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Conventionally, women are perceived to feel colder than men, but controlled comparisons are sparse. We measured the response of healthy, lean, young women and men to a range of ambient temperatures typical of the daily environment (17 to 31 °C). The Scholander model of thermoregulation defines the lower critical temperature as threshold of the thermoneutral zone, below which additional heat production is required to defend core body temperature. This parameter can be used to characterize the thermoregulatory phenotypes of endotherms on a spectrum from "arctic" to "tropical." We found that women had a cooler lower critical temperature (mean ± SD: 21.9 ± 1.3 °C vs. 22.9 ± 1.2 °C, P = 0.047), resembling an "arctic" shift compared to men. The more arctic profile of women was predominantly driven by higher insulation associated with more body fat compared to men, countering the lower basal metabolic rate associated with their smaller body size, which typically favors a "tropical" shift. We did not detect sex-based differences in secondary measures of thermoregulation including brown adipose tissue glucose uptake, muscle electrical activity, skin temperatures, cold-induced thermogenesis, or self-reported thermal comfort. In conclusion, the principal contributors to individual differences in human thermoregulation are physical attributes, including body size and composition, which may be partly mediated by sex.
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Regulação da Temperatura Corporal , Humanos , Feminino , Masculino , Regulação da Temperatura Corporal/fisiologia , Adulto , Regiões Árticas , Adulto Jovem , Tecido Adiposo Marrom/fisiologia , Tecido Adiposo Marrom/metabolismo , Caracteres Sexuais , Fatores Sexuais , Temperatura Corporal/fisiologia , Termogênese/fisiologia , Metabolismo Basal/fisiologiaRESUMO
Spatial transcriptomics technologies have shed light on the complexities of tissue structures by accurately mapping spatial microenvironments. Nonetheless, a myriad of methods, especially those utilized in platforms like Visium, often relinquish spatial details owing to intrinsic resolution limitations. In response, we introduce TransformerST, an innovative, unsupervised model anchored in the Transformer architecture, which operates independently of references, thereby ensuring cost-efficiency by circumventing the need for single-cell RNA sequencing. TransformerST not only elevates Visium data from a multicellular level to a single-cell granularity but also showcases adaptability across diverse spatial transcriptomics platforms. By employing a vision transformer-based encoder, it discerns latent image-gene expression co-representations and is further enhanced by spatial correlations, derived from an adaptive graph Transformer module. The sophisticated cross-scale graph network, utilized in super-resolution, significantly boosts the model's accuracy, unveiling complex structure-functional relationships within histology images. Empirical evaluations validate its adeptness in revealing tissue subtleties at the single-cell scale. Crucially, TransformerST adeptly navigates through image-gene co-representation, maximizing the synergistic utility of gene expression and histology images, thereby emerging as a pioneering tool in spatial transcriptomics. It not only enhances resolution to a single-cell level but also introduces a novel approach that optimally utilizes histology images alongside gene expression, providing a refined lens for investigating spatial transcriptomics.
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Perfilação da Expressão Gênica , Expressão GênicaRESUMO
Respiratory viral infections remain a leading cause of morbidity and mortality. Using a murine model of human metapneumovirus (HMPV), we identified recruitment of a C1q-expressing inflammatory monocyte population concomitant with viral clearance by adaptive immune cells. Genetic ablation of C1q led to reduced CD8+ T cell function. Production of C1q by a myeloid lineage was necessary to enhance CD8+ T cell function. Activated and dividing CD8+ T cells expressed a C1q receptor, gC1qR. Perturbation of gC1qR signaling led to altered CD8+ T cell IFN-γ production, metabolic capacity, and cell proliferation. Autopsy specimens from fatal respiratory viral infections in children demonstrated diffuse production of C1q by an interstitial population. Humans with severe COVID-19 infection also demonstrated upregulation of gC1qR on activated and rapidly dividing CD8+ T cells. Collectively, these studies implicate C1q production from monocytes as a critical regulator of CD8+ T cell function following respiratory viral infection. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).
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GDF15 (growth differentiation factor 15) is a stress cytokine with several proposed roles, including support of stress erythropoiesis. Higher circulating GDF15 levels are prognostic of mortality during acute respiratory distress syndrome, but the cellular sources and downstream effects of GDF15 during pathogen-mediated lung injury are unclear. We quantified GDF15 in lower respiratory tract biospecimens and plasma from patients with acute respiratory failure. Publicly available data from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection were reanalyzed. We used mouse models of hemorrhagic acute lung injury mediated by Pseudomonas aeruginosa exoproducts in wild-type mice and mice genetically deficient for Gdf15 or its putative receptor, Gfral. In critically ill humans, plasma levels of GDF15 correlated with lower respiratory tract levels and were higher in nonsurvivors. SARS-CoV-2 infection induced GDF15 expression in human lung epithelium, and lower respiratory tract GDF15 levels were higher in coronavirus disease (COVID-19) nonsurvivors. In mice, intratracheal P. aeruginosa type II secretion system exoproducts were sufficient to induce airspace and plasma release of GDF15, which was attenuated with epithelial-specific deletion of Gdf15. Mice with global Gdf15 deficiency had decreased airspace hemorrhage, an attenuated cytokine profile, and an altered lung transcriptional profile during injury induced by P. aeruginosa type II secretion system exoproducts, which was not recapitulated in mice deficient for Gfral. Airspace GDF15 reconstitution did not significantly modulate key lung cytokine levels but increased circulating erythrocyte counts. Lung epithelium releases GDF15 during pathogen injury, which is associated with plasma levels in humans and mice and can increase erythrocyte counts in mice, suggesting a novel lung-blood communication pathway.
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COVID-19 , Fator 15 de Diferenciação de Crescimento , Pulmão , Pseudomonas aeruginosa , SARS-CoV-2 , Fator 15 de Diferenciação de Crescimento/genética , Fator 15 de Diferenciação de Crescimento/metabolismo , Animais , COVID-19/metabolismo , COVID-19/virologia , Humanos , Camundongos , Pulmão/metabolismo , Pulmão/patologia , Pulmão/virologia , Masculino , Infecções por Pseudomonas/metabolismo , Lesão Pulmonar Aguda/patologia , Lesão Pulmonar Aguda/metabolismo , Feminino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mucosa Respiratória/metabolismo , Mucosa Respiratória/patologia , Modelos Animais de DoençasRESUMO
BACKGROUND: A ketogenic diet (KD) may benefit people with neurodegenerative disorders marked by mitochondrial depolarization/insufficiency, including Parkinson's disease (PD). OBJECTIVE: Evaluate whether a KD supplemented by medium chain triglyceride (MCT-KD) oil is feasible and acceptable for PD patients. Furthermore, we explored the effects of MCT-KD on blood ketone levels, metabolic parameters, levodopa absorption, mobility, nonmotor symptoms, simple motor and cognitive tests, autonomic function, and resting-state electroencephalography (rsEEG). METHODS: A one-week in-hospital, double-blind, randomized, placebo-controlled diet (MCT-KD vs. standard diet (SD)), followed by an at-home two-week open-label extension. The primary outcome was KD feasibility and acceptability. The secondary outcome was the change in Timed Up & Go (TUG) on day 7 of the diet intervention. Additional exploratory outcomes included the N-Back task, Unified Parkinson's Disease Rating Scale, Non-Motor Symptom Scale, and rsEEG connectivity. RESULTS: A total of 15/16 subjects completed the study. The mean acceptability was 2.3/3, indicating willingness to continue the KD. Day 7 TUG time was not significantly different between the SD and KD groups. The nonmotor symptom severity score was reduced at the week 3 visit and to a greater extent in the KD group. UPDRS, 3-back, and rsEEG measures were not significantly different between groups. Blood ketosis was attained by day 4 in the KD group and to a greater extent at week 3 than in the SD group. The plasma levodopa metabolites DOPAC and dopamine both showed nonsignificant increasing trends over 3 days in the KD vs. SD groups. CONCLUSIONS: An MCT-supplemented KD is feasible and acceptable to PD patients but requires further study to understand its effects on symptoms and disease. TRIAL REGISTRATION: Trial Registration Number NCT04584346, registration dates were Oct 14, 2020 - Sept 13, 2022.
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Dieta Cetogênica , Doença de Parkinson , Humanos , Estudos de Viabilidade , Levodopa , Triglicerídeos , Método Duplo-CegoRESUMO
OBJECTIVES: Low social standing and teasing are independently associated with increased body mass index (BMI) and overeating in children. However, children with low social status may be vulnerable to teasing. METHODS: We tested the statistical interaction of subjective social status (SSS) and subjective socioeconomic status (SSES) and teasing distress on BMI, fat mass index (FMI), and eating in the absence of hunger (EAH) in children (Mage = 13.09 years, SD = 2.50 years; 27.8% overweight/obese). Multiple linear regressions identified the main effects of self-reported SSS (compared to peers in school), distress due to teasing, and theirâ¯interaction on BMI (n = 115), FMI (n = 114), and child- (n = 100) and parent-reported (n = 97) EAH. RESULTS: Teasing distress was associated with greater BMI, FMI, and child-reported EAH due to negative affect (a subscale of EAH) and total EAH scores. There were no associations of SSS with these outcomes. However, there was an interaction between SSS and teasing distress for BMI, FMI, and EAH from negative affect such that lower SSS was associated with higher BMI, FMI, and EAH from negative affect in the presence of teasing distress. However, there were no main effects or interactions (with teasing distress) of SSES on the outcomes. CONCLUSIONS: These findings suggest that the relationship between lower SSS and increased adiposity and overeating behaviors may be exacerbated by other threats to social standing, such as teasing. Children exposed to multiple social threats may be more susceptible to eating beyond physiological need and obesity than those who experience a single form of perceived social disadvantage.
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Adiposidade , Índice de Massa Corporal , Autorrelato , Humanos , Feminino , Masculino , Adolescente , Adiposidade/fisiologia , Criança , Bullying/psicologia , Status Social , Fome , Obesidade Infantil/psicologia , Comportamento Alimentar/psicologia , Afeto , Angústia PsicológicaRESUMO
Background and aims: Gender differences in the written language of autistic individuals are an overlooked but important area of research. We contend that the gender differences in spoken language of autistic individuals may extend to written language, mirroring the gender differences of writing in the general population and reflecting the shared dimensionality of oral and written language. Our research question was: Do autistic adolescent females demonstrate written language characteristics, across persuasive, expository, and narrative genres, that are distinct from those of autistic adolescent males and non-autistic (NA) adolescent females? Methods: We performed a secondary, exploratory analysis on writing samples collected from 18 participants (11 autistic males, three autistic females, and four NA females) from a larger investigation of autistic adolescents' writing skills. Each participant completed three writing samples-one persuasive, one expository, and one narrative (for a total of 54 writing samples). We compared sample length (total number of words), writing productivity (words written per minute), syntactic length (mean length of T-unit in words), vocabulary diversity (type-token ratio), and macrostructure of autistic females' samples to autistic males' and NA females' samples. Results: Based on non-parametric analyses using variable medians, autistic males, but not autistic females, wrote significantly shorter expository samples than NA females. Autistic males' writing productivity was significantly lower in the persuasive and expository genres than both autistic females and NA females. Several other comparisons of sample length, productivity, vocabulary diversity, and persuasive and narrative macrostructure yielded large effect sizes but were not statistically significant. Conclusions: Though our small sample sizes prevent us from drawing generalizable conclusions, we observed that some gender-specific findings of the current study differ from previous findings based on a single autistic group (females and males combined). Combining data of autistic females with autistic males may cloud the distinct written language characteristics of each group. Implications: Our findings, especially when situated in the context of relevant literature, suggest that larger-scale investigation of gender differences in written language is essential in order to more fully describe the unique characteristics of autistic females. Clinicians should be prepared to support autistic writers' needs for producing written language to meet their developmental, academic, social, and employment-related goals.
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BACKGROUND: Lifting of masking restrictions at key periods during the COVID-19 pandemic may have disproportionately negatively impacted the mental health of individuals with disabilities. OBJECTIVE: This study examines the prevalence of depression-related symptoms in individuals with and without disabilities preceding and following the US rollback of COVID-19 masking mandates. METHODS: Pandemic-era data on reported symptoms of depression from the federal Household Pulse Survey from dates surrounding two major announcements on masking relaxations were analyzed. Possible interactions between disability status and type, age grouping, educational attainment, race/Hispanic ethnicity, and sex variables were considered. RESULTS: Following relaxation of major masking restrictions, people with disabilities experienced elevation in depression symptom presence while people without disabilities experienced lessening in these symptoms. Differences between people with and without disabilities were significant. CONCLUSIONS: Direct causation between masking mandate relaxations and changes in symptoms of depression cannot be drawn from the available data. However, when considered with greater vulnerabilities to COVID-19 experienced by many individuals with disabilities and dismissive rhetoric surrounding masking decisions, negative feelings arising from mandate changes may have led to elevations in symptoms of depression in people with disabilities in sharp contrast to people without disabilities who may have felt relief. Findings indicate future public health decision making, even in times of crisis, should be undertaken with as much caution as possible regarding and in partnership with populations already at risk.
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COVID-19 , Depressão , Pessoas com Deficiência , Máscaras , SARS-CoV-2 , Humanos , COVID-19/psicologia , COVID-19/epidemiologia , Pessoas com Deficiência/psicologia , Pessoas com Deficiência/estatística & dados numéricos , Depressão/epidemiologia , Adulto , Masculino , Feminino , Pessoa de Meia-Idade , Estados Unidos/epidemiologia , Adulto Jovem , Idoso , Adolescente , Prevalência , Pandemias , Saúde MentalRESUMO
To achieve rapid detection of enramycin in feed, we employed the competitive inhibition method to develop a colloidal gold immunochromatographic test strip based on the anti-enramycin A monoclonal antibody (anti-Er.A-mAb). Colloidal gold probes were prepared with a laboratory-prepared high-purity anti-Er.A-mAb. The effects of pH, antibody titer, and antigen concentration (test line) on the test strip performance were investigated. The colloidal gold test strip prepared with 8 µL potassium carbonate addition, 4 µg/mL antibody, 1.0 mg/mL antigen (test line), and 3 µL gold-labeled antibody showed acceptable specificity and a low limit of detection. The test strip showed the detection limit of 25 ng/mL for enramycin A, with a linear range of 25-300 ng/mL. The experiments on the feed with positive sample addition proved that the test strip had good repeatability and was more sensitive than high-performance liquid chromatography, being applicable for the rapid detection of enramycin in large batches of feed samples.
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Ração Animal , Anticorpos Monoclonais , Cromatografia de Afinidade , Coloide de Ouro , Coloide de Ouro/química , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/química , Cromatografia de Afinidade/métodos , Ração Animal/análise , Nebramicina/análise , Nebramicina/análogos & derivados , Contaminação de Alimentos/análise , Resíduos de Drogas/análiseRESUMO
This study aimed to investigate how the decomposing scale effect, technique effect and composition effect of foreign direct investment (FDI) impact on carbon dioxide (CO2) emissions for 115 nations spanning 1999 to 2019 by employing Generalised Method of Moments (GMM) model. The results indicated that FDI, real GDP per capita, capital-labor ratio, institutional quality and urbanization increase CO2 emissions while the square of real GDP per capita and trade openness contributed to reducing CO2 emissions. Also, our findings fail to support Environmental Kuznets Curve (EKC) theory. The outcomes of this research illustrated that scale effect dominates composition effect and followed by technique effect. The interaction effect of FDI and technique effect has the least influence on CO2 levels in reducing the harmful effects of FDI on CO2. Furthermore, it should be highlighted that although FDI increases CO2 emissions, its detrimental impact on CO2 emissions is moderately mitigated by its interactions with three economic mechanisms. Therefore, it is necessary to enhance the technical processes of production as well as the development of modern technologies. We recommended that policymakers balance sustainable economic development with environmental sustainability by considering the indirect effects of factors on CO2 emissions.
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Dióxido de Carbono , Investimentos em Saúde , Dióxido de Carbono/análise , Desenvolvimento Econômico , Meio AmbienteRESUMO
Klebsiella pneumoniae (KP) presents a global health threat, leading to significant morbidity and mortality due to its multidrug-resistant profile and the limited availability of therapeutic options. To eliminate KP lung infection, the host initiates a robust inflammatory response. One of the host's mechanisms for mitigating excessive inflammation involves the RNA-binding protein regnase-1 (Reg1, MCPIP1, or ZC3H12A). Reg1 has an RNA binding domain that recognizes stem-loop structures in the 3' untranslated region of various proinflammatory transcripts, leading to mRNA decay. However, excessive suppression of inflammation by Reg1 results in suboptimal KP control. Reg1 deficiency within the nonhematopoietic compartment confers resistance to KP in the lung. Given that lung epithelium is crucial for KP resistance, we hypothesized that selective deletion of Reg1 in lung epithelial cells might enhance proinflammatory signals, leading to a better control of KP. Our transcriptomic analysis of epithelial cells in KP-infected wild-type mice revealed the presence of three distinct alveolar type 2 cell (AT2) subpopulations (conventional, inflammatory, and cycling) and enrichment of Reg1 in inflammatory AT2 cells. We conditionally deleted Reg1 in lung AT2 cells (ΔReg1), which amplified the local inflammatory response in the lung and increased macrophage cell numbers compared with controls. However, when ΔReg1 mice were subjected to KP infection, there were no significant differences in bacterial burden or survival compared with controls. These findings suggest that the local inflammatory response enhanced by Reg1 deletion in AT2 cells is insufficient to control KP infection.
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Células Epiteliais , Klebsiella pneumoniae , Ribonucleases , Animais , Camundongos , Regiões 3' não Traduzidas , Inflamação , Pulmão , Ribonucleases/genéticaRESUMO
Our circadian world shapes much of metabolic physiology. In mice â¼40% of the light and â¼80% of the dark phase time is characterized by bouts of increased energy expenditure (EE). These ultradian bouts have a higher body temperature (Tb) and thermal conductance and contain virtually all of the physical activity and awake time. Bout status is a better classifier of mouse physiology than photoperiod, with ultradian bouts superimposed on top of the circadian light/dark cycle. We suggest that the primary driver of ultradian bouts is a brain-initiated transition to a higher defended Tb of the active/awake state. Increased energy expenditure from brown adipose tissue, physical activity, and cardiac work combine to raise Tb from the lower defended Tb of the resting/sleeping state. Thus, unlike humans, much of mouse metabolic physiology is episodic with large ultradian increases in EE and Tb that correlate with the active/awake state and are poorly aligned with circadian cycling.
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Temperatura Corporal , Ritmo Circadiano , Metabolismo Energético , Fotoperíodo , Ritmo Ultradiano , Animais , Camundongos , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Marrom/fisiologia , Temperatura Corporal/fisiologia , Ritmo Circadiano/fisiologia , Metabolismo Energético/fisiologia , Sono/fisiologia , Ritmo Ultradiano/fisiologia , Vigília/fisiologiaRESUMO
We tested whether spontaneous physical activity (SPA) from accelerometers could be used in a whole room calorimeter to estimate thermic effect of food (TEF). Eleven healthy participants (n = 7 females; age: 27 ± 4 yr; body mass index: 22.8 ± 2.6 kg/m2) completed two 23-h visits in randomized order: one "fed" with meals provided and one "fasted" with no food. SPA was measured by ActivPAL and Actigraph accelerometers. Criterion TEF was calculated as the difference in total daily energy expenditure (TDEE) between fed and fasted visits and compared with three methods of estimating TEF: 1) SPA-adjusted TEF (adjTEF)-difference in TDEE without SPA between visits, 2) Wakeful TEF-difference in energy expenditure obtained from linear regression and basal metabolic rate during waking hours, 3) 24-h TEF-increase in TDEE above SPA and sleeping metabolic rate. Criterion TEF was 9.4 ± 4.5% of TDEE. AdjTEF (difference in estimated vs. criterion TEF: activPAL: -0.3 ± 3.3%; Actigraph: -1.8 ± 8.0%) and wakeful TEF (activPAL: -0.9 ± 6.1%; Actigraph: -2.8 ± 7.6%) derived from both accelerometers did not differ from criterion TEF (all P > 0.05). ActivPAL-derived 24-h TEF overestimated TEF (6.8 ± 5.4%, P = 0.002), whereas Actigraph-derived 24-h TEF was not significantly different (4.3 ± 9.4%, P = 0.156). TEF estimations using activPAL tended to show better individual-level agreement (i.e., smaller coefficients of variation). Both accelerometers can be used to estimate TEF in a whole room calorimeter; wakeful TEF using activPAL is the most viable option given strong group-level accuracy and reasonable individual agreement.NEW & NOTEWORTHY Two research-grade accelerometers can effectively estimate spontaneous physical activity and improve the estimation of thermic effect of food (TEF) in whole room calorimeters. The activPAL demonstrates strong group-level accuracy and reasonable individual-level agreement in estimating wakeful TEF, whereas a hip-worn Actigraph is an acceptable approach for estimating 24-h TEF. These results highlight the promising potential of accelerometers in advancing energy balance research by improving the assessment of TEF within whole room calorimeters.
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Acelerometria , Metabolismo Energético , Exercício Físico , Humanos , Feminino , Adulto , Masculino , Acelerometria/métodos , Acelerometria/instrumentação , Metabolismo Energético/fisiologia , Exercício Físico/fisiologia , Calorimetria/métodos , Adulto Jovem , Jejum/fisiologia , Calorimetria Indireta/métodos , Metabolismo Basal/fisiologia , AlimentosRESUMO
Human metapneumovirus (HMPV) is a primary cause of acute respiratory infection, yet there are no approved vaccines or antiviral therapies for HMPV. Early host responses to HMPV are poorly characterized, and further understanding could identify important antiviral pathways. Type III interferon (IFN-λ) displays potent antiviral activity against respiratory viruses and is being investigated for therapeutic use. However, its role in HMPV infection remains largely unknown. Here, we show that IFN-λ is highly upregulated during HMPV infection in vitro in human and mouse airway epithelial cells and in vivo in mice. We found through several immunological and molecular assays that type II alveolar cells are the primary producers of IFN-λ. Using mouse models, we show that IFN-λ limits lung HMPV replication and restricts virus spread from upper to lower airways but does not contribute to clinical disease. Moreover, we show that IFN-λ signaling is predominantly mediated by CD45- non-immune cells. Mice lacking IFN-λ signaling showed diminished loss of ciliated epithelial cells and decreased recruitment of lung macrophages in early HMPV infection along with higher inflammatory cytokine and interferon-stimulated gene expression, suggesting that IFN-λ may maintain immunomodulatory responses. Administration of IFN-λ for prophylaxis or post-infection treatment in mice reduced viral load without inflammation-driven weight loss or clinical disease. These data offer clinical promise for IFN-λ in HMPV treatment. IMPORTANCE: Human metapneumovirus (HMPV) is a common respiratory pathogen and often contributes to severe disease, particularly in children, immunocompromised people, and the elderly. There are currently no licensed HMPV antiviral treatments or vaccines. Here, we report novel roles of host factor IFN-λ in HMPV disease that highlight therapeutic potential. We show that IFN-λ promotes lung antiviral responses by restricting lung HMPV replication and spread from upper to lower airways but does so without inducing lung immunopathology. Our data uncover recruitment of lung macrophages, regulation of ciliated epithelial cells, and modulation of inflammatory cytokines and interferon-stimulated genes as likely contributors. Moreover, we found these roles to be distinct and non-redundant, as they are not observed with knockout of, or treatment with, type I IFN. These data elucidate unique antiviral functions of IFN-λ and suggest IFN-λ augmentation as a promising therapeutic for treating HMPV disease and promoting effective vaccine responses.
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Interferon lambda , Pulmão , Metapneumovirus , Infecções por Paramyxoviridae , Replicação Viral , Animais , Humanos , Camundongos , Antivirais/farmacologia , Modelos Animais de Doenças , Células Epiteliais/virologia , Células Epiteliais/imunologia , Interferon lambda/imunologia , Interferon lambda/farmacologia , Interferons/imunologia , Interferons/farmacologia , Pulmão/imunologia , Pulmão/virologia , Metapneumovirus/imunologia , Metapneumovirus/genética , Camundongos Endogâmicos C57BL , Infecções por Paramyxoviridae/imunologia , Infecções por Paramyxoviridae/virologia , Replicação Viral/efeitos dos fármacosRESUMO
BACKGROUND: Up to 50% of adolescents who undergo metabolic and bariatric surgery (MBS) have obesity 3 years post-MBS, placing them at continued risk for the consequences of obesity. OBJECTIVES: We conducted an open-label, 16-week pilot study of liraglutide in adolescents with obesity after sleeve gastrectomy (SG) to investigate liraglutide effects on weight and body mass index (BMI) post-SG. METHODS: Adolescents aged 12-20.99 years with obesity and a history of SG ≥1 year prior were enrolled. Liraglutide was initiated at 0.6 mg/day, escalated weekly to a maximum of 3 mg/day, with treatment duration 16 weeks. Fasting laboratory assessments and an oral glucose tolerance test were performed at baseline and end-treatment. RESULTS: A total of 43 participants were screened, 34 initiated liraglutide (baseline BMI 41.2 ± 7.7 kg/m2), and 31 (91%) attended the end-treatment visit. BMI decreased by 4.3% (p < 0.001) with liraglutide. Adolescents who had poor initial response to SG (<20% BMI reduction at BMI nadir) had less weight loss with liraglutide. Fasting glucose and haemoglobin A1C concentrations significantly decreased. There were no serious treatment-emergent adverse events reported. CONCLUSIONS: Liraglutide treatment was feasible and associated with a BMI reduction of 4.3% in adolescents who had previously undergone SG, quantitatively similar to results obtained in adolescents with obesity who have not undergone MBS.
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Respiratory infection by Pseudomonas aeruginosa, common in hospitalized immunocompromised and immunocompetent ventilated patients, can be life-threatening because of antibiotic resistance. This raises the question of whether the host's immune system can be educated to combat this bacterium. Here we show that prior exposure to a single low dose of lipopolysaccharide (LPS) protects mice from a lethal infection by P. aeruginosa. LPS exposure trained the innate immune system by promoting expansion of neutrophil and interstitial macrophage populations distinguishable from other immune cells with enrichment of gene sets for phagocytosis- and cell-killing-associated genes. The cell-killing gene set in the neutrophil population uniquely expressed Lgals3, which encodes the multifunctional antibacterial protein, galectin-3. Intravital imaging for bacterial phagocytosis, assessment of bacterial killing and neutrophil-associated galectin-3 protein levels together with use of galectin-3-deficient mice collectively highlight neutrophils and galectin-3 as central players in LPS-mediated protection. Patients with acute respiratory failure revealed significantly higher galectin-3 levels in endotracheal aspirates (ETAs) of survivors compared to non-survivors, galectin-3 levels strongly correlating with a neutrophil signature in the ETAs and a prognostically favorable hypoinflammatory plasma biomarker subphenotype. Taken together, our study provides impetus for harnessing the potential of galectin-3-expressing neutrophils to protect from lethal infections and respiratory failure.
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Galectina 3 , Lipopolissacarídeos , Camundongos Endogâmicos C57BL , Neutrófilos , Infecções por Pseudomonas , Pseudomonas aeruginosa , Animais , Galectina 3/metabolismo , Galectina 3/genética , Neutrófilos/imunologia , Neutrófilos/metabolismo , Humanos , Camundongos , Infecções por Pseudomonas/imunologia , Masculino , Feminino , Insuficiência Respiratória/metabolismo , Camundongos Knockout , Fagocitose , Imunidade Inata , Galectinas/metabolismo , Galectinas/genéticaRESUMO
Klebsiella pneumoniae (KP) is an extracellular Gram-negative bacterium that causes infections in the lower respiratory and urinary tracts and the bloodstream. STAT1 is a master transcription factor that acts to maintain T cell quiescence under homeostatic conditions. Although STAT1 helps defend against systemic spread of acute KP intrapulmonary infection, whether STAT1 regulation of T cell homeostasis impacts pulmonary host defense during acute bacterial infection and injury is less clear. Using a clinical KP respiratory isolate and a pneumonia mouse model, we found that STAT1 deficiency led to an early neutrophil-dominant transcriptional profile and neutrophil recruitment in the lung preceding widespread bacterial dissemination and lung injury development. Yet, myeloid cell STAT1 was dispensable for control of KP proliferation and dissemination, because myeloid cell-specific STAT1-deficient (LysMCre/WT;Stat1fl/fl) mice showed bacterial burden in the lung, liver, and kidney similar to that of their wild-type littermates. Surprisingly, IL-17-producing CD4+ T cells infiltrated Stat1-/- murine lungs early during KP infection. The increase in Th17 cells in the lung was not due to preexisting immunity against KP and was consistent with circulating rather than tissue-resident CD4+ T cells. However, blocking global IL-17 signaling with anti-IL-17RC administration led to increased proliferation and dissemination of KP, suggesting that IL-17 provided by other innate immune cells is essential in defense against KP. Contrastingly, depletion of CD4+ T cells reduced Stat1-/- murine lung bacterial burden, indicating that early CD4+ T cell activation in the setting of global STAT1 deficiency is pathogenic. Altogether, our findings suggest that STAT1 employs myeloid cell-extrinsic mechanisms to regulate neutrophil responses and provides protection against invasive KP by restricting nonspecific CD4+ T cell activation and immunopathology in the lung.
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Infecções por Klebsiella , Neutrófilos , Fator de Transcrição STAT1 , Animais , Camundongos , Interleucina-17 , Klebsiella pneumoniae , Pulmão/microbiologia , Células Mieloides , Neutrófilos/imunologia , Fator de Transcrição STAT1/metabolismo , Infecções por Klebsiella/imunologiaRESUMO
Dieting is theorized as a risk factor for loss-of-control (LOC)-eating (i.e., feeling a sense of lack of control while eating). Support for this association has largely relied on retrospective self-report data, which does not always correlate with objectively assessed eating behavior in youth. We hypothesized that during a laboratory-based LOC-eating paradigm, children and adolescents who reported current (at the time of the visit) dieting would consume meals consistent with LOC-eating (greater caloric intake, and intake of carbohydrates and fats, but less intake of protein). Participants were presented with a buffet-style meal and instructed to "Let yourself go and eat as much as you want." Current dieting (i.e., any deliberate change to the amount or type of food eaten to influence shape or weight, regardless of how effective the changes are) was assessed via interview. General linear models were adjusted for fat mass (%), lean mass (kg), height, sex, protocol, race and ethnicity, pre-meal hunger and minutes since consumption of a breakfast shake. Of 337 participants (Mage 12.8 ± 2.7y; 62.3 % female; 45.7 % non- Hispanic White and 26.1 % non-Hispanic Black; MBMIz 0.78 ± 1.11), only 33 (9.8 %) reported current dieting. Current dieting was not significantly associated with total energy intake (F = 1.63, p = .20, ηp2 = 0.005), or intake from carbohydrates (F = 2.45, p = .12, ηp2 = 0.007), fat (F = 2.65, p = .10, ηp2 = 0.008), or protein (F = 0.39, p = .53, ηp2 = 0.001). Contrary to theories that dieting promotes LOC-eating, current dieting was not associated with youth's eating behavior in a laboratory setting. Experimental approaches for investigating dieting are needed to test theories that implicate dieting in pediatric LOC-eating.
Assuntos
Ingestão de Energia , Comportamento Alimentar , Humanos , Feminino , Masculino , Ingestão de Energia/fisiologia , Adolescente , Comportamento Alimentar/psicologia , Criança , Dieta Redutora/psicologia , Autocontrole/psicologia , Refeições/psicologiaRESUMO
Diabetes Technology Society hosted its annual Diabetes Technology Meeting from November 1 to November 4, 2023. Meeting topics included digital health; metrics of glycemia; the integration of glucose and insulin data into the electronic health record; technologies for insulin pumps, blood glucose monitors, and continuous glucose monitors; diabetes drugs and analytes; skin physiology; regulation of diabetes devices and drugs; and data science, artificial intelligence, and machine learning. A live demonstration of a personalized carbohydrate dispenser for people with diabetes was presented.
RESUMO
A distinct adipose tissue distribution pattern was observed in patients with methylmalonyl-CoA mutase deficiency, an inborn error of branched-chain amino acid (BCAA) metabolism, characterized by centripetal obesity with proximal upper and lower extremity fat deposition and paucity of visceral fat, that resembles familial multiple lipomatosis syndrome. To explore brown and white fat physiology in methylmalonic acidemia (MMA), body composition, adipokines, and inflammatory markers were assessed in 46 patients with MMA and 99 matched controls. Fibroblast growth factor 21 levels were associated with acyl-CoA accretion, aberrant methylmalonylation in adipose tissue, and an attenuated inflammatory cytokine profile. In parallel, brown and white fat were examined in a liver-specific transgenic MMA mouse model (Mmut-/- TgINS-Alb-Mmut). The MMA mice exhibited abnormal nonshivering thermogenesis with whitened brown fat and had an ineffective transcriptional response to cold stress. Treatment of the MMA mice with bezafibrates led to clinical improvement with beiging of subcutaneous fat depots, which resembled the distribution seen in the patients. These studies defined what we believe to be a novel lipodystrophy phenotype in patients with defects in the terminal steps of BCAA oxidation and demonstrated that beiging of subcutaneous adipose tissue in MMA could readily be induced with small molecules.