Environmental factors may alter the fetal genome to cause metabolic diseases. It is unknown whether embryonic immune cell programming impacts the risk of type 2 diabetes in later life. We demonstrate ...that transplantation of fetal hematopoietic stem cells (HSCs) made vitamin D deficient in utero induce diabetes in vitamin D-sufficient mice. Vitamin D deficiency epigenetically suppresses Jarid2 expression and activates the Mef2/PGC1a pathway in HSCs, which persists in recipient bone marrow, resulting in adipose macrophage infiltration. These macrophages secrete miR106-5p, which promotes adipose insulin resistance by repressing PIK3 catalytic and regulatory subunits and down-regulating AKT signaling. Vitamin D-deficient monocytes from human cord blood have comparable Jarid2/Mef2/PGC1a expression changes and secrete miR-106b-5p, causing adipocyte insulin resistance. These findings suggest that vitamin D deficiency during development has epigenetic consequences impacting the systemic metabolic milieu.
In this study, a suite of complementary environmental geochemical analyses, including NMR and gas chromatography-mass spectrometry (GC-MS) analyses of central metabolites, Fourier transform ion ...cyclotron resonance mass spectrometry (FTICR-MS) of secondary metabolites, and lipidomics, was used to investigate the influence of organic matter (OM) quality on the heterotrophic microbial mechanisms controlling peatland CO
, CH
, and CO
:CH
porewater production ratios in response to climate warming. Our investigations leverage the Spruce and Peatland Responses under Changing Environments (SPRUCE) experiment, where air and peat warming were combined in a whole-ecosystem warming treatment. We hypothesized that warming would enhance the production of plant-derived metabolites, resulting in increased labile OM inputs to the surface peat, thereby enhancing microbial activity and greenhouse gas production. Because shallow peat is most susceptible to enhanced warming, increases in labile OM inputs to the surface, in particular, are likely to result in significant changes to CO
and CH
dynamics and methanogenic pathways. In support of this hypothesis, significant correlations were observed between metabolites and temperature consistent with increased availability of labile substrates, which may stimulate more rapid turnover of microbial proteins. An increase in the abundance of methanogenic genes in response to the increase in the abundance of labile substrates was accompanied by a shift toward acetoclastic and methylotrophic methanogenesis. Our results suggest that as peatland vegetation trends toward increasing vascular plant cover with warming, we can expect a concomitant shift toward increasingly methanogenic conditions and amplified climate-peatland feedbacks.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Municipal wastewater treatment plant (WWTP) effluents are a ubiquitous source of contamination whose impacts on fish and other aquatic organisms span across multiple levels of biological ...organization. Despite this, few studies have addressed the impacts of WWTP effluents on fish communities, especially during the winter—a season seldom studied. Here, we assessed the impacts of wastewater on fish community compositions and various water quality parameters during the summer and winter along two effluent gradients in Hamilton Harbour, an International Joint Commission Area of Concern in Hamilton, Canada. We found that fish abundance, species richness, and species diversity were generally highest in sites closest to the WWTP outfalls, but only significantly so in the winter. Fish community compositions differed greatly along the effluent gradients, with sites closest and farthest from the outfalls being the most dissimilar. Furthermore, the concentrations of numerous contaminants of emerging concern (CECs) in the final treated effluent were highest during the winter. Water quality of sites closer to the outfalls was poorer than at sites farther away, especially during the winter. We also demonstrated that WWTPs can significantly alter the thermal profile of effluent-receiving environments, increasing temperature by as much as ~9 °C during the winter. Our results suggest that wastewater plumes may act as ecological traps in winter, whereby fish are attracted to the favourable temperatures near WWTPs and are thus exposed to higher concentrations of CECs. This study highlights the importance of winter research as a key predictor in further understanding the impacts of wastewater contamination in aquatic ecosystems.
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•Fish communities sampled in the summer and winter along two effluent gradients•Higher abundance, richness, and diversity near effluent outfall, only in winter•Communities of fish closest and farthest from the outfall were most dissimilar.•WWTP effluents impacted water quality downstream, particularly in winter.•WWTP effluent quality (concentrations of CECs) was poorer in winter than summer.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Lung immaturity is a major cause of morbidity and mortality in premature infants. Understanding the molecular mechanisms driving normal lung development could provide insights on how to ameliorate ...disrupted development. While transcriptomic and proteomic analyses of normal lung development have been previously reported, characterization of changes in the lipidome is lacking. Lipids play significant roles in the lung, such as dipalmitoylphosphatidylcholine in pulmonary surfactant; however, many of the roles of specific lipid species in normal lung development, as well as in disease states, are not well defined. In this study, we used liquid chromatography-mass spectrometry (LC-MS/MS) to investigate the murine lipidome during normal postnatal lung development. Lipidomics analysis of lungs from post-natal day 7, day 14 and 6-8 week mice (adult) identified 924 unique lipids across 21 lipid subclasses, with dramatic alterations in the lipidome across developmental stages. Our data confirmed previously recognized aspects of post-natal lung development and revealed several insights, including in sphingolipid-mediated apoptosis, inflammation and energy storage/usage. Complementary proteomics, metabolomics and chemical imaging corroborated these observations. This multi-omic view provides a unique resource and deeper insight into normal pulmonary development.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Abstract Background A key to understanding potential anterior cruciate ligament injury mechanisms is to determine joint loading characteristics associated with an injury-causing event. However, ...direct measurement of anterior cruciate ligament loading during athletic tasks is invasive. Thus, previous research has been unable to study the association between neuromuscular variables and anterior cruciate ligament loading. Therefore, the purpose of this study was to determine the influence of movement anticipation on anterior cruciate ligament loading using a musculoskeletal modeling approach. Methods Twenty healthy recreationally active females were recruited to perform anticipated and unanticipated sidestep cutting. Three-dimensional kinematics and kinetics of the right leg were calculated. Muscle, joint and anterior cruciate ligament forces were then estimated using a musculoskeletal model. Dependent t-tests were conducted to investigate differences between the two cutting conditions. Findings ACL loading significantly increased during unanticipated sidestep cutting (p < 0.05). This increase was primarily due to a significant increase in the sagittal plane ACL loading, which contributed 62% of the total loading. Frontal plane ACL loading contributed 26% and transverse plane ACL loading contributed 12%. Interpretation These results suggest that anterior cruciate ligament loading resulted from a multifaceted interaction of the sagittal plane shear forces (i.e., quadriceps, hamstrings, and tibiofemoral), as well as the frontal and transverse plane knee moments. Additionally, the results of this study confirm the hypothesis in the current literature that unanticipated movements such as sidestep cutting increase anterior cruciate ligament loading.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Pandemic influenza viruses modulate proinflammatory responses that can lead to immunopathogenesis. We present an extensive and systematic profiling of lipids, metabolites, and proteins in respiratory ...compartments of ferrets infected with either 1918 or 2009 human pandemic H1N1 influenza viruses. Integrative analysis of high-throughput omics data with virologic and histopathologic data uncovered relationships between host responses and phenotypic outcomes of viral infection. Proinflammatory lipid precursors in the trachea following 1918 infection correlated with severe tracheal lesions. Using an algorithm to infer cell quantity changes from gene expression data, we found enrichment of distinct T cell subpopulations in the trachea. There was also a predicted increase in inflammatory monocytes in the lung of 1918 virus-infected animals that was sustained throughout infection. This study presents a unique resource to the influenza research community and demonstrates the utility of an integrative systems approach for characterization of lipid metabolism alterations underlying respiratory responses to viruses.
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•Conducted lipidomic, metabolomic, and proteomic profiling of virus-infected ferrets•1918 and CA04 viruses produce different histologic lesions and metabolic changes•Integrated omics analysis shows dynamic host responses in respiratory immunity•Proinflammatory lipid precursors correlate with influenza virus pathogenesis
Influenza virus induces immune responses that contribute to respiratory disease. Tisoncik-Go et al. integrate multiomics data with histopathologic and virologic phenotypes in respiratory tissues of ferrets infected with either a contemporary or historic pandemic H1N1 influenza virus to uncover a correlation between alterations in lipid metabolism and enhanced inflammation.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Individuals seen in Primary Care with behavioral health concerns who decline behavioral health treatment may benefit from the support of peers (consumers in recovery from behavioral health concerns ...employed to support other consumers). Whole Health STEPS is a new intervention for Veterans in Primary Care with behavioral health concerns which combines essential elements of peers' role and the Whole Health model using a stepped-care design. We incorporated stakeholder feedback in the Whole Health STEPS design to improve fit with Veterans, peers, and primary care settings.
We conducted semi-structured qualitative interviews with VA staff using questions derived from the Consolidated Framework for Implementation Research (CFIR). Participants were recruited via a maximum variation strategy across a national sample and interviewed between January 2021-April 2021. The analytic design was a rapid qualitative analysis. Interviews addressed design decisions and potential barriers and facilitators to future implementation. Then, we made adaptations to Whole Health STEPS and catalogued changes using the Framework for Adaptations and Modifications-Enhanced (FRAME). A VA peer conducted the interviews, participated in analyses, assisted with design modifications, and co-wrote this paper.
Sixteen staff members from 9 VA primary care peer programs participated (8 peers and 8 supervisors/administrators). Feedback themes included: capitalizing on peer skills (e.g., navigation), ensuring patient-centered and flexible design, and making it easy and efficient (e.g., reducing session length). Understanding the structure of primary care peers' roles and their interactions with other programs helped us identify role conflicts (e.g., overlap with Whole Health Coaches and Health Behavior Coordinators), which led to design modifications to carve out a unique role for Whole Health STEPS. Staff also made recommendations about marketing materials and training tools to support Whole Health STEPS roll out.
Feedback from frontline staff, including peers, in the design process was crucial to identifying essential modifications that would not have been possible after initial trials without re-evaluating efficacy due to the extent of the changes. Whole Health STEPS was adapted to fit within a range of program structures, emphasize peers' unique contributions, and streamline delivery. Lessons learned can be applied to other interventions.
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CEKLJ, DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Pulmonary alveolar microlithiasis is an autosomal recessive lung disease caused by a deficiency in the pulmonary epithelial Npt2b sodium-phosphate co-transporter that results in accumulation of ...phosphate and formation of hydroxyapatite microliths in the alveolar space. The single cell transcriptomic analysis of a pulmonary alveolar microlithiasis lung explant showing a robust osteoclast gene signature in alveolar monocytes and the finding that calcium phosphate microliths contain a rich protein and lipid matrix that includes bone resorbing osteoclast enzymes and other proteins suggested a role for osteoclast-like cells in the host response to microliths. While investigating the mechanisms of microlith clearance, we found that Npt2b modulates pulmonary phosphate homeostasis through effects on alternative phosphate transporter activity and alveolar osteoprotegerin, and that microliths induce osteoclast formation and activation in a receptor activator of nuclear factor-κB ligand and dietary phosphate dependent manner. This work reveals that Npt2b and pulmonary osteoclast-like cells play key roles in pulmonary homeostasis and suggest potential new therapeutic targets for the treatment of lung disease.
Abstract
Objective
Limited staffing and initial transmission concerns have limited rehabilitation services during the COVID-19 pandemic. The purpose of this analysis was to determine the associations ...between Activity Measure for Post-Acute Care (AM-PAC) mobility categories and allocation of rehabilitation, and in-hospital AM-PAC score change and receipt of rehabilitation services for patients with COVID-19.
Methods
This was a retrospective cohort study of electronic health record data from 1 urban hospital, including adults with a COVID-19 diagnosis, admitted August 2020 to April 2021. Patients were stratified by level of medical care (intensive care unit ICU and floor). Therapy allocation (referral for rehabilitation, receipt of rehabilitation, and visit frequency) was the primary outcome; change in AM-PAC score was secondary. AM-PAC Basic Mobility categories (None 21–24, Minimum 18–21, Moderate 10–17, and Maximum 6–9) were the main predictor variable. Primary analysis included logistic and linear regression, adjusted for covariates.
Results
A total of 1397 patients (ICU: n = 360; floor: n = 1037) were included. AM-PAC mobility category was associated with therapy allocation outcomes for floor but not patients in the ICU: the Moderate category had greater adjusted odds of referral (adjusted odds ratio aOR = 10.88; 95% CI = 5.71–21.91), receipt of at least 1 visit (aOR = 3.45; 95% CI = 1.51–8.55), and visit frequency (percentage mean difference) (aOR = 42.14; 95% CI = 12.45–79.67). The secondary outcome of AM-PAC score improvement was highest for patients in the ICU who were given at least 1 rehabilitation therapy visit (aOR = 5.31; 95% CI = 1.90–15.52).
Conclusion
AM-PAC mobility categories were associated with rehabilitation allocation outcomes for floor patients. AM-PAC score improvement was highest among patients requiring ICU-level care with at least 1 rehabilitation therapy visit.
Impact
Use of AM-PAC Basic Mobility categories may help improve decisions for rehabilitation therapy allocation among patients who do not require critical care, particularly during times of limited resources.
Tissue- and cell-specific expression patterns are highly variable within and across individuals, leading to altered host responses after acute virus infection. Unraveling key tissue-specific response ...patterns provides novel opportunities for defining fundamental mechanisms of virus-host interaction in disease and the identification of critical tissue-specific networks for disease intervention in the lung. Currently, there are no approved therapeutics for Middle East respiratory syndrome coronavirus (MERS-CoV) patients, and little is understood about how lung cell types contribute to disease outcomes. MERS-CoV replicates equivalently in primary human lung microvascular endothelial cells (MVE) and fibroblasts (FB) and to equivalent peak titers but with slower replication kinetics in human airway epithelial cell cultures (HAE). However, only infected MVE demonstrate observable virus-induced cytopathic effect. To explore mechanisms leading to reduced MVE viability, donor-matched human lung MVE, HAE, and FB were infected, and their transcriptomes, proteomes, and lipidomes were monitored over time. Validated functional enrichment analysis demonstrated that MERS-CoV-infected MVE were dying via an unfolded protein response (UPR)-mediated apoptosis. Pharmacologic manipulation of the UPR in MERS-CoV-infected primary lung cells reduced viral titers and in male mice improved respiratory function with accompanying reductions in weight loss, pathological signatures of acute lung injury, and times to recovery. Systems biology analysis and validation studies of global kinetic transcript, protein, and lipid data sets confirmed that inhibition of host stress pathways that are differentially regulated following MERS-CoV infection of different tissue types can alleviate symptom progression to end-stage lung disease commonly seen following emerging coronavirus outbreaks.
Middle East respiratory syndrome coronavirus (MERS-CoV) causes severe atypical pneumonia in infected individuals, but the underlying mechanisms of pathogenesis remain unknown. While much has been learned from the few reported autopsy cases, an in-depth understanding of the cells targeted by MERS-CoV in the human lung and their relative contribution to disease outcomes is needed. The host response in MERS-CoV-infected primary human lung microvascular endothelial (MVE) cells and fibroblasts (FB) was evaluated over time by analyzing total RNA, proteins, and lipids to determine the cellular pathways modulated postinfection. Findings revealed that MERS-CoV-infected MVE cells die via apoptotic mechanisms downstream of the unfolded protein response (UPR). Interruption of enzymatic processes within the UPR in MERS-CoV-infected male mice reduced disease symptoms, virus-induced lung injury, and time to recovery. These data suggest that the UPR plays an important role in MERS-CoV infection and may represent a host target for therapeutic intervention.
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