Human SARS-CoV-2 challenge uncovers local and systemic response dynamics.

The COVID-19 pandemic is an ongoing global health threat, yet our understanding of the dynamics of early cellular responses to this disease remains limited1. Here in our SARS-CoV-2 human challenge study, we used single-cell multi-omics profiling of nasopharyngeal swabs and blood to temporally resolve abortive, transient and sustained infections in seronegative individuals challenged with pre-Alpha SARS-CoV-2. Our analyses revealed rapid changes in cell-type proportions and dozens of highly dynamic cellular response states in epithelial and immune cells associated with specific time points and infection status. We observed that the interferon response in blood preceded the nasopharyngeal response. Moreover, nasopharyngeal immune infiltration occurred early in samples from individuals with only transient infection and later in samples from individuals with sustained infection. High expression of HLA-DQA2 before inoculation was associated with preventing sustained infection. Ciliated cells showed multiple immune responses and were most permissive for viral replication, whereas nasopharyngeal T cells and macrophages were infected non-productively. We resolved 54 T cell states, including acutely activated T cells that clonally expanded while carrying convergent SARS-CoV-2 motifs. Our new computational pipeline Cell2TCR identifies activated antigen-responding T cells based on a gene expression signature and clusters these into clonotype groups and motifs. Overall, our detailed time series data can serve as a Rosetta stone for epithelial and immune cell responses and reveals early dynamic responses associated with protection against infection.

Vacuolar ATPase-mediated regulation of neutral lipid dynamics: Insights into lipid droplet homeostasis and stress response mechanisms.

This study explores the intricate relationship between the yeast vacuolar H+-ATPase (V-ATPase) and neutral lipid metabolism. We show that LD generation observed upon loss of V-ATPase activity is crucial for survival in lipotoxic conditions. Moreover, the study uncovers a link between V-ATPase function, inositol metabolism and the activation of the oxidative pentose phosphate pathway, highlighting its pivotal role in counteracting oxidative stress. This work provides foundational insights into metabolic adaptations triggered by V-ATPase dysfunction, shedding light on cellular adaptability under lipotoxic and oxidative stress conditions.

The effect of menthol rinsing before intermittent exercise on physiological, physical, and thermo-behavioral responses of male football referees in hot and humid environment.

Introduction: In the current experiment, we aimed to evaluate whether eliciting pre-exercise non-thermal cooling sensations would alter perceptual measures, and physical and physiological responses in football referees. Methods: Nine highly trained male football referees undertook two 45-minute intermittent exercise protocols in hot and humid conditions (34.2 ± 0.6°C, 62.5 ± 1.0% relative humidity). In a randomized counterbalanced crossover design, 1 of 2 beverages were given before the warm-up: a 0.01% menthol solution or a placebo noncaloric solution. Physical performance was quantified as total distance covered in each of the three 15-minute exercise blocks. Core temperature, heart rate, thermal sensation and thermal comfort were measured at rest and after each exercise block. Results: No changes were observed between trials and over time for distance covered. No main effect of mouth rinse was observed for core temperature and heart rate, but both increased over time in all conditions (P < 0.001). Thermal sensation and thermal comfort were significantly improved with menthol after mouth-rinsing (P < 0.05), but with no differences at any other time-point. Discussion: These results indicate that non-thermal cooling oral stimuli provide immediate behavioral changes but may not influence physiological or physical responses in football referees, during intermittent exercise in hot and humid environments. Clinical Trial Registration: www.clinicaltrials.gov, identifier NCT05632692.

Endobronchial Ulceration: A Different Manifestation of Antineutrophil Cytoplasmic Antibodies (ANCA)-Associated Vasculitis.

Vasculitis with pulmonary involvement is often associated with antineutrophil cytoplasmic antibody (ANCA). We describe a case involving a 66-year-old male patient diagnosed with granulomatosis with polyangiitis (GPA). Following the onset of hemoptysis, bronchoscopy revealed endobronchial ulcers correlated with GPA. Bronchial biopsies and bronchoalveolar lavage identified Staphylococcus aureus (S. aureus), which is associated with GPA relapses. The patient began immunosuppression to induce remission, and Avacopan was subsequently introduced for the treatment of GPA and microscopic polyangiitis (MPA).

Eight Weeks of Intermittent Exercise in Hypoxia, with or without a Low-Carbohydrate Diet, Improves Bone Mass and Functional and Physiological Capacity in Older Adults with Type 2 Diabetes.

In an increasingly aging and overweight population, osteoporosis and type 2 diabetes (T2DM) are major public health concerns. T2DM patients experience prejudicial effects on their bone health, affecting their physical capacity. Exercise in hypoxia (EH) and a low-carbohydrate diet (LCD) have been suggested for therapeutic benefits in T2DM, improving bone mineral content (BMC) and glycemic control. This study investigated the effects of EH combined with an LCD on body composition and functional and physiologic capacity in T2DM patients. Older T2DM patients (n = 42) were randomly assigned to the following groups: (1) control group: control diet + exercise in normoxia; (2) EH group: control diet + EH; (3) intervention group: LCD + EH. Cardiopulmonary tests (BRUCE protocol), body composition (DEXA), and functional capacity (6MWT, handgrip strength) were evaluated. Body mass index (kg/m2) and body fat (%) decreased in all groups (p < 0.001). BMC (kg) increased in all groups (p < 0.001) and was significantly higher in the EH and EH + LCD groups (p < 0.001). VO2peak improved in all groups (p < 0.001), but more so in the hypoxia groups (p = 0.019). Functional capacity was increased in all groups (p < 0.001), but more so in the EH group in 6MWT (p = 0.030). EH with and without an LCD is a therapeutic strategy for improving bone mass in T2DM, which is associated with cardiorespiratory and functional improvements.

Trends and Missing Links in (De)Hydration Research: A Narrative Review.

Despite decades of literature on (de)hydration in healthy individuals, many unanswered questions remain. To outline research and policy priorities, it is fundamental to recognize the literature trends on (de)hydration and identify current research gaps, which herein we aimed to pinpoint. From a representative sample of 180 (de)hydration studies with 4350 individuals, we found that research is mainly limited to small-scale laboratory-based sample sizes, with high variability in demographics (sex, age, and level of competition); to non-ecological (highly simulated and controlled) conditions; and with a focus on recreationally active male adults (e.g., Tier 1, non-athletes). The laboratory-simulated environments are limiting factors underpinning the need to better translate scientific research into field studies. Although, consistently, dehydration is defined as the loss of 2% of body weight, the hydration status is estimated using a very heterogeneous range of parameters. Water is the most researched hydration fluid, followed by alcoholic beverages with added carbohydrates (CHO). The current research still overlooks beverages supplemented with proteins, amino acids (AA), and glycerol. Future research should invest more effort in "real-world" studies with larger and more heterogeneous cohorts, exploring the entire available spectrum of fluids while addressing hydration outcomes more harmoniously.

Anxiety and depression in patients with giant cell arteritis.

Objectives: To compare the prevalence of anxiety and depression in patients with GCA with that in the general population, using the Hospital Anxiety and Depression Scale (HADS), and to identify independent predictors of these psychiatric manifestations in patients with GCA. Methods: We conducted a cross-sectional study including all patients diagnosed with GCA followed during 1 year in a vasculitis outpatient clinic. The HADS and 36-item Short Form (SF-36) questionnaires were prospectively collected. Patients' HADS results were compared with an age- and gender-matched control group. HADS anxiety (HADS-A) and HADS depression (HADS-D) scores between 8 and 10 defined possible anxiety and depression and ≥11 defined probable anxiety and depression, respectively. Results: We included 72 patients and 288 controls. Compared with controls, patients with GCA had a statistically significant higher prevalence of HADS-A ≥8 (48.6% vs 26.4%), HADS-A ≥11 (30.6% vs 12.2%) and HADS-D ≥11 (33.3% vs 18.1%). GCA was an independent predictor of HADS-A ≥8 [odds ratio (OR) 3.3 (95% CI 1.9, 5.9)], HADS-A ≥11 [OR 3.8 (95% CI 2.0, 7.4)] and HADS-D ≥11 [OR 2.6 (95% CI 1.4, 4.7)]. Among patients with GCA, a negative correlation was observed between HADS-A/D and SF-36 mental health scores (r = -0.780 and r = -0.742, respectively). Glucocorticoid therapy was a predictor of HADS-A ≥8 [OR 10.4 (95% CI 1.2, 94.2)] and older age of HADS-D ≥8 [OR 1.2 (95% CI 1.1, 1.3)] and HADS-D ≥11 [OR 1.1 (95% CI 1.0, 1.2)]. Conclusions: Compared with the general population, patients with GCA have a higher prevalence of anxiety and depression and GCA is an independent predictor of these symptoms. Glucocorticoid treatment and older age are predictors of anxiety and depression, respectively, in patients with GCA.

Portuguese Recommendations for the management of Raynaud's phenomenon and digital ulcers in systemic sclerosis and other connective tissue diseases.

OBJECTIVE: To develop evidence-based recommendations for the non-pharmacological and pharmacological management of Raynaud's phenomenon (RP) and digital ulcers (DUs) in patients with systemic sclerosis and other immune-mediated connective tissue diseases (CTDs). METHODS: A task force comprising 21 rheumatologists, two surgeons (vascular and plastic), two nurses, and one patient representative was established. Following a systematic literature review performed to inform the recommendations, statements were formulated and discussed during two meetings (one online and one in-person). Levels of evidence, grades of recommendation (GoR), and level of agreement (LoA) were determined. RESULTS: Five overarching principles and 13 recommendations were developed. GoR ranged from A to D. The mean ± standard difference (SD) LoA with the overarching principles and recommendations ranged from 7.8±2.1 to 9.8±0.4. Briefly, the management of RP and DUs in patients with CTDs should be coordinated by a multidisciplinary team and based on shared decisions with patients. Nifedipine should be used as first-line therapy for RP and/or DUs. Sildenafil, tadalafil, and/or iloprost IV are second-line options for severe and/or refractory patients with RP and/or DUs. Sildenafil, tadalafil and/or Iloprost IV, should be prescribed for healing and prevention (also including bosentan) of DUs. In patients with RP and/or DUs, non-pharmacological interventions might be considered as add-ons, but there is limited quality and quantity of scientific evidence supporting their use. CONCLUSIONS: These recommendations will inform rheumatologists, specialist nurses, other healthcare professionals, and patients about a comprehensive and personalized management of RP and DUs. A research agenda was developed to address unmet needs, particularly for non-pharmacologic interventions.

Early human lung immune cell development and its role in epithelial cell fate.

Studies of human lung development have focused on epithelial and mesenchymal cell types and function, but much less is known about the developing lung immune cells, even though the airways are a major site of mucosal immunity after birth. An unanswered question is whether tissue-resident immune cells play a role in shaping the tissue as it develops in utero. Here, we profiled human embryonic and fetal lung immune cells using scRNA-seq, smFISH, and immunohistochemistry. At the embryonic stage, we observed an early wave of innate immune cells, including innate lymphoid cells, natural killer cells, myeloid cells, and lineage progenitors. By the canalicular stage, we detected naive T lymphocytes expressing high levels of cytotoxicity genes and the presence of mature B lymphocytes, including B-1 cells. Our analysis suggests that fetal lungs provide a niche for full B cell maturation. Given the presence and diversity of immune cells during development, we also investigated their possible effect on epithelial maturation. We found that IL-1ß drives epithelial progenitor exit from self-renewal and differentiation to basal cells in vitro. In vivo, IL-1ß-producing myeloid cells were found throughout the lung and adjacent to epithelial tips, suggesting that immune cells may direct human lung epithelial development.

Bioethanol production with different dosages of the commercial Acrylamide polymer compared to a Bioextract in clarifying sugarcane juice

ABSTRACT One of the most important steps is to clarify the juice, which are added synthetic polymer acrylamide base, aiming the fast settling of impurities present in the juice. However, this input is expensive and may have carcinogenic and neurotoxic actions to humans. The search for new natural flocculants that have similarity with the commercial product is of great value. A bioextract that may be promising and has coagulant action is the Moringa oleifera Lam. In this context, the objective of the research was to evaluate the consequences of the use of moringa seed extracts and various concentrations of commercial polymer, such as sedimentation aids in clarifying sugarcane juice in the ethanol production, comparing the efficiency of the bioextract moringa. In the treatment of the juice, excessive addition of flocculants can result in reduction of sugars. The bioflocculant moringa was similar in technological features and the fermentative viability compared to usual dose of commercial polymer in Brazil. The fermentation efficiency was also higher for this flocculant, followed by moringa extract. The results obtained in this research indicate potential to the moringa bioextract, particularly in countries where the doses of flocculants are higher than 5 mg.L-1.

Upper gastrointestinal bleeding in a patient with Sjögren syndrome

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Validação da bioimpedância elétrica por multifrequência em atletas / Validation of multifrequency bioelectrical impedance analysis in athletes

É reconhecida a importância de avaliar a composição corporal na população atlética. Para o efeito é preciso utilizar técnicas válidas na determinação dos principais componentes moleculares. A Densitometria Radiológica de Dupla Energia (DXA) é um método preciso e válido para avaliação decomposição corporal. No entanto, a DXA é uma técnica ainda pouco acessível em contextos não laboratoriais. Desta forma, é importante utilizar técnicas mais simples e práticas como a bioimpedância eléctrica (BIA). No entanto poucos estudos validaram a BIA especialmente de multifrequência na avaliação da composição corporal em atletas. Assim, o objetivo desta investigação é testar a validade da BIA de multifrequência (Tanita, modelo MC-180) na determinação do conteúdo mineral ósseo (CMO),massa gorda (MG) e massa isenta de gordura e osso (MIGO) em atletas. Um total de 79 atletas (35 homens) foram avaliados pela BIA e pela DXA. Comparação de médias, coeficiente de correlação de concordância, regressão múltipla, e o método Bland-Altman foram realizados. A Tanita apresentou um poder explicativo de 76 %, 72%, 95% e 73% da variabilidade total observada a partir do método de referência para a MG (kg), MG (%), MIGO e CMO, respectivamente. O coeficiente de correlação de concordância para a MIGO apresentou uma força de concordância substancial de 0.927. Observaram-selimites de concordância relativamente elevados na estimativa dos vários componentes corporais. Em conclusão, a Tanita MC-180 é uma alternativa válida especialmente na estimação da massa isenta de gordura e de osso, num grupo de atletas. Contudo, devido aos limites de concordância obtidos na determinação das vários componentes este equipamento apresenta uma validade limitada na estimação individual da composição corporal...

It is recognized the importance of assessing body composition in athletic populations.Therefore, it is necessary to use valid techniques for the determination of the main molecular components.Dual-energy X-ray absorptiometry (DXA) is a precise and valid method for assessing body composition.However, DXA is still not available at the clinical and field settings. Thus, it is important to use simpletechniques such as electrical bioimpedance analysis (BIA) but few studies validated this techniquespecifically multifrequency BIA in body composition assessment in athletes. Therefore, the aim of thisresearch is to test the validity of multifrequency BIA (Tanita, Model MC-180) in the determination ofbone mineral content (BMC), lean soft tissue (LST) and fat mass (FM) in athletes. A total of 79 eliteathletes (35 males) were assessed by DXA and BIA. Comparison of means, concordance coefficientcorrelation, multiple regression and Bland–Altman analysis were performed. Tanita explained 76%, 72%,95% and 73% of the total variability observed from the reference method for FM (kg), FM (%), LST andBMC, respectively. The concordance coefficient correlation for MIGO presented a substantial strength ofagreement of 0,927. However, relatively larger limits of agreement were found between BIA and DXA forthe several body components. These findings reveal that the Tanita MC-180 is a valid alternative,particularly in the estimation of LST, in a group of athletes. However, due to the limits of agreementobtained in the determination of the body components this equipment presents a more limited validity inthe estimation of individual body composition...