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Abstract The transcriptional repressor REV-ERB-α, encoded by Nuclear Receptor Subfamily 1 Group D Member 1 (Nr1d1), has been considered to play an essential role in the skeletal muscle oxidative capacity adaptation and muscle mass control. Also, this molecule regulates autophagy via the repression of autophagy-related genes both in skeletal muscle and brain regions. Classically, training programs based on endurance or strength characteristics enhance skeletal muscle mass content and/or oxidative capacity, leading to autophagy activation in several tissues. Thus, it seems that REV-ERB-α regulates similar responses induced by exercise. However, how this molecule responds to different exercise models/intensities in different tissues is still unclear. Therefore, the main aim was to characterize the responses of REV-ERB-α and autophagy-related genes to different exercise protocols (endurance/interval run/strength) in distinct tissues (gastrocnemius, soleus and hippocampus). Since REV-ERB-α presents a circadian rhythm, the analyses were performed in a time-course manner. The endurance and strength groups attenuated REV-ERB-α transcriptional response during the time course in gastrocnemius and soleus. Conversely, the interval group enhanced the Nr1d1 expression in the hippocampus. All protocols downregulated the REV-ERB-α protein levels in gastrocnemius following the exercise session with concomitant nuclear exclusion. The major autophagy-related genes presented downregulation after the exercise session in all analyzed tissues. Altogether, these results highlight that REV-ERB-α is extremely sensitive to physical exercise stimuli, including different models and intensities in skeletal muscle and the hippocampus.

Abstract Chimeric fusion transcription factors are oncogenic hallmarks of several devastating cancer entities including pediatric sarcomas, such as Ewing sarcoma (EwS) and alveolar rhabdomyosarcoma (ARMS). Despite their exquisite specificity, these driver oncogenes have been considered largely undruggable due to their lack of enzymatic activity. Here, we show in the EwS model that – capitalizing on neomorphic DNA-binding preferences – the addiction to the respective fusion transcription factor EWSR1-FLI1 can be leveraged to express therapeutic genes. We genetically engineered a de novo enhancer-based, synthetic and highly potent expression cassette that can elicit EWSR1-FLI1-dependent expression of a therapeutic payload as evidenced by episomal and CRISPR-edited genomic reporter assays. Combining in silico screens and immunohistochemistry, we identified GPR64 as a highly specific cell surface antigen for targeted transduction strategies in EwS. Functional experiments demonstrated that anti-GPR64-pseudotyped lentivirus harboring our expression cassette can specifically transduce EwS cells to promote the expression of viral thymidine kinase sensitizing EwS for treatment to otherwise relatively non-toxic (Val)ganciclovir and leading to strong anti-tumorigenic, but no adverse effects in vivo. Further, we prove that similar vector designs can be applied in PAX3-FOXO1-driven ARMS, and to express immunomodulatory cytokines, such as IL-15 and XCL1, in tumor entities typically considered to be immunologically ‘cold’. Collectively, these results generated in pediatric sarcomas indicate that exploiting, rather than suppressing, the neomorphic functions of chimeric transcription factors may open inroads to innovative and personalized therapies, and that our highly versatile approach may be translatable to other cancers addicted to oncogenic transcription factors with unique DNA-binding properties.

Abstract Introduction Helmet noninvasive support may provide advantages over other noninvasive oxygenation strategies in the management of acute hypoxemic respiratory failure. In this narrative review based on a systematic search of the literature, we summarize the rationale, mechanism of action and technicalities for helmet support in hypoxemic patients. Main results In hypoxemic patients, helmet can facilitate noninvasive application of continuous positive-airway pressure or pressure-support ventilation via a hood interface that seals at the neck and is secured by straps under the arms. Helmet use requires specific settings. Continuous positive-airway pressure is delivered through a high-flow generator or a Venturi system connected to the inspiratory port of the interface, and a positive end-expiratory pressure valve place at the expiratory port of the helmet; alternatively, pressure-support ventilation is delivered by connecting the helmet to a mechanical ventilator through a bi-tube circuit. The helmet interface allows continuous treatments with high positive end-expiratory pressure with good patient comfort. Preliminary data suggest that helmet noninvasive ventilation (NIV) may provide physiological benefits compared to other noninvasive oxygenation strategies (conventional oxygen, facemask NIV, high-flow nasal oxygen) in non-hypercapnic patients with moderate-to-severe hypoxemia (PaO2/FiO2 ≤ 200 mmHg), possibly because higher positive end-expiratory pressure (10–15 cmH2O) can be applied for prolonged periods with good tolerability. This improves oxygenation, limits ventilator inhomogeneities, and may attenuate the potential harm of lung and diaphragm injury caused by vigorous inspiratory effort. The potential superiority of helmet support for reducing the risk of intubation has been hypothesized in small, pilot randomized trials and in a network metanalysis. Conclusions Helmet noninvasive support represents a promising tool for the initial management of patients with severe hypoxemic respiratory failure. Currently, the lack of confidence with this and technique and the absence of conclusive data regarding its efficacy render helmet use limited to specific settings, with expert and trained personnel. As per other noninvasive oxygenation strategies, careful clinical and physiological monitoring during the treatment is essential to early identify treatment failure and avoid delays in intubation.

Solid tumours are infiltrated by effector T cells with the potential to control or reject them, as well as by regulatory T (Treg) cells that restrict the function of effector T cells and thereby promote tumour growth1. The anti-tumour activity of effector T cells can be therapeutically unleashed, and is now being exploited for the treatment of some forms of human cancer. However, weak tumour-associated inflammatory responses and the immune-suppressive function of Treg cells remain major hurdles to broader effectiveness of tumour immunotherapy2. Here we show that, after disruption of the CARMA1-BCL10-MALT1 (CBM) signalosome complex, most tumour-infiltrating Treg cells produce IFNγ, resulting in stunted tumour growth. Notably, genetic deletion of both or even just one allele of CARMA1 (also known as Card11) in only a fraction of Treg cells-which avoided systemic autoimmunity-was sufficient to produce this anti-tumour effect, showing that it is not the mere loss of suppressive function but the gain of effector activity by Treg cells that initiates tumour control. The production of IFNγ by Treg cells was accompanied by activation of macrophages and upregulation of class I molecules of the major histocompatibility complex on tumour cells. However, tumour cells also upregulated the expression of PD-L1, which indicates activation of adaptive immune resistance3. Consequently, blockade of PD-1 together with CARMA1 deletion caused rejection of tumours that otherwise do not respond to anti-PD-1 monotherapy. This effect was reproduced by pharmacological inhibition of the CBM protein MALT1. Our results demonstrate that partial disruption of the CBM complex and induction of IFNγ secretion in the preferentially self-reactive Treg cell pool does not cause systemic autoimmunity but is sufficient to prime the tumour environment for successful immune checkpoint therapy.

Background Melanoma is an immune sensitive disease, as demonstrated by the activity of immune check point blockade (ICB), but many patients will either not respond or relapse. More recently, tumor infiltrating lymphocyte (TIL) therapy has shown promising efficacy in melanoma treatment after ICB failure, indicating the potential of cellular therapies. However, TIL treatment comes with manufacturing limitations, product heterogeneity, as well as toxicity problems, due to the transfer of a large number of phenotypically diverse T cells. To overcome said limitations, we propose a controlled adoptive cell therapy approach, where T cells are armed with synthetic agonistic receptors (SAR) that are selectively activated by bispecific antibodies (BiAb) targeting SAR and melanoma-associated antigens.Methods Human as well as murine SAR constructs were generated and transduced into primary T cells. The approach was validated in murine, human and patient-derived cancer models expressing the melanoma-associated target antigens tyrosinase-related protein 1 (TYRP1) and melanoma-associated chondroitin sulfate proteoglycan (MCSP) (CSPG4). SAR T cells were functionally characterized by assessing their specific stimulation and proliferation, as well as their tumor-directed cytotoxicity, in vitro and in vivo.Results MCSP and TYRP1 expression was conserved in samples of patients with treated as well as untreated melanoma, supporting their use as melanoma-target antigens. The presence of target cells and anti-TYRP1 × anti-SAR or anti-MCSP × anti-SAR BiAb induced conditional antigen-dependent activation, proliferation of SAR T cells and targeted tumor cell lysis in all tested models. In vivo, antitumoral activity and long-term survival was mediated by the co-administration of SAR T cells and BiAb in a syngeneic tumor model and was further validated in several xenograft models, including a patient-derived xenograft model.Conclusion The SAR T cell-BiAb approach delivers specific and conditional T cell activation as well as targeted tumor cell lysis in melanoma models. Modularity is a key feature for targeting melanoma and is fundamental towards personalized immunotherapies encompassing cancer heterogeneity. Because antigen expression may vary in primary melanoma tissues, we propose that a dual approach targeting two tumor-associated antigens, either simultaneously or sequentially, could avoid issues of antigen heterogeneity and deliver therapeutic benefit to patients.

Introduction: This study aimed to verify whether implicit and explicit informational constraints generate differences in tactical performance and behavior in U-20 national-level soccer players. Methods: Thirty-two under-20 male athletes from two clubs participated. Four 4-a-side small-sided games (SSG) protocols were used: R1 - explicit rule for highpress marking, R2 - implicit rule for high-press marking, R3 - game with both previous rules simultaneous and FR - free game, without additional rules. SSGs comprised 4 vs. 4+ goalkeepers games on a 42 m × 29 m field. Position data from 10 Hz Global Positioning System (GPS) devices were used to evaluate individual and collective tactical behavior (spatial occupation metrics) and performance (interpersonal coordination). MANOVA was used for normally distributed variables, and Friedman's with Dunn or Bonferroni post hoc was used for variables without normal distribution. For SEI, an ANOVA was used with Bonferroni post hoc. Results: The R1 protocol showed higher SEI, length, width, and LpWratio than the FR protocol (p = 0.009). There was an effect of the different protocols in SEI values (p < 0.001). Under the explicit rule, players also showed the highest in-phase interpersonal coordination values (p < 0.001). Discussion: Providing players with explicit tactical instructions improves tactical performance acutely for high-pressing defensive actions. [ABSTRACT FROM AUTHOR]

Environmental contamination by potentially toxic elements (PTEs) poses a significant challenge, particularly in the metropolitan regions of developing countries. This issue arises from the high levels of pollution driven by industrial growth and the increased traffic from fossil fuel-powered vehicles. Even after the wastewater treatment in treatment plants, PTEs often persist, posing risks to stream structure and function. This form of pollution is persistent, long-term, and irreversible, presenting a significant challenge in terms of freshwater conservation. This study aimed to assess the water quality and PTE concentrations in urban streams in Santo André, SP, Brazil, to identify the PTEs relevant to stream pollution. We analyzed the water quality in seven catchments in the Santo André municipality, in the metropolitan region of São Paulo, Brazil. The samples were collected during the dry (2021) and rainy periods (2022), and the concentrations of potentially toxic elements (PTEs) were analyzed via inductively coupled plasma–mass spectrometry (ICP-MS). The results showed elevated electrical conductivity (429 ± 211 μS·cm) and low dissolved oxygen concentrations in the streams (2.3 ± 0.95 μg·L), indicating potential problems such as eutrophication and toxicity to aquatic organisms. PTE concentrations, particularly those of Mn (30.8 ± 22.3 μg·L), Fe (91.1 ± 72.1 μg·L), and Zn (38.1 ± 28.7 μg·L), were among the highest concentrations. Seasonal variations affected the PTE concentrations, with Cr and Fe predominating during the dry season and Zn increasing during the rainy season. Associations were found between the PTE concentrations and the water pH, indicating the importance of continuous monitoring and remediation efforts. [ABSTRACT FROM AUTHOR]

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Endangered sharks and rays usually often lack basic information specific to conservation, such as population size. Previous studies have reconstructed shark and ray catch statistics between 1950 and 2019 for the southeast = south of Brazil, but lacking detail at the species level, because the catches were grouped by family, genus or even common name (e.g., skates and rays, Dasyatidae, Rhinobatos, Sphyrnidae, Squatinidae). In this study, we used proportions between species from scientific observer fishing trips and Dirichlet regression modelling to reclassify these categories. This model is a multivariate extension of beta regression and enables the modeling of asymmetric and heteroscedastic compositional data, allowing multinomial data to be obtained in a more informative way. The reconstruction of catches for unclassified data showed a massive dominance of the Squatinidae family until the late 1970s, when catches showed signs of decline. At the same time, the rays of the "emplastro" family showed a progressive increase from 2006 onwards. However, this scenario changed after the reclassification. The category Squatinidae was maintained almost exclusively by S. guggenheim, while 16 categories of species were observed within "emplastro" rays, many of which fall into "endangered", "vulnerable" and "critically endangered" criteria. These reconstructed series provide a more reliable scenario of the catches of thirty elasmobranch species in the southeast and south of Brazil and serve as baseline information for understanding the conservation status of these species. [ABSTRACT FROM AUTHOR]

People are infected with Leishmania donovani when the parasite is deposited in the dermis during the blood meal of the sand fly vector. Most infected people develop a subclinical latent infection, but some develop progressive visceral leishmaniasis. Malnutrition is a risk factor for the development of active VL. We previously demonstrated increased parasite dissemination from the skin to visceral organs in a murine model of malnutrition. Here we investigated the mechanism of early parasite dissemination. After delivery of L. donovani to the skin, we found enhanced capture of parasites by inflammatory monocytes and neutrophils in the skin of malnourished mice. However, parasite dissemination in malnourished mice was driven primarily by infected inflammatory monocytes, which showed increased CCR7 expression, greater intrinsic migratory capacity, and increased trafficking from skin to spleen. PGE2 production, which was increased at the site of skin infection, increased monocyte CCR7 expression and promoted CCR7-related monocyte-mediated early parasite dissemination in malnourished mice. Parasite dissemination in monocytes was reduced by inhibition of PGE2, knockdown or silencing of CCR7 in monocytes, and depletion of inflammatory monocytes through administration of diphtheria toxin to CSFR1-DTR transgenic mice that have monocyte-specific DT receptor expression. CCR7-driven trafficking of infected inflammatory monocytes through the lymph node was accompanied by increased expression of its ligands CCL19 and CCL21. These results show that the CCR7/PGE2 axis is responsible for the increased trafficking of L. donovani-infected inflammatory monocytes from the skin to the spleen in the malnourished host. Undernutrition and production of PGE2 are potential targets to reduce the risk of people developing VL. Nutritional interventions that target improved immune function and reduced PGE2 synthesis should be studied in people at risk of developing VL.

Background Precision oncology has a prominent role in nonsquamous non-small cell lung cancer (nsNSCLC) treatment progress; however, its access in a real-world scenario might be limited.Objective To investigate the time spent in nsNSCLC molecular profile evaluation and its influence on clinical decisions.Methods nsNSCLC patients who underwent molecular testing in a private referral Brazilian center between November 2015 and February 2020 were identified. The interval from nsNSCLC diagnosis to the characterization of the molecular profile was determined. Other outcomes, focusing on the biomarker tissue journey, were also assessed.Results In this cohort (n = 78), the median time between the advanced nsNSCLC diagnosis and biomarker characterization was 40.5 days (range, 29.5–68.5). The median interval between the diagnosis and the test request was longer than the interval between the request and the results (respectively 29.0 versus 12.0 days; p