Search

BackgroundPhysical activity (PA), sedentary behavior (SB), and sleep are collectively referred to as 24-h movement behaviors, which may be linked to cognitive development in children. However, most of the evidence was based on cross-sectional studies and/or solely relied on parent-reported information on children’s behaviors, and it remains uncertain whether all domains/contexts of PA and SB are similarly associated with executive function and academic achievement.ObjectiveWe investigated the prospective associations of accelerometer-measured 24 h-movement behaviors and domain-specific PA and SB with executive function and academic achievement among school-aged children in Singapore.MethodsThe Growing Up in Singapore Toward healthy Outcomes (GUSTO) cohort used a wrist-worn accelerometer (Actigraph-GT3x+) to measure 24 h-movement behaviors data at ages 5.5 and 8 years. Executive function and academic achievement were assessed using NEuroPSYchology (NEPSY) and Wechsler Individual Achievement Tests at ages 8.5 and 9-years, respectively. Compositional data analyses were conducted to explore the associations of 24 h-movement behavior with outcomes, and multiple linear regression models to examine the associations of domain-specific PA and SB with outcomes (n = 432).ResultsAmong 432 children whose parents agreed to cognitive assessments (47% girls and 58% Chinese), the composition of 24 h-movement behaviors at ages 5.5 and 8 years was not associated with executive function and academic achievement. However, higher moderate-to-vigorous PA (MVPA) relative to remaining movement behaviors at age 5.5 years was associated with lower academic achievement [Mean difference (95% confidence interval): −0.367 (−0.726, −0.009) z-score], and reallocating MVPA time to sleep showed higher academic achievement scores [30 min from MVPA to sleep: 0.214 (0.023, 0.404) z-score]. Certain domains of PA and SB, notably organized PA/sports, outdoor play, and reading books were favorably associated with outcomes of interest, while indoor play and screen-viewing were unfavorably associated.ConclusionThe associations between movement behaviors and cognitive outcomes are multifaceted, influenced by specific domains of PA and SB. This study underscores the importance of participation in organized PA/sports, outdoor active play, and reading books, while ensuring adequate sleep and limiting screen viewing, to enhance cognitive outcomes. These findings underscore the need for further research into time-use trade-offs. Such studies could have major implications for revising current guidelines or strategies aimed at promoting healthier 24 h-movement behaviors in children.Study registrationhttps://clinicaltrials.gov/, NCT01174875.

Abstract Insulin resistance and glucose metabolism have been associated with neurodevelopmental disorders. However, in the metabolically more susceptible Asian populations, it is not clear whether the genetic burden of glycaemic dysregulation influences early-life neurodevelopment. In a multi-ethnic Asian prospective cohort study in Singapore (Growing Up in Singapore Towards healthy Outcomes (GUSTO)), we constructed child and parental polygenic risk scores (PRS) for glycaemic dysregulation based on the largest genome-wide association studies of type 2 diabetes and fasting glucose among Asians. We found that child PRS for HOMA-IR was associated with a lower perceptual reasoning score at ~7 years (β = −0. 141, p-value = 0.024, 95% CI −0. 264 to −0. 018) and a lower WIAT-III mean score at ~9 years (β = −0.222, p-value = 0.001, 95% CI −0.357 to −0.087). This association were consistent in direction among boys and girls. These inverse associations were not influenced by parental PRS and were likely mediated via insulin resistance rather than mediators such as birth weight and childhood body mass index. Higher paternal PRS for HOMA-IR was suggestively associated with lower child perceptual reasoning at ~7 years (β = −0.172, p-value = 0.002, 95% CI −0.280 to −0.064). Replication analysis in a European cohort, the Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort, showed that higher child PRS for fasting glucose was associated with lower verbal IQ score while higher maternal PRS for insulin resistance was associated with lower performance IQ score in their children at ~8.5 years. In summary, our findings suggest that higher child PRS for HOMA-IR was associated with lower cognitive scores in both Asian and European replication cohorts. Differential findings between cohorts may be attributed to genetic and environmental factors. Further investigation of the functions of the genetic structure and ancestry-specific PRS and a more comprehensive investigation of behavioural mediators may help to understand these findings better.

Biopolymers are natural macromolecules obtained from animal, plant and microbial sources, with the potential to be used in a wide range of applications. A key process step, which is still underdeveloped, is the downstream processing. In this work, water immiscible and water miscible ionic liquids (ILs) were investigated regarding their ability to fractionate a mixture of polysaccharide and proteins. Alginate and bovine serum albumin (BSA) were used as model compounds to mimic natural polymer crude extract. Phosphonium ILs composed of different anions (bromide, dicyanamide and phosphinate) were used as water immiscible ILs while imidazolium ILs, combined with phosphate salts to form biphasic system, were selected as water miscible ILs. In water immiscible IL systems, the partitioning behavior of biopolymers depended on IL's anions and there was formation of insoluble precipitate. The insolubility of precipitate in diverse aqueous and organic solvents hindered the processibility of water immiscible phosphonium IL for fractionation of biopolymers. The partitioning of biopolymers in water miscible ILs systems also depended on the IL's anion, as well the concentration of IL. Separation of alginate (yield = 90% and purity = 99%) from BSA (yield = 89% and purity = 99%) was best achieved by the [C4mim]Cl-based extraction system. After fractionation, regeneration of IL and salt used was carried out by ultrafiltration, with recovery yields up to 100%. The high extraction yields and recyclability of phase-forming compounds confirm the potential of water miscible ILs systems to fractionate polysaccharide and protein.

Major advances in RNA secondary structural motif prediction have been achieved in the last few years; however, few methods harness the predictive power of multiple approaches to deliver in-depth characterizations of local RNA motifs and their potential functionality. Additionally, most available methods do not predict RNA pseudoknots. This work combines complementary bioinformatic systems into one robust discovery pipeline where: • RNA sequences are folded to search for thermodynamically favorable motifs utilizing ScanFold. • Motifs are expanded and refolded into alternate pseudoknot conformations by Knotty/Iterative HFold. • All conformations are evaluated for covariance via the cm-builder pipeline (Infernal and R-scape).

Hematopoietic acute radiation syndrome (H-ARS) involves injury to multiple organ systems following total body irradiation (TBI). Our laboratory demonstrated that captopril, an angiotensin-converting enzyme inhibitor, mitigates H-ARS in Göttingen minipigs, with improved survival and hematopoietic recovery, as well as the suppression of acute inflammation. However, the effects of captopril on the gastrointestinal (GI) system after TBI are not well known. We used a Göttingen minipig H-ARS model to investigate captopril’s effects on the GI following TBI (60Co 1.79 or 1.80 Gy, 0.42–0.48 Gy/min), with endpoints at 6 or 35 days. The vehicle or captopril (0.96 mg/kg) was administered orally twice daily for 12 days, starting 4 h post-irradiation. Ilea were harvested for histological, protein, and RNA analyses. TBI increased congestion and mucosa erosion and hemorrhage, which were modulated by captopril. GPX-4 and SLC7A11 were downregulated post-irradiation, consistent with ferroptosis at 6 and 35 days post-irradiation in all groups. Interestingly, p21/waf1 increased at 6 days in vehicle-treated but not captopril-treated animals. An RT-qPCR analysis showed that radiation increased the gene expression of inflammatory cytokines IL1B, TNFA, CCL2, IL18, and CXCL8, and the inflammasome component NLRP3. Captopril suppressed radiation-induced IL1B and TNFA. Rectal microbiome analysis showed that 1 day of captopril treatment with radiation decreased overall diversity, with increased Proteobacteria phyla and Escherichia genera. By 6 days, captopril increased the relative abundance of Enterococcus, previously associated with improved H-ARS survival in mice. Our data suggest that captopril mitigates senescence, some inflammation, and microbiome alterations, but not ferroptosis markers in the intestine following TBI.

Abstract Background COVID-19, caused by the SARS-CoV-2 virus, is a severe inflammatory condition. Patients with pre-existing conditions including diabetes, hypertension, and cardiovascular disease are at particularly high risk of complications. Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare and debilitating genetic disorder that is characterized by a pro-inflammatory state, which leads to progressive heterotopic ossification and complications after trauma, including intramuscular vaccinations. To better understand the impact of COVID-19 on patients with FOP, we first examined the social impact of the pandemic using data from the FOP Registry managed by the International FOP Association. We also identified patients with FOP who were exposed to or contracted the SARS-CoV-2 virus, or who received a COVID-19 vaccine, to investigate if patients with FOP were at increased risks of complications from SARS-CoV2 exposure or vaccination. Results Data from 326 individuals in 69 countries in the International FOP Association FOP Connection Registry were examined using patient-reported outcomes measurement information system (PROMIS) global health scale scores. Twenty-six (28.9%) participants aged ≥ 15 years old rated their satisfaction with their social activities and relationships as poor in 2020, which was an increase from 18 (18.9%) in 2019, prior to the SARS-CoV-2 outbreak. Similar trends were noted for physical and mental health in the pediatric population. Frequency of physician visits was not changed, but a larger portion of patients reported missing dental visits in 2020 compared with 2019 (31.5% vs. 41.7%). A second cohort with 32 subjects was tracked after SARS-CoV-2 exposure or vaccination. Ten subjects were positively diagnosed with COVID-19, 15 received a COVID-19 vaccine, and seven had high-risk SARS-CoV-2 exposure but either did not have a confirmed clinical diagnosis or tested negative. Subjects who tested positive for the virus showed no major complications or increased FOP disease activity, though our sample size is very limited. Among the 15 subjects who received a COVID-19 vaccine, using the International Clinical Council on FOP guidelines for prophylaxis with ibuprofen or acetaminophen, only one person experienced flare-like activity at the injection site. Conclusions Patients with FOP showed a significant decrease in social activities that was reflective of the isolation and mobility changes in this debilitated population. In our limited cohort, the majority of the patients with FOP who tested positive for COVID-19 showed no major complications. Also, although limited in sample size, the majority of patients who received a COVID-19 vaccination and followed guidelines from the FOP International Clinical Council tolerated vaccination well. Only one person experiencing flare activity following their injection. Thus, the risks and benefits of COVID-19 vaccination needs to be discussed carefully so as to support informed decisions.

Abstract Diabetic kidney disease (DKD) is a highly prevalent complication of diabetes and the leading cause of end‐stage kidney disease. Inflammation is recognized as an important driver of progression of DKD. Activation of the immune response promotes a pro‐inflammatory milieu and subsequently renal fibrosis, and a progressive loss of renal function. Although the role of the innate immune system in diabetic renal disease has been well characterized, the potential contribution of the adaptive immune system remains poorly defined. Emerging evidence in experimental models of DKD indicates an increase in the number of T cells in the circulation and in the kidney cortex, that in turn triggers secretion of inflammatory mediators such as interferon‐γ and tumor necrosis factor‐α, and activation of cells in innate immune response. In human studies, the number of T cells residing in the interstitial region of the kidney correlates with the degree of albuminuria in people with type 2 diabetes. Here, we review the role of the adaptive immune system, and associated cytokines, in the development of DKD. Furthermore, the potential therapeutic benefits of targeting the adaptive immune system as a means of preventing the progression of DKD are discussed.

Nitrate (NO3--N) leaching into groundwater as a result of high nitrogen (N) fertilizer rates to annual crops presents human health risks and high costs associated with water treatment. Leaching is a particularly serious concern on sandy soils overlying porous bedrock. Intermediate wheatgrass (IWG) [Thinopyrum intermedium (Host.) Barkw. & D.R. Dewey], is a perennial grass that is being bred to produce agronomically and economically viable grain, which is commercially available as Kernza®. Intermediate wheatgrass is a low-input crop has the potential to produce profitable grain and biomass yields while reducing NO3--N leaching on sandy soils compared with common annual row crop rotations in the Upper Midwest. We compared grain yields, biomass yields, soil solution NO3--N concentration, soil extractable NO3--N, soil water content, and root biomass under IWG and a conventionally managed corn (Zea mays L.) and soybean [Glycine max (L.) Merr.] rotation for 3 years on a Verndale sandy loam in Central Minnesota. Mean soil solution NO3--N was 77–96% lower under IWG than the annual crop rotation. Soil water content was greater under annuals compared to IWG early in the growing season, suggesting greater water use by IWG during this time. Interactions between crop treatments and depth were observed for soil water content in Year 3. Root biomass from 0 to 60 cm below the soil surface was five times greater beneath IWG compared to soybean, which may explain differences in soil extractable and solution NO3--N among crops. With irrigation on coarse structured soils, IWG grain yields were 854, 434, and 222 kg ha−1 for Years 1–3 and vegetative biomass averaged 4.65 Mg ha−1 yr−1; comparable to other reports on heavier soils in the region. Annual crop grain yields were consistent with local averages. These results confirm that IWG effectively reduces soil solution NO3--N concentrations even on sandy soils, supporting its potential for broader adoption on land vulnerable to NO3--N leaching.

High case counts after the Gamma (P. 1) variant of severe acute respiratory syndrome coronavirus 2 emerged in Brazil raised concerns that previously infected persons might become reinfected. Investigation of a cluster of coronavirus disease cases in Parintins, in the Brazilian Amazon, suggested household transmission but did not identify high rates of reinfection.

Background: While socioeconomic position (SEP) is consistently related to pregnancy and birth outcome disparities, relevant biological mechanisms are manifold, thus necessitating more comprehensive characterization of SEP-exposome associations during pregnancy. Objectives: We implemented an exposomic approach to systematically characterize the socioeconomic landscape of prenatal exposures in a setting where social segregation was less distinct in a hypotheses-generating manner. Methods: We described the correlation structure of 134 prenatal exogenous and endogenous sources (e.g., micronutrients, hormones, immunomodulatory metabolites, environmental pollutants) collected in a diverse, population-representative, urban, high-income longitudinal mother-offspring cohort (N = 1341; 2009–2011). We examined the associations between maternal, paternal, household, and areal level SEP indicators and 134 exposures using multiple regressions adjusted for precision variables, as well as potential effect measure modification by ethnicity and nativity. Finally, we generated summary SEP indices using Multiple Correspondence Analysis to further explore possible curved relationships. Results: Individual and household SEP were associated with anthropometric/adiposity measures, folate, omega-3 fatty acids, insulin-like growth factor-II, fasting glucose, and neopterin, an inflammatory marker. We observed paternal education was more strongly and consistently related to maternal exposures than maternal education. This was most apparent amongst couples discordant on education. Analyses revealed additional non-linear associations between areal composite SEP and particulate matter. Environmental contaminants (e.g., per- and polyfluoroalkyl substances) and micronutrients (e.g., folate and copper) showed opposing associations by ethnicity and nativity, respectively. Discussion: SEP-exposome relationships are complex, non-linear, and context specific. Our findings reinforce the potential role of paternal contributions and context-specific modifiers of associations, such as between ethnicity and maternal diet-related exposures. Despite weak presumed areal clustering of individual exposures in our context, our approach reinforces subtle non-linearities in areal-level exposures.

Neste trabalho, vazoes máximas observadas na bacia do rio Paranapanema sao modelados por uma mistura de duas distribuicoes GEV cujas componentes correspondemás subpopulacoes de verao e inverno. A funcao discriminante nao linear permitiu confirmar a hipótese do modelo de mistura. O modelo proposto é entao usado para determinar as probabilidades de excedencias e períodos de retorno associados a vazoes extremas, que sao de fundamental importancia para projetos hidráulicos. Os resultados mostram diferencas significativas quando um modelo de mistura é usado e, portanto, uma abordagem mais coerente com os dados observados.

Many theories of verbal humour postulate that the funniness of jokes is caused by an incongruency in the punchline whose resolution yields a feeling of mirth. While there are studies testing the prediction that this situation model updating leads to increases in processing costs, there are few studies directly assessing the time course of when the alternative situation models are entertained. In a visual world paradigm, stories were presented auditorily and displays were presented illustrating either the situation implied by the context or the final interpretation after the punchline. Eye movement data confirmed the switch from the initial to the final interpretation for jokes as well as for non-funny control stories that also required a situation model revision. In addition to these effects of the cognitive revision requirements, the pupil dilations were sensitive to the affective component of joke comprehension. These results are discussed in light of incongruency theories of verbal humour.

Background Neurological COVID-19 disease has been reported widely, but published studies often lack information on neurological outcomes and prognostic risk factors. We aimed to describe the spectrum of neurological disease in hospitalised COVID-19 patients; characterise clinical outcomes; and investigate factors associated with a poor outcome. Methods We conducted an individual patient data (IPD) meta-analysis of hospitalised patients with neurological COVID-19 disease, using standard case definitions. We invited authors of studies from the first pandemic wave, plus clinicians in the Global COVID-Neuro Network with unpublished data, to contribute. We analysed features associated with poor outcome (moderate to severe disability or death, 3 to 6 on the modified Rankin Scale) using multivariable models. Results We included 83 studies (31 unpublished) providing IPD for 1979 patients with COVID-19 and acute new-onset neurological disease. Encephalopathy (978 [49%] patients) and cerebrovascular events (506 [26%]) were the most common diagnoses. Respiratory and systemic symptoms preceded neurological features in 93% of patients; one third developed neurological disease after hospital admission. A poor outcome was more common in patients with cerebrovascular events (76% [95% CI 67–82]), than encephalopathy (54% [42–65]). Intensive care use was high (38% [35–41]) overall, and also greater in the cerebrovascular patients. In the cerebrovascular, but not encephalopathic patients, risk factors for poor outcome included breathlessness on admission and elevated D-dimer. Overall, 30-day mortality was 30% [27–32]. The hazard of death was comparatively lower for patients in the WHO European region. Interpretation Neurological COVID-19 disease poses a considerable burden in terms of disease outcomes and use of hospital resources from prolonged intensive care and inpatient admission; preliminary data suggest these may differ according to WHO regions and country income levels. The different risk factors for encephalopathy and stroke suggest different disease mechanisms which may be amenable to intervention, especially in those who develop neurological symptoms after hospital admission.

Abstract Understanding what processes drive community structure is fundamental to ecology. Many wild animals are simultaneously infected by multiple parasite species, so host–parasite communities can be valuable tools for investigating connections between community structures at multiple scales, as each host can be considered a replicate parasite community. Like free‐living communities, within‐host–parasite communities are hierarchical; ecological interactions between hosts and parasites can occur at multiple scales (e.g., host community, host population, parasite community within the host), therefore, both extrinsic and intrinsic processes can determine parasite community structure. We combine analyses of community structure and assembly at both the host population and individual scales using extensive datasets on wild wood mice (Apodemus sylvaticus) and their parasite community. An analysis of parasite community nestedness at the host population scale provided predictions about the order of infection at the individual scale, which were then tested using parasite community assembly data from individual hosts from the same populations. Nestedness analyses revealed parasite communities were significantly more structured than random. However, observed nestedness did not differ from null models in which parasite species abundance was kept constant. We did not find consistency between observed community structure at the host population scale and within‐host order of infection. Multi‐state Markov models of parasite community assembly showed that a host's likelihood of infection with one parasite did not consistently follow previous infection by a different parasite species, suggesting there is not a deterministic order of infection among the species we investigated in wild wood mice. Our results demonstrate that patterns at one scale (i.e., host population) do not reliably predict processes at another scale (i.e., individual host), and that neutral or stochastic processes may be driving the patterns of nestedness observed in these communities. We suggest that experimental approaches that manipulate parasite communities are needed to better link processes at multiple ecological scales.

Screening for autism in childhood has been advocated as a part of standard care. Challenges exist with screening implementation and performance of screening tools in clinical practice. This study aimed to examine the validity and feasibility of using the Modified Checklist for Autism in Toddlers, Revised with Follow-Up (M-CHAT-R/F) for screening of autism in Singapore. Caregivers completed the M-CHAT-R/F as a part of the routine 18-month well-child visit in seven primary care clinics. Screening and follow-up interviews were administered by trained nursing staff. Children screened positive and a subset of those screened negative underwent diagnostic assessments for autism, which included an Autism Diagnostic Observation Schedule, Second Edition. Participants were 5336 multiethnic children (mean age 18.6 ± 0.9 months, 51.3% male gender). In total, 113 (2.1%) were screened positive, of which 54 (1.0%) were classified to have autism after their diagnostic assessment. Sensitivity of the M-CHAT-R/F was 88.6%, specificity 71.4%, and positive predictive value 90.7% for an autism diagnosis. The majority of respondents rated the screening process as feasible within the clinic setting. The M-CHAT-R/F had acceptable psychometric properties and high feasibility when used in primary care settings in Singapore. Recommendations for implementation of systematic screening and future research are presented.

Phonemic awareness is the ability to notice and manipulate language sounds in their base form (phonemes). It is associated with emerging literacy skills and predictive of skilled reading. The aim of the present study was to investigate phonemic awareness in German and its association with speaking a German-origin, but predominantly unwritten language. We investigated speakers of Hunsrückisch, a Brazilian minority language predominantly used in its spoken form. Participants were literate Brazilian Portuguese speakers who spoke Hunsrückisch and German or Hunsrückisch only. The results show faster, more accurate performance in the phonemic awareness task among participants who spoke Hunsrückisch and German, relative to those who spoke Hunsrückisch only. Participants who spoke Hunsrückisch only were able to perform the phonemic awareness tasks but having learned to read and write in German allowed for faster, more accurate performance, especially in relation to pseudowords.

Abstract Background Although infant media exposure has received attention for its implications on child development, upstream risk factors contributing to media exposure have rarely been explored. The study aim was to examine the relationship between maternal risk factors, infant television (TV) viewing, and later child cognition. Methods We used a prospective population-based birth cohort study, Growing Up in Singapore Towards healthy Outcomes (GUSTO), with 1247 pregnant mothers recruited in their first trimester. We first explored the relationship of infant TV exposure at 12 months and the composite IQ score at 4.5 years, as measured by the Kaufman Brief Intelligence Test, Second Edition (KBIT-2). Multivariable linear regressions were adjusted for maternal education, maternal mental health, child variables, birth parameters, and other relevant confounders. We then examined the associations of maternal risk factors with the amount of daily TV viewing of 12-month-old infants. Path analysis followed, to test a conceptual model designed a priori to test our hypotheses. Results The average amount of TV viewing at 12 months was 2.0 h/day (SD 1.9). TV viewing in hours per day was a significant exposure variable for composite IQ (ß = − 1.55; 95% CI: − 2.81 to − 0.28) and verbal IQ (ß = − 1.77; 95% CI: − 3.22 to − 0.32) at 4.5 years. Our path analysis demonstrated that lower maternal education and worse maternal mood (standardized ß = − 0.27 and 0.14, respectively, p 0.99, AIC 15249.82, RMSEA

Abstract Aim Exercise is able to increase both muscle protein synthesis and mitochondrial biogenesis. However, acidosis, which can occur in pathological states as well as during high‐intensity exercise, can decrease mitochondrial function, whilst its impact on muscle protein synthesis is disputed. Thus, the aim of this study was to determine the effect of a mild physiological decrease in pH, by administration of ammonium chloride, on myofibrillar and mitochondrial protein synthesis, as well as associated molecular signaling events. Methods Male Wistar rats were given either a placebo or ammonium chloride prior to a short interval training session. Rats were killed before exercise, immediately after exercise, or 3 h after exercise. Results Myofibrillar (p = 0.036) fractional protein synthesis rates was increased immediately after exercise in the soleus muscle of the placebo group, but this effect was absent in the ammonium chloride group. However, in the gastrocnemius muscle NH4Cl increased myofibrillar (p = 0.044) and mitochondrial protein synthesis (0 h after exercise p = 0.01; 3 h after exercise p = 0.003). This was accompanied by some small differences in protein phosphorylation and mRNA expression. Conclusion This study found ammonium chloride administration immediately prior to a single session of exercise in rats had differing effects on mitochondrial and myofibrillar protein synthesis rates in soleus (type I) and gastrocnemius (type II) muscle in rats.

Introduction Sex hormone binding globulin (SHBG) levels are reported to be inversely associated with diabetes risk. It is unknown whether diabetes prevention interventions increase SHBG and whether resultant changes in SHBG affect diabetes risk. The purpose of this analysis was to determine whether intensive lifestyle intervention (ILS) or metformin changed circulating SHBG and if resultant changes influenced diabetes risk in the Diabetes Prevention Program (DPP).Research design and methods This is a secondary analysis from the DPP (1996–2001), a randomized trial of ILS or metformin versus placebo on diabetes risk over a mean follow-up of 3.2 years. The DPP was conducted across 27 academic study centers in the USA. Men, premenopausal and postmenopausal women without hormone use in the DPP were evaluated. The DPP included overweight/obese persons with elevated fasting glucose and impaired glucose tolerance. Main outcomes measures were changes in SHBG levels at 1 year and risk of diabetes over 3 years.Results ILS resulted in significantly higher increases (postmenopausal women: p

Echimidine is the main pyrrolizidine alkaloid of Echium plantagineum L., a plant domesticated in many countries. Because of echimidine’s toxicity, this alkaloid has become a target of the European Food Safety Authority regulations, especially in regard to honey contamination. In this study, we determined by NMR spectroscopy that the main HPLC peak purified from zinc reduced plant extract with an MS [M + H]+ signal at m/z 398 corresponding to echimidine (1), and in fact also represents an isomeric echihumiline (2). A third isomer present in the smallest amount and barely resolved by HPLC from co-eluting (1) and (2) was identified as hydroxymyoscorpine (3). Before the zinc reduction, alkaloids (1) and (2) were present mostly (90%) in the form of an N-oxide, which formed a single peak in HPLC. This is the first report of finding echihumiline and hydroxymyoscorpine in E. plantagineum. Retroanalysis of our samples of E. plantagineum collected in New Zealand, Argentina and the USA confirmed similar co-occurrence of the three isomeric alkaloids. In rat hepatocyte primary culture cells, the alkaloids at 3 to 300 µg/mL caused concentration-dependent inhibition of hepatocyte viability with mean IC50 values ranging from 9.26 to 14.14 µg/mL. Our discovery revealed that under standard HPLC acidic conditions, echimidine co-elutes with its isomers, echihumiline and to a lesser degree with hydroxymyoscorpine, obscuring real alkaloidal composition, which may have implications for human toxicity.

In an era where it becomes less and less accepted to just send waste to landfills and release wastewater into the environment without treatment, numerous initiatives are pursued to facilitate chemical production from waste. This includes microbial conversions of waste in digesters, and with this type of approach, a variety of chemicals can be produced. Typical for digestion systems is that the products are present only in (very) dilute amounts. For such productions to be technically and economically interesting to pursue, it is of key importance that effective product recovery strategies are being developed. In this review, we focus on the recovery of biologically produced carboxylic acids, including volatile fatty acids (VFAs), medium-chain carboxylic acids (MCCAs), long-chain dicarboxylic acids (LCDAs) being directly produced by microorganisms, and indirectly produced unsaturated short-chain acids (USCA), as well as polymers. Key recovery techniques for carboxylic acids in solution include liquid-liquid extraction, adsorption, and membrane separations. The route toward USCA is discussed, including their production by thermal treatment of intracellular polyhydroxyalkanoates (PHA) polymers and the downstream separations. Polymers included in this review are extracellular polymeric substances (EPS). Strategies for fractionation of the different fractions of EPS are discussed, aiming at the valorization of both polysaccharides and proteins. It is concluded that several separation strategies have the potential to further develop the wastewater valorization chains.

Academic integrity is a key measure of the quality, efficiency and competitiveness of higher education systems. This article explores how a quality assurance agency can foster a conducive environment for academic quality and integrity. A self-study methodology was used, with a focus on the insights and experiences of the Zimbabwe Council for Higher Education over a 10-year period. The findings show that by assuming an innovative and transformational leadership role in instilling a culture of self-evaluation, as well as maintaining its own integrity, an external quality assurance agency can improve academic integrity. The article adds value to the existing knowledge by advancing the higher education ecosystem approach as an integrity-based panacea and conducive way to induce integrity to flow from all players as opposed to the use of heavy-handed regulatory approaches. Significance: • This article highlights the importance of academic integrity and situates quality assurance agencies as playing a central role in fostering academic integrity.

Despite significant social and legal progress, LGBTQ+ (lesbian, gay, bisexual, transgender, and other sexual and gender minority) populations continue to experience higher rates of mental health and substance use disorders than their heterosexual and cisgender counterparts. Effective LGBTQ+ affirmative mental health care is essential for addressing these disparities but is often limited and difficult to access. The shortage of LGBTQ+ affirmative mental health care providers results from the absence of required and accessible LGBTQ+ -focused training and technical assistance opportunities for mental health care professionals. This study evaluates the implementation of our COVID-19 adapted, completely virtual, organization- and therapist-focused training program to improve the mental health workforce's cultural competence in working with the LGBTQ+ community: the "Sexual and Gender Diversity Learning Community" (SGDLC). Guided by an expanded RE-AIM model, we used administrator and therapist feedback to assess SGDLC implementation factors to understand how it may be best translated for scaled-up promotion and widespread adoption. Assessment of the initial reach, adoption, and implementation of the SGDLC indicated that it had strong feasibility; reports on satisfaction and relevance support the SGDLC's acceptability. Maintenance could not be fully assessed from the short study follow-up period. Still, administrators and therapists expressed an intent to continue their newfound practices, a desire for continued training and technical assistance in this area, but also concerns about finding additional opportunities for this education.

Abstract Background Preterm birth is in quantity and in severity the most important topic in obstetric care in the developed world. Progestogens and cervical pessaries have been studied as potential preventive treatments with conflicting results. So far, no study has compared both treatments. Methods/design The Quadruple P study aims to compare the efficacy of vaginal progesterone and cervical pessary in the prevention of adverse perinatal outcome associated with preterm birth in asymptomatic women with a short cervix, in singleton and multiple pregnancies separately. It is a nationwide open-label multicentre randomized clinical trial (RCT) with a superiority design and will be accompanied by an economic analysis. Pregnant women undergoing the routine anomaly scan will be offered cervical length measurement between 18 and 22 weeks in a singleton and at 16–22 weeks in a multiple pregnancy. Women with a short cervix, defined as less than, or equal to 35 mm in a singleton and less than 38 mm in a multiple pregnancy, will be invited to participate in the study. Eligible women will be randomly allocated to receive either progesterone or a cervical pessary. Following randomization, the silicone cervical pessary will be placed during vaginal examination or 200 mg progesterone capsules will be daily self-administered vaginally. Both interventions will be continued until 36 weeks gestation or until delivery, whichever comes first. Primary outcome will be composite adverse perinatal outcome of perinatal mortality and perinatal morbidity including bronchopulmonary dysplasia, intraventricular haemorrhage grade III and IV, periventricular leukomalacia higher than grade I, necrotizing enterocolitis higher than stage I, Retinopathy of prematurity (ROP) or culture proven sepsis. These outcomes will be measured up until 10 weeks after the expected due date. Secondary outcomes will be, among others, time to delivery, preterm birth rate before 28, 32, 34 and 37 weeks, admission to neonatal intensive care unit, maternal morbidity, maternal admission days for threatened preterm labour and costs. Discussion This trial will provide evidence on whether vaginal progesterone or a cervical pessary is more effective in decreasing adverse perinatal outcome in both singletons and multiples. Trial registration Trial registration number: NTR 4414 . Date of registration January 29th 2014.

Some interpersonal verbs show a bias in the proportion of times their subject and object arguments are rementioned in a sample of explanations for the eventuality the verb describes. This bias is known as the implicit causality bias. Several studies have shown that readers and listeners rapidly use the implicit causality bias during pronoun resolution. Whether listeners also rapidly incorporate relevant contextual information during pronoun resolution, is an open question. In the current paper, we report two visual world eye-tracking studies intended to answer this question. Participants listened to stories that included implicit causality verbs followed by a “because” clause with an ambiguous pronoun in its subject position. During the story, the participants looked at a screen on which potential referents of the ambiguous pronoun were displayed. In Experiment 1, a simple main effect of implicit causality bias on looks toward the character that was congruent with the bias was found among items in one of the two discourse conditions. Discourse context, however, only affected looks for a subset of verbs and in the opposite direction of what was hypothesized. In Experiment 2, no main effects of IC Bias or discourse context were found, but there was a marginally significant interaction which was not hypothesized. In both experiments, discourse context influenced looks only for a subset of verbs and never in the predicted direction. The results favor an account in which the influence of lexical semantics is, at least initially, stronger than the influence of world knowledge, and discourse context. Additional exploratory analyses suggested that eye movements already reveal remention biases at an early point in the sentence, whereas the causal potency of the subject argument is predicted by looks starting from the onset of the causal connective.

Recent calls for widespread police reform include re-examination of existing training and practice surrounding the use of force (UOF, e.g., verbal and non-verbal communication, physical tactics, firearms). Visual models representing police UOF decision-making are used for both police training and public communication. However, most models have not been empirically developed or assessed in either the applied police or vision science literatures, representing significant gaps in knowledge. The purpose of the current review is to provide a novel, relevant, and practical analysis of the visual components of three common police UOF decision-making model types (circular, cyclical, staircase). We begin with a critical evaluation of the visual features specific to each model type (i.e., shape), followed by critical reviews of common visual features, including colour, implied motion, text, and clarity. The insights provided by the current work afford scientists from visual disciplines a unique opportunity to contribute meaningfully to the improvement of existing police UOF practices, with the goal of promoting public and occupational safety. To this end, we conclude with evidence-based recommendations for designing visual models that effectively promote training of police and communication of police UOF decision-making to the public.

Parasitic helminths are extremely resilient in their ability to maintain chronic infection burdens despite (or maybe because of) their hosts’ immune response. Explaining how parasites maintain these lifelong infections, identifying the protective immune mechanisms that regulate helminth infection burdens, and designing prophylactics and therapeutics that combat helminth infection, while preserving host health requires a far better understanding of how the immune system functions in natural habitats than we have at present. It is, therefore, necessary to complement mechanistic laboratory-based studies with studies on wild populations and their natural parasite communities. Unfortunately, the relative paucity of immunological tools for non-model species has held these types of studies back. Thankfully, recent progress in high-throughput ‘omics platforms provide powerful and increasingly practical means for immunologists to move beyond traditional lab-based model organisms. Yet, assigning both metabolic and immune function to genes, transcripts, and proteins in novel species and assessing how they interact with other physiological and environmental factors requires identifying quantitative relationships between their expression and infection. Here, we used supervised machine learning to identify gene networks robustly associated with burdens of the gastrointestinal nematode Heligmosomoides polygyrus in its natural host, the wild wood mice Apodemus sylvaticus. Across 34 mice spanning two wild populations and across two different seasons, we found 17,639 transcripts that clustered in 131 weighted gene networks. These clusters robustly predicted H. polygyrus burden and included well-known effector and regulatory immune genes, but also revealed a number of genes associated with the maintenance of tissue homeostasis and hematopoiesis that have so far received little attention. We then tested the effect of experimentally reducing helminth burdens through drug treatment on those putatively protective immune factors. Despite the near elimination of H. polygyrus worms, the treatment had surprisingly little effect on gene expression. Taken together, these results suggest that hosts balance tissue homeostasis and protective immunity, resulting in relatively stable immune and, consequently, parasitological profiles. In the future, applying our approach to larger numbers of samples from additional populations will help further increase our ability to detect the immune pathways that determine chronic gastrointestinal helminth burdens in the wild.

Background: Salmonella is a Gram-negative bacterium and the principal cause of human gastroenteritis that originates from the consumption of animal products.Objective: to determine serotype and antibiotic resistance of Salmonella spp. isolated from pork meat and environmental samples in 6 slaughterhouses and 14 butcheries in Tolima, Colombia. Methods: slaughterhouses and butcheries were selected depending on their slaughter capacity and compliance with good manufacturing practices. Samples (n = 507) were taken from carcasses, the environment, and fomites (i.e., surfaces of knives, hooks, floor, siphons, work surfaces, and transport trucks), then cultured in Salmonella selective media. Following this, the isolated Salmonella spp. was identified using a conventional biochemical test and genus antiserum (Poli A + Vi). The Kauffman-Whyte scheme was used for serotyping and the agar diffusion method (Kirby-Bauer) was used to determine antibiotic sensitivity. Results:Manhattan, Derby, Typhimurium, Javiana, Muenster, Hvittingfoss, Sinsfort, Kattbus, and Saint Paul serotypes of Salmonella were isolated from both pork meat and environmental samples, being Derby the most common serotype. Salmonella isolates showed antibiotic multiresistance mainly to tetracycline, lincomycin and nalidixic acid. Conclusion: several Salmonella serotypes are present in slaughterhouses and meat samples from butcheries, and they show similar antibiotic resistance patterns. This work represents the first report on Salmonella serotypes in slaughterhouses and pork meat from butcheries in Tolima, Colombia.

The rubber tree (Hevea brasiliensis) is exploited mainly for latex in view of its economic importance. However, one of its auxiliary products, the rubber seed, does not find any major applications, and hence, even the natural production of seeds itself remains underutilized. In this study, microwave-assisted Soxhlet extraction is used as a green alternative to extract the oil from seeds at a reaction time of 90 min and microwave power of 300 W. The objective of the study is to evaluate the effects of the processing conditions, including drying time, temperature, solid–solvent ratio, and extraction solvent, on the yield of rubber seed oil. Moreover, the microwave-assisted aqueous extraction (MAAE) under acidic conditions is also investigated. Based on the results, n-hexane gave the best yield at an optimized 1:20 seed–hexane ratio at 72 °C compared with the conventional Soxhlet method and the acidic MAAE. Furthermore, the chemical characteristics of the oil showed a high value of free fatty acids (% FFA) (1.15–7.61%) and an iodine value (IV) that ranges from 100–150. As a semi-drying oil, rubber seed oil (RSO) can be used as an ingredient for surface coating and in the formulation of products where the presence of unsaturation is important.

OBJETIVO: Comparar o ganho pôndero-estatural e a frequência de complicações clínicas em recém-nascidos pré-termo com peso inferior a 1.500 g, alimentados exclusivamente com leite humano cru da própria mãe com e sem aditivo até atingirem o peso de 1.800 g. MÉTODOS: Ensaio clínico prospectivo randomizado duplo-cego em 40 recém-nascidos pré-termo com peso de nascimento < 1.500 g e ≤ 34 semanas, internados em unidade de terapia intensiva neonatal no período de agosto de 2005 a abril de 2007. Foram randomizados em 2 grupos: controle (leite humano puro) e intervenção (leite humano com aditivo). A fortificação foi feita no leite humano cru ordenhado no momento da oferta, quando a dieta atingiu 100 mL/kg/dia (até os neonatos atingirem peso de 1.800 g). Foram comparados ganho de peso diário, crescimento e perímetro cefálico semanalmente, variáveis nutricionais e complicações clínicas. RESULTADOS: A fortificação resultou em melhor crescimento, com ganho de 1,09 e 0,87 cm/semana (p = 0,003) e perímetro cefálico observado de 0,73 e 1,02 cm/semana (p = 0,0001), respectivamente grupo intervenção e controle. O ganho de peso foi de 24,4 e 21,2 g/dia (p = 0,075). Quanto às complicações clínicas observadas, não houve diferença significante. CONCLUSÕES: O uso de aditivo no leite humano cru da própria mãe proporcionou melhor crescimento, com aumento significativo do comprimento e do perímetro cefálico.OBJECTIVE: To compare the weight and height gain and the frequency of clinical complications in preterm newborns weighing less than 1,500 g, exclusively fed human milk or fortified human milk until reaching 1,800 g. METHODS: Prospective double-blind randomized controlled trial involving 40 preterm infants weighing < 1,500 g at birth and ≤ 34 weeks of gestational age, admitted to a neonatal intensive care unit from August 2005 to April 2007. Preterm infants were randomized into two groups: control (human milk) and intervention (fortified human milk). Fortifiers were added to manually expressed human milk when feeding volume reached 100 mL/kg/day until newborns reached 1,800 g. Daily weight gain, weekly length and head circumference gain, nutritional variables and clinical complications were compared. RESULTS: Human milk fortification resulted in better growth, with length gain of 1.09 and 0.87 cm/week (p = 0.003) and head circumference gain of 0.73 and 1.02 cm/week (p = 0.0001), respectively, for intervention and control groups. The weight gain was 24.4 and 21.1 g/day (p = 0.075). There were no significant clinical complications. CONCLUSIONS: Human milk fortification resulted in better growth, significant increase in length and head circumference.

Veillonella spp. are predominant bacteria found in all oral biofilms. In this study, a metatranscriptomic approach was used to investigate the gene expression levels of three oral Veillonella spp. (V. parvula, V. dispar and V. atypica) in whole stimulated saliva from caries-free volunteers and in carious lesions (n=11 for each group). In the lesions the greatest proportion of reads were assigned to V. parvula and genes with the highest level of expression in carious samples were those coding for membrane transport systems. All three Veillonella spp. increased expression of genes involved in the catabolism of lactate and succinate, notably the alpha- and beta-subunits of L(+)-tartrate dehydratase (EC 4.2.1.32). There was also significantly increased expression of histidine biosynthesis pathway in V. parvula, suggesting higher intra-cellular levels of histidine that could provide intra-cellular buffering capacity and, therefore, assist survival in the acidic environment. Various other systems such as potassium uptake systems were also up regulated that may aid in the survival and proliferation of V. parvula in carious lesions.

Cumulative evidence indicates that Wnt pathways play crucial and diverse roles to assemble the neuromuscular junction (NMJ), a peripheral synapse characterized by the clustering of acetylcholine receptors (AChR) on postsynaptic densities. The molecular determinants of Wnt effects at the NMJ are still to be fully elucidated. We report here that the Wnt receptor Frizzled-9 (Fzd9) is expressed in developing skeletal muscles during NMJ synaptogenesis. In cultured myotubes, gain- and loss-of-function experiments revealed that Fzd9-mediated signaling impairs the AChR-clustering activity of agrin, an organizer of postsynaptic differentiation. Overexpression of Fzd9 induced the cytosolic accumulation of β-catenin, a key regulator of Wnt signaling. Consistently, Fzd9 and β-catenin localize in the postsynaptic domain of embryonic NMJs in vivo. Our findings represent the first evidence pointing to a crucial role of a Fzd-mediated, β-catenin-dependent signaling on the assembly of the vertebrate NMJ.

This study examines by means of fMRI the neural mechanisms underlying adolescents’ risk decision-making in social contexts. We hypothesize that the social context could engage brain regions associated with social cognition processes and developmental changes are also expected. Sixty participants (adolescents: 17-18, and young adults: 21-22 years old) read narratives describing typical situations of decision-making in the presence of peers. They were asked to make choices in risky situations (e.g., taking or refusing a drug) or ambiguous situations (e.g., eating a hamburger or a hotdog). Risky as compared to ambiguous scenarios activated bilateral temporoparietal junction (TPJ), bilateral middle temporal gyrus (MTG), right medial prefrontal cortex (mPFC), and the precuneus bilaterally; i.e., brain regions related to social cognition processes, such as self-reflection and theory of mind. In addition, brain structures related to cognitive control were active (right ACC, bilateral DLPFC, bilateral OFC), whereas no significant clusters were obtained in the reward system (VS). Choosing the dangerous option involved a further activation of control areas (ACC) and emotional and social cognition areas (temporal pole). Adolescents employed more neural resources than young adults in the right DLPFC and the right TPJ in risk situations. When choosing the dangerous option, young adults showed a further engagement in theory of mind related regions (bilateral middle temporal gyrus) and in motor control regions related to the planning of actions (pre-supplementary motor area). Finally, the right insula and the right superior temporal gyrus were more activated in women than in men, suggesting more emotional involvement and more intensive modeling of the others’ perspective in the risky conditions. These findings call for more comprehensive developmental accounts of decision-making in social contexts that incorporate the role of emotional and social cognition processes.

Hemodialysis vascular access can develop venous neointimal hyperplasia (VNH) causing stenosis. Recent clinical and experimental data has demonstrated that there is increased expression of a disintegrin and metalloproteinase thrombospondin motifs-1 (ADAMTS-1) at site of VNH. The experiments outlined in the present paper were designed to test the hypothesis that targeting of the adventitia of the outflow vein of murine arteriovenous fistula (AVF) using a small hairpin RNA that inhibits ADAMTS-1 expression (LV-shRNA-ADAMTS-1) at the time of fistula creation will decrease VNH. At early time points, ADAMTS-1 expression was significantly decreased associated with a reduction in vascular endothelial growth factor-A (VEGF-A) and matrix metalloproteinase-9 (MMP-9) (LV-shRNA-ADAMTS-1 transduced vessels vs. controls). These changes in gene and protein expression resulted in favorable vascular remodeling with a significant increase in mean lumen vessel area, decrease in media/adventitia area, with a significant increase in TUNEL staining accompanied with a decrease in cellular proliferation accompanied with a reduction in CD68 staining. Collectively, these results demonstrate that ADAMTS-1 transduced vessels of the outflow vein of AVF have positive vascular remodeling.

The smoking of tobacco continues to be the leading cause of premature death worldwide and is linked to the development of a number of serious illnesses including heart disease, respiratory diseases, stroke and cancer. Currently, cell line based toxicity assays are typically used to gain information on the general toxicity of cigarettes and other tobacco products. However, they provide little information regarding the complex disease-related changes that have been linked to smoking. The ethical concerns and high cost associated with mammalian studies have limited their widespread use for in vivo toxicological studies of tobacco. The zebrafish has emerged as a low-cost, high-throughput, in vivo model in the study of toxicology. In this study, smoke condensates from 2 reference cigarettes and 6 Canadian brands of cigarettes with different design features were assessed for acute, developmental, cardiac, and behavioural toxicity (neurotoxicity) in zebrafish larvae. By making use of this multifaceted approach we have developed an in vivo model with which to compare the toxicity profiles of smoke condensates from cigarettes with different design features. This model system may provide insights into the development of smoking related disease and could provide a cost-effective, high-throughput platform for the future evaluation of tobacco products.

Exposure to an adverse environment in utero appears to programme physiology and metabolism permanently, with long-term consequences for health of the fetus or offspring. It was observed that the offspring from dams submitted to high-sodium intake during pregnancy present disturbances in renal development and in blood pressure. These alterations were associated with lower plasma levels of angiotensin II (AII) and changes in renal AII receptor I (AT1) and mitogen-activated protein kinase (MAPK) expressions during post natal kidney development. Clinical and experimental evidence show that the renin-angiotensin system (RAS) participates in renal development. Many effects of AII are mediated through MAPK pathways. Extracellular signal-regulated protein kinases (ERKs) play a pivotal role in cellular proliferation and differentiation. In conclusion, high-sodium intake during pregnancy and lactation can provoke disturbances in renal development in offspring leading to functional and structural alterations that persist in adult life. These changes can be related at least in part with the decrease in RAS activity considering that this system has an important role in renal development.

The public debate on the use of the German nonbinary gender asterisk ("Lehrer*in" 'teacher') is emotionally charged. While it has been adopted by political and educational institutions, opponents argue that it is inappropriate for making persons identifying themselves beyond the male-female-dichotomy more visible. We investigated this claim by using a word-picture matching task directly assessing mental representations activated by the asterisk. Students evaluated whether pictures of persons read as male, female, or nonbinary were suitable illustrations of immediately preceding role nouns in masculine, feminine, or star form. Processing difficulties for female pictures following masculine nouns confirmed that the latter was not automatically read as generic. High acceptance rates and low reaction times for all pictures following the asterisk suggest it leads to inclusive mental representations including men, women, and persons beyond the gender binary. These results are the first to confirm that the asterisk elicits the intended inclusive interpretation.

This qualitative case study explored the perspectives of school administrators on implementing structured English immersion (SEI) and dual-language bilingual education (DLBE) programs serving emergent bilingual learners at one urban Arizona elementary school. Using a sociocultural policy perspective, I analyzed findings from a series of interviews examining the ways the participating administrators navigated and implemented restrictive language policies, while simultaneously providing pathways to DLBE opportunities for emergent bilingual learners. I found there was ongoing tension between compliance and resistance to state-mandated policies. In addition, there were differences in how the administrators positioned emergent bilingual learners as a good or bad fit for the DLBE program at the focal school site. The results and discussion underscore both the continued challenges of SEI policy in Arizona and the role of educational leaders in fostering spaces for biliteracy development.