Combined screening and retroactive data mining for emerging perfluoroethers in wildlife and pets in the Cape Fear region of North Carolina.

The recent application of non-targeted analysis (NTA) techniques in environmental monitoring has revealed numerous novel fluorinated species in surface water, wildlife, and humans in the Cape Fear River (CFR) region of North Carolina. In this study, we have re-examined archived alligator, striped bass, horse, and dog serum as well as archived seabird tissue data from previously reported exposure studies in order to extend the panel of detected novel PFAS. In this study, the compounds CF3-(OCF2)x-COOH, x = 6, 7, 8 (Abbreviated PFO6TeDA, PFO7HxDA, PFO8OcDA, respectively), and 6H-Perfluoro-3-oxa,4-methylhexanesulfonic acid (Nafion byproduct 6) were detected for the first time in environmental tissues even though these analytes were not previously detected in the CFR. Analytical standards were available for PFO6TeDA and Nafion Byproduct 6, and therefore, were quantitated in investigated tissues. PFO7HxDA and PFO8OcDA had no available standards and were semi-quantitated using NTA techniques. Of note, PFO6TeDA, PFO7HxDA, and PFO8OcDA were observed in alligator, bass, and seabird but not horse and dog. PFO6TeDA was detected at the highest frequency in all investigated tissues with PFO7HxDA and PFO8OcDA detected at lower frequencies. No Nafion Byproduct 6 values are reported in serum due to poor analytical reproducibility of the measurements. Seabird tissue to blood ratios suggests PFO6TeDA is highest in the heart, kidney, and liver and lowest in the brain. Overall, additional studies are needed to fully understand the potential impact of these additional novel PFAS on both wildlife and humans in the CFR region.

Establishing Predictors of Acute Sarcopenia: A Proof-Of-Concept Study Utilising Network Analysis.

Dynamic changes in sarcopenia status following stressor events are defined as acute sarcopenia; it is currently unknown how to stratify risk. Prospective observational study involving elective colorectal surgery, emergency abdominal surgery, and medical patients with infections aged ≥70 years-old. Handgrip strength, muscle quantity (ultrasound Bilateral Anterior Thigh Thickness, BATT, and Bioelectrical Impedance Analysis), and muscle quality (rectus femoris echogenicity) were measured preoperatively in the elective group, and within 48hours, 7days after, and 13weeks after admission/surgery. Serum/plasma samples were collected preoperatively (elective group) and within 48hours of admission/surgery (all groups). LASSO models adjusting for baseline sarcopenia status were performed. Seventy-nine participants were included (mean age 79.1, 39.2% female). Chronic Obstructive Pulmonary Disease (COPD) (48hours ß 0.67, CI 0.59-0.75), and prescription of steroids during admission (48hours ß 1.11, CI 0.98-1.24) were positively associated with sarcopenia at 7days. Delirium was negatively associated with change in BATT to 7days (7days ß -0.47, CI -0.5- -0.44). COPD (Preoperative ß 0.35, CI 0.12-0.58) and delirium (48hours ß 0.13, CI 0.06-0.2) were positively associated with change in echogenicity to 7days in analysis including systemic biomarkers. Participants with sarcopenia at baseline had higher IL-7 concentrations during acute phase of illness (median 8.78pg/mL vs 6.52pg/mL; p=0.014). IL-1b within 48hours of admission/surgery was positively associated with sarcopenia status at 7days (ß 0.24, CI 0.06-0.42). Patients most at risk of acute sarcopenia or reductions in muscle quantity and quality included those prescribed steroids, with COPD or delirium, or with heightened systemic inflammation.

Wood-Ljungdahl pathway encoding anaerobes facilitate low-cost primary production in hypersaline sediments at Great Salt Lake, Utah.

Little is known of primary production in dark hypersaline ecosystems despite the prevalence of such environments on Earth today and throughout its geologic history. Here we generated and analyzed metagenome assembled genomes (MAGs) organized as operational taxonomic units (OTUs) from three depth intervals along a 30 cm sediment core from the north arm of Great Salt Lake, Utah. The sediments and associated porewaters were saturated with NaCl, exhibited redox gradients with depth, and harbored nitrogen depleted organic carbon. Metabolic predictions of MAGs representing 36 total OTUs recovered from the core indicated that communities transitioned from aerobic and heterotrophic at the surface to anaerobic and autotrophic at depth. Dark CO2 fixation was detected in sediments and the primary mode of autotrophy was predicted to be via the Wood-Ljungdahl pathway. This included novel hydrogenotrophic acetogens affiliated with the bacterial class Candidatus Bipolaricaulia. Minor populations were dependent on the Calvin Cycle and the reverse Tricarboxylic Acid Cycle, including in a novel Thermoplasmatota MAG. These results are interpreted to reflect the favorability of and selectability for populations that operate the lowest energy requiring CO2 fixation pathway known, the Wood-Ljungdahl (WL) pathway, in anoxic and hypersaline conditions that together impart a higher energy demand on cells.

Ethnicity and deprivation negatively impact the access to disease-modifying therapy for relapsing-remitting multiple sclerosis: a retrospective, single-centre study.

BACKGROUND: A growing body of evidence suggests inequitable access to disease-modifying therapies (DMTs) for multiple sclerosis (MS) in publicly funded healthcare systems. This retrospective study examined the impact of ethnicity and deprivation on the access to DMTs. METHODS: All adults diagnosed with relapsing-remitting MS between 2010 and 2020 were included. The impact of ethnicity and deprivation on being offered and starting any DMTs and high-efficacy DMTs were measured using binary, multinomial logistic and Cox regression models. These analyses were adjusted for sex, age at diagnosis and year of diagnosis. RESULTS: 164/1648 people with MS (PwMS) were from non-white ethnicities. 461/1648 who were living in the most deprived areas, were less likely to be offered DMTs, with an OR of 0.66 (95% CI 0.47 to 0.93), less likely to start high-efficacy DMTs with an OR of 0.67 (95% CI 0.48 to 0.93) and more likely to experience a delay in starting high-efficacy DMTs with an HR of 0.76 (95% CI 0.63 to 0.92), when also adjusted for ethnicity. Although the offer of DMTs did not depend on ethnicity, PwMS from non-white ethnicities were more likely to decline DMTs, less likely to start any DMTs and high-efficacy DMTs with ORs of 0.60 (95% CI 0.39 to 0.93) and 0.61 (95% CI 0.38 to 0.98), respectively, and more likely to experience a delay in starting DMTs with an HR of 0.79 (95% CI 0.66 to 0.95), when also adjusted for deprivation. CONCLUSIONS: In a publicly funded healthcare system, the access to DMTs varied depending on ethnicities and levels of deprivation.

Reduced Protein Import via TIM23 SORT Drives Disease Pathology in TIMM50-Associated Mitochondrial Disease.

TIMM50 is a core subunit of the TIM23 complex, the mitochondrial inner membrane translocase responsible for the import of pre-sequence-containing precursors into the mitochondrial matrix and inner membrane. Here we describe a mitochondrial disease patient who is homozygous for a novel variant in TIMM50 and establish the first proteomic map of mitochondrial disease associated with TIMM50 dysfunction. We demonstrate that TIMM50 pathogenic variants reduce the levels and activity of endogenous TIM23 complex, which significantly impacts the mitochondrial proteome, resulting in a combined oxidative phosphorylation (OXPHOS) defect and changes to mitochondrial ultrastructure. Using proteomic data sets from TIMM50 patient fibroblasts and a TIMM50 HEK293 cell model of disease, we reveal that laterally released substrates imported via the TIM23SORT complex pathway are most sensitive to loss of TIMM50. Proteins involved in OXPHOS and mitochondrial ultrastructure are enriched in the TIM23SORT substrate pool, providing a biochemical mechanism for the specific defects in TIMM50-associated mitochondrial disease patients. These results highlight the power of using proteomics to elucidate molecular mechanisms of disease and uncovering novel features of fundamental biology, with the implication that human TIMM50 may have a more pronounced role in lateral insertion than previously understood.

A community health worker led approach to cardiovascular disease prevention in the UK-SPICES-Sussex (scaling-up packages of interventions for cardiovascular disease prevention in selected sites in Europe and Sub-saharan Africa): an implementation research project.

Background: This paper describes a UK-based study, SPICES-Sussex, which aimed to co-produce and implement a community-based cardiovascular disease (CVD) risk assessment and reduction intervention to support under-served populations at moderate risk of CVD. The objectives were to enhance stakeholder engagement; to implement the intervention in four research sites and to evaluate the use of Voluntary and Community and Social Enterprises (VCSE) and Community Health Worker (CHW) partnerships in health interventions. Methods: A type three hybrid implementation study design was used with mixed methods data. This paper represents the process evaluation of the implementation of the SPICES-Sussex Project. The evaluation was conducted using the RE-AIM framework. Results: Reach: 381 individuals took part in the risk profiling questionnaire and forty-one women, and five men participated in the coaching intervention. Effectiveness: quantitative results from intervention participants showed significant improvements in CVD behavioural risk factors across several measures. Qualitative data indicated high acceptability, with the holistic, personalised, and person-centred approach being valued by participants. Adoption: 50% of VCSEs approached took part in the SPICES programme, The CHWs felt empowered to deliver high-quality and mutually beneficial coaching within a strong project infrastructure that made use of VCSE partnerships. Implementation: Co-design meetings resulted in local adaptations being made to the intervention. 29 (63%) of participants completed the intervention. Practical issues concerned how to embed CHWs in a health service context, how to keep engaging participants, and tensions between research integrity and the needs and expectations of those in the voluntary sector. Maintenance: Several VCSEs expressed an interest in continuing the intervention after the end of the SPICES programme. Conclusion: Community-engagement approaches have the potential to have positively impact the health and wellbeing of certain groups. Furthermore, VCSEs and CHWs represent a significant untapped resource in the UK. However, more work needs to be done to understand how links between the sectors can be bridged to deliver evidence-based effective alternative preventative healthcare. Reaching vulnerable populations remains a challenge despite partnerships with VCSEs which are embedded in the community. By showing what went well and what did not, this project can guide future work in community engagement for health.

Development of a Novel, Reusable Task Trainer for Foreign Body Removal and Abscess Incision and Drainage.

INTRODUCTION: Cutaneous abscess incision and drainage and foreign body removal are 2 common procedures in a variety of outpatient settings. The goal of this project was to create a novel, clean, reusable task trainer that could more accurately reproduce all the steps necessary to perform cutaneous abscess drainage or foreign body removal including ultrasound to identify the abscess cavity or foreign body. METHODS: The novel task trainer was constructed using silicone for both the base and the top skin. Toothpaste mixed with saline was used for the abscess material as this produced an ultrasound image that mimicked purulent material. A piece of a metal paper clip was imbedded in the top skin to mimic a cutaneous foreign body. Physician assistant (PA) students given a didactic lecture then used the novel task trainer as part of a clinical skills course. RESULTS: After the activity, the PA students were asked to voluntarily complete a brief preretrospective/postretrospective survey comprised 8 questions that addressed their self-perceived knowledge and skills using a 5-point Likert scale. Survey data from an initial cohort of PA students at one university show effectiveness of the models when used with the associated curriculum. DISCUSSION: This study demonstrates the feasibility of constructing a practical, low-cost, non-animal-based task trainer for the purpose of training incision and drainage of cutaneous abscesses and removal of cutaneous foreign bodies. This novel task trainer allows for ultrasound skill development and provides realistic imaging experience.

A combination nutritional supplement reduces DNA methylation age only in older adults with a raised epigenetic age.

An increase in systemic inflammation (inflammaging) is one of the hallmarks of aging. Epigenetic (DNA methylation) clocks can quantify the degree of biological aging and this can be reversed by lifestyle and pharmacological intervention. We aimed to investigate whether a multi-component nutritional supplement could reduce systemic inflammation and epigenetic age in healthy older adults.We recruited 80 healthy older participants (mean age ± SD: 71.85 ± 6.23; males = 31, females = 49). Blood and saliva were obtained pre and post a 12-week course of a multi-component supplement, containing: Vitamin B3, Vitamin C, Vitamin D, Omega 3 fish oils, Resveratrol, Olive fruit phenols and Astaxanthin. Plasma GDF-15 and C-reactive protein (CRP) concentrations were quantified as markers of biological aging and inflammation respectively. DNA methylation was assessed in whole blood and saliva and used to derive epigenetic age using various clock algorithms.No difference between the epigenetic and chronological ages of participants was observed pre- and post-treatment by the blood-based Horvath or Hannum clocks, or the saliva-based InflammAge clock. However, in those with epigenetic age acceleration of ≥ 2 years at baseline, a significant reduction in epigenetic age (p = 0.015) and epigenetic age acceleration (p = 0.0058) was observed post-treatment using the saliva-based InflammAge clock. No differences were observed pre- and post-treatment in plasma GDF-15 and CRP, though participants with CRP indicative of an elevated cardiovascular disease risk (hsCRP ≥ 3µg/ml), had a reduction in CRP post-supplementation (p = 0.0195).Our data suggest a possible benefit of combined nutritional supplementation in individuals with an accelerated epigenetic age and inflammaging.

Caspase-2 protects against ferroptotic cell death.

Caspase-2, one of the most evolutionarily conserved members of the caspase family, is an important regulator of the cellular response to oxidative stress. Given that ferroptosis is suppressed by antioxidant defense pathways, such as that involving selenoenzyme glutathione peroxidase 4 (GPX4), we hypothesized that caspase-2 may play a role in regulating ferroptosis. This study provides the first demonstration of an important and unprecedented function of caspase-2 in protecting cancer cells from undergoing ferroptotic cell death. Specifically, we show that depletion of caspase-2 leads to the downregulation of stress response genes including SESN2, HMOX1, SLC7A11, and sensitizes mutant-p53 cancer cells to cell death induced by various ferroptosis-inducing compounds. Importantly, the canonical catalytic activity of caspase-2 is not required for its role and suggests that caspase-2 regulates ferroptosis via non-proteolytic interaction with other proteins. Using an unbiased BioID proteomics screen, we identified novel caspase-2 interacting proteins (including heat shock proteins and co-chaperones) that regulate cellular responses to stress. Finally, we demonstrate that caspase-2 limits chaperone-mediated autophagic degradation of GPX4 to promote the survival of mutant-p53 cancer cells. In conclusion, we document a novel role for caspase-2 as a negative regulator of ferroptosis in cells with mutant p53. Our results provide evidence for a novel function of caspase-2 in cell death regulation and open potential new avenues to exploit ferroptosis in cancer therapy.

Quantitative cross-species comparison of serum albumin binding of per- and polyfluoroalkyl substances from five structural classes.

Per- and polyfluoroalkyl substances (PFAS) are a class of over 8000 chemicals, many of which are persistent, bioaccumulative, and toxic to humans, livestock, and wildlife. Serum protein binding affinity is instrumental in understanding PFAS toxicity, yet experimental binding data is limited to only a few PFAS congeners. Previously, we demonstrated the usefulness of a high-throughput, in vitro differential scanning fluorimetry assay for determination of relative binding affinities of human serum albumin for 24 PFAS congeners from 6 chemical classes. In the current study, we used this assay to comparatively examine differences in human, bovine, porcine, and rat serum albumin binding of 8 structurally informative PFAS congeners from 5 chemical classes. With the exception of the fluorotelomer alcohol 1H, 1H, 2H, 2H-perfluorooctanol (6:2 FTOH), each PFAS congener bound by human serum albumin was also bound by bovine, porcine, and rat serum albumin. The critical role of the charged functional headgroup in albumin binding was supported by the inability of albumin of each species tested to bind 6:2 FTOH. Significant interspecies differences in serum albumin binding affinities were identified for each of the bound PFAS congeners. Relative to human albumin, perfluoroalkyl carboxylic and sulfonic acids were bound with greater affinity by porcine and rat serum albumin, and the perfluoroalkyl ether acid congener bound with lower affinity to porcine and bovine serum albumin. These comparative affinity data for PFAS binding by serum albumin from human, experimental model, and livestock species reduce critical interspecies uncertainty and improve accuracy of predictive bioaccumulation and toxicity assessments for PFAS.

Gut metabolic changes during pregnancy reveal the importance of gastrointestinal region in sample collection.

INTRODUCTION: Studies of gastrointestinal physiology and the gut microbiome often consider the influence of intestinal region on experimental endpoints. However, this same consideration is not often applied to the gut metabolome. Understanding the contribution of gut regionality may be critically important to the rapidly changing metabolic environments, such as during pregnancy. OBJECTIVES: We sought to characterize the difference in the gut metabolome in pregnant mice stratified by region-comparing the small intestine, cecum, and feces. Pre-pregnancy feces were collected to understand the influence of pregnancy on the fecal metabolome. METHODS: Feces were collected from CD-1 female mice before breeding. On gestation day (GD) 18, gut contents were collected from the small intestine, cecum, and descending colon. Metabolites were analyzed with LC-MS/MS using the Biocrates MetaboINDICATOR™ MxP® Quant 500 kit. RESULTS: Of the 104 small molecule metabolites meeting analysis criteria, we found that 84 (81%) were differentially abundant based on gut region. The most significant regional comparison observed was between the cecum and small intestines, with 52 (50%) differentially abundant metabolites. Pregnancy itself altered 41 (39.4%) fecal small molecule metabolites. CONCLUSIONS: The regional variation observed in the gut metabolome are likely due to the microbial and physiological differences between the different parts of the intestines. Additionally, pregnancy impacts the fecal metabolome, which may be due to evolving needs of both the dam and fetus.

Role of pyroptosis in the pathogenesis of various neurological diseases.

Pyroptosis, an inflammatory programmed cell death process, has recently garnered significant attention due to its pivotal role in various neurological diseases. This review delves into the intricate molecular signaling pathways governing pyroptosis, encompassing both caspase-1 dependent and caspase-1 independent routes, while emphasizing the critical role played by the inflammasome machinery in initiating cell death. Notably, we explore the Nucleotide-binding domain leucine-rich repeat (NLR) containing protein family, the Absent in melanoma 2-like receptor family, and the Pyrin receptor family as essential activators of pyroptosis. Additionally, we comprehensively examine the Gasdermin family, renowned for their role as executioner proteins in pyroptosis. Central to our review is the interplay between pyroptosis and various central nervous system (CNS) cell types, including astrocytes, microglia, neurons, and the blood-brain barrier (BBB). Pyroptosis emerges as a significant factor in the pathophysiology of each cell type, highlighting its far-reaching impact on neurological diseases. This review also thoroughly addresses the involvement of pyroptosis in specific neurological conditions, such as HIV infection, drug abuse-mediated pathologies, Alzheimer's disease, and Parkinson's disease. These discussions illuminate the intricate connections between pyroptosis, chronic inflammation, and cell death in the development of these disorders. We also conducted a comparative analysis, contrasting pyroptosis with other cell death mechanisms, thereby shedding light on their unique aspects. This approach helps clarify the distinct contributions of pyroptosis to neuroinflammatory processes. In conclusion, this review offers a comprehensive exploration of the role of pyroptosis in various neurological diseases, emphasizing its multifaceted molecular mechanisms within various CNS cell types. By elucidating the link between pyroptosis and chronic inflammation in the context of neurodegenerative disorders and infections, it provides valuable insights into potential therapeutic targets for mitigating these conditions.

Perceptions on artificial intelligence-based decision-making for coexisting multiple long-term health conditions: protocol for a qualitative study with patients and healthcare professionals.

INTRODUCTION: Coexisting multiple health conditions is common among older people, a population that is increasing globally. The potential for polypharmacy, adverse events, drug interactions and development of additional health conditions complicates prescribing decisions for these patients. Artificial intelligence (AI)-generated decision-making tools may help guide clinical decisions in the context of multiple health conditions, by determining which of the multiple medication options is best. This study aims to explore the perceptions of healthcare professionals (HCPs) and patients on the use of AI in the management of multiple health conditions. METHODS AND ANALYSIS: A qualitative study will be conducted using semistructured interviews. Adults (≥18 years) with multiple health conditions living in the West Midlands of England and HCPs with experience in caring for patients with multiple health conditions will be eligible and purposively sampled. Patients will be identified from Clinical Practice Research Datalink (CPRD) Aurum; CPRD will contact general practitioners who will in turn, send a letter to patients inviting them to take part. Eligible HCPs will be recruited through British HCP bodies and known contacts. Up to 30 patients and 30 HCPs will be recruited, until data saturation is achieved. Interviews will be in-person or virtual, audio recorded and transcribed verbatim. The topic guide is designed to explore participants' attitudes towards AI-informed clinical decision-making to augment clinician-directed decision-making, the perceived advantages and disadvantages of both methods and attitudes towards risk management. Case vignettes comprising a common decision pathway for patients with multiple health conditions will be presented during each interview to invite participants' opinions on how their experiences compare. Data will be analysed thematically using the Framework Method. ETHICS AND DISSEMINATION: This study has been approved by the National Health Service Research Ethics Committee (Reference: 22/SC/0210). Written informed consent or verbal consent will be obtained prior to each interview. The findings from this study will be disseminated through peer-reviewed publications, conferences and lay summaries.

Advancing specificity in delirium: The delirium subtyping initiative.

BACKGROUND: Delirium, a common syndrome with heterogeneous etiologies and clinical presentations, is associated with poor long-term outcomes. Recording and analyzing all delirium equally could be hindering the field's understanding of pathophysiology and identification of targeted treatments. Current delirium subtyping methods reflect clinically evident features but likely do not account for underlying biology. METHODS: The Delirium Subtyping Initiative (DSI) held three sessions with an international panel of 25 experts. RESULTS: Meeting participants suggest further characterization of delirium features to complement the existing Diagnostic and Statistical Manual of Mental Disorders Fifth Edition Text Revision diagnostic criteria. These should span the range of delirium-spectrum syndromes and be measured consistently across studies. Clinical features should be recorded in conjunction with biospecimen collection, where feasible, in a standardized way, to determine temporal associations of biology coincident with clinical fluctuations. DISCUSSION: The DSI made recommendations spanning the breadth of delirium research including clinical features, study planning, data collection, and data analysis for characterization of candidate delirium subtypes. HIGHLIGHTS: Delirium features must be clearly defined, standardized, and operationalized. Large datasets incorporating both clinical and biomarker variables should be analyzed together. Delirium screening should incorporate communication and reasoning.

Differential transcriptomic alterations in nasal versus lung tissue of acrolein-exposed rats.

Introduction: Acrolein is a significant component of anthropogenic and wildfire emissions, as well as cigarette smoke. Although acrolein primarily deposits in the upper respiratory tract upon inhalation, patterns of site-specific injury in nasal versus pulmonary tissues are not well characterized. This assessment is critical in the design of in vitro and in vivo studies performed for assessing health risk of irritant air pollutants. Methods: In this study, male and female Wistar-Kyoto rats were exposed nose-only to air or acrolein. Rats in the acrolein exposure group were exposed to incremental concentrations of acrolein (0, 0.1, 0.316, 1 ppm) for the first 30 min, followed by a 3.5 h exposure at 3.16 ppm. In the first cohort of male and female rats, nasal and bronchoalveolar lavage fluids were analyzed for markers of inflammation, and in a second cohort of males, nasal airway and left lung tissues were used for mRNA sequencing. Results: Protein leakage in nasal airways of acrolein-exposed rats was similar in both sexes; however, inflammatory cells and cytokine increases were more pronounced in males when compared to females. No consistent changes were noted in bronchoalveolar lavage fluid of males or females except for increases in total cells and IL-6. Acrolein-exposed male rats had 452 differentially expressed genes (DEGs) in nasal tissue versus only 95 in the lung. Pathway analysis of DEGs in the nose indicated acute phase response signaling, Nrf2-mediated oxidative stress, unfolded protein response, and other inflammatory pathways, whereas in the lung, xenobiotic metabolism pathways were changed. Genes associated with glucocorticoid and GPCR signaling were also changed in the nose but not in the lung. Discussion: These data provide insights into inhaled acrolein-mediated sex-specific injury/inflammation in the nasal and pulmonary airways. The transcriptional response in the nose reflects acrolein-induced acute oxidative and cytokine signaling changes, which might have implications for upper airway inflammatory disease susceptibility.

Serum metabolome and liver transcriptome reveal acrolein inhalation-induced sex-specific homeostatic dysfunction.

Acrolein, a respiratory irritant, induces systemic neuroendocrine stress. However, peripheral metabolic effects have not been examined. Male and female WKY rats were exposed to air (0 ppm) or acrolein (3.16 ppm) for 4 h, followed by immediate serum and liver tissue collection. Serum metabolomics in both sexes and liver transcriptomics in males were evaluated to characterize the systemic metabolic response. Of 887 identified metabolites, > 400 differed between sexes at baseline. An acrolein biomarker, 3-hydroxypropyl mercapturic acid, increased 18-fold in males and 33-fold in females, indicating greater metabolic detoxification in females than males. Acrolein exposure changed 174 metabolites in males but only 50 in females. Metabolic process assessment identified higher circulating free-fatty acids, glycerols, and other lipids in male but not female rats exposed to acrolein. In males, acrolein also increased branched-chain amino acids, which was linked with metabolites of nitrogen imbalance within the gut microbiome. The contribution of neuroendocrine stress was evident by increased corticosterone in males but not females. Male liver transcriptomics revealed acrolein-induced over-representation of lipid and protein metabolic processes, and pathway alterations including Sirtuin, insulin-receptor, acute-phase, and glucocorticoid signaling. In sum, acute acrolein inhalation resulted in sex-specific serum metabolomic and liver transcriptomic derangement, which may have connections to chronic metabolic-related diseases.

Activin type I receptor polymorphisms and body composition in older individuals with sarcopenia-Analyses from the LACE randomised controlled trial.

BACKGROUND: Ageing is associated with changes in body composition including an overall reduction in muscle mass and a proportionate increase in fat mass. Sarcopenia is characterised by losses in both muscle mass and strength. Body composition and muscle strength are at least in part genetically determined, consequently polymorphisms in pathways important in muscle biology (e.g., the activin/myostatin signalling pathway) are hypothesised to contribute to the development of sarcopenia. METHODS: We compared regional body composition measured by DXA with genotypes for two polymorphisms (rs10783486, minor allele frequency (MAF) = 0.26 and rs2854464, MAF = 0.26) in the activin 1B receptor (ACVR1B) determined by PCR in a cross-sectional analysis of DNA from 110 older individuals with sarcopenia from the LACE trial. RESULTS: Neither muscle mass nor strength showed any significant associations with either genotype in this cohort. Initial analysis of rs10783486 showed that males with the AA/AG genotype were taller than GG males (174±7cm vs 170±5cm, p = 0.023) and had higher arm fat mass, (median higher by 15%, p = 0.008), and leg fat mass (median higher by 14%, p = 0.042). After correcting for height, arm fat mass remained significantly higher (median higher by 4% padj = 0.024). No associations (adjusted or unadjusted) were seen in females. Similar analysis of the rs2854464 allele showed a similar pattern with the presence of the minor allele (GG/AG) being associated with greater height (GG/AG = 174±7 cm vs AA = 170 ±5cm, p = 0.017) and greater arm fat mass (median higher by 16%, p = 0.023). Again, the difference in arm fat remained after correction for height. No similar associations were seen in females analysed alone. CONCLUSION: These data suggest that polymorphic variation in the ACVR1B locus could be associated with body composition in older males. The activin/myostatin pathway might offer a novel potential target to prevent fat accumulation in older individuals.

Exploring fraity and sarcopenia in older adults admitted to acute medical unit, looking at prevalence, trajectory, and outcomes: A protocol testing the feasibility and acceptability of the TYSON study.

BACKGROUND: Frailty and sarcopenia are common in older people and are associated with adverse outcomes including increased mortality and morbidity. It is unclear whether screening for frailty and sarcopenia would identify specific populations most at risk of poor outcomes during unplanned hospital admissions, which screening tools should be used and what the trajectory of both conditions are over the course of an admission. The TYSON study is an observational cohort study aiming to determine the prevalence, trajectory and outcomes associated with frailty and sarcopenia in different patient cohorts. This protocol tests the feasibility and acceptability of TYSON processes. OBJECTIVES: To determine in acutely admitted medical patients who are older adults: Primary: The feasibility and acceptability of frailty and sarcopenia assessments; Secondary: (1) Differences in community and hospital frailty assessments, as assessed by the medical team, the patient and elderly care physicians, (2) The dynamic changes in frailty and sarcopenia during a hospital admission, and patient outcomes; Exploratory: Inflammatory and metabolic mediators associated with frailty and sarcopenia. METHODS: A single centre, prospective observational study including patients aged ≥ 65 years admitted to an acute medical unit. Frailty assessments include the Rockwood clinical frailty and e-frailty index. Sarcopenia assessments include the Bilateral Anterior Thigh Thickness (BATT) measurement. Each participant will be asked to complete 5 visits, at day 0, day 3, day 7, month 3 and month 6. Blood samples will be collected to explore inflammatory and metabolic markers associated with frailty and sarcopenia. The study and protocol have been ethically approved by the Health Research Authority (REC 20/WA/0263). DISCUSSION: The study will determine the feasibility and acceptability of frailty and sarcopenia assessments in an acute hospital setting, and inform on the prevalence, trajectory and associated outcomes of frailty and sarcopenia in this group of patients. An inflammatory and metabolic profile will be explored in frailty and sarcopenia.

Influence of Mild Chronic Stress and Social Isolation on Acute Ozone-Induced Alterations in Stress Biomarkers and Brain-Region-Specific Gene Expression in Male Wistar-Kyoto Rats.

Individuals with psychosocial stress often experience an exaggerated response to air pollutants. Ozone (O3) exposure has been associated with the activation of the neuroendocrine stress-response system. We hypothesized that preexistent mild chronic stress plus social isolation (CS), or social isolation (SI) alone, would exacerbate the acute effects of O3 exposure on the circulating adrenal-derived stress hormones, and the expression of the genes regulating glucocorticoid stress signaling via an altered stress adaptation in a brain-region-specific manner. Male Wistar-Kyoto rats (5 weeks old) were socially isolated, plus were subjected to either CS (noise, confinement, fear, uncomfortable living, hectic activity, and single housing), SI (single housing only, restricted handling and no enrichment) or no stress (NS; double housing, frequent handling and enrichment provided) for 8 weeks. The rats were then exposed to either air or O3 (0.8 ppm for 4 h), and the samples were collected immediately after. The indicators of sympathetic and hypothalamic-pituitary axis (HPA) activation (i.e., epinephrine, corticosterone, and lymphopenia) increased with O3 exposure, but there were no effects from CS or SI, except for the depletion of serum BDNF. CS and SI revealed small changes in brain-region-specific glucocorticoid-signaling-associated markers of gene expression in the air-exposed rats (hypothalamic Nr3c1, Nr3c2 Hsp90aa1, Hspa4 and Cnr1 inhibition in SI; hippocampal HSP90aa1 increase in SI; and inhibition of the bed nucleus of the stria terminalis (BNST) Cnr1 in CS). Gene expression across all brain regions was altered by O3, reflective of glucocorticoid signaling effects, such as Fkbp5 in NS, CS and SI. The SI effects on Fkbp5 were greatest for SI in BNST. O3 increased Cnr2 expression in the hypothalamus and olfactory bulbs of the NS and SI groups. O3, in all stress conditions, generally inhibited the expression of Nr3c1 in all brain regions, Nr3c2 in the hippocampus and hypothalamus and Bdnf in the hippocampus. SI, in general, showed slightly greater O3-induced changes when compared to NS and CS. Serum metabolomics revealed increased sphingomyelins in the air-exposed SI and O3-exposed NS, with underlying SI dampening some of the O3-induced changes. These results suggest a potential link between preexistent SI and acute O3-induced increases in the circulating adrenal-derived stress hormones and brain-region-specific gene expression changes in glucocorticoid signaling, which may partly underlie the stress dynamic in those with long-term SI.

Quantitative Cross-Species Comparison of Serum Albumin Binding of Per- and Polyfluoroalkyl Substances from Five Structural Classes.

Per- and polyfluoroalkyl substances (PFAS) are a class of over 8,000 chemicals that are persistent, bioaccumulative, and toxic to humans, livestock, and wildlife. Serum protein binding affinity is instrumental in understanding PFAS toxicity, yet experimental binding data is limited to only a few PFAS congeners. Previously, we demonstrated the usefulness of a high-throughput, in vitro differential scanning fluorimetry assay for determination of relative binding affinities of human serum albumin for 24 PFAS congeners from 6 chemical classes. In the current study, we used this differential scanning fluorimetry assay to comparatively examine differences in human, bovine, porcine, and rat serum albumin binding of 8 structurally informative PFAS congeners from 5 chemical classes. With the exception of the fluorotelomer alcohol 1H,1H,2H,2H-perfluorooctanol (6:2 FTOH), each PFAS congener bound by human serum albumin was also bound by bovine, porcine, and rat serum albumin. The critical role of the charged functional headgroup in albumin binding was supported by the inability of serum albumin of each species tested to bind 6:2 FTOH. Significant interspecies differences in serum albumin binding affinities were identified for each of the bound PFAS congeners. Relative to human albumin, perfluoroalkyl carboxylic and sulfonic acids were bound with greater affinity by porcine and rat serum albumin, and perfluoroalkyl ether congeners bound with lower affinity to porcine and bovine serum albumin. These comparative affinity data for PFAS binding by serum albumin from human, experimental model and livestock species reduce critical interspecies uncertainty and improve accuracy of predictive toxicity assessments for PFAS.