Whole genome sequence analysis of population structure and insecticide resistance markers in Anopheles melas from the Bijagós Archipelago, Guinea-Bissau.

BACKGROUND: Anopheles melas is an understudied malaria vector with a potential role in malaria transmission on the Bijagós Archipelago of Guinea-Bissau. This study presents the first whole-genome sequencing and population genetic analysis for this species from the Bijagós. To our knowledge, this also represents the largest population genetic analysis using WGS data from non-pooled An. melas mosquitoes. METHODS: WGS was conducted for 30 individual An. melas collected during the peak malaria transmission season in 2019 from six different islands on the Bijagós Archipelago. Bioinformatics tools were used to investigate the population structure and prevalence of insecticide resistance markers in this mosquito population. RESULTS: Insecticide resistance mutations associated with pyrethroid resistance in Anopheles gambiae s.s. from the Bijagós were absent in the An. melas population, and no signatures of selective sweeps were identified in insecticide resistance-associated genes. Analysis of structural variants identified a large duplication encompassing the cytochrome-P450 gene cyp9k1. Phylogenetic analysis using publicly available mitochondrial genomes indicated that An. melas from the Bijagós split into two phylogenetic groups because of differentiation on the mitochondrial genome attributed to the cytochrome C oxidase subunits COX I and COX II and the NADH dehydrogenase subunits 1, 4, 4L and 5. CONCLUSIONS: This study identified an absence of insecticide-resistant SNPs common to An. gambiae in the An. melas population, but did identify structural variation over insecticide resistance-associated genes. Furthermore, this study presents novel insights into the population structure of this malaria vector using WGS analysis. Additional studies are required to further understand the role of this vector in malaria transmission.

Bias intervention messaging in student evaluations of teaching: The role of gendered perceptions of bias.

Many studies have documented discrepancies in student evaluation of teaching ratings between male and female instructors and between ethnic majority and minority instructors. Given the importance of such ratings to academic careers and the likelihood of potential intergroup bias, it is crucial that institutions consider approaches to mitigate such biases. Several recent studies have found that simple bias mitigation messaging can be effective in reducing gender and other biases. In the present research, students enrolled in several large Faculty of Science undergraduate courses at an Australian university were recruited on a volunteer basis via the course learning management system. Half of the participants were randomly assigned an intervention message highlighting potential biases relating to gender and language background. Data from 185 respondents were analysed using Bayesian ordinal regression models assessing the impact of message exposure on evaluation scores. Reading a bias intervention message caused students to significantly adjust their scores, with the nature of that change dependent on student and instructor characteristics. Among male students, the bias intervention message significantly increased scores for all except male instructors with English speaking backgrounds, for whom there was no significant impact of the message. In contrast, among female students, the bias intervention message significantly decreased scores for male instructors with English speaking backgrounds only. The sample showed an overall decrease in scores in the intervention group relative to the control group. This is the first study to detect a negative impact of bias intervention messaging on SET scores. Our results suggest students may not acknowledge their own potential bias towards instructors with whom they share similar demographic backgrounds. In conclusion, bias intervention messaging may be a simple method of mitigating bias, but it may lead to consequences in which one or more groups receive lower ratings as a result of the correction.

Racial and ethnic sleep health disparities in adolescents and risk for type 2 diabetes: a narrative review.

INTRODUCTION: Sleep is an essential factor for health and wellbeing in people across the age spectrum; yet many adolescents do not meet the recommended 8-10 h of nightly sleep. Unfortunately, habitually insufficient sleep, along with the metabolic changes of puberty, puts adolescents at increased risk for a host of adverse health outcomes such as obesity and type 2 diabetes (T2D). Furthermore, individuals from historically minoritized racial and ethnic groups (e.g. Hispanic/Latinx, African American/Black) are more likely to experience shorter sleep duration compared to adolescents of White/European origin, placing them at even greater risk for disparities in T2D risk. METHODS: We conducted a literature review on the role of race and ethnicity in adolescent sleep health and its relation to cardiometabolic outcomes, specifically T2D. We use the minority stress model and the stress and coping theory as guiding theoretical frameworks to examine individual and societal level factors that may contribute to sleep health disparities and their downstream effects on T2D risk. RESULTS: This review highlights that the unique race-related stressors adolescents from minoritized groups face may play a role in the sleep and T2D connection on a biological, psychological, and social level. However, although there has been advancement in the current research on adolescent racial and ethnic sleep health disparities in relation to T2D, mechanisms underlying these disparities in sleep health need further investigation. Addressing these gaps is crucial for identifying and mitigating sleep health disparities and T2D among racial and ethnic minority youth. CONCLUSION: We conclude with a discussion of the implications and future research directions of racial and ethnic disparities in sleep health and T2D prevention research. A comprehensive understanding of adolescent sleep health disparities has potential to better inform preventative and educational programs, interventions, and policies that promote sleep health equity and improve cardiometabolic outcomes like T2D.

The effects of dairy on the gut microbiome and symptoms in gastrointestinal disease cohorts: a systematic review.

Bovine dairy foods provide several essential nutrients. Fermented bovine dairy foods contain additional compounds, increasing their potential to benefit gastrointestinal health. This review explores the effects of dairy consumption on the gut microbiome and symptoms in gastrointestinal disease cohorts. Human subjects with common gastrointestinal diseases (functional gastrointestinal disorders and inflammatory bowel disease) or associated symptoms, and equivalent animal models were included. A systematic literature search was performed using PubMed, Embase and Web of Science. The search yielded 3014 studies in total, with 26 meeting inclusion criteria, including 15 human studies (1550 participants) and 11 animal studies (627 subjects). All test foods were fermented bovine dairy products, primarily fermented milk and yogurt. Six studies reported increases in gastrointestinal bacterial alpha diversity, with nine studies reporting increases in relative Lactobacillus and Bifidobacterium abundance. Six studies reported increases in beneficial short-chain fatty acids, while three reported decreases. Gastrointestinal symptoms, specifically gut comfort and defecation frequency, improved in 14 human studies. Five animal studies demonstrated reduced colonic damage and improved healing. This review shows fermented bovine dairy consumption may improve gut microbial characteristics and gastrointestinal symptoms in gastrointestinal disease cohorts. Further human intervention studies are needed, expanding test foods and capturing non-self-reported gastrointestinal measures.

Plug and play virus-like particles for the generation of anti-toxin antibodies.

Snakebite is a major global health concern, for which antivenom remains the only approved treatment to neutralise the harmful effects of the toxins. However, some medically important toxins are poorly immunogenic, resulting in reduced efficacy of the final product. Boosting the immunogenicity of these toxins in the commercial antivenom immunising mixtures could be an effective strategy to improve the final dose efficacy, and displaying snake antigens on Virus-like particles (VLPs) is one method for this. However, despite some applications in the field of snakebite, VLPs have yet to be explored in methods that could be practical at an antivenom manufacturing scale. Here we describe the utilisation of a "plug and play" VLP system to display immunogenic linear peptide epitopes from three finger toxins (3FTxs) and generate anti-toxin antibodies. Rabbits were immunised with VLPs displaying individual consensus linear epitopes and their antibody responses were characterised by immunoassay. Of the three experimental consensus sequences, two produced antibodies capable of recognising the consensus peptides, whilst only one of these could also recognise native whole toxins. Further characterisation of antibodies raised against this peptide demonstrated a sub-class specific response, and that these were able to elicit partially neutralising antibody responses, resulting in increased survival times in a murine snakebite envenoming model.

The incidence of hypertension among children after renal trauma: A matched cohort analysis.

PURPOSE: To describe the intermediate-term incidence of hypertension following pediatric renal trauma relative to that in an extremity (control group) trauma cohort. METHODS: This was a single-institution matched cohort study of pediatric patients presenting to a Level I trauma center between 2010 and 2019. The primary cohort included patients who sustained renal trauma, and a comparator cohort of sex- and age-matched patients with isolated extremity fracture was identified. The primary outcome was new hypertension, and a sensitivity analysis was conducted of any elevated blood pressure (EBP). Conditional logistic regression was performed and adjusted for overweight/obese status. RESULTS: There were 62 renal trauma patients included, representing 35% of all eligible patients seen in the study period. Hypertension was not found to be more prevalent with renal trauma (OR 1.18, 95% CI: 0.41, 3.39). The incidence of hypertension (9.7-11.3%) and EBP (22.6-32.3%) was comparable between renal trauma and control groups. CONCLUSION: Despite a high incidence of EBP and hypertension in pediatric patients after renal or extremity trauma, we did not observe an association between renal trauma and postinjury hypertension. We identified no cases of malignant or symptomatic hypertension, and no surgical interventions for renovascular hypertension was performed. Our findings suggest that only select patients, rather than most renal trauma patients, may benefit from monitoring for postinjury hypertension.

Cruciferous vegetables lower blood pressure in adults with mildly elevated blood pressure in a randomized, controlled, crossover trial: the VEgetableS for vaScular hEaLth (VESSEL) study.

BACKGROUND: Higher cruciferous vegetable intake is associated with lower cardiovascular disease risk in observational studies. The pathways involved remain uncertain. We aimed to determine whether cruciferous vegetable intake (active) lowers 24-h brachial systolic blood pressure (SBP; primary outcome) compared to root and squash vegetables (control) in Australian adults with mildly elevated BP (SBP 120-160 mmHg inclusive). METHODS: In this randomized, controlled, crossover trial, participants completed two 2-week dietary interventions separated by a 2-week washout. Cruciferous vegetables were compared to root and squash vegetables (~ 300 g/day) consumed with lunch and dinner meals. Participants were blinded to which interventions were the active and control. Adherence was assessed using food diaries and biomarkers (S-methyl cysteine sulfoxide (SMCSO, active) and carotenoids (control)). Twenty-four-hour brachial ambulatory SBP and secondary outcomes were assessed pre- and post each intervention. Differences were tested using linear mixed effects regression. RESULTS: Eighteen participants were recruited (median (IQR) age: 68 (66-70); female: n = 16/18; mean ± SD clinic SBP: 135.9 ± 10.0 mmHg). For both interventions, 72% participants had 100% adherence (IQR: 96.4-100%). SMCSO and carotenoids were significantly different between interventions (mean difference active vs. control SMCSO: 22.93 mg/mL, 95%CI 15.62, 30.23, P < 0.0001; carotenoids: - 0.974 mg/mL, 95%CI - 1.525, - 0.423, P = 0.001). Twenty-four-hour brachial SBP was significantly reduced following the active vs. control (mean difference - 2.5 mmHg, 95%CI - 4.2, - 0.9, P = 0.002; active pre: 126.8 ± 12.6 mmHg, post: 124.4 ± 11.8 mmHg; control pre: 125.5 ± 12.1 mmHg, post: 124.8 ± 13.1 mmHg, n = 17), driven by daytime SBP (mean difference - 3.6 mmHg, 95%CI - 5.4, - 1.7, P < 0.001). Serum triglycerides were significantly lower following the active vs. control (mean difference - 0.2 mmol/L, 95%CI - 0.4, - 0.0, P = 0.047). CONCLUSIONS: Increased intake of cruciferous vegetables resulted in reduced SBP compared to root and squash vegetables. Future research is needed to determine whether targeted recommendations for increasing cruciferous vegetable intake benefits population health. TRIAL REGISTRATION: Clinical trial registry ACTRN12619001294145.  https://www.anzctr.org.au.

Patient Participant Perspectives on Implementation of Long-Acting Cabotegravir and Rilpivirine: Results From the Cabotegravir and Rilpivirine Implementation Study in European Locations (CARISEL) Study.

INTRODUCTION: CARISEL is an implementation-effectiveness "hybrid" study examining the perspectives of people living with HIV-1 (patient study participants [PSPs]) on cabotegravir (CAB) plus rilpivirine (RPV) long-acting (LA) dosed every 2 months (Q2M) across 5 European countries. METHODS: PSPs completed questionnaires on acceptability (Acceptability of Intervention Measure), appropriateness (Intervention Appropriateness Measure), and feasibility (Feasibility of Intervention Measure) at their first (Month [M] 1), third (M4), and seventh (M12) injection visits. Semistructured qualitative interviews were also conducted. RESULTS: Overall, 437 PSPs were enrolled, of whom 430 received treatment. Median (interquartile range) age was 44 (37-51) years, 25.3% (n = 109/430) were female (sex at birth), and 21.9% (n = 94/430) were persons of color. Across time points, PSPs found CAB + RPV LA highly acceptable, appropriate, and feasible (mean scores ≥4.47/5). Qualitative data supported these observations. CONCLUSIONS: PSPs found CAB + RPV LA Q2M to be an acceptable, appropriate, and feasible treatment option.

Contextualising Experiences of Co-Occurring Mental Ill-Health and Substance Use Among Trans, Non-Binary, and Gender Diverse Young People: Implications for Tailored Harm Reduction Approaches.

Though significant research highlights higher rates of mental ill-health and substance use among trans, non-binary and gender diverse (henceforth 'trans') young people, little research has considered patterns, contextual characteristics, and correlates of co-occurring experiences of mental ill-health and substance use among trans young people. Using data from the Trans Pathways study, we used prevalence ratios and age- and gender-adjusted logistic regression models to examine prevalence and differences of co-occurring substance use (past six-month cigarette use, alcohol use, and other drug use) and contextual characteristics of substance use (past six-month solitary alcohol and/or drug use, substance use for coping) by mental ill-health (depression disorder, anxiety disorder, past 12-month self-harm thoughts and behaviours, suicidal thoughts, planning, and attempt/s). Age- and gender-adjusted models assessed associations between co-occurring depressive and anxiety disorders and recent cigarette, alcohol, and other drug use (six co-occurring items total) and 18 interpersonal stressors. Significantly increased odds of smoking or recent use of cannabis or sedatives was observed among trans young people reporting depressive disorder, anxiety disorder (aORs ranging 1.8-3.1). Trans young people who reported recent smoking or use of cannabis, inhalants, or sedatives, had 40% to 80% reduced odds of past 12-month self-harm thoughts, self-harm behaviours, suicidal thoughts, and suicide attempt/s (aORs ranging 0.2-0.6). On the other hand, solitary alcohol and/or other drug use and substance use for coping was significantly associated with increased odds of all mental ill-health outcomes. Issues with school, secure housing, and intimate partner abuse were the most robust correlates of co-occurring mental ill-health and substance use. Trans young people using substances, especially cigarettes, cannabis, and sedatives, often so do with co-occurring experiences of depression and anxiety though limited substance use in more 'social' contexts may confer benefits for preventing self-harm and suicide thoughts and behaviours. Continued research in partnership with trans young people is warranted to conceptualise more nuanced and precise conceptual parameters of trans-affirming substance use harm reduction approaches.

Large-scale CSF proteome profiling identifies biomarkers for accurate diagnosis of Frontotemporal Dementia.

Diagnosis of Frontotemporal dementia (FTD) and the specific underlying neuropathologies (frontotemporal lobar degeneration; FTLD- Tau and FTLD-TDP) is challenging, and thus fluid biomarkers are needed to improve diagnostic accuracy. We used proximity extension assays to analyze 665 proteins in cerebrospinal fluid (CSF) samples from a multicenter cohort including patients with FTD (n = 189), Alzheimer's Disease dementia (AD; n = 232), and cognitively unimpaired individuals (n = 196). In a subset, FTLD neuropathology was determined based on phenotype or genotype (FTLD-Tau = 87 and FTLD-TDP = 68). Forty three proteins were differentially regulated in FTD compared to controls and AD, reflecting axon development, regulation of synapse assembly, and cell-cell adhesion mediator activity pathways. Classification analysis identified a 14- and 13-CSF protein panel that discriminated FTD from controls (AUC: 0.96) or AD (AUC: 0.91). Custom multiplex panels confirmed the highly accurate discrimination between FTD and controls (AUCs > 0.96) or AD (AUCs > 0.88) in three validation cohorts, including one with autopsy confirmation (AUCs > 0.90). Six proteins were differentially regulated between FTLD-TDP and FTLD-Tau, but no reproducible classification model could be generated (AUC: 0.80). Overall, this study introduces novel FTD-specific biomarker panels with potential use in diagnostic setting.

The Percentage of Patients Experiencing Financial Strain Depends on the Screening Measure: Evidence From a Cross-Sectional Survey of Adult Members of an Integrated Healthcare Delivery System.

OBJECTIVES: Financial strain has important consequences for patients, providers, and health care systems. However, there is currently no gold standard measure to screen for financial strain. This study compared the performance of 3 single-item screeners using a composite measure of financial strain as a "gold standard." METHODS: We conducted a secondary analysis of unweighted data from a 2021 survey of Kaiser Permanente Northern California health plan members comparing the percentages of adults who experienced financial strain based on 3 general single-item screeners, a screener specific to medical and dental health care use, and a composite financial strain measure. The study sample was comprised of 2734 non-Medicaid insured adults who answered all financial strain questions. Kappa statistics evaluating agreement of the 3 general screeners with the composite measure were calculated for the sample overall, by age group, and within age group, by 4 levels of income and 4 racial/ethnic subgroups. RESULTS: Among 947 adults aged 35 to 65, 30.7% had just enough money or not enough money to make ends meet, 23.3% had a somewhat hard or hard time paying for basics, 18.8% had trouble paying for ≥1 type of expense, 20.5% had delayed/used less medical/dental care, and 41.5% had experienced financial strain based on the composite measure. Among 1787 adults aged 66 to 85, the percentages who screened positive on these measures were 22.7%, 19.4%, 12.9%, 19.8%, and 34.4%, respectively. Across the sample, by income categories and racial/ethnic groups, the making ends meet screener identified higher percentages of adults experiencing financial strain and performed better when compared with the composite measure than the hard to pay for the very basics and trouble paying for expenses screeners. Overall, substantial decreases in the percentages of adults who screened positive on the financial strain measures were seen as level of income increased. Within income categories, middle-aged adults were more likely than older adults to have experienced financial strain based on the composite and general single-item screeners. CONCLUSIONS: As social risk screening becomes part of the standard of care, it will be important to assess how well different brief screeners for financial strain perform with diverse patient populations.

Tuberculosis reactivation following apremilast therapy for psoriasis: Time to consider routine TB screening?

Apremilast is a relatively new oral treatment for psoriasis, which reduces expression of pro-inflammatory factors, including tumour necrosis factor-α (TNFα), critical to the immune control of Mycobacterium tuberculosis infection. In randomised controlled trials (RCTs) for apremilast no new cases of active tuberculosis (TB) were identified, thus, screening for latent TB infection (LTBI) is not currently recommended prior to apremilast initiation. We describe a case of M.tuberculosis reactivation shortly after commencement of apremilast for psoriasis. We are recommending clinicians perform LTBI risk assessment in all patients, and appropriate LTBI screening in select populations prior to apremilast initiation.

Wastewater-based evaluation of the efficacy of oxycodone regulations in Australia.

BACKGROUND AND AIMS: Between 2018 and 2020, Australia implemented major policy changes to improve the quality and safety of opioid prescribing, with a specific focus on oxycodone. This study used wastewater-based epidemiology to assess the efficacy of Australia's regulatory reforms by measuring change in consumption of oxycodone via exploratory analysis. DESIGN, SETTING, PARTICIPANTS, MEASUREMENTS: Wastewater analysis data on oxycodone consumption was from the National Wastewater Drug Monitoring Program. The program captures data from more than 50 wastewater treatment plant catchments across Australia, equivalent to more than 50% of the national population. Geographic trend analyses were conducted for both major cities and regional areas within all states and territories of Australia over a 6-year period between 2017 and 2023. FINDINGS: Oxycodone consumption showed a statistically significant increase nationally from 78 mg/day/1000 people (95% confidence interval [CI] = 71, 84) in 2017 to 120 mg/day/1000 people in August 2019 (95% CI = 110, 120), an increase of 52% (95% CI = 42, 62, P < 0.0001). From August 2019 to December 2020, there was a statistically significant decrease from 120 to 65 mg/day/1000 people (95% CI = 60, 71), a decrease of 45% (95% CI = 40, 51), followed by a modest 2.4% increase to the end of the study period in April 2023 (95% CI [2.0,2.7]). CONCLUSIONS: A 45% reduction in oxycodone consumption in Australia from 2019 to 2020 coincided with national policy changes that aimed to reduce consumption of prescription opioids. The overall declining trend in consumption was suggestive of the effectiveness of national interventions in reducing pharmaceutical opioid use. Wastewater-based epidemiology provides an effective approach for assessing the effectiveness of controlled substances policy changes.

Mismanagement and poor transparency in the European processed seafood supply revealed by DNA metabarcoding.

In the global processed seafood industry, disparate actors play different roles along the supply chain, creating multiple opportunities for mistakes, malpractice, and fraud. As a consequence, consumers may be exposed to non-authentic products, which hinder informed purchasing decisions and broader efforts to improve trade transparency and sustainability. Here, we characterised the taxonomic composition of 62 processed seafood products in Italian, British and Albanian retailers, purposefully obtained from different supply routes, using multiple DNA metabarcoding markers. By combining molecular results with metadata reported on labels, we revealed patterns of mislabelling in 24 products (39%) across sampling regions, denoting lack of transparency of processed seafood products based on resources sourced from either Europe or globally. We show that the accuracy of label claims and the mis-represented and underestimated levels of traded biodiversity are largely determined by the management of raw material by global processors. Our study shows that DNA metabarcoding is a powerful and novel authentication tool that is mature for application at different stages of the seafood supply chain to protect consumers and improve the sustainable management of fish stocks.

TRAF3 regulates STAT6 activation and T helper cell differentiation by modulating the phosphatase PTP1B.

The adaptor protein TNFR associated factor 3 (TRAF3) is a multifaceted regulator of lymphocyte biology that plays key roles in modulation of the molecular signals required for T cell activation and function. TRAF3 regulates signals mediated by the T cell receptor (TCR), costimulatory molecules, and cytokine receptors, which each drive activation of the serine/threonine kinase Akt. The impact of TRAF3 upon TCR/CD28-mediated activation of Akt, and thus on the diverse cellular processes regulated by Akt, including CD4 T cell fate decisions, remains poorly understood. We show here that TRAF3 deficiency led to impaired Akt activation, and thus to impaired in vitro skewing of CD4 T cells into the TH1 and TH2 fates. We investigated the role of TRAF3 in regulation of signaling pathways that drive TH1 and TH2 differentiation, and found that TRAF3 enhanced activation of Signal transducer and activator of transcription 6 (STAT6), thus promoting skewing toward the TH2 fate. TRAF3 promoted STAT6 activation by regulating recruitment of the inhibitory molecule Protein tyrosine phosphatase 1B (PTP1B) to the IL-4R signaling complex, in a manner that required integration of TCR/CD28- and IL-4R-mediated signals. This work reveals a new mechanism for TRAF3-mediated regulation of STAT6 activation in CD4 T cells, and adds to our understanding of the diverse roles played by TRAF3 as an important regulator of T cell biology.

Androgen receptor monomers and dimers regulate opposing biological processes in prostate cancer cells.

Most prostate cancers express the androgen receptor (AR), and tumor growth and progression are facilitated by exceptionally low levels of systemic or intratumorally produced androgens. Thus, absolute inhibition of the androgen signaling axis remains the goal of current therapeutic approaches to treat prostate cancer (PCa). Paradoxically, high dose androgens also exhibit considerable efficacy as a treatment modality in patients with late-stage metastatic PCa. Here we show that low levels of androgens, functioning through an AR monomer, facilitate a non-genomic activation of the mTOR signaling pathway to drive proliferation. Conversely, high dose androgens facilitate the formation of AR dimers/oligomers to suppress c-MYC expression, inhibit proliferation and drive a transcriptional program associated with a differentiated phenotype. These findings highlight the inherent liabilities in current approaches used to inhibit AR action in PCa and are instructive as to strategies that can be used to develop new therapeutics for this disease and other androgenopathies.

Reporting population size in wastewater-based epidemiology: A scoping review.

Knowledge of the number of people present in a catchment is fundamental for the assessment of spatio-temporal trends in wastewater-based epidemiology (WBE). Accurately estimating the number of people connected to wastewater catchments is challenging however, because populations are dynamic. Methods used to estimate population size can significantly influence the calculation and interpretation of population-normalised wastewater data (PNWD). This paper systematically reviews the reporting of population data in 339 WBE studies. Studies were evaluated based on their reporting of population size, the source of population data, the population calculation methods, and the uncertainties in population estimates. Most papers reported population size (96 %) and the source of population data (60 %). Fewer studies reported the uncertainties in their population data (50 %) and the methods used to calculate these estimates (28 %). This is relevant because different methods have unique strengths and limitations which can affect the accuracy of PNWD. Only 64 studies (19 %) reported all four components of population data. The reporting of population data has remained consistent in the past decade. Based on the findings, we recommend generalised reporting criteria for population data in WBE. As WBE is further mainstreamed and applied, the clear and comprehensive reporting of population data will only become increasingly important.

Long-read transcript sequencing identifies differential isoform expression in the entorhinal cortex in a transgenic model of tau pathology.

Increasing evidence suggests that alternative splicing plays an important role in Alzheimer's disease (AD) pathology. We used long-read sequencing in combination with a novel bioinformatics tool (FICLE) to profile transcript diversity in the entorhinal cortex of female transgenic (TG) mice harboring a mutant form of human tau. Our analyses revealed hundreds of novel isoforms and identified differentially expressed transcripts - including specific isoforms of Apoe, App, Cd33, Clu, Fyn and Trem2 - associated with the development of tau pathology in TG mice. Subsequent profiling of the human cortex from AD individuals and controls revealed similar patterns of transcript diversity, including the upregulation of the dominant TREM2 isoform in AD paralleling the increased expression of the homologous transcript in TG mice. Our results highlight the importance of differential transcript usage, even in the absence of gene-level expression alterations, as a mechanism underpinning gene regulation in the development of AD neuropathology.

Effectiveness of marine protected areas in safeguarding important migratory megafauna habitat.

Marine protected areas (MPAs) are a commonly used management tool to safeguard marine life from anthropogenic impacts, yet their efficacy often remains untested. Evaluating how highly dynamic marine species use static MPAs is challenging but becoming more feasible with the advancement of telemetry data. Here, we focus on southern right whales (Eubalaena australis, SRWs) in the waters off Aotearoa/New Zealand, which declined from 30,000 whales to fewer than 40 mature females due to whaling. Now numbering in the low thousands, the key socializing and nursery areas for this population in the remote subantarctic islands are under the protection of different types of MPAs. However, the effectiveness of these MPAs in encompassing important whale habitat and protecting the whales from vessel traffic has not been investigated. To address this, we analyzed telemetry data from 29 SRWs tagged at the Auckland Islands between 2009 and 2022. We identified two previously unknown and currently unprotected areas that were used by the whales for important behaviors such as foraging, socializing, or resting. Additionally, by combining whale locations and vessel tracking data (2020-2022) during peak breeding period (June to October), we found high spatiotemporal overlap between whales and vessels within several MPAs, suggesting the whales could still be vulnerable to multiple anthropogenic stressors even when within areas designated for protection. Our results identify areas to be prioritized for future monitoring and investigation to support the ongoing recovery of this SRW population, as well as highlight the overarching importance of assessing MPA effectiveness post-implementation, especially in a changing climate.

Using electrodermal activity to estimate fear learning differences in anxiety: A multiverse analysis.

Meta-analyses indicate differences in Pavlovian fear responses between anxious and non-anxious individuals using electrodermal activity (EDA). Recent research, however, has cast doubt on whether these effects are robust to different analytic choices. Using the multiverse approach conceived by Steegen et al. (2016), we surveyed analytic choices typically implemented in clinical fear conditioning research by conducting 1240 analyses reflecting different choice permutations. Only 1.45% of our analyses produced theoretically congruent statistically significant effects, and the strength and direction of the estimated effects varied substantially across EDA processing methods. We conclude that EDA-estimated fear learning differences are vulnerable to researcher degrees of freedom and make recommendations regarding which analytical choices should be approached with a high degree of caution.