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Because of the long history of anti-drug policing in the United States and the criminalization of substance use, clients who use substances are vulnerable to direct and vicarious experiences of police violence. Consequently, those who use substances may face a greater risk of experiencing symptoms of trauma that counselors should address in treatment. We recommend the use of a trauma-informed and abolitionist praxis in clinical and social justice practices as a framework to support clients who use substances and have histories of exposure to police violence.

Abstract Background Exercise-induced pulmonary haemorrhage (EIPH) in athletic horses is characterized by the presence of blood from the lungs in the tracheobronchial tree after intense exercise. Despite the high prevalence of EIPH in horses, the primary aetiology remains unknown. Variants in the genes encoding CD39 and CD39L1 (ENTPD1 and ENTPD2, respectively) were previously reported as potential genetic causes involved in EIPH pathogenesis. However, the role of these variants in haemostatic functions is unknown. Results To investigate the association between EIPH and missense variants in the ENTPD1 (rs1152296272, rs68621348, and rs68621347) and ENTPD2 genes (rs782872967), 76 Thoroughbred horses diagnosed with EIPH and 56 without clinical signs of EIPH (control group) by trachea-bronchial endoscopy were genotyped. The rs1152296272 and rs68621347 variants were linked, which explained why the same results were found in all horses. Approximately 96% and 95% of the EIPH and control horses, respectively, carried at least one nonreference allele for these variants. In contrast, 100% of the control horses and 96% of the EIPH horses were homozygous for the reference allele for the rs68621348 variant. In the EIPH group, 1.5% of the horses were homozygotes and 24% were heterozygous for the nonreference allele of the rs782872967 variant. In the control group, the nonreference allele of this variant was observed only in heterozygotes (16%). There were no significant differences between groups for any of the variants. Conclusions The variants previously described in the genes encoding the CD39 and CD39L1 enzymes were highly present in the studied population. However, no association was found between the occurrence of EIPH and the presence of these variants in Thoroughbred horses in this study.

S100A8/A9 is an endogenous alarmin secreted by myeloid cells during many acute and chronic inflammatory disorders. Despite increasing evidence of the proinflammatory effects of extracellular S100A8/A9, little is known about its intracellular function. Here, we show that cytosolic S100A8/A9 is indispensable for neutrophil post-arrest modifications during outside-in signaling under flow conditions in vitro and neutrophil recruitment in vivo, independent of its extracellular functions. Mechanistically, genetic deletion of S100A9 in mice caused dysregulated Ca2+ signatures in activated neutrophils resulting in reduced Ca2+ availability at the formed LFA-1/F-actin clusters with defective β2 integrin outside-in signaling during post-arrest modifications. Consequently, we observed impaired cytoskeletal rearrangement, cell polarization, and spreading, as well as cell protrusion formation in S100a9-/- compared to wildtype (WT) neutrophils, making S100a9-/- cells more susceptible to detach under flow, thereby preventing efficient neutrophil recruitment and extravasation into inflamed tissue.

Abstract Exposure to nanoparticles (NPs) is frequently associated with adverse cardiovascular effects. In contrast, NPs in nanomedicine hold great promise for precise lung‐specific drug delivery, especially considering the extensive pulmonary capillary network that facilitates interactions with bloodstream‐suspended particles. Therefore, exact knowledge about effects of engineered NPs within the pulmonary microcirculation are instrumental for future application of this technology in patients. To unravel the real‐time dynamics of intravenously delivered NPs and their effects in the pulmonary microvasculature, we employed intravital microscopy of the mouse lung. Only PEG‐amine‐QDs, but not carboxyl‐QDs triggered rapid neutrophil recruitment in microvessels and their subsequent recruitment to the alveolar space and was linked to cellular degranulation, TNF‐α, and DAMP release into the circulation, particularly eATP. Stimulation of the ATP‐gated receptor P2X7R induced expression of E‐selectin on microvascular endothelium thereby mediating the neutrophilic immune response. Leukocyte integrins LFA‐1 and MAC‐1 facilitated adhesion and decelerated neutrophil crawling on the vascular surface. In summary, this study unravels the complex cascade of neutrophil recruitment during NP‐induced sterile inflammation. Thereby we demonstrate novel adverse effects for NPs in the pulmonary microcirculation and provide critical insights for optimizing NP‐based drug delivery and therapeutic intervention strategies, to ensure their efficacy and safety in clinical applications.

O presente artigo, tendo em vista o avanço do direito internacional e a necessidade de efetivação interna das normas da Convenção-Quadro de Controle do Tabaco (CQCT), tem como objeto a análise da competência Para concretizar a regulamentação interna e internacional, com o intuito de se criarem políticas públicas coordenadas de controle do tabaco. Para tanto, foram analisadas as normas internacionais e internas sobre o tema, visitando-se a interpretação a elas dada pela doutrina e pelas decisões judiciais, tanto pela ótica do direito interno quanto internacional e comparado. Nesse sentido, é possível defender que a CQCT abre espaço para regulação internacional por meio das diretrizes, estabelecidas nas Conferências das Partes (COPs), que são, assim, vinculantes a todos os Estados-Membros da convenção. A regulação internacional nasce do chamado direito administrativo internacional, que permite o exercício do poder regulamentar, ou normativo, da administração. Internamente, a regulação deve seguir as diretrizes da COP, havendo espaço para que órgãos, como a Anvisa, no Brasil, concretizem as diretrizes, como a referente aos arts. 9 e 10 da CQCT, que limitou o uso de aditivos de sabores nos produtos de tabaco, sendo uma forma de efetivação das normas internacionais internamente. Também não existe conflito entre a livre iniciativa e o controle do tabaco, pois, como dito pela Corte Constitucional colombiana, no processo em que se discutia a constitucionalidade das restrições à publicidade do tabaco, é um mercado que não deve ser incentivado, apenas tolerado.

Abstract The human intestinal tract is colonized with microorganisms, which present a diverse array of immunological challenges. A number of antimicrobial mechanisms have evolved to cope with these challenges. A key defense mechanism is the expression of inducible antimicrobial peptides (AMPs), such as beta-defensins, which rapidly inactivate microorganisms. We currently have a limited knowledge of mechanisms regulating the inducible expression of AMP genes, especially factors from the host required in these regulatory mechanisms. To identify the host factors required for expression of the beta-defensin-2 gene (HBD2) in intestinal epithelial cells upon a bacterial challenge, we performed a RNAi screen using a siRNA library spanning the whole human genome. The screening was performed in duplicate to select the strongest 79 and 110 hit genes whose silencing promoted or inhibited HBD2 expression, respectively. A set of 57 hits selected among the two groups of genes was subjected to a counter-screening and a subset was subsequently validated for its impact onto HBD2 expression. Among the 57 confirmed hits, we brought out the TLR5-MYD88 signaling pathway, but above all new signaling proteins, epigenetic regulators and transcription factors so far unrevealed in the HBD2 regulatory circuits, like the GATA6 transcription factor involved in inflammatory bowel diseases. This study represents a significant step toward unveiling the key molecular requirements to promote AMP expression in human intestinal epithelial cells, and revealing new potential targets for the development of an innovative therapeutic strategy aiming at stimulating the host AMP expression, at the era of antimicrobial resistance.

Abstract Innate immune responses are linked to key metabolic pathways, yet the proximal signaling events that connect these systems remain poorly understood. Here we show that phosphofructokinase 1, liver type (PFKL), a rate-limiting enzyme of glycolysis, is phosphorylated at Ser775 in macrophages following several innate stimuli. This phosphorylation increases the catalytic activity of PFKL, as shown by biochemical assays and glycolysis monitoring in cells expressing phosphorylation-defective PFKL variants. Using a genetic mouse model in which PFKL Ser775 phosphorylation cannot take place, we observe that upon activation, glycolysis in macrophages is lower than in the same cell population of wild-type animals. Consistent with their higher glycolytic activity, wild-type cells have higher levels of HIF1α and IL-1β than Pfkl S775A/S775A after LPS treatment. In an in vivo inflammation model, Pfkl S775A/S775A mice show reduced levels of MCP-1 and IL-1β. Our study thus identifies a molecular link between innate immune activation and early induction of glycolysis.

Wood fuel from the agroforestry sector is one of the main strategies cited by the EU for reducing energetic dependance on foreign markets. Its sustainability, both economic and environmental, can be improved through the optimization of harvesting and chipping operations. This study was focused on the dynamic and energetic balance of the chipping phase carried out by a chipper operated by the power-take-off (PTO) of a medium-power tractor. Both machines were equipped with sensors for real-time monitoring of fuel consumption, PTO torque and speed, trunk diameter and working time during the comminution of 61 poplar trees grown in a medium rotation coppice system. The data analysis was carried out on the entire dataset (about 29,000 records) without considering their belonging to different trees. By means of proper data ordinations, it has been possible to define all the intervals in which the chipping stopped (e.g., between two trees) and to exclude them from the intervals of actual chipping. This has allowed forcomputation of operative and actual working time, as well as of the basic power required to operate the chipper and the power for actual chipping. Subsequently, the parameter values observed during actual chipping were related to the cutting diameters measured at the same instant. Subsequently, the dataset was divided according to seven diameter classes, and, for each class, the descriptive statistical indices of working time, work productivity, CO2 emissions, energy requirement and fuel consumption were calculated. Eventually, the correlation between the variations in trunk diameter and other parameters was verified both on the whole dataset and based on the class average values. The analysis made it possible to identify the conditions of greatest efficiency for the chipper. More generally, the method could help to increase the accuracy of measurements aimed at characterizing the performance of chippers from the point of view of dynamic energy requirements as well as in relation to different wood species.

ABSTRACT Atypical enteropathogenic Escherichia coli (aEPEC) is a significant cause of diarrhea in low- and middle-income countries. Certain aEPEC strains, including the Brazilian representative strain of serotype O51:H40 called aEPEC 1711-4, can use flagella to attach to, invade, and persist in T84 and Caco-2 intestinal cells. It can also translocate from the gut to extraintestinal sites in a rat model. Although various aspects of the virulence of this strain were studied and the requirement of a type III secretion system for the efficiency of the invasion process was demonstrated, the expression of the locus of enterocyte effacement (LEE) genes during the invasion and intracellular persistence remains unclear. To address this question, the expression of flagella and the different LEE operons was evaluated during kinetic experiments of the interaction of aEPEC 1711-4 with enterocytes in vitro. The genome of the strain was also sequenced. The results showed that flagella expression remained unchanged, but the expression of eae and escJ increased during the early interaction and invasion of aEPEC 1711-4 into Caco-2 cells, and there was no change 24 h post-infection during the persistence period. The number of actin accumulation foci formed on HeLa cells also increased during the 6-h analysis. No known gene related to the invasion process was identified in the genome of aEPEC 1711-4, which was shown to belong to the global EPEC lineage 10. These findings suggest that the LEE components and the intimate adherence promoted by intimin are necessary for the invasion and persistence of aEPEC 1711-4, but the detailed mechanism needs further study.IMPORTANCEAtypical enteropathogenic Escherichia coli (aEPEC) is a major cause of diarrhea, especially in low- and middle-income countries, like Brazil. However, due to the genome heterogeneity of each clonal group, it is difficult to comprehend the pathogenicity of this strain fully. Among aEPEC strains, 1711-4 can invade eukaryotic cells in vitro, cross the gut barrier, and reach extraintestinal sites in animal models. By studying how different known aEPEC virulence factors are expressed during the invasion process, we can gain insight into the commonalities of this phenotype among other aEPEC strains. This will help in developing preventive measures to control infections caused by invasive strains. No known virulence-encoding genes linked to the invasion process were found. Nevertheless, additional studies are still necessary to evaluate the role of other factors in this phenotype.

IntroductionIn adult horses, the development and evaluation of enteral electrolyte solutions containing sodium acetate for correcting hyperchloremic metabolic acidosis are still lacking, although these electrolyte and acid–base imbalances are commonly observed. The objective of this study was to evaluate the alkalinizing effect of two enteral electrolyte solutions containing different concentrations of acetate, administered via nasogastric tube in continuous flow, in adult horses with experimental hyperchloremic metabolic acidosis.MethodsSix mares aged between 3 and 10 years were used in a 6×2 crossover design, with each animal receiving both treatments. The horses were subjected to a protocol to induce hyperchloremic metabolic acidosis. They then received one of two treatments: HighAcetate (81.4 mmol/L) and LowAcetate (22.7 mmol/L) at an infusion rate of 15 mL/kg/h for 12 h. Plasma, serum, and urinary biochemical assessments; hematocrit; urinary volume, pH, and specific gravity; and blood gas analysis were measured at the following time points: T-12 h (beginning of the 12-h fast), T0h (end of fasting and beginning of the acidosis induction phase), every 2 h during the hyperchloremic metabolic acidosis induction phase (Ti2h and Ti4h), every 2 h during the 12-h enteral hydration phase (Tt2h, Tt4h, Tt6h, Tt8h, Tt10h, and Tt12h), with one sample taken at T24h (24 h after the start of acidosis induction) and another at T36h (36 h after the start of acidosis induction). Data were analyzed using descriptive statistics and analysis of variance based on a factorial design of repeated measures, with Tukey’s post-hoc test or the Kruskal-Wallis test with Dunn’s post-hoc test for non-parametric tests.ResultsAt the end of the induction phase, the animals developed moderate to severe hyperchloremic metabolic acidosis. The HighAcetate solution effectively corrected electrolyte and acid–base imbalances before the end of the treatment phase (Tt12h), while the LowAcetate solution was not effective in correcting those changes.ConclusionThe HighAcetate (81.4 mmol/L) solution is deemed an effective and safe alternative for the treatment of hyperchloremic metabolic acidosis in horses.

BackgroundA better understanding of the consequences of the Coronavirus Disease 2019 (COVID-19) pandemic on lifestyle of patients with Chagas disease (ChD) is of paramount importance to facilitate the implementation of intervention strategies tailored to this specific population.ObjectiveThe present study aimed to evaluate the level of physical activity (PA) in Chagas disease (ChD) patients during the Coronavirus Disease 2019 (COVID-19) pandemic and its main associated factors.MethodsThis is a cross-sectional study with 187 patients of both sexes, aged ≥18 years, followed in a national infectious disease center (Rio de Janeiro, Brazil). The level of PA was determined by the International Physical Activity Questionnaire short version and expressed in terms of total volume of physical activity (PA) (MET-minutes per week). Individuals were classified as physically active following the 2020 World Health Organization PA guideline. The exposure variables were age, sex, race, marital status, schooling, income per capita, number of rooms per domicile, number of residents per domicile, body mass index, clinical form of ChD, COVID-19 antibodies, comorbidities, self-reported anxiety, self-reported depression, self-reported fear, and self-reported sadness. The association between the exposure variables with total PA (as a continuous variable) was determined using univariate and multivariate linear regression models.ResultsMean age was 61.1 ± 11.6 years. Most (62%) were women and self-declared their race as mixed (50.8%). The percentage of physically active individuals according to was 52%. The variables independently associated with total PA levels were non-white race (Exp β = 1.39; 95% CI 1.02 to 1.90), dyslipidemia (Exp β = 0.73; 95% CI 0.56 to 0.95) and self-reported depression during quarantine (Exp β = 0.71; 95% CI 0.52 to 0.96).ConclusionNon-white race was positively associated with total levels of PA, while dyslipidemia, and self-reported depression during quarantine were negatively associated with total levels of PA. The identification of associated factors can facilitate the development of tailored strategies to increase PA levels ChD patients.

O veganismo tem como premissa excluir todas as formas de exploração e crueldade contra animais, seja na alimentação, no vestuário ou em qualquer outra finalidade, provocando, por consequência, uma série de desafios ao convívio social. Na prática da comensalidade, posturas alimentares diferentes podem despertar reações tanto de hospitalidade quanto de hostilidade. Este artigo, com base construtivista e de caráter qualitativo, tem como objetivo analisar as relações de comensalidade entre indivíduos veganos e onívoros sob a perspectiva da hospitalidade e da hostilidade na ótica de indivíduos veganos, a partir de uma pesquisa bibliográfica e entrevistas semiestruturadas com 12 indivíduos veganos. Os resultados indicam como principais desafios a aceitação dos novos hábitos por parte de amigos, familiares e colegas de trabalho, bem como eventuais constrangimentos nos momentos de comensalidade, inclusive pela falta de alimentos veganos disponíveis. Evidenciaram também que ações de hospitalidade propiciam reações igualmente hospitaleiras, enquanto ações de hostilidade geram reações igualmente hostis.

Esophagogastric cancers are aggressive malignancies, with poor prognosis despite current standard-of-care therapies. PD-1 inhibitors are a newer class of antitumor agents with the potential to improve outcomes among appropriately selected patients. This review provides an overview of the key trials that have guided the use of PD-1 and PD-L1 inhibitors in the refractory and first-line settings. We highlight recent studies investigating the role of genomic classification in predicting therapeutic activity of PD-1 inhibitors. In addition, there is a discussion of the use of different scoring systems and criteria to determine PD-L1 positivity, the impact on the therapeutic use of immune checkpoint inhibition with anti-PD-1 agents, and the controversies in current methods of PD-L1 testing and their implications in patient selection for anti-PD-1 therapy.

Author(s): Richard Klaus [sup.1] , Teresa K. Barth [sup.2] , Axel Imhof [sup.2] , Franziska Thalmeier [sup.1] , Bärbel Lange-Sperandio [sup.1] Author Affiliations: (1) https://ror.org/05591te55, grid.5252.0, 0000 0004 1936 973X, [...], Background Urinary proteomics identifies the totality of urinary proteins and can therefore help in getting an early and precise diagnosis of various pathological processes in the kidneys. In infants, non-invasive urine collection is most commonly accomplished with a urine bag or clean catch. The influence of those two collection methods on urinary proteomics was assessed in this study. Methods Thirty-two urine samples were collected in infants using urine bag and clean catch within 24 h. Nine boys and seven girls with a mean age of 4.3 ± 2.9 months were included (5 x post-pyelonephritis, 10 x non-kidney disease, 1 x chronic kidney disease (CKD)). Liquid chromatography-mass spectrometry (LC-MS/MS) was performed in data-independent acquisition (DIA) mode. Protein identification and quantification were achieved using Spectronaut. Results A total of 1454 urinary proteins were detected. Albumin and [alpha]-1-microglobulin were detected the most. The 18 top-abundant proteins accounted for 50% of total abundance. The number of proteins was slightly, but insignificantly higher in clean catch (957 ± 245) than in bag urine (876 ± 255). The median intensity was 1.2 x higher in the clean catch. Overall, differential detection of proteins was 29% between the collection methods; however, it diminished to 3% in the 96 top-abundant proteins. Pearson's correlation coefficient was 0.81 ± 0.11, demonstrating a high intraindividual correlation. A principal component analysis and a heat map showed clustering according to diagnoses and patients rather than to the collection method. Conclusion Urinary proteomics shows a high correlation with minor variation in low-abundant proteins between the two urine collection methods. The biological characteristics overrule this variation.

Abstract The design and implementation of Philaenus spumarius control strategies can take advantage of properly calibrated models describing and predicting the phenology of vector populations in agroecosystems. We developed a temperature-driven physiological-based model based on the system of Kolmogorov partial differential equations to predict the phenological dynamics of P. spumarius. The model considers the initial physiological age distribution of eggs, the diapause termination process, and the development rate functions of post-diapausing eggs and nymphal stages, estimated from data collected in laboratory experiments and field surveys in Italy. The temperature threshold and cumulative degree days for egg diapause termination were estimated as 6.5 °C and 120 DD, respectively. Preimaginal development rate functions exhibited lower thresholds ranging between 2.1 and 5.0 °C, optimal temperatures between 26.6 and 28.3 °C, and upper threshold between 33.0 and 35 °C. The model correctly simulates the emergence of the 3rd, 4th, and 5th nymphal instars, key stages to target monitoring actions and control measures against P. spumarius. Precision in simulating the phenology of the 1st and 2nd nymphal stages was less satisfactory. The model is a useful rational decision tool to support scheduling monitoring and control actions against the late and most important nymphal stages of P. spumarius.

Abstract To investigate the effect of an exercise-based cardiac rehabilitation program on the quality of life (QoL) of patients with chronic Chagas cardiomyopathy (CCC). PEACH study was a single-center, superiority randomized clinical trial of exercise training versus no exercise (control). The sample comprised Chagas disease patients with CCC, left ventricular ejection fraction

Abstract This dataset represents a collection of pocket-centric structural data related to protein-protein interactions (PPIs) and PPI-related ligand binding sites. The dataset includes high-quality structural information on more than 23,000 pockets, 3,700 proteins on more than 500 organisms, and nearly 3500 ligands that can aid researchers in the fields of bioinformatics, structural biology, and drug discovery. It encompasses a diverse set of PPI complexes with more than 1,700 unique protein families including some with associated ligands, enabling detailed investigations into molecular interactions at the atomic level. This article introduces an indispensable resource designed to unlock the full potential of PPIs while pioneering a novel metric for pocket similarity for hypothesizing protein partners repurposing.

Abstract Urinary tract obstruction during renal development leads to inflammation, leukocyte infiltration, tubular cell death, and interstitial fibrosis. Interleukin-10 (IL-10) is an anti-inflammatory cytokine, produced mainly by monocytes/macrophages and regulatory T-cells. IL-10 inhibits innate and adaptive immune responses. IL-10 has a protective role in the adult model of obstructive uropathy. However, its role in neonatal obstructive uropathy is still unclear which led us to study the role of IL-10 in neonatal mice with unilateral ureteral obstruction (UUO). UUO serves as a model for congenital obstructive nephropathies, a leading cause of kidney failure in children. Newborn Il-10 −/− and C57BL/6 wildtype-mice (WT) were subjected to complete UUO or sham-operation on the 2nd day of life. Neonatal kidneys were harvested at day 3, 7, and 14 of life and analyzed for different leukocyte subpopulations by FACS, for cytokines and chemokines by Luminex assay and ELISA, and for inflammation, programmed cell death, and fibrosis by immunohistochemistry and western blot. Compared to WT mice, Il-10 −/− mice showed reduced infiltration of neutrophils, CD11bhi cells, conventional type 1 dendritic cells, and T-cells following UUO. Il-10 −/− mice with UUO also showed a reduction in pro-inflammatory cytokine and chemokine release compared to WT with UUO, mainly of IP-10, IL-1α, MIP-2α and IL-17A. In addition, Il-10 −/− mice showed less necroptosis after UUO while the rate of apoptosis was not different. Finally, α-SMA and collagen abundance as readout for fibrosis were similar in Il-10 −/− and WT with UUO. Surprisingly and in contrast to adult Il-10 −/− mice undergoing UUO, neonatal Il-10 −/− mice with UUO showed a reduced inflammatory response compared to respective WT control mice with UUO. Notably, long term changes such as renal fibrosis were not different between neonatal Il-10 −/− and neonatal WT mice with UUO suggesting that IL-10 signaling is different in neonates and adults with UUO.