and anxiety. The fragile X mental retardation-1 (FMR1) premutation is a common genetic mutation that affects ~1:150 women and is associated with psychological vulnerability. This study examined cardiac indicators of autonomic function among women with the FMR1 premutation and control women as potential biomarkers for psychological risk that may be linked to FMR1.MethodsBaseline inter-beat interval and respiratory sinus arrhythmia (a measure of parasympathetic vagal tone) were measured in 35 women with the FMR1 premutation and 28 controls. The women completed anxiety and depression questionnaires. FMR1 genetic indices (i.e., CGG repeat, quantitative FMRP, FMR1 mRNA, activation ratio) were obtained for the premutation group.ResultsRespiratory sinus arrhythmia was reduced in the FMR1 premutation group relative to controls. While depression symptoms were associated with reduced respiratory sinus arrhythmia among control women, these variables were unrelated in the FMR1 premutation. Elevated FMR1 mRNA was associated with higher respiratory sinus arrhythmia.ConclusionsWomen with the FMR1 premutation demonstrated autonomic dysregulation characterized by reduced vagal tone. Unlike patterns observed in the general population and in study controls, vagal activity and depression symptoms were decoupled in women with the FMR1 premutation, suggesting independence between autonomic regulation and psychopathological symptoms that is atypical and potentially specific to the FMR1 premutation. The association between vagal tone and mRNA suggests that molecular variation associated with FMR1 plays a role in autonomic regulation.

Our understanding of fragile X syndrome (FXS) pathophysiology continues to improve and numerous potential drug targets have been identified. Yet, current prescribing practices are only symptom-based in order to manage difficult behaviors, as no drug to date is approved for the treatment of FXS. Drugs impacting a diversity of targets in the brain have been studied in recent FXS-specific clinical trials. While many drugs have focused on regulation of enhanced glutamatergic or deficient GABAergic neurotransmission, compounds studied have not been limited to these mechanisms. As a single-gene disorder, it was thought that FXS would have consistent drug targets that could be modulated with pharmacotherapy and lead to significant improvement. Unfortunately, despite promising results in FXS animal models, translational drug treatment development in FXS has largely failed. Future success in this field will depend on learning from past challenges to improve clinical trial design, choose appropriate outcome measures and age range choices, and find readily modulated drug targets. Even with many negative placebo-controlled study results, the field continues to move forward exploring both the new mechanistic drug approaches combined with ways to improve trial execution. This review summarizes the known phenotype and pathophysiology of FXS and past clinical trial rationale and results, and discusses current challenges facing the field and lessons from which to learn for future treatment development efforts.

PurposeThis study used a prospective longitudinal design to evaluate the trajectory and predictors of noncomprehension signaling in male and female youth with fragile X syndrome (FXS).MethodA direction-following task in which some of the directions were inadequate was administered. Participants were 52 youth (36 boys, 16 girls) with FXS. Upon study entry, participants ranged from 10 to 16 years. The average number of annual assessments per participant was 3.65 (range = 1-4), providing 198 data points for analysis.ResultsParticipants with FXS were less likely to signal noncomprehension than younger, typically developing, cognitively matched children. The average rate of change in noncomprehension signaling was not significantly different from 0 for either boys or girls, suggesting a plateau. Both FMRP and nonverbal IQ were significant independent predictors of noncomprehension signaling for boys. Variability in noncomprehension signaling among girls was not explained by any of the predictors, but trends similar to those observed for boys were observed.ConclusionsNoncomprehension signaling appears to be an area of weakness for individuals with FXS. Because the failure to signal noncomprehension can have negative, cumulative effects on comprehension, the results suggest a need for interventions targeting the requisite cognitive skills.

Family-based methods are a potentially powerful tool to identify trait-defining genetic variants in extended families, particularly when used to complement conventional association analysis. We utilized two-point linkage analysis and single variant association analysis to evaluate whole exome sequencing (WES) data from 1205 Hispanic Americans (78 families) from the Insulin Resistance Atherosclerosis Family Study. WES identified 211,612 variants above the minor allele frequency threshold of ≥0.005. These variants were tested for linkage and/or association with 50 cardiometabolic traits after quality control checks. Two-point linkage analysis yielded 10,580,600 logarithm of the odds (LOD) scores with 1148 LOD scores ≥3, 183 LOD scores ≥4, and 29 LOD scores ≥5. The maximal novel LOD score was 5.50 for rs2289043:T>C, in UNC5C with subcutaneous adipose tissue volume. Association analysis identified 13 variants attaining genome-wide significance (P T in APOA5 and triglyceride levels (P  =  3.67 × 10-10 ). Overall, there was a 5.2-fold increase in the number of informative variants detected by WES compared to exome chip analysis in this population, nearly 30% of which were novel variants relative to the Database of Single Nucleotide Polymorphisms (dbSNP) build 138. Thus, integration of results from two-point linkage and single-variant association analysis from WES data enabled identification of novel signals potentially contributing to cardiometabolic traits.