Exercise activates AMPK in mouse and human pancreatic islets to decrease senescence.

Beta (ß)-cell senescence contributes to type 2 diabetes mellitus (T2DM). While exercise is vital for T2DM management and significantly affects cellular ageing markers, its effect on ß-cell senescence remains unexplored. Here, we show that short-term endurance exercise training (treadmill running, 1 h per day for 10 days) in two male and female mouse models of insulin resistance decreases ß-cell senescence. In vivo and in vitro experiments revealed that this effect is mediated, at least in part, by training-induced increases in serum glucagon, leading to activation of 5'-AMP-activated protein kinase (AMPK) signalling in ß-cells. AMPK activation resulted in the nuclear translocation of NRF2 and decreased expression of senescence markers and effectors. Remarkably, human islets from male and female donors with T2DM treated with serum collected after a 10-week endurance exercise training programme showed a significant decrease in the levels of senescence markers. These findings indicate that exercise training decreases senescence in pancreatic islets, offering promising therapeutic implications for T2DM.

Placenta-derived SOD3 deletion impairs maternal behavior via alterations in FGF/FGFR-prolactin signaling axis.

Offspring growth requires establishing maternal behavior associated with the maternal endocrine profile. Placentae support the adaptations of the mother, producing bioactive molecules that affect maternal organs. We recently reported that placentae produce superoxide dismutase 3 (SOD3) that exerts sustained effects on the offspring liver via epigenetic modifications. Here, we demonstrate that placenta-specific Sod3 knockout (Sod3-/-) dams exhibited impaired maternal behavior and decreased prolactin levels. Most fibroblast growth factor (FGF)-regulated pathways were downregulated in the pituitary tissues from Sod3-/- dams. FGF1-, FGF2-, and FGF4-induced prolactin expression and signaling via the phosphoinositide 3-kinase (PI3K)-phospholipase C-γ1 (PLCγ1)-protein kinase-Cδ (PKC)δ axis were reduced in primary pituitary cells from Sod3-/- dams. Mechanistically, FGF1/FGF receptor (FGFR)2 expressions were inhibited by the suppression of the ten-eleven translocation (TET)/isocitrate dehydrogenase (IDH)/α-ketoglutarate pathway and DNA demethylation levels at the zinc finger and BTB domain containing 18 (ZBTB18)-targeted promoters of Fgf1/Fgfr2. Importantly, offspring from Sod3-/- dams also showed impaired nurturing behavior to their grandoffspring. Collectively, placenta-derived SOD3 promotes maternal behavior via epigenetic programming of the FGF/FGFR-prolactin axis.

A qualitative study on general practitioners' perspectives on late-life depression in Singapore-part I: patient presentations and behaviours.

Background: Detection and management of late-life depression largely relies on primary care. Yet in Singapore, older adults are unlikely to seek help for their mental health from their primary care providers. This qualitative descriptive study explores how late-life depression manifests to general practitioners (GPs) in the Singaporean primary care setting. Methods: Twenty-eight private GPs practicing in Singapore were asked about their clinical experience with late-life depression during semi-structured group and individual discussions conducted online. Participants were purposively sampled across age, gender, and ethnicity (Chinese, Malay, Indian). Transcripts were analysed with reflexive thematic analysis. Findings: To GPs, depression in older patients often manifests through somatic symptoms or subtle behavioural changes, only detectable through follow-ups or collateral history. GPs reported that older patients attribute depressive symptoms to normal ageing or do not mention them, particularly within an Asian culture encouraging stoic endurance. GPs perceived late-life depression as reactions to ageing-related stressors, with male, low-income, or institutionalised patients being at particular risk of insidious, severe depression. GPs noted ethnic differences regarding families' involvement in care, which they described as helpful, but sometimes stress-provoking for patients. Fear of burdensomeness or loss of autonomy/social role could prompt rejection of diagnosis and treatment in patients. GPs considered good patient-doctor rapport as a facilitator at every step of the care process, noting more favourable prognosis in care-concordant patients. Interpretation: Depression in older adults in Singapore can be covert, with favourable outcomes relying on GPs' ability to pick up on subtle changes, assess patients holistically, and build rapport with patients and families. Funding: This work was funded by the Division of Family Medicine Research Capabilities Building Budget under the project "Technology and Compassion: Improving Patient Outcomes Through Data Analytics and Patients' Voice in Primary Care" [NUHSRO/2022/049/NUSMed/DFM].

Post-COVID-19 condition symptoms among emergency department patients tested for SARS-CoV-2 infection.

Symptoms of the Post-COVID-19 Condition are often non-specific making it a challenge to distinguish them from symptoms due to other medical conditions. In this study, we compare the proportion of emergency department patients who developed symptoms consistent with the World Health Organization's Post-COVID-19 Condition clinical case definition between those who tested positive for Severe Acute Respiratory Syndrome Coronavirus-2 infection and time-matched patients who tested negative. Our results show that over one-third of emergency department patients with a proven acute infection meet Post-COVID-19 Condition criteria 3 months post-index visit. However, one in five test-negative patients who claim never having been infected also report symptoms consistent with Post-COVID-19 Condition highlighting the lack of specificity of the clinical case definition. Testing for SARS-CoV-2 during the acute phase of a suspected infection should continue until specific biomarkers of Post-COVID-19 Condition become available for diagnosis and treatment.

Lessons Learned from a Community-led, Pilot Teletherapy Group for Older Women Living with Depression and HIV.

Older women with HIV face challenges to their quality of life, including neurocognitive decline, early-onset menopause, and chronic health issues. Chief among these concerns is depression, the most common psychiatric comorbidity among people living with HIV, with rates twice as high among women as men. However, tailored interventions among older women living with HIV and depression are lacking. Following the ADAPT-ITT framework to adapt existing interventions for cultural relevance among groups of people living with HIV, the study team revised an evidence-based intervention, the 'Stress Management and Relaxation Training/Expressive Supportive Therapy Women's Project (SMART/EST),' for online implementation. Working with two community stakeholders, the study team conducted focus groups, theater testing, and manual adaptation. This resulted in the development of e-SMART/EST, an online teletherapy group co-facilitated by a Licensed Psychologist and a credentialed Peer Counselor. The adapted, eight-session weekly intervention was tested with an exploratory pilot sample of eight older women (55 years and older) with HIV and depression. Participants rated the acceptability, feasibility, and appropriateness of the intervention, as well as symptoms of depression and HIV-related quality of life before and after the group. The e-SMART/EST Women's Project demonstrated high acceptability, feasibility, and appropriateness. Engagement was high, as women attended an average of 6.8 sessions. In qualitative interviews, participants reported peer co-facilitation, culturally relevant themes (e.g., HIV-related minority stress, critical consciousness, grief, and sex and pleasure), mindfulness techniques, and cohesion with other women as main favorable elements of the intervention. Barriers to online implementation included technological issues, distractions due to remote participation, and hindered emotional attunement compared with in-person group therapy. Findings support further research to test similar interventions in full-scale trials with older women living with depression and HIV.

Improving Xenon-129 lung ventilation image SNR with deep-learning based image reconstruction.

PURPOSE: To evaluate the feasibility and utility of a deep learning (DL)-based reconstruction for improving the SNR of hyperpolarized 129Xe lung ventilation MRI. METHODS: 129Xe lung ventilation MRI data acquired from patients with asthma and/or chronic obstructive pulmonary disease (COPD) were retrospectively reconstructed with a commercial DL reconstruction pipeline at five different denoising levels. Quantitative imaging metrics of lung ventilation including ventilation defect percentage (VDP) and ventilation heterogeneity index (VHI) were compared between each set of DL-reconstructed images and alternative denoising strategies including: filtering, total variation denoising and higher-order singular value decomposition. Structural similarity between the denoised and original images was assessed. In a prospective study, the feasibility of using SNR gains from DL reconstruction to allow natural-abundance xenon MRI was evaluated in healthy volunteers. RESULTS: 129Xe ventilation image SNR was improved with DL reconstruction when compared with conventionally reconstructed images. In patients with asthma and/or COPD, DL-reconstructed images exhibited a slight positive bias in ventilation defect percentage (1.3% at 75% denoising) and ventilation heterogeneity index (˜1.4) when compared with conventionally reconstructed images. Additionally, DL-reconstructed images preserved structural similarity more effectively than data denoised using alternative approaches. DL reconstruction greatly improved image SNR (greater than threefold), to a level that 129Xe ventilation imaging using natural-abundance xenon appears feasible. CONCLUSION: DL-based image reconstruction significantly improves 129Xe ventilation image SNR, preserves structural similarity, and leads to a minor bias in ventilation metrics that can be attributed to differences in the image sharpness. This tool should help facilitate cost-effective 129Xe ventilation imaging with natural-abundance xenon in the future.

Paternal obesity decreases infant MSC mitochondrial functional capacity.

Besides the well-recognized influence of maternal health on fetal in utero development, recent epidemiological studies appoint paternal preconception metabolic health as a significant factor in shaping fetal metabolic programming and subsequently offspring metabolic health; however, mechanisms behind these adaptations remain confined to animal models. To elucidate the effects of paternal obesity (P-OB) on infant metabolism in humans, we examined mesenchymal stem cells (MSCs), which give rise to infant tissue, remain involved in mature tissue maintenance, and resemble the phenotype of the offspring donor. Here, we assessed mitochondrial functional capacity, content, and insulin action in MSC from infants of fathers with overweight [body mass index (BMI: 25-30 kg/m2); paternal overweight (P-OW)] or obesity (BMI ≥ 30 kg/m2; P-OB) while controlling for maternal intrauterine environment. Compared with P-OW, infant MSCs in the P-OB group had lower intact cell respiration, OXPHOS, and electron transport system capacity, independent of any changes in mitochondrial content. Furthermore, glucose handling, insulin action, lipid content, and oxidation were similar between groups. Importantly, infants in the P-OB group had a greater weight-to-length ratio, which could be in part due to changes in MSC metabolic functioning, which precedes and, therefore, influences infant growth trajectories. These data suggest that P-OB negatively influences infant MSC mitochondria. ClinicalTrials.gov Identifier: NCT03838146.NEW & NOTEWORTHY Paternal obesity decreases infant mesenchymal stem cell (MSC) basal and maximal respiration. Lower OXPHOS and electron transport system capacity could be explained by lower complex I and IV respiratory capacity but not changes in OXPHOS expression in infant MSC from fathers with obesity. Paternal obesity and altered MSC mitochondrial functional capacity are associated with a greater infant weight-to-length ratio at birth.

Generation of the First Transgenic Line of the Iconic Coral Reef Fish Amphiprion ocellaris.

The common clownfish, Amphiprion ocellaris, is an iconic coral reef fish, ubiquitous in the marine aquarium hobby and useful for studying a variety of biological processes (e.g., mutual symbiosis, ultraviolet vision, and protandrous sex change). Recently, CRISPR/Cas9 methods were developed for knocking out specific genes for mechanistic studies. Here, we expand the genetic toolkit for A. ocellaris by creating the first transgenic line using the Tol2 transposon system. Fertilized eggs were co-injected with Tol2 transposase mRNA and a plasmid encoding an elongation factor-1α (Ef1α): green fluorescent protein (GFP) cassette at various concentrations, needle tip dimensions, and timepoints post-fertilization. We compared various injection parameters and sterilization methods to maximize the survival of injected eggs. F0s (n = 10) that were genotyped GFP + were then raised to 6 months of age and crossed with wild-type (WT) females to confirm germline transmission. F1 offspring were also raised and crossed in the same manner. The highly efficient Tol2 transposon system resulted in a 37% rate of transgenesis for surviving eggs amounting to a 2.7% yield of all injected eggs surviving and being GFP + (n = 160). Of these, 10 were raised to adulthood, 8 spawned, and 5/8 (62.5%) produced GFP + offspring. Further, two F1s crossed with WT females produced 54.2% and 44.6% GFP + offspring respectively, confirming the creation of a stable line. This is, to our knowledge, the first generation of a transgenic line in any coral reef fish. The ability to express transgenes of interest in the iconic anemonefish opens the door to a new era of exploration into their fascinating biology.

Framework for Multistakeholder Patient Registries in the Field of Rare Diseases: Focus on Neurogenetic Diseases.

Progress in genetic diagnosis and orphan drug legislation has opened doors to new therapies in rare neurogenetic diseases (RNDs). Innovative therapies such as gene therapy can improve patients' quality of life but come with academic, regulatory, and financial challenges. Registries can play a pivotal role in generating evidence to tackle these, but their development requires multidisciplinary knowledge and expertise. This study aims to develop a practical framework for creating and implementing patient registries addressing common challenges and maximizing their impact on care, research, drug development, and regulatory decision making with a focus on RNDs. A comprehensive 3-step literature and qualitative research approach was used to develop the framework. A qualitative systematic literature review was conducted, extracting guidance and practices leading to the draft framework. Subsequently, we interviewed representatives of 5 established international RND registries to add learnings from hands-on experiences to the framework. Expert input on the draft framework was sought in digital multistakeholder focus groups to refine the framework. The literature search; interviews with 5 registries; and focus groups with patient representatives (n = 4), clinicians (n = 6), regulators, health technology assessment (HTA) bodies and payers (n = 7), industry representatives (n = 7), and data/information technology (IT) specialists (n = 5) informed development of the framework. It covers the interests of different stakeholders, purposes for data utilization, data aspects, IT infrastructure, governance, and financing of rare disease registries. Key principles include that data should be rapidly accessible, independent, and trustworthy. Governance should involve multiple stakeholders. In addition, data should be highly descriptive, machine-readable, and accessible through a shared infrastructure and not spread over multiple isolated repositories. Sustainable and independent financing of registries is deemed important but remains challenging because of a lack of widely supported funding models. The proposed framework will guide stakeholders in establishing or improving rare disease registries that fulfill requirements of academics and patients as well as regulators, HTA bodies, and commercial parties. There is a need for more clarity regarding quality requirements for registries in regulatory and HTA context. In addition, independent financing models for registries should be developed, as well as well-defined policies on technical uniformity in health data.

Physiological Adaptations to Progressive Endurance Exercise Training in Adult and Aged Rats: Insights from the Molecular Transducers of Physical Activity Consortium (MoTrPAC).

While regular physical activity is a cornerstone of health, wellness, and vitality, the impact of endurance exercise training on molecular signaling within and across tissues remains to be delineated. The Molecular Transducers of Physical Activity Consortium (MoTrPAC) was established to characterize molecular networks underlying the adaptive response to exercise. Here, we describe the endurance exercise training studies undertaken by the Preclinical Animal Sites Studies component of MoTrPAC, in which we sought to develop and implement a standardized endurance exercise protocol in a large cohort of rats. To this end, Adult (6-mo) and Aged (18-mo) female (n = 151) and male (n = 143) Fischer 344 rats were subjected to progressive treadmill training (5 d/wk, ∼70%-75% VO2max) for 1, 2, 4, or 8 wk; sedentary rats were studied as the control group. A total of 18 solid tissues, as well as blood, plasma, and feces, were collected to establish a publicly accessible biorepository and for extensive omics-based analyses by MoTrPAC. Treadmill training was highly effective, with robust improvements in skeletal muscle citrate synthase activity in as little as 1-2 wk and improvements in maximum run speed and maximal oxygen uptake by 4-8 wk. For body mass and composition, notable age- and sex-dependent responses were observed. This work in mature, treadmill-trained rats represents the most comprehensive and publicly accessible tissue biorepository, to date, and provides an unprecedented resource for studying temporal-, sex-, and age-specific responses to endurance exercise training in a preclinical rat model.

Exercise training and cold exposure trigger distinct molecular adaptations to inguinal white adipose tissue.

Exercise training and cold exposure both improve systemic metabolism, but the mechanisms are not well established. Here, we tested the hypothesis that inguinal white adipose tissue (iWAT) adaptations are critical for these beneficial effects and determined the impact of exercise-trained and cold-exposed iWAT on systemic glucose metabolism and the iWAT proteome and secretome. Transplanting trained iWAT into sedentary mice improves glucose tolerance, while cold-exposed iWAT transplantation shows no such benefit. Compared to training, cold leads to more pronounced alterations in the iWAT proteome and secretome, downregulating >2,000 proteins but also boosting the thermogenic capacity of iWAT. In contrast, only training increases extracellular space and vesicle transport proteins, and only training upregulates proteins that correlate with favorable fasting glucose, suggesting fundamental changes in trained iWAT that mediate tissue-to-tissue communication. This study defines the unique exercise training- and cold exposure-induced iWAT proteomes, revealing distinct mechanisms for the beneficial effects of these interventions on metabolic health.

Unveiling Fall Risk Factors: Nurse-Driven Corpus Development for Natural Language Processing.

Hospital-acquired falls are a continuing clinical concern. The emergence of advanced analytical methods, including NLP, has created opportunities to leverage nurse-generated data, such as clinical notes, to better address the problem of falls. In this nurse-driven study, we employed an iterative process for expert manual annotation of RNs clinical notes to enable the training and testing of an NLP pipeline to extract factors related to falls. The resulting annotated data corpus had moderately high interrater reliability (F-score=0.74) and captured a breadth of clinical concepts for extraction with potential utility beyond patient falls. Further research is needed to determine which annotation tasks most benefit from nursing expert annotators, to optimize efficiency when tapping into the invaluable resource represented by the nursing workforce.

Parental education and children's depression, anxiety, and ADHD traits, a within-family study in MoBa.

Children born to parents with fewer years of education are more likely to have depression, anxiety, and attention-deficit hyperactivity disorder (ADHD), but it is unclear to what extent these associations are causal. We estimated the effect of parents' educational attainment on children's depressive, anxiety, and ADHD traits at age 8 years, in a sample of 40,879 Norwegian children born in 1998-2009 and their parents. We used within-family Mendelian randomization, which employs genetic variants as instrumental variables, and controlled for direct genetic effects by adjusting for children's polygenic indexes. We found little evidence that mothers' or fathers' educational attainment independently affected children's depressive, anxiety, or ADHD traits. However, children's own polygenic scores for educational attainment were independently and negatively associated with these traits. Results suggest that differences in these traits according to parents' education may reflect direct genetic effects more than genetic nurture. Consequences of social disadvantage for children's mental health may however be more visible in samples with more socioeconomic variation, or contexts with larger socioeconomic disparities than present-day Norway. Further research is required in populations with more educational and economic inequality and in other age groups.

COVID-19 Pandemic Quarantines and Mental Health Among Adolescents in Norway.

Importance: Adolescence is a critical developmental phase when mental health disorders, such as anxiety and depression, often emerge. Stringent public health measures and quarantine mandates during the COVID-19 pandemic could threaten adolescent mental health. Objective: To investigate the associations of public health measures and quarantine experiences with mental distress among Norwegian adolescents and to explore if certain vulnerability factors moderate these associations. Design, Setting, and Participants: This longitudinal cohort study used repeated measures to capture variations in mental distress explained by the stringency of public health measures and quarantine experiences. Data from the Norwegian Mother, Father, and Child cohort study were linked to national health registries and a national stringency index from April 1, 2020, to February 17, 2021. Participant included 7787 Norwegian adolescents aged 16 to 18 years. Data were analyzed from October 2022 to October 2023. Exposures: Stringency index of public health measures and quarantine experiences including recent quarantine (within the last 2 weeks) and quarantine frequency (cumulative number of quarantine episodes). Main Outcome and Measures: Mental distress was measured using the Hopkins Symptom Checklist across 6 data collection waves. Results: In this study, 7787 participants were included in the analysis (4473 female [57%]; mean [SD] age, 17.0 [0.6] years). Stringent public health measures (ß = 0.18; SE, 0.02; P < .001), recent quarantine (ß = 0.11; SE, 0.02; P < .001), and frequent quarantine (ß = 0.08; SE, 0.01; P < .001) were associated with higher levels of mental distress. The associations between public health measures and mental distress were not moderated by sex, age, prepandemic anxiety or depression, or genetic liability for mental health conditions. Frequency of quarantine appeared to be more strongly associated with mental distress among younger adolescents (ß = -0.04; SE, 0.01; P = .008), those with parents with lower education (ß = -0.04; SE, 0.01; P = .007), and those with lower genetic risk for depression (ß = -0.03; SE, 0.01; P = .006). Conclusions and Relevance: In this study, younger adolescents, those with parents with lower education, or those with low genetic liability for depression appeared more vulnerable when being quarantined several times. These findings emphasize the need for targeted support strategies to better protect adolescent well-being during future crises. Adolescents who experienced increased mental distress during the COVID-19 pandemic may be at risk of continued mental health problems and in need of ongoing support.

Genetic and phenotypic heterogeneity in early neurodevelopmental traits in the Norwegian Mother, Father and Child Cohort Study.

BACKGROUND: Autism and different neurodevelopmental conditions frequently co-occur, as do their symptoms at sub-diagnostic threshold levels. Overlapping traits and shared genetic liability are potential explanations. METHODS: In the population-based Norwegian Mother, Father, and Child Cohort study (MoBa), we leverage item-level data to explore the phenotypic factor structure and genetic architecture underlying neurodevelopmental traits at age 3 years (N = 41,708-58,630) using maternal reports on 76 items assessing children's motor and language development, social functioning, communication, attention, activity regulation, and flexibility of behaviors and interests. RESULTS: We identified 11 latent factors at the phenotypic level. These factors showed associations with diagnoses of autism and other neurodevelopmental conditions. Most shared genetic liabilities with autism, ADHD, and/or schizophrenia. Item-level GWAS revealed trait-specific genetic correlations with autism (items rg range = - 0.27-0.78), ADHD (items rg range = - 0.40-1), and schizophrenia (items rg range = - 0.24-0.34). We find little evidence of common genetic liability across all neurodevelopmental traits but more so for several genetic factors across more specific areas of neurodevelopment, particularly social and communication traits. Some of these factors, such as one capturing prosocial behavior, overlap with factors found in the phenotypic analyses. Other areas, such as motor development, seemed to have more heterogenous etiology, with specific traits showing a less consistent pattern of genetic correlations with each other. CONCLUSIONS: These exploratory findings emphasize the etiological complexity of neurodevelopmental traits at this early age. In particular, diverse associations with neurodevelopmental conditions and genetic heterogeneity could inform follow-up work to identify shared and differentiating factors in the early manifestations of neurodevelopmental traits and their relation to autism and other neurodevelopmental conditions. This in turn could have implications for clinical screening tools and programs.

Evaluating parental personal utility of pediatric genetic and genomic testing in a diverse, multilingual population.

There is increasing evidence of the clinical utility of genetic and genomic testing (GT); however, factors influencing personal utility of GT, especially in diverse, multilingual populations, remain unclear. We explored these factors in a diverse cohort of parents/guardians (participants) whose children received clinical GT through the NYCKidSeq program. A total of 847 participants completed surveys at baseline, post-results disclosure, and 6 months (6m) post-results. The largest population groups were Hispanic/Latino(a) (48%), White/European American (24%), and Black/African American (16%). Personal utility was assessed using the Personal Utility (PrU) scale, adapted for pediatric populations and included on the surveys. Three PrU subscales were identified using factor analysis: practical, educational, and parental psychological utility. Overall personal utility summary score and the three subscales significantly decreased after receiving results and over time. Hispanic/Latino(a) participants identified greater overall personal utility than European American and African American participants at all time points (p < 0.001) as did participants whose children received positive/likely positive results compared with those with negative and uncertain results (post-results: p < 0.001 and p < 0.001; 6m post-results: p = 0.002 and p < 0.001, respectively). Post-results, higher subscale scores were associated with lower education levels (practical, parental psychological: p ≤ 0.02) and higher levels of trust in the healthcare system (practical, parental psychological: p ≤ 0.04). These findings help to understand the perspectives of diverse parents/guardians, which is critical to tailoring pre- and post-test counseling across a variety of populations and clinical settings.

Correction: CRISPR/Cas9-mediated generation of biallelic F0 anemonefish (Amphiprion ocellaris) mutants.

[This corrects the article DOI: 10.1371/journal.pone.0261331.].