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Autophagy is a key innate immune defense mechanism in intestinal epithelial cells. Bacterial invasion of epithelial cells activates antibacterial autophagy through a process that requires the innate immune adaptor protein MYD88, yet how MYD88 signaling connects to the autophagy machinery is unknown. Here, we show that the mouse intestinal pathogen Salmonella enterica Serovar Typhimurium ( Salmonella Typhimurium) triggers MYD88 signaling that regulates binding of the anti-autophagy factor B cell lymphoma 2 (BCL2) to the essential autophagy protein Beclin1 (BECN1) in small intestinal enterocytes, a key epithelial cell lineage. Salmonella infection activated the kinase c-Jun N-terminal protein kinase 1 (JNK1) downstream of MYD88. JNK1 induced enterocyte BCL2 phosphorylation, promoting dissociation of the inhibitory BCL2-BECN1 complex and releasing BECN1 to initiate autophagy. Mice with BCL2 phosphorylation site mutations that prevent BCL2-BECN1 dissociation showed increased Salmonella invasion of enterocytes and dissemination to extraintestinal sites. These findings reveal that BCL2 links MYD88 signaling to enterocyte autophagy initiation, providing mechanistic insight into how invading bacteria trigger autophagy in the intestinal epithelium., Competing Interests: Competing interests statement:The authors declare no competing interest.

The evolution of SARS-CoV-2 has led to the emergence of numerous variants of concern (VOCs), marked by changes in the viral spike glycoprotein, the primary target for neutralising antibody (nAb) responses. Emerging VOCs, particularly omicron sub-lineages, show resistance to nAbs induced by prior infection or vaccination. The precise spike protein changes contributing to this resistance remain unclear in infectious cell culture systems. In the present study, a large panel of infectious SARS-CoV-2 mutant viruses, each with spike protein changes found in VOCs, including omicron JN.1 and its derivatives KP.2 and KP.3, was generated using a reverse genetic system. The susceptibility of these viruses to antibody neutralisation was measured using plasma from convalescent and vaccinated individuals. Synergistic roles of combined substitutions in the spike receptor binding domain (RBD) were observed in neutralisation resistance. However, recombinant viruses with the entire spike protein from a specific VOC showed enhanced resistance, indicating that changes outside the RBD are also significant. In silico analyses of spike antibody epitopes suggested that changes in neutralisation could be due to altered antibody binding affinities. Assessing ACE2 usage for entry through anti-ACE2 antibody blocking and ACE2 siRNA revealed that omicron BA.2.86 and JN.1 mutant viruses were less dependent on ACE2 for entry. However, surface plasmon resonance analysis showed increased affinity for ACE2 for both BA.2.86 and JN.1 compared to the ancestral spike. This detailed analysis of specific changes in the SARS-CoV-2 spike enhances understanding of coronavirus evolution, particularly regarding neutralising antibody evasion and ACE2 entry receptor dependence.

The development of disease-modifying therapies (DMTs) for neurological disorders is an important goal in modern neurology, and the associated challenges are similar in many chronic neurological conditions. Major advances have been made in the multiple sclerosis (MS) field, with a range of DMTs being approved for relapsing MS and the introduction of the first DMTs for progressive MS. By contrast, people with Parkinson disease (PD) still lack such treatment options, relying instead on decades-old therapeutic approaches that provide only symptomatic relief. To address this unmet need, an in-person symposium was held in Toronto, Canada, in November 2022 for international researchers and experts in MS and PD to discuss strategies for advancing DMT development. In this Roadmap article, we highlight discussions from the symposium, which focused on therapeutic targets and preclinical models, disease spectra and subclassifications, and clinical trial design and outcome measures. From these discussions, we propose areas for novel or deeper exploration in PD using lessons learned from therapeutic development in MS. In addition, we identify challenges common to the PD and MS fields that need to be addressed to further advance the discovery and development of effective DMTs., Competing Interests: Competing interests: L.V.K. has received research support from Canadian Institutes of Health Research (CIHR), Cure Parkinson’s, Krembil Foundation, Michael J. Fox Foundation for Parkinson’s Research (MJFF), Natural Sciences and Engineering Research Council of Canada, and Parkinson Canada; consultancy fees from Cure Ventures, Ipsen, Knight Therapeutics, Right Brain Bio, and UCB; and honoraria from Canadian Movement Disorders Society, Critical Path for Parkinson’s, International Parkinson and Movement Disorder Society, and IOS Press. A.B.-O. has received personal fees for advisory board participation and/or consulting from Abata, Accure, Atara Biotherapeutics, Biogen, Bristol Myers Squibb (BMS)/Celgene/Receptos, GlaxoSmithKline, Gossamer, Horizon Therapeutics, Immunic, Janssen/Actelion, Medimmune, Merck/EMD Serono, Novartis, Roche/Genentech, Sangamo, Sanofi-Genzyme, and Viracta; and institutional grant support from Biogen Idec, Roche/Genentech, Merck/EMD Serono, and Novartis. R.B. has received research support from Biogen, Eli Lilly, and Roche Genentech, and consulting fees from EMD Serono, Novartis, TG Therapeutics, and Horizon, Jansen. S.F. has received consultancy or speaker fees from Abbvie, Bial, Ipsen, and Lundbeck. U.J.K. holds stock options as a Scientific Advisory Board member for Amprion and has received consultancy fees as a Scientific Advisory Board member for NurrOn and as a member of the data monitoring committee for UCB. E.C.K. has received research funding from Abbvie, Biogen, and Genentech and consulting fees from Banner Life Sciences, EMO Serano, Galen/Atlantica, Greenwich Biosciences, INmune Bio, Myrobalan Therapeutics, OM 1, and TG Therapeutics. M.K. has received travel support and honoraria for advisory boards from Biogen, Roche, Novartis, and EMD Serono. S.K. has received institutional grant support from Biogen, Roche, and Sanofi-Genzyme. A.E.L. has acted as an adviser for AbbVie, Alector, Amylyx, Aprinoia, Biogen, BioAdvance, BlueRock, Biovie, BMS, Denali, Janssen, Jazz, Lilly, Novartis, Paladin, Pharma 2B, PsychoGenetics, Retrophin, Roche, Sun Pharma, and UCB; has received honoraria from Sun Pharma, AbbVie, and Sunovion; has received grants from Brain Canada, CIHR, Edmond J Safra Philanthropic Foundation, MJFF, Ontario Brain Institute, Parkinson Foundation, Parkinson Canada, and W. Garfield Weston Foundation; has acted as an expert witness in litigation related to paraquat and Parkinson disease; and has received publishing royalties from Elsevier, Saunders, Wiley-Blackwell, Johns Hopkins Press, and Cambridge University Press. M.J.M. has received travel support and honoraria for advisory boards from Ipsen, Merz, and Abbvie. D.O. has received research support from the National Institutes of Health, National Multiple Sclerosis Society, Patient Centered Outcomes Research Institute, Race to Erase MS Foundation, Genentech, Genzyme, Bristol Myers Squibb, and Novartis and consulting fees from Biogen Idec, Bristol Myers Squibb, Genentech/Roche, Novartis, Pipeline Therapeutics, and Merck. R.S. has received grants from MS Society of Canada and J.P. Bickell Foundation; consulting fees from Novartis; payment or honoraria for lectures, presentations, speaker’s bureaus, manuscript writing or educational events from Biogen Idec, Sanofi-Genzyme, EMD Serono, and Roche; has served on advisory boards for Novartis; and has received support to attend a scientific meeting from EMD Serono. J.O. has received personal compensation for consulting from Biogen Idec, BMS, Eli Lilly, EMD Serono, Novartis, Roche, and Sanofi-Genzyme, and institutional grant support from Biogen Idec and Roche. A.A., N.A., D.G.D.L., E.A.F., K.K.L., Z.G.-O., J.L.G., M.R.L., P.A.M., T.A.M., V.E.M., M.W.C.R., M.G.S. and A.J.S. declare no competing interests., (© 2024. Springer Nature Limited.)

Background: Women with Sjögren's Disease are more likely to experience pregnancy complications compared to their counterparts without the disease. Attention to detail and familiarity with the most recent research and guidelines in this field are required to achieve optimal maternal and fetal outcomes. Such complications include pregnancy induced hypertension, fetal growth restriction, thromboembolic events, and preterm delivery. Among the most life-threatening sequela of maternal Sjogren's Disease is fetal autoimmune congenital heart block (ACHB), which has high potential to cause intrauterine fetal death, neonatal mortality, developmental delay, and other long-term pediatric complications. Currently, surveillance with weekly echocardiograms and obstetric sonograms in the second trimester are recommended to screen for ACHB with the goal of early detection and intervention before progression from first- or second- of heart block to complete heart block., Objective: We describe a case of maternal Sjogren's Disease, which prompted us to raise questions regarding the optimal frequency of obtaining fetal echocardiograms, and the ideal management in case a prolonged PR interval was to be found. We use this case to provide a springboard for discussion on updated antenatal management strategies for ACHB prevention., Methods: To conduct this analysis, we searched PubMed for articles published over the last 10 years, with attention focused on articles written since 2016. Additionally, updated guidelines by other specialties such as Rheumatology, Cardiology and Pediatrics on this issue were reviewed., Results: Thorough search of the literature yielded several meta-analyses concurring that the mothers with Sjogren's Disease had increased rates of premature birth, pregnancy induced hypertension, increased risks of delivering infants with intrauterine growth restriction (IUGR), with the most life-threatening risk being that of congenital heart block. Literature supporting prophylactic hydroxychloroquine and the use of steroids to reverse or halt the progression of congenital heart block at the time of diagnoses appeared at the forefront of search results., Conclusion: Pregnant women with SS have an increased risk for complications such as intrauterine growth restriction, thromboembolic events, pregnancy-induced hypertension, preterm delivery, and cesarean delivery and should prioritize obtaining pre- or peri-conceptional counseling. In women with anti SSA/SSB antibodies, a medication regimen should be considered with the object of decreasing the concentration of these antibodies, and hence decrease the risks of ACHB. Current literature supports the inclusion of hydroxychloroquine for this purpose, even prior to conception. Although the most recent studies recommend against prophylactic use of steroids, their potential to prevent progression to complete block should be weighed against their potential negative effects. Short and long-term treatment with corticosteroids has been associated with increased maternal risk of infection, weight gain, osteonecrosis, hypertension and bone mineral density disorders. Intrauterine growth restriction, oligohydramnios, and adrenal suppression have been among the fetal risks associated with steroids while improved infant survival or decreased need for pacing have not been demonstrated. Management of these pregnancies is complex and should include a multidisciplinary approach involving a maternal-fetal medicine sub-specialist, a rheumatologist, a pediatrician, a neonatologist, and the patient herself with her family in a model of shared decision-making.

Objective: The gastrointestinal tract (GIT) is the most commonly affected internal organ in systemic sclerosis (SSc). We sought to determine the prevalence and impact of GIT symptoms on survival and patient-reported outcomes., Methods: A total of 907 consecutive patients from the Australian Scleroderma Cohort Study who had prospectively completed the University of California, Los Angeles, Scleroderma Clinical Trials Consortium Gastrointestinal Tract 2.0 Questionnaire (UCLA GIT) between 2015 and 2021 were included. The associations between UCLA GIT scores and physical function (Scleroderma Health Assessment Questionnaire), quality of life (QoL; Short Form 36), mood (Patient-Reported Outcomes Measurement Information System [PROMIS] anxiety and depression domains), fatigue (Functional Assessment of Chronic Illness Therapy-Fatigue score), and employment were investigated using multivariable population-averaged panel models using generalized estimating equations (GEEs). Kaplan-Meier curves and multivariable Cox proportional hazard regression models were used to evaluate survival according to total UCLA GIT scores., Results: GIT symptoms were reported in 87% of participants, with 46% to 52% reporting moderate to very severe symptoms of reflux, distension, diarrhea, and constipation. Higher total UCLA GIT scores were associated with worse QoL, physical function, fatigue, anxiety, and depression (P < 0.001). In the multivariable GEE analysis, moderate and severe to very severe total scores, reflux scores, and distension scores were associated with worse physical function, QoL, fatigue, anxiety, and depression compared to mild scores (P < 0.05). Patients with severe total scores and diarrhea scores were more likely to be unemployed compared to those with mild scores (P < 0.05). UCLA GIT total scores were not independently associated with death in our cohort., Conclusion: GIT manifestations are common in SSc and negatively impact QoL, physical function, and employment but are not directly associated with increased death., (© 2024 The Author(s). Arthritis Care & Research published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Introduction: Estimated glomerular filtration rate (eGFR) and urine albumin/creatinine ratio (ACR) are insensitive biomarkers for early detection of hypertension-mediated organ damage (HMOD). In this nationwide cross-sectional study, we assessed potential biomarkers for early HMOD in healthy persons and patients with hypertension. We hypothesised that plasma levels of biomarkers: (1) are different between healthy controls and patients with hypertension, (2): can classify patients with hypertension according to the degree of hypertension severity., Design and Methods: Patients with hypertension prescribed ≥2 antihypertensive agents were selected from a multicentre study. Healthy controls were selected from an ongoing study of living kidney donor candidates. Uncontrolled hypertension was defined as systolic daytime ambulatory blood pressure ≥135 mmHg. Kidney HMOD was defined by ACR > 3.0 mg/mmol or eGFR < 60 mL/min/1.73 m 2 . Patients with hypertension were categorised into three groups: (1) controlled hypertension; (2) uncontrolled hypertension without kidney HMOD; (3) uncontrolled hypertension with kidney HMOD. Fifteen biomarkers were analysed using a Luminex bead-based immunoassay, and nine fell within the specified analytical range., Results: Plasma levels of Interleukin 1 receptor antagonist (IL-1RA), neutrophil gelatinase-associated lipocalin (NGAL) and uromodulin were significantly different between healthy controls ( n  = 39) and patients with hypertension ( n  = 176). In regression models, with controlled hypertension ( n  = 55) as the reference category, none of the biomarkers were associated with uncontrolled hypertension without ( n  = 59) and with ( n  = 62) kidney HMOD. In models adjusted for cardiovascular risk factors and eGFR, osteopontin (OPN) was associated with uncontrolled hypertension without kidney HMOD (odds ratio (OR) 1.77 (1.05-2.98), p  = 0.03), and regulated upon activation normal T-cell expressed and secreted (RANTES) with uncontrolled hypertension with kidney HMOD (OR 0.57 (0.34-0.95), p  = 0.03)., Conclusions: None of the biomarkers could differentiate our hypertension groups when established risk factors were considered. Plasma OPN may identify patients with uncontrolled hypertension at risk for kidney HMOD.

Biological age is a construct that seeks to evaluate the biological wear and tear process of the organism that cannot be observed by chronological age. We estimate individuals' biological age based on biomarkers from multiple systems and validate it through its association with mortality from natural causes. Biological age was estimated in 12,109 participants (6621 women and 5488 men) from the first visit of the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil) who had valid data for the biomarkers used in the analyses. Biological age was estimated using the Klemera and Doubal method. The difference between chronological age and biological age (Δage) was computed. Cox proportional hazard models stratified by sex were used to assess whether Δage was associated with mortality risk after a median follow-up of 9.1 years. The accuracy of the models was estimated by the area under the curve (AUC). Δage had equal mean for men and women, with greater variability for men. Cox models showed that every 1-year increase in Δage was associated with increased mortality in men (HR (95% CI) 1.21; 1.17-1.25) and women (HR (95% CI) 1.24; 1.15-1.34), independently of chronological age. Results of the AUC demonstrated that the predictive power of models that only included chronological age (AUC chronological age = 0.7396) or Δage (AUC Δage = 0.6842) was lower than those that included both, chronological age and Δage (AUC chronological age + Δage = 0.802), in men. This difference was not observed in women. We demonstrate that biological age is strongly related to mortality in both genders and is a valid predictor of death in Brazilian adults, especially among men., (© 2024. The Author(s), under exclusive licence to American Aging Association.)

Regenerative approaches towards neuronal loss following traumatic brain or spinal cord injury have long been considered a dogma in neuroscience and remain a cutting-edge area of research. This is reflected in a large disparity between the number of studies investigating primary and secondary injury as therapeutic targets in spinal cord and traumatic brain injuries. Significant advances in biotechnology may have the potential to reshape the current state-of-the-art and bring focus to primary injury neurotrauma research. Recent studies using neural-glial factor/antigen 2 (NG2) cells indicate that they may differentiate into neurons even in the developed brain. As these cells show great potential to play a regenerative role, studies have been conducted to test various manipulations in neurotrauma models aimed at eliciting a neurogenic response from them. In the present study, we systematically reviewed the experimental protocols and findings described in the scientific literature, which were peer-reviewed original research articles (1) describing preclinical experimental studies, (2) investigating NG2 cells, (3) associated with neurogenesis and neurotrauma, and (4) in vitro and/or in vivo, available in PubMed/MEDLINE, Web of Science or SCOPUS, from 1998 to 2022. Here, we have reviewed a total of 1504 papers, and summarized findings that ultimately suggest that NG2 cells possess an inducible neurogenic potential in animal models and in vitro. We also discriminate findings of NG2 neurogenesis promoted by different pharmacological and genetic approaches over functional and biochemical outcomes of traumatic brain injury and spinal cord injury models, and provide mounting evidence for the potential benefits of manipulated NG2 cell ex vivo transplantation in primary injury treatment. These findings indicate the feasibility of NG2 cell neurogenesis strategies and add new players in the development of therapeutic alternatives for neurotrauma., (Copyright © 2024 Copyright: © 2024 Neural Regeneration Research.)

Objective: To examine the relationship between the penetration (or reach) of a national program aiming to integrate mental health clinicians into all primary care clinics (PC-MHI) and rates of guideline-concordant follow-up and treatment among clinic patients newly identified with depression in the Veterans Health Administration (VA)., Data Sources/study Setting: 15,155 screen-positive patients 607,730 patients with 2-item Patient Health Questionnaire scores in 82 primary care clinics, 2015-2019., Study Design: In this retrospective cohort study, we used established depression care quality measures to assess primary care patients who (a) newly screened positive (score ≥3) and (b) were identified with depression by clinicians via diagnosis and/or medication (n = 15,155; 15,650 patient-years). Timely follow-up included ≥3 mental health, ≥3 psychotherapy, or ≥3 primary care visits for depression. Minimally appropriate treatment included ≥4 mental health visits, ≥3 psychotherapy, or ≥60 days of medication. In multivariate regressions, we examined whether higher rates of PC-MHI penetration in clinic (proportion of total primary care patients in a clinic who saw any PC-MHI clinician) were associated with greater depression care quality among cohort patients, adjusting for year, healthcare system, and patient and clinic characteristics., Data Collection/extraction Methods: Electronic health record data from 82 VA clinics across three states., Principal Findings: A median of 9% of all primary care patients were seen by any PC-MHI clinician annually. In fully adjusted models, greater PC-MHI penetration was associated with timely depression follow-up within 84 days (∆P = 0.5; SE = 0.1; p < 0.001) and 180 days (∆P = 0.3; SE = 0.1; p = 0.01) of a positive depression screen. Completion of at least minimal treatment within 12 months was high (77%), on average, and not associated with PC-MHI penetration., Conclusions: Greater PC-MHI program penetration was associated with early depression treatment engagement at 84-/180-days among clinic patients newly identified with depression, with no effect on already high rates of completion of minimally sufficient treatment within the year., (Published 2024. This article is a U.S. Government work and is in the public domain in the USA. Health Services Research published by Wiley Periodicals LLC on behalf of Health Research and Educational Trust.)

Clarifying the underlying mechanisms that govern ordering transitions in condensed matter systems is crucial for comprehending emergent properties and phenomena. While transitions are often classified as electronically driven or lattice-driven, we present a departure from this conventional picture in the case of the double perovskite Ba 2 MgReO 6 . Leveraging resonant and non-resonant elastic x-ray scattering techniques, we unveil the simultaneous ordering of structural distortions and charge quadrupoles at a critical temperature of T q  ~ 33 K. Using a variety of complementary first-principles-based computational techniques, we demonstrate that, while electronic interactions drive the ordering at T q , it is ultimately the lattice distortions that dictate the specific ground state that emerges. Our findings highlight the crucial interplay between electronic and lattice degrees of freedom, providing a unified framework to understand and predict unconventional emergent phenomena in quantum materials., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

The separation between people and nature is a key driver of environmental decline. Despite increased interest in nature connectedness, we know little about nature disconnection or the degree of connectedness required for pro-environmental choices. Using a large probability sample of Australians (N = 1101), we explore differences in the characteristics, attitudes, and priorities among those with low, moderate, and high nature connectedness levels. Compared to those more connected, individuals with low connectedness were younger, more urban, and less educated. They spent less time in nature, enjoyed nature less, were less impacted by environmental problems, and rated climate change as less severe, suggesting insulation or detachment from the natural environment. Even a moderate level of connectedness was linked to a significant uplift in pro-environmental attitudes, behaviours, and priorities (e.g. environmental vs. economic issues). Our work contributes towards a comprehensive understanding of nature (dis)connection, with practical implications for interventions targeting a more sustainable future., Competing Interests: Declarations. Conflict of interest: The authors declare that they have no conflict of interest., (© 2024. The Author(s) under exclusive licence to Royal Swedish Academy of Sciences.)

Background: According to data from the USA, the incidence of incidentally discovered pulmonary nodules is 5.8 per 1000 person-years for women and 5.2 per 1000 person-years for men. Their management as recommended in the pertinent guidelines can substantially improve clinical outcomes. More than 95% of all pulmonary nodules revealed by computed tomography (CT) are benign, but many cases are not managed in conformity with the guidelines. In this article, we summarize the appropriate clinical approach and provide an overview of the pertinent diagnostic studies and when they should be performed., Methods: This review is based on relevant publications retrieved by a selective search in PubMed. The authors examined English-language recommendations issued since 2010 for the management of pulmonary nodules, supplemented by comments from the German lung cancer guideline., Results: In general, the risk that an incidentally discovered pulmonary nodule is malignant is low but rises markedly with increasing size and the presence of risk factors. When such a nodule is detected, the further recommendation, depending on size, is either for follow-up examinations with chest CT or else for an extended evaluation with positron emission tomography-CT and biopsy for histology. The diagnostic evaluation should include consideration of any earlier imaging studies that may be available as an indication of possible growth over time. Single nodules measuring less than 6 mm, in patients with few or no risk factors, do not require any follow-up. Lung cancer is diagnosed in just under 10% of patients with a nodule measuring more than 8 mm., Conclusion: The recommendations of the guidelines for the management of incidentally discovered pulmonary nodules are intended to prevent both over- and undertreatment. If a tumor is suspected, further care should be provided by an interdisciplinary team.

Background: Respiratory viruses are linked to cardiovascular complications. We aim to compare cardiovascular complications due to COVID-19, influenza and RSV., Methods: We analyzed cross-sectional data from hospitalized children and young adults (≤ 20 years) from 2020 and 2021 using National Inpatient Sample (NIS). We included individuals hospitalized for COVID-19, RSV, and influenza, and weighted data were used to compare cardiovascular complications., Results: Of 212,655 respiratory virus admissions, 85,055 were from COVID-19, 103,185 were from RSV, and 24,415 were from influenza. Myocarditis was higher in COVID-19 [0.9%, n = 740] as compared to influenza [0.2%, n = 55] and RSV [0.1%, n = 65]. In the adjusted logistic regression, the odds of myocarditis was 61% lower in influenza [aOR = 0.39 (0.20-0.76), P = 0.006], and 85% lower in RSV [aOR = 0.15 (0.07-0.34) P < 0.001] as compared to COVID-19. Bradyarrhythmias/heart block was higher in COVID-19 [0.8%, n = 690] versus influenza [0.5%, n = 110] and RSV [0.2%, n = 205]. After adjusting for confounders for bradyarrhythmias/heart block, compared to COVID-19, the odds were 49% lower in RSV [aOR = 0.51 (0.33-0.80), P = 0.004] but no statistically significant difference in influenza [aOR = 0.79 (0.48-1.31), P = 0.374] was seen. Tachyarrhythmias, sudden cardiac arrest, and in-hospital mortality showed no differences after adjusting for covariates., Conclusion: Individuals with COVID-19 infection are more likely to develop cardiovascular complications compared to influenza and RSV, highlighting the need for higher index of suspicion and prompt treatment, as well as steps to limit infection and transmission of this virus in children., Competing Interests: Declarations. Ethics approval and consent to participate: Approval from an institutional review board and informed consent were not required for this study, as it adheres to the regulations set forth in 45 CFR §46, which exempts certain research involving publicly available or de-identified data from these requirements. As this study utilized publicly available de-identified data, it received expedited review approval from the University of California San Francisco, Fresno Community Medical Regional Center. IRB No: 2023024. The need for informed consent to participate was waived by the ethics committee of University of California San Francisco, Fresno Community Medical Regional Center. IRB No: 2023024. The authors listed in this manuscript are not employed by any government agency whose primary role is not research or education. Moreover, none of the authors are presenting this manuscript as an official representative or on behalf of the government. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Diabetic kidney disease (DKD) is the leading cause of chronic renal pathology. Understanding the molecular underpinnings of DKD is critical to designing tailored therapeutic approaches. Here we focused on sex differences and the contribution of aging towards the progression of DKD. To explore these questions, we utilized young (12 weeks old) and aged (approximately 50 weeks old) type 2 diabetic nephropathy (T2DN) rats. We revealed that the cyclic GMP-AMP synthase (cGAS)-Stimulator of Interferon Genes (STING) pathway was upregulated in T2DN rats compared to non-diabetic Wistar rats and in type 2 diabetic human kidneys. The activation of the cGAS-STING signaling pathway exhibited distinct protein expression profiles between male and female T2DN rats, with these differences becoming more pronounced with aging. RNA-Seq analysis of the kidney cortex in both male and female T2DN rats, at both younger and older ages, revealed several key molecules, highlighting crucial genes within the cGAS-STING pathway. Thus, our study delved deep into understanding the intricate sexual differences in the development and progression of DKD and proposed the cGAS-STING pathway as an essential contributor to disease development.

Background: Virtual health care has transformed health care delivery, with its use dramatically increasing since the COVID-19 pandemic. While it has been quickly adopted for its convenience and efficiency, there has been a relative lack of in-depth exploration of its human impact, specifically how both patients and providers experience clinical encounters., Objective: This analysis aims to identify and explore themes of change in how patients and providers in a geographically dispersed renal service described their experiences with virtual care, including those changes that occurred during the COVID-19 pandemic., Methods: Hermeneutics is an interpretive research methodology that treats human experience as inherently interpretive, generating meaning through interactions with others in specific, historically conditioned, social contexts. A total of 17 patients and 10 providers from various disciplines were interviewed by phone as part of a study on health care implementation in the context of a kidney care service in northern British Columbia, Canada. The interview data were analyzed using a hermeneutic approach, which emphasizes careful attention to reported experiences in relation to the relationships and contexts of care., Results: During analysis, the interdisciplinary team identified themes related to changes in the clinical encounter and how virtual care influenced perceptions of care among both providers and patients. We organized these themes into 2 categories: the structure and content of the encounter. The structure category included the convenience for patients, who no longer had to travel long distances for appointments, as well as changes in care networks. For example, communication between specialist services and local primary care providers became more crucial for ensuring continuity of care. The content category included issues related to trust-building and assessment. Providers expressed concerns about the difficulty in assessing and understanding their patients' physical and social well-being beyond laboratory results., Conclusions: Patients in the study appreciated the convenience of not needing to travel for appointments, while still having the option for in-person contact with local providers or specialists if their condition changed. Providers were more concerned about the loss of visual cues and sensory data for assessments, as well as the reduced opportunity to build relationships through conversation with patients. Providers also described changes in the locus of control and boundaries, as patients could join phone encounters from anywhere, bypassing traditional privacy and confidentiality boundaries. The study offers a nuanced view of the effects of virtual care on clinical encounters in one setting, seen through the experiences of both patients and providers., (©Graham McCaffrey, Erin Wilson, Lela V Zimmer, Anurag Singh, Steinunn Jonatansdottir, Peter Zimmer, David Snadden, Ian D Graham, Martha MacLeod. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 26.11.2024.)

Vaccination timeliness is often not considered among standard performance indicators of routine vaccination programmes, such as vaccination coverage, yet quantifying vaccination delay could inform policies to promote in-time vaccination and help design vaccination schedules. Here, we analysed vaccination timeliness for 24 routine childhood immunisations for 54 countries. We extracted individual vaccination status and timing from Demographic and Health Surveys data from 54 countries with surveys from 2010 onwards. Individual data was used to estimate age at vaccination for <5 year-old children. Recommended age of vaccination for each country and vaccine was compared to the age at vaccination to determine vaccination delay. The evolution of vaccination delay over time was described using estimates from different birth cohorts. To identify socio-demographic indicators associated with delayed vaccination, we used multivariable Cox regression models with country as random effect and estimated the Hazard Ratio for vaccination with each vaccine-dose for each week post recommended vaccination age. Vaccine coverage at the recommended age was highest for birth and first doses (e.g. 50.5% BCG, 18.5% DTP-D1) and lowest for later doses (e.g. 5.5% DTP-D3, 16.3% MCV-D1, 8.2% MCV-D2). Median delay was lowest for birth doses, e.g. BCG (1 week (IQR: 0 to 4)), and it increased with later doses in vaccination courses: 1 (0, 4) week for DTP-D1 versus 4 (2, 9) weeks for DTP-D3. Although the median delay for each vaccine-dose remained largely constant over time, the range of delay estimates moderately decreased. Children living in rural areas, their countries' poorer wealth quintiles and whose mothers had no formal education were more likely to received delayed vaccinations. Although we report most children are vaccinated within the recommended age window, we found little reduction on routine immunisation delays over the last decade and that children from deprived socioeconomic backgrounds are more likely to receive delayed vaccinations., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: KAMG reports speaker fees from Sanofi Pasteur outside the submitted work. All other authors declare no competing interests., (Copyright: © 2024 Derqui et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Using high-resolution quantitative mass spectrometry, we present comprehensive human and mouse microglia proteomic datasets consisting of over 11,000 proteins across six microglia groups. Microglia share a core protein signature of over 5,600 proteins, yet fundamental differences are observed between species and culture conditions. Mouse microglia demonstrate proteome differences in inflammation- and Alzheimer's disease-associated proteins. We identify differences in the protein content of ex vivo and in vitro cells and significant proteome differences associated with protein synthesis, metabolism, microglia marker expression, and environmental sensors. Culturing microglia induces rapidly increased growth, protein content, and inflammatory protein expression. These changes are restored by engrafting in vitro cells into the brain, with xenografted human embryonic stem cell (hESC)-derived microglia closely resembling microglia from the human brain. These data provide an important resource for the field and highlight important considerations needed when using model systems to study human physiology and pathology of microglia., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Numerous areas of the Semipalatinsk Test Site (STS) were subjected to radioactive contamination, including tritium. The tritium content in plants was determined in free water (TFWT) and in the organic component (OBT). It has been established that the OBT content in plants for the "Sary-Uzen" site between combat boreholes ranges from <7-125 Bq/kg and the background OBT content is 21.5 Bq/kg. The maximum OBT values in plants have been recorded in the vicinity of boreholes and range from 7.1 (near the borehole numbered 106) to 200,000 Bq/kg (near the borehole numbered 101). Overall, the tritium content in the vegetation cover at the "Sary-Uzen" site is negligible and does not pose a threat. Isolated cases of tritium content in drinking water exceeding the intervention level have been identified in plants in the "Lazurit" area, as well as near combat boreholes numbered 125 and 101., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Context.—: Genomic reports are primarily organized in a narrative and unstructured format with variations in content and format. Regulatory requirements and professional guidelines for genetic test reporting exist but provide little guidance for effective communication of information., Objective.—: To assess clinical genomic reporting practices across 5 disciplines within molecular diagnostics, including germline, somatic solid tumors, somatic hematologic malignancies, pharmacogenomics, and prenatal cell-free DNA screening., Design.—: Reporting practices were assessed by using a structured review of clinical genomic reports from multiple laboratories in 5 molecular disciplines spanning different practice settings. Report content was reviewed by the presence/absence of from 27 to 44 elements, including 23 elements required by the College of American Pathologists and/or the Clinical Laboratory Improvement Amendments of 1988 (CLIA). If present, the element's location on the report was recorded., Results.—: A total of 69 genomics reports from 31 laboratories were reviewed. Overall, the reports were compliant with regulatory requirements but showed variability in both format and content. Six of 7 required reporting elements (per CLIA, 42 CFR [Code of Federal Regulations] 493.1291) were included in 90% of the reports. However, these elements were often located in different report sections. Only patient demographics were always found in a specific report section (header)., Conclusions.—: These results show that reports are overall compliant with regulatory requirements, despite some reporting elements being less consistently reported. The lack of consistent presentation of the data elements presents an opportunity to improve the communication of molecular testing results to clinicians and patients., (© 2024 College of American Pathologists.)

Background: The associations of high-density lipoprotein (HDL) level and functionality with lipid metabolism, inflammation, and innate immunity in coronary artery disease (CAD) remain controversial. The differential expression of a set of genes related to HDL metabolism (24 genes) and atherogenesis (41 genes) in peripheral blood mononuclear cells (PBMC) from CAD and control patients with varied HDL cholesterol (HDL-C) levels was compared., Methods: 76 male patients 40-60 years old with CAD diagnosed by angiography and 63 control patients were divided into three groups with low, normal (1.0-1.4 mM), and increased HDL-C levels. Transcript levels were measured by real-time PCR. The differentially expressed genes (DEGs) and associated metabolic pathways were analyzed for three groups, with prevalent CAD as an outcome., Results: The common feature was the increased odds ratio values for liver X receptor (LXR) gene expression for three patient groups. CAD patients with low HDL-C possessed 24 DEGs with lower expression of genes involved in cholesterol efflux, and down-regulated SREBF1 and ABCG1 are suggested as gene signatures. CAD patients with normal HDL-C possessed nine DEGs with down-regulated ITGAM and ALB as gene signatures. CAD patients with increased HDL-C possessed 19 DEGs with down-regulated APOA1 and HMGCR as gene signatures. With gene expression signatures, one standard deviation higher average gene expressions were associated with 5.1-, 48.8-, and 38.9-fold fewer CAD cases for three patient groups. As HDL-C increased in CAD patients, the expression of ABCG1 , CUBN , and HDLBP genes increased, while the expression of HMGCR and NPC2 genes, involved in cholesterol synthesis and trafficking, decreased. The expression of CD14 , CD36 , S100A8 , S100A9 , S100A12 , TLR5 , TLR8 , and VEGFA genes, involved in angiogenesis and inflammation mainly via nuclear factor-κB (NF-κB), decreased., Conclusions: The increased accumulation of cholesteryl ester in PBMC from patients with low HDL-C was suggested. This assumption contrasts with the suggested accumulation of free cholesterol in PBMC from patients with increased HDL-C, concomitant with suppression of cholesterol synthesis and traffic to the plasma membrane, and with an inflammatory state controlled by depressed CD36-mediated and upregulated apoE-mediated immunometabolic signaling. Gene signatures may be used for the diagnosis, prognosis, and treatment of CAD in dependence on HDL-C levels., (© 2024 The Author(s). Published by IMR Press.)

Cell cycle progression is tightly controlled by the regulated synthesis and degradation of Cyclins, such as Cyclin A and Cyclin B, which activate CDK1 to trigger mitosis. Mutations affecting Cyclin regulation are often linked to tumorigenesis, making the study of cyclin mRNA regulation critical for identifying new cancer therapies. In this study, we demonstrate via super-resolution microscopy that cyclin A and cyclin B mRNAs associate with Bruno 1 and Cup in nurse cells. The depletion of either protein leads to abnormal Cyclin A and Cyclin B protein expression and a reduction in mRNA levels for both Cyclins. We further reveal that both cyclin A and cyclin B mRNAs accumulate in P-bodies marked by Me31B. Interestingly, Me31B is not involved in regulating cyclin A mRNA, as no changes in cyclin A mRNA levels or repression are observed upon Me31B depletion. However, cyclin B mRNA shows stage-specific derepression and reduced levels when Me31B is absent. Notably, the association between cyclin B and Cup is strengthened in the absence of Me31B, indicating that this interaction occurs independently of P-bodies. These results highlight the nuanced, mRNA-specific roles of P-body condensates in post-transcriptional regulation, challenging the idea of a uniform, binary mechanism of mRNA repression in P-bodies.

Animals navigate the auditory world by recognizing complex sounds, from the rustle of a predator to the call of a potential mate. This ability depends in part on the octopus cells of the auditory brainstem, which respond to multiple frequencies that change over time, as occurs in natural stimuli. Unlike the average neuron, which integrates inputs over time on the order of tens of milliseconds, octopus cells must detect momentary coincidence of excitatory inputs from the cochlea during an ongoing sound on both the millisecond and submillisecond time scale. Here, we show that octopus cells receive inhibitory inputs on their dendrites that enhance opportunities for coincidence detection in the cell body, thereby allowing for responses both to rapid onsets at the beginning of a sound and to frequency modulations during the sound. This mechanism is crucial for the fundamental process of integrating the synchronized frequencies of natural auditory signals over time.

Background: Academic Burnout (ABO) is prevalent among medical students and is characterized by mental and physical exhaustion, cynicism, and a sense of inadequacy. Informal Peer-Assisted Learning (IPAL) is recognized as an effective strategy to enhance student wellness and mitigate ABO by fostering collaborative learning and support without direct faculty oversight. This study evaluates the effectiveness of IPAL in reducing ABO, focusing on the mediation of the observed variables and its impact on student well-being., Methods: This study extends previous research using Structural Equation Modeling (SEM) to include mediation analysis of the observed variables within the latent constructs of Cynicism (CY) and Inadequacy (IN) that are thought to influence the relationship between IPAL and ABO. Data were sourced from a validated Student Burnout Inventory (SBI-8) across a sample of medical students with varied IPAL engagement levels. Our approach used General Linear Model (GLM) mediation models to explore both direct and indirect effects of IPAL on ABO., Results: The indirect effect of IPAL on ABO is mediated through specific observed variables, including CY2 "loss of interest in academic work" (β = -0.092, CI, -0.174/-0.011, p = 0.027), IN1 "feeling of inadequacy" (β = -0.062, CI, -0.12/-0.005, p = 0.035), and IN2 "reduced academic expectations" (β = -0.042, CI, -0.079/-0.007, p = 0.025). The total effect of IPAL on ABO was significant (β = 0.170 CI, -0.326/-0.010, p = 0.034), the total indirect effect was significant (β = -0.197, CI, -0.338/-0.055, p = 0.006)., Conclusions: IPAL effectively addresses critical aspects of burnout, specifically through reducing feelings of cynicism and inadequacy among medical students. These results provide a valuable framework in designing targeted interventions to reduce ABO., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

In mammals, early embryonic gastrulation process is high energy demanding. Previous studies showed that, unlike endoderm and mesoderm cells, neuroectoderm differentiated from human embryonic stem cells relied on aerobic glycolysis as the major energy metabolic process, which generates lactate as the final product. Here we explored the function of intracellular lactate during neuroectoderm differentiation. Our results revealed that the intracellular lactate level was elevated in neuroectoderm and exogenous lactate could further promote hESCs differentiation towards neuroectoderm. Changing intracellular lactate levels by sodium lactate or LDHA inhibitors had no obvious effect on BMP or WNT/β-catenin signaling during neuroectoderm differentiation. Notably, histone lactylation, especially H3K18 lactylation was significant upregulated during this process. We further performed CUT&Tag experiments and the results showed that H3K18la is highly enriched at gene promoter regions. By analyzing data from CUT&Tag and RNA-seq experiments, we further identified that four genes, including PAX6, were transcriptionally upregulated by lactate during neuroectoderm differentiation. A H3K18la modification site at PAX6 promoter was verified and exogenous lactate could also rescue the level of PAX6 after shPAX6 inhibition., Competing Interests: Declarations Ethical approval Not applicable. Consent to participate Not applicable. Consent to publish Not applicable. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

This clinical study aimed to assess the effectiveness and safety of Vuong Hoat (VH) natural health supplement for reducing the negative impact of low back pain, improving the quality of life, and enhancing functional activities in patients with lumbar degenerative disc disease (LDD). The open-label, randomized, controlled clinical trial involved 60 patients suffering from low back pain caused by LDD. The participants were randomly assigned to either a study group (SG) comprising 30 subjects or a control group (CG) comprising 30 subjects. Patients in the CG received treatment with electro-acupuncture, while those in the SG were administered VH in conjunction with the same electro-acupuncture protocol for 28 days. The clinical progression and tolerability of both groups were compared based on seven objective measurements: visual analog scale index, Schober test, fingertip-to-floor distance, spinal flexion, spinal extension, spinal tilt, and spinal rotation. After 14 days of treatment, the SG showed a significant improvement in overall outcomes compared to the CG. Specifically, 43.3% of SG patients achieved very good results, 53.3% had good results, and 3.4% had moderate results, whereas corresponding figures for the CG were 6.7%, 76.7%, and 16.6%, respectively ( P < .05). After 28 days of treatment, both groups demonstrated a shift toward very good results, with the SG continuing to show better outcomes than the CG ( P < .05). In the SG, the very good results increased to 76.7%, good results decreased to 20%, and moderate results were 3.3%. On the other hand, the CG had 46.7% very good results, 43.3% good results, and 10% moderate results. Notably, no side effects were reported from the VH treatments during the study. The findings of this study indicate that VH health supplement is a safe and effective approach for managing low back pain and limited spinal movement in patients with LDD.

This study aimed to compare the flexural strength, surface roughness, and microhardness of a resin for three-dimensional (3D) printing and a conventional composite resin and to evaluate whether the printing orientation influences these properties. To evaluate the flexural resistance, test specimens were produced and divided into four groups: three groups of resins for 3D printing with inclinations of 0°, 45°, and 90° and one group of conventional composite resin. Forty discs were produced and subjected to a sandpaper-polishing sequence, and the surface roughness was measured using a roughness meter. The Vickers microhardness (HV) test was performed at three different points, and the average was obtained. The results were subjected to ANOVA statistical analysis and Tukey's test. There were statistical differences in the flexural strength and microhardness between the conventional resin and the resin used for 3D printing. No statistical difference in surface roughness was observed. The resin for 3D printing exhibited lower flexural strength and microhardness than conventional composite resins. We concluded that the resin for 3D printing had lower flexural strength and HV than the conventional composite resin but similar surface roughness. The printing orientation did not affect the flexural strength, whereas the hardness increased as the printing angle increased.

Introduction: In recent decades, centralization of health care has resulted in a number of obstetric unit closures. While studies support better infant outcomes in larger facilities, few have investigated maternal outcomes. We investigated obstetric unit closures over time and whether obstetric volume is associated with onset of labor, postpartum hemorrhage (PPH) and obstetric anal sphincter injury (OASIS)., Material and Methods: All births registered in Sweden between 1992 and 2019 (Medical Birth Register, N = 2 931 140), linked with data on sociodemographic characteristics and maternal/infant diagnoses, were used to describe obstetric unit closures. After excluding congenital malformations, obstetric volume was categorized (low: 0-1999, medium: 2000-3999, high: ≥4000 births per year). Restricting to 2004 onwards (after most closures), the association between volume and onset of labor (spontaneous as reference) was estimated. Restricting to spontaneous, full-term (≥37 weeks gestation) cephalic births, we then investigated the association between volume and PPH and, after excluding planned cesarean sections, OASIS. Odds ratios from multilevel (logistic) models clustered by hospital were estimated., Results: The 20 dissolved obstetric units (1992-2019) had relatively stable volume until their closure. Compared to the average, women birthing in the highest volume hospitals were older (31.3 years vs. 30.4) and a higher proportion had >12 years of education (57 vs. 51%). Compared to high-volume hospitals, there was no significant difference in labor starting by elective cesarean section or induction, rather than spontaneously, among low (OR 0.88, 95% CI: 0.73-1.06) and medium (OR 0.84, 95% CI 0.71-1.01) volume hospitals. There were lower odds of PPH among low (OR 0.72, 95% CI 0.63-0.85) and medium (OR 0.83, 95% CI 0.72-0.97) volume hospitals. No significant association was found between obstetric volume and OASIS (low: OR 0.98, 95% CI 0.82-1.18; medium: OR 0.90, 95% CI 0.77-1.05)., Conclusions: There was not a strong relationship between obstetric volume and maternal outcomes. Reduced odds of PPH for women birthing in smaller units may be due to triaging high-risk pregnancies to larger hospitals. While there was no significant association between obstetric volume and onset of labor or OASIS, other important factors related to closures, such as workload and overcrowding, should be investigated., (© 2024 The Author(s). Acta Obstetricia et Gynecologica Scandinavica published by John Wiley & Sons Ltd on behalf of Nordic Federation of Societies of Obstetrics and Gynecology (NFOG).)

As global temperatures rise, improving crop yields will require enhancing the thermotolerance of crops. One approach for improving thermotolerance is using bioengineering to increase the thermostability of enzymes catalysing essential biological processes. Photorespiration is an essential recycling process in plants that is integral to photosynthesis and crop growth. The enzymes of photorespiration are targets for enhancing plant thermotolerance as this pathway limits carbon fixation at elevated temperatures. We explored the effects of temperature on the activity of the photorespiratory enzyme glycerate kinase (GLYK) from various organisms and the homologue from the thermophilic alga Cyanidioschyzon merolae was more thermotolerant than those from mesophilic plants, including Arabidopsis thaliana. To understand enzyme features underlying the thermotolerance of C. merolae GLYK (CmGLYK), we performed molecular dynamics simulations using AlphaFold-predicted structures, which revealed greater movement of loop regions of mesophilic plant GLYKs at higher temperatures compared to CmGLYK. Based on these simulations, hybrid proteins were produced and analysed. These hybrid enzymes contained loop regions from CmGLYK replacing the most mobile corresponding loops of AtGLYK. Two of these hybrid enzymes had enhanced thermostability, with melting temperatures increased by 6 °C. One hybrid with three grafted loops maintained higher activity at elevated temperatures. Whilst this hybrid enzyme exhibited enhanced thermostability and a similar K m for ATP compared to AtGLYK, its K m for glycerate increased threefold. This study demonstrates that molecular dynamics simulation-guided structure-based recombination offers a promising strategy for enhancing the thermostability of other plant enzymes with possible application to increasing the thermotolerance of plants under warming climates., (© 2024 The Author(s). Plant Biotechnology Journal published by Society for Experimental Biology and The Association of Applied Biologists and John Wiley & Sons Ltd.)

Background: Neuroblastoma (NB) remains one of the deadliest pediatric solid tumors. Recent advancements aimed at improving outcomes have been insufficient, and patients with high-risk NB continue to have a poor prognosis. Protein phosphatase 2A (PP2A) is a tumor suppressor protein downregulated in many cancers, including NB. PP2A activation has been shown to affect the malignant phenotype in other solid tumors. The present studies aim to investigate the effects of two novel PP2A activators as a NB therapeutic., Methods: Four established NB cell lines and a patient-derived xenoline were utilized to study the effect on cell viability, proliferation, motility, and in vivo tumor growth using two novel tricyclic sulfonamide PP2A activators, ATUX-3364 and ATUX-8385., Results: ATUX-3364 and ATUX-8385 increased PP2A activity. These PP2A activators led to decreased viability, proliferation, and motility of NB cells. Treatment of animals bearing NB tumors with ATUX-3364 or ATUX-8385 resulted in decreased tumor growth in MYCN -amplified SK-N-BE(2) tumors. At the molecular level, PP2A-based reactivation led to dephosphorylation of MYCN-S62 and decreased MYCN protein expression., Conclusions: PP2A activators decreased NB cell viability, proliferation, and motility. In vivo experiments show that PP2A activators have more significant effects on tumorigenesis in MYCN-amplified tumors. Finally, phosphorylation of MYCN protein was decreased following treatment with novel sulfonamide PP2A activators. These data and mechanistic insights may be useful for developing new PP2A-based therapies that target MYCN for the treatment of NB.

Aging is a complex process associated with multimorbidity. Hypertension, one of widespread states, is among main causes of age-related alterations in behavior, emotionality and sociability. We studied the effects of long-term isolated housing on anxiety, depressive-like and social behavior as well as changes in the adrenocortical and sympathetic systems in the aging normotensive Wistar Kyoto (WKY) and spontaneously hypertensive rats (SHR). Ten-month-old male rats of both strains were subjected to 90-day isolated or group housing. Surprisingly, social isolation induced only mild effect on anxiety without influencing other affective-related behaviors. No effects of isolated housing on sociability or social novelty preferences were revealed. Despite the adrenal gland hypertrophy in the SHRs, corticosterone levels remained stable within the period of isolation but the expression of nuclear glucocorticoid receptor (Nr3c1) mRNA in the adrenals was lower in the SHR as compared to WKY rats. Pre-existing hypertension, associated with SHR genotype, did not significantly contribute to the effects of social isolation. The data suggest that the aged WKY and SHR rats are relatively resilient to chronic social stress associated with isolated housing., Competing Interests: Declarations Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Musculoskeletal simulations are a useful tool for improving our understanding of the human body. However, the physiological validity of predicted kinematics and forces is highly dependent upon the correct calibration of muscle parameters and the structural integrity of a model's internal skeletal structure. In this study, we show how ill-tuned muscle parameters and unphysiological deformations of a model's skeletal structure can be detected by using muscle elements as sensors with which modelling and parameterization inconsistencies can be identified through muscle and tendon strain injury assessment. To illustrate our approach, two modelling issues were recreated. First, a model repositioning simulation using the THUMS AM50 occupant model version 5.03 was performed to show how internal model deformations can occur during a change of model posture. Second, the muscle material parameters of the OpenSim gait2354 model were varied to illustrate how unphysiological muscle forces can arise if material parameters are inadequately calibrated. The simulations were assessed for muscle and tendon strain injuries using previously published injury criteria and a newly developed method to determine tendon strain injury threshold values. Muscle strain injuries in the left and right musculus pronator teres were detected during the model repositioning. This straining was caused by an unphysiologically large gap (12.92 mm) that had formed in the elbow joint. Similarly, muscle and tendon strain injuries were detected in the modified right-hand musculus gastrocnemius medialis of the gait2354 model where an unphysiological reduction of the tendon slack length introduced large pre-strain of the muscle-tendon unit. The results of this work show that the proposed method can quantify the internal distortion behaviour of musculoskeletal human body models and the plausibility of Hill-type muscle parameter choice via strain injury assessment. Furthermore, we highlight possible actions to avoid the presented issues and inconsistencies in literature data concerning the material characteristics of human tendons., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Nölle et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Human induced pluripotent stem cells (hiPSCs) have great potential to be used as alternatives to embryonic stem cells (hESCs) in regenerative medicine and disease modelling. In this study, we characterise the proteomes of multiple hiPSC and hESC lines derived from independent donors and find that while they express a near-identical set of proteins, they show consistent quantitative differences in the abundance of a subset of proteins. hiPSCs have increased total protein content, while maintaining a comparable cell cycle profile to hESCs, with increased abundance of cytoplasmic and mitochondrial proteins required to sustain high growth rates, including nutrient transporters and metabolic proteins. Prominent changes detected in proteins involved in mitochondrial metabolism correlated with enhanced mitochondrial potential, shown using high-resolution respirometry. hiPSCs also produced higher levels of secreted proteins, including growth factors and proteins involved in the inhibition of the immune system. The data indicate that reprogramming of fibroblasts to hiPSCs produces important differences in cytoplasmic and mitochondrial proteins compared to hESCs, with consequences affecting growth and metabolism. This study improves our understanding of the molecular differences between hiPSCs and hESCs, with implications for potential risks and benefits for their use in future disease modelling and therapeutic applications., Competing Interests: AB, LS, LD, AP, FS, EH, CE, HJ, HY, GF, DC No competing interests declared, EG Now works for Boehringer Ingelheim Pharma GmbH & Co KG, MP Board member of Tartan Cell Technologies Ltd, JS Board member of Tartan Cell Technologies Ltd and Glencoe Software Ltd, AL Board member of Tartan Cell Technologies Ltd and Platinum Informatics Ltd, (© 2024, Brenes et al.)

8-oxoguanine DNA glycosylase-1 (OGG1) is a DNA glycosylase mediating the first step in base excision repair which removes 7,8-dihydro-8-oxoguanine (8-oxoG) and repairs oxidized nuclear and mitochondrial DNA. Previous studies showed that OGG1 deficiency results in an increased susceptibility to high-fat diet (HFD)-induced obesity and metabolic dysfunction in mice, suggesting a crucial role of OGG1 in metabolism. However, the tissue-specific mechanisms of how OGG1 deficiency leads to insulin resistance is unknown. Thus, in the current study, we used a hyperinsulinemic-euglycemic clamp to evaluate in-depth glucose metabolism in male wild-type (WT) mice and Ogg1-/- ( Ogg1-KO ) mice fed an HFD. Ogg1-KO mice fed HFD were more obese, with significantly lower hepatic insulin action compared to WT/HFD mice. Targeting human OGG1 to mitochondria protected against HFD-induced obesity, insulin resistance, oxidative mitochondrial DNA damage in the liver and showed decreased expression of liver gluconeogenic genes in Ogg1-KO mice, suggesting a putative protective mechanism. Additionally, several subunits of oxidative phosphorylation protein levels were noticeably increased in Ogg1-KO/Tg compared to Ogg1-KO mice fed an HFD which was associated with improved insulin signaling. Our findings demonstrate the crucial role of mitochondrial hOGG1 in HFD-induced insulin resistance and propose several protective mechanisms which can further direct the development of therapeutic treatment.

In this study, Zirconium-modified Engelhard Titanium Silicate 4 (Na-K-ETS-4/xZr) catalysts were synthesized and evaluated for their photocatalytic efficiency in degrading crystal violet (CV) and methylene blue (MB) in aqueous solutions. The catalysts were characterized using XRD, FTIR, SEM, WDXRF, and nitrogen adsorption/desorption isotherms. The results confirmed the successful incorporation of Zr into the ETS-4 framework, with the highest Zr content reaching 9.2 wt %. The photocatalytic performance under visible light irradiation was studied at varying pH levels. The Na-K-ETS-4/6.3Zr catalyst exhibited the highest photodegradation efficiency for CV (76.6 %), while Na-K-ETS-4/8.9Zr achieved 86.6 % efficiency for MB. A combination of Engelhard Titanium Silicate 10, Na-K-ETS-10/6.3Zr and Na-K-ETS-4/8.9Zr significantly enhanced dye degradation, achieving up to 96.5 % efficiency for MB. Kinetic studies indicated that the degradation process follows a non-linear pseudo-first-order model. The catalysts also demonstrated excellent reusability, with minimal efficiency loss after five cycles, and full recovery after an ethanol wash. These findings suggest that Na-K-ETS-4/xZr is a promising candidate for environmental water treatment applications due to its efficient photodegradation performance and stability., (© 2024 The Authors. ChemistryOpen published by Wiley-VCH GmbH.)

Background: Clowning has been used in many hospitals, particularly for children. Studies suggest the effectiveness of this methodology, but more evidence is needed. The aim of this study was to evaluate the impact of a humour therapy intervention on biological markers, pain and anxiety levels in paediatric patients., Methods: Three different clinical contexts were chosen to assess the effect of clowning interventions: patients who were subjected to venepuncture (group 1), patients undergoing general anesthesia for any cause (group 2)and patients hospitalized in the pediatric ward without distinction of their disease (group 3). Groups 1 and 2 were divided into control (C) and intervention (I) subgroups. A saliva sample was taken from all the children to measure oxytocin and cortisol levels by ELISAs. Validated scales and crying time were used to determine pain, stress, and anxiety levels. Children in group 3 were assessed before and after the intervention, employing the same methods., Results: A total of 272 patients were included. The children in group 1 (n = 125) were 7.7 ± 3.2 years old, and 53.6% were females. 48% were in the I group, which showed decreased cortisol levels and increased oxytocin levels. The I group exhibited a decrease in perceived pain and crying time. The children in group 2 (n = 69) were aged 7.1 ± 3.5 years, and 36% were females. 51% were in the I group, which showed increased oxytocin levels and decreased cortisol levels, acute stress levels, perceived pain, and crying time. The children in group 3 (n = 78) were 8.6 ± 3.3 years old, and 54% of the children were females. There was an increase in oxytocin levels and a decrease in cortisol levels, stress levels and perceived pain following the intervention., Conclusions: This study suggested that an intervention based on clowning is an effective strategy for decreasing pain, stress, and anxiety levels in paediatric patients in different clinical contexts. These findings support the implementation of humour therapy programs in paediatric units., Competing Interests: Declarations Ethics approval and consent to participate This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of Universidad Tecnológica de Pereira (Code 32–160421). Written informed consent was obtained from the parents or proxies. Consent for publication Not applicable. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

The gut-brain axis (GBA) plays a pivotal role in human health and wellness by orchestrating complex bidirectional regulation and influencing numerous critical processes within the body. Over the past decade, research has increasingly focused on the GBA in the context of inflammatory bowel disease (IBD). Beyond its well-documented effects on the GBA-enteric nervous system and vagus nerve dysregulation, and gut microbiota misbalance-IBD also leads to impairments in the metabolic and cellular functions: metabolic dysregulation, mitochondrial dysfunction, cationic transport, and cytoskeleton dysregulation. These systemic effects are currently underexplored in relation to the GBA; however, they are crucial for the nervous system cells' functioning. This review summarizes the studies on the particular mechanisms of metabolic dysregulation, mitochondrial dysfunction, cationic transport, and cytoskeleton impairments in IBD. Understanding the involvement of these processes in the GBA may help find new therapeutic targets and develop systemic approaches to improve the quality of life in IBD patients.

Targeted reproductive management (TRM) aims to improve the fertility efficiency of the dairy herd by applying group-level management strategies based on expected reproductive performance. Key to the utility of TRM is the accuracy with which an animal's reproductive performance can be predicted. Automatic milking systems (AMS) allow for the collection of data relating to milk quantity, quality, and robot visit behavior throughout the transition period. In addition to this, auxiliary data sources such as rumination and activity monitors, as well as historical cow-level data are often readily available. The utility of this data for the prediction of fertility has not been previously explored. The objective of this study was first, to assess the accuracy with which the likelihood of expression of oestrus between 22 and 65 d in milk (DIM) and conception to first insemination between 22 and 80 DIM could be predicted using data collected by AMS from 1 to 21 DIM. Our second objective was to assess the change in model performance following the addition of 2 auxiliary data sources. Using data derived solely from the AMS (RBT data set) a binary random forest classification model was constructed for both outcomes of interest. The performance of these models was compared with models constructed using AMS data in conjunction with 2 auxiliary sources (RBT+ data set). Expression of oestrus was classified with an area under the receiver operator curve (AUC-ROC) of 0.6 and 0.65, conception to first insemination with an AUC-ROC of 0.56 and 0.62 for the RBT and RBT+ data sets respectively. No statistically significant improvement in classification accuracy was achieved by the addition of auxiliary data sources. This is the first study to report the utility of data collected by AMS for the prediction of reproductive performance. Though the performance described is comparable with previously reported models, their utility for the implementation of TRM is limited by poor classification accuracy within key sub-groups. Of note within this study is the failure of the addition of auxiliary data sources to increase the accuracy of prediction over models built using AMS data alone. We discuss the advantages and limitations the integration of additional data sources imposes on model training and deployment and suggest alternative methods to improve performance while preserving model parsimony., (The Authors. Published by Elsevier Inc. on behalf of the American Dairy Science Association®. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).)

Laboratory diagnostic methods are the main tools in the practice of a doctor of any specialty, including an endocrinologist. Factors were identified that could change the concentration of the biologically active fraction of the test substance, subsequently complicating the interpretation of laboratory results and making the right clinical decision. The literature describes a variety of circulating autoantibodies involved in binding to pituitary hormones (prolactin (PRL), thyroid-stimulating hormone (TSH), growth hormone, luteinizing, follicle-stimulating, and adrenocorticotropic hormones), hypothalamus (vasopressin and oxytocin), pancreas (insulin and glucagon) , parathyroid glands (parathyroid hormone), as well as with thyroid hormones. As a rule, the resulting macromolecules lead to an increase in laboratory parameters, in which the prevailing fraction of the hormone does not have biological activity, which determines the main problem of this phenomenon. The most common variants include immune complexes with PRL and TSH, causing the phenomena of macroprolactinemia and macrothyrotropinemia (macro-TSH-emia/macro-TSH), respectively. Most laboratory test systems used in clinical practice are capable of determining only the total amount of PRL and TSH. The presented clinical observation describes a combination of the phenomena of macro-TSH and macroprolactinemia in a patient with autoimmune thyroiditis (AIT) and vitiligo.

Leptin is not only the main regulator of energy balance, but also it affects the reproductive and immune systems. Leptin and its receptors are expressed in the endometrium and are actively involved in the embryo implantation. According to numerous studies, expression and level changes of leptin are associated with the inflammatory and autoimmune diseases, including endometriosis and chronic endometritis. Hyperplastic and inflammatory diseases of the uterus are accompanied by a violation of the receptivity of the endometrium due to the dysregulation of many factors involved in proliferation, vascularization and decidualization of cells. Activity of most of these factors is due to the leptin action, however, there are no studies of the direct effect of leptin in the pathogenesis of disorders of the endometrium in hyperplastic and inflammatory diseases.Thus, the purpose of this literature review was to describe the putative molecular mechanisms of the effect of leptin on the development of endometrial pathology.Literature search was carried out from 03/20/2023 to 05/11/2023 using scientific literature databases: NCBI PubMed, Google Scholar (foreign sources), Cyberleninka, Elibrary (domestic sources): references for the period 1995-2023 were analyzed. The following keywords were used for the search: leptin, endometrial dysfunction, endometrial receptivity, inflammation, pelvic inflammatory disease.

The National Heart, Lung, and Blood Institute convened a virtual workshop in September 2022 to discuss "Optimal Instruments for Measurement of Diet, Physical Activity, and Sleep." This report summarizes the proceedings, identifying current research gaps and future directions for measuring different lifestyle behaviors in adult population-based studies. Key discussions centered on integrating report-based methods, like questionnaires, with device-based assessments, including wearables and physiological measures such as biomarkers and omics to enhance self-reported metrics and better understand the underlying biologic mechanisms of chronic diseases. Emphasis was placed on the need for data harmonization, including the adoption of standard terminology, reproducible metrics, and accessible raw data, to enhance the analysis through artificial intelligence and machine learning techniques. The workshop highlighted the importance of standardizing procedures for integrated behavioral phenotypes using time-series data. These efforts aim to refine data accuracy and comparability across studies and populations, thereby advancing our understanding of lifestyle behaviors and their impact on chronic disease outcomes over the life course.

This article is a continuation of our previous research on the catalytic capability of a chiral copper complex based on commercially available ( S )-2-aminomethylpyrrolidine and 3,5-di- tert -butylsalicylaldehyde with various counter-anions in the asymmetric Henry reaction. Our findings indicate that depending on the type of base used, chiral nitroalcohols with yields up to 98% and ee values up to 77%, as well as β-nitrostyrenes with yields up to 88%, can be produced. Additionally, it has been found that the outcome of the reaction and the catalytic properties of copper (II) complexes ( S )- Cu1 and ( S )- Cu2 are influenced by the structure of the aldehyde used.

Objectives: The main aim of our experiments was to demonstrate the suitability of cell-based biosensors for searching for new anticancer medicinal preparations. Methods: The effect of the substance doxorubicin, doxorubicin embedded in phospholipid nanoparticles, and doxorubicin with phospholipid nanoparticles modified by targeting vectors (cRGD and folic acid) on dsDNA and breast cancer cell lines (MCF-7, MDA-MB-231) was studied. Results: In the obtained doxorubicin nanoforms, the particle size was less than 60 nm. Our study of the percentage of doxorubicin inclusion showed the almost complete embeddability of the substance into nanoparticles for all samples, with an average of 95.4 ± 4.6%. The calculation of the toxicity index of the studied doxorubicin samples showed that all substances were moderately toxic drugs in terms of adenine and guanine. The biosensor analysis using electrodes modified with carbon nanotubes showed an intercalation interaction between doxorubicin and its derivatives and dsDNA, except for the composition of doxorubicin with folic acid with a linker length of 2000 (NPh-Dox-Fol(2.0)). The results of the electroanalysis were normalized to the total cell protein (mg) and cell concentration. The highest intensity of the electrochemical signals was observed in intact control cells of the MCF-7 and MDA-MB-231 cell lines. Conclusions: The proposed electrochemical approach is useful for the analysis of cell line responses to the medicinal preparations.

A joint analysis of dendrochronological and genomic data was performed to identify genetic mechanisms of adaptation and assess the adaptive genetic potential of Siberian stone pine ( Pinus sibirica Du Tour) populations. The data obtained are necessary for predicting the effect of climate change and mitigating its negative consequences. Presented are the results of an association analysis of the variation of 84,853 genetic markers (single nucleotide polymorphisms-SNPs) obtained by double digest restriction-site associated DNA sequencing (ddRADseq) and 110 individual phenotypic traits, including dendrophenotypes based on the dynamics of tree-ring widths (TRWs) of 234 individual trees in six natural populations of Siberian stone pine, which have a history of extreme climatic stresses (e.g., droughts) and outbreaks of defoliators (e.g., pine sawfly [ Neodiprion sertifer Geoff.]). The genetic structure of studied populations was relatively weak; samples are poorly differentiated and belong to genetically similar populations. Genotype-dendrophenotype associations were analyzed using three different approaches and corresponding models: General Linear Model (GLM), Bayesian Sparse Linear Mixed Model (BSLMM), and Bayesian-information and Linkage-disequilibrium Iteratively Nested Keyway (BLINK), respectively. Thirty SNPs were detected by at least two different approaches, and two SNPs by all three. In addition, three SNPs associated with mean values of recovery dendrophenotype (Rc) averaged across multiple years of climatic stresses were also found by all three methods. The sequences containing these SNPs were annotated using genome annotation of a very closely related species, whitebark pine ( P. albicaulis Engelm.). We found that most of the SNPs with supposedly adaptive variation were located in intergenic regions. Three dendrophenotype-associated SNPs were located within the 10 Kbp regions and one in the intron of the genes encoding proteins that play a crucial role in ensuring the integrity of the plant's genetic information, particularly under environmental stress conditions that can induce DNA damage. In addition, we found a correlation of individual heterozygosity with some dendrophenotypes. Heterosis was observed in most of these statistically significant cases; signs of homeostasis were also detected. Although most of the identified SNPs were not assigned to a particular gene, their high polymorphism and association with adaptive traits likely indicate high adaptive potential that can facilitate adaptation of Siberian stone pine populations to the climatic stresses and climate change.

In addition to its fundamental interest, the long-distance spin transport is essential for spintronic devices. However, the spin relaxation caused by scattering of the particles carrying the spin limits spin transport. We explored spatially indirect excitons (IXs) in van der Waals heterostructures composed of atomically thin layers of transition-metal dichalcogenides as spin carries. We observed the long-distance spin transport: the spin polarized excitons travel over the entire sample,  ~10 micron away from the excitation spot, with no spin density decay. This transport is characterized by the 1/e decay distances reaching  ~100 micron. The 1/e decay distances are extracted from fits over the  ~10 micron sample size. The emergence of long-distance spin transport is observed at the densities and temperatures where the IX transport decay distances and, in turn, scattering times are strongly enhanced. The suppression of IX scattering suppresses the spin relaxation and enables the long-distance spin transport., (© 2024. The Author(s).)

Amphibians represent a diverse group of tetrapods, marked by deep divergence times between their three systematic orders and families. Studying amphibian biology through the genomics lens increases our understanding of the features of this animal class and that of other terrestrial vertebrates. The need for amphibian genomic resources is more urgent than ever due to the increasing threats to this group. Amphibians are one of the most imperiled taxonomic groups, with approximately 41% of species threatened with extinction due to habitat loss, changes in land use patterns, disease, climate change, and their synergistic effects. Amphibian genomic resources have provided a better understanding of ontogenetic diversity, tissue regeneration, diverse life history and reproductive modes, anti-predator strategies, and resilience and adaptive responses. They also serve as essential models for studying broad genomic traits, such as evolutionary genome expansions and contractions, as they exhibit the widest range of genome sizes among all animal taxa and possess multiple mechanisms of genetic sex determination. Despite these features, genome sequencing of amphibians has significantly lagged behind that of other vertebrates, primarily due to the challenges of assembling their large, repeat-rich genomes and the relative lack of societal support. The emergence of long-read sequencing technologies, combined with advanced molecular and computational techniques that improve scaffolding and reduce computational workloads, is now making it possible to address some of these challenges. To promote and accelerate the production and use of amphibian genomics research through international coordination and collaboration, we launched the Amphibian Genomics Consortium (AGC, https://mvs.unimelb.edu.au/amphibian-genomics-consortium ) in early 2023. This burgeoning community already has more than 282 members from 41 countries. The AGC aims to leverage the diverse capabilities of its members to advance genomic resources for amphibians and bridge the implementation gap between biologists, bioinformaticians, and conservation practitioners. Here we evaluate the state of the field of amphibian genomics, highlight previous studies, present challenges to overcome, and call on the research and conservation communities to unite as part of the AGC to enable amphibian genomics research to "leap" to the next level., (© 2024. The Author(s).)