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Abstract Coronavirus disease 2019 (COVID-19) is caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Recent research has demonstrated how epigenetic mechanisms regulate the host–virus interactions in COVID-19. It has also shown that microRNAs (miRNAs) are one of the three fundamental mechanisms of the epigenetic regulation of gene expression and play an important role in viral infections. A pilot study published by our research group identified, through next-generation sequencing (NGS), that miR-4433b-5p, miR-320b, and miR-16–2-3p are differentially expressed between patients with COVID-19 and controls. Thus, the objectives of this study were to validate the expression of these miRNAs using quantitative real-time polymerase chain reaction (qRT-PCR) and to perform in silico analyses. Patients with COVID-19 (n = 90) and healthy volunteers (n = 40) were recruited. MiRNAs were extracted from plasma samples and validated using qRT-PCR. In addition, in silico analyses were performed using mirPath v.3 software. MiR-320b was the only miRNA upregulated in the case group com-pared to the control group. The in silico analyses indicated the role of miR-320b in the regulation of the KITLG gene and consequently in the inflammatory process. This study confirmed that miR-320b can distinguish patients with COVID-19 from control participants; however, further research is needed to determine whether this miRNA can be used as a target or a biomarker.

Abstract Efficient predictive biomarkers are needed for immune checkpoint inhibitor (ICI)-based immunotherapy in non-small cell lung cancer (NSCLC). Testing the predictive value of single nucleotide polymorphisms (SNPs) in programmed cell death 1 (PD-1) or its ligand 1 (PD-L1) has shown contrasting results. Here, we aim to validate the predictive value of PD-L1 SNPs in advanced NSCLC patients treated with ICIs as well as to define the molecular mechanisms underlying the role of the identified SNP candidate. rs822336 efficiently predicted response to anti-PD-1/PD-L1 immunotherapy in advanced non-oncogene addicted NSCLC patients as compared to rs2282055 and rs4143815. rs822336 mapped to the promoter/enhancer region of PD-L1, differentially affecting the induction of PD-L1 expression in human NSCLC cell lines as well as their susceptibility to HLA class I antigen matched PBMCs incubated with anti-PD-1 monoclonal antibody nivolumab. The induction of PD-L1 expression by rs822336 was mediated by a competitive allele-specificity binding of two identified transcription factors: C/EBPβ and NFIC. As a result, silencing of C/EBPβ and NFIC differentially regulated the induction of PD-L1 expression in human NSCLC cell lines carrying different rs822336 genotypes. Analysis by binding microarray further validated the competitive allele-specificity binding of C/EBPβ and NFIC to PD-L1 promoter/enhancer region based on rs822336 genotype in human NSCLC cell lines. These findings have high clinical relevance since identify rs822336 and induction of PD-L1 expression as novel biomarkers for predicting anti-PD-1/PD-L1-based immunotherapy in advanced NSCLC patients.

The purpose of the study was to evaluate dry matter phytomass production, percentage of soil cover, and dry matter phytomass decomposition curve of cover crops in single and mix cultivation, in a low-altitude subtropical environment. The study was conducted in Santa Maria - RS, in agricultural years 2019/2020 and 2021/2022. The experimental design used was randomized blocks, with ten treatments and four replications. The experiments were conducted with four winter cover crops: White oat (WO), black oat (BO), forage turnip (FT), and common vetch (CV), in single cultivation and as a mix of cover plants. For the total production of dry matter phytomass, the FT and BO+CV+FT treatments stand out which present the highest averages between the experimental years, with values ​​4365.32 and 4109.87 kg ha-1. FT in single cultivation has a high potential for soil coverage in periods of 45 DAS, and the common vetch crop showed greater soil coverage in the late period, with 84% coverage at 90 days after sowing. The BO and WO treatments showed greater maintenance of dry phytomass in soil cover at the end of the 150-day period, presenting values greater than 40% of the initial volume of dry phytomass present in the production system. Recommending the exclusive cultivation of the species that meets the rural producer's objective.

Chronic obstructive pulmonary disease (COPD) represents an independent risk factor for lung cancer development. Accelerated cell senescence, induced by oxidative stress and inflammation, is a common pathogenic determinant of both COPD and lung cancer. The post transcriptional regulation of genes involved in these processes is finely regulated by RNA-binding proteins (RBPs), which regulate mRNA turnover, subcellular localization, splicing and translation. Multiple pro-inflammatory mediators (including cytokines, chemokines, proteins, growth factors and others), responsible of lung microenvironment alteration, are regulated by RBPs. Several mouse models have shown the implication of RBPs in multiple mechanisms that sustain chronic inflammation and neoplastic transformation. However, further studies are required to clarify the role of RBPs in the pathogenic mechanisms shared by lung cancer and COPD, in order to identify novel biomarkers and therapeutic targets. This review will therefore focus on the studies collectively indicating the role of RBPs in oxidative stress and chronic inflammation as common pathogenic mechanisms shared by lung cancer and COPD.

Strawberry (Fragaria × ananassa Duch.) production can be evaluated as repeated measurements, since the same plant is harvested multiple times during the production season. The objectives were to evaluate the production of fresh mass and fruit number in successive harvests and compare three strawberry clones in two cultivation conditions. Two experiments were carried out in two environmental cultivations: the rural property and the experimental area of the Plant Science Department, Federal University of Santa Maria, Brazil. The parameters of the nonlinear logistic model and their critical points were estimated via bootstrap for each condition and clone for fresh mass and fruit number with accumulated values, depending on the thermal sum accumulated during the production season. For nonlinear regression analysis, the ordinary least squares method was used with the Gauss–Newton algorithm. Confidence intervals were obtained for each parameter and estimated critical points, and they did not cross; the treatments were considered different. There were significant differences between clones and cultivation conditions for fruit mass and number. The nonlinear logistic models, adjusted for mass and number of strawberry fruits, detailed the production season, highlighting the main differences between cultivation conditions and clones.

The BRAFV600E mutation, found in approximately 50% of melanoma cases, plays a crucial role in the activation of the MAPK/ERK signaling pathway, which promotes tumor cell proliferation. This study aimed to evaluate its impact on the melanoma immune microenvironment and therapeutic responses, particularly focusing on immunogenic cell death (ICD), a pivotal cytotoxic process triggering anti-tumor immune responses. Through comprehensive in silico analysis of the Cancer Genome Atlas data, we explored the association between the BRAFV600E mutation, immune subtype dynamics, and tumor mutation burden (TMB). Our findings revealed that the mutation correlated with a lower TMB, indicating a reduced generation of immunogenic neoantigens. Investigation into immune subtypes reveals an exacerbation of immunosuppression mechanisms in BRAFV600E-mutated tumors. To assess the response to ICD inducers, including doxorubicin and Me-ALA-based photodynamic therapy (PDT), compared to the non-ICD inducer cisplatin, we used distinct melanoma cell lines with wild-type BRAF (SK-MEL-2) and BRAFV600E mutation (SK-MEL-28, A375). We demonstrated a differential response to PDT between the WT and BRAFV600E cell lines. Further transcriptomic analysis revealed upregulation of IFNAR1, IFNAR2, and CXCL10 genes associated with the BRAFV600E mutation, suggesting their involvement in ICD. Using a gene reporter assay, we showed that PDT robustly activated the IFN-1 pathway through cGAS-STING signaling. Collectively, our results underscore the complex interplay between the BRAFV600E mutation and immune responses, suggesting a putative correlation between tumors carrying the mutation and their responsiveness to therapies inducing the IFN-1 pathway, such as the ICD inducer PDT, possibly mediated by the elevated expression of IFNAR1/2 receptors

Abstract Macroautophagy, hereafter referred to as autophagy, represents a highly conserved catabolic process that maintains cellular homeostasis. At present, the role of autophagy in cutaneous melanoma (CM) is still controversial, since it appears to be tumor-suppressive at early stages of malignant transformation and cancer-promoting during disease progression. Interestingly, autophagy has been found to be often increased in CM harboring BRAF mutation and to impair the response to targeted therapy. In addition to autophagy, numerous studies have recently conducted in cancer to elucidate the molecular mechanisms of mitophagy, a selective form of mitochondria autophagy, and secretory autophagy, a process that facilitates unconventional cellular secretion. Although several aspects of mitophagy and secretory autophagy have been investigated in depth, their involvement in BRAF-mutant CM biology has only recently emerged. In this review, we aim to overview autophagy dysregulation in BRAF-mutant CM, along with the therapeutic advantages that may arise from combining autophagy inhibitors with targeted therapy. In addition, the recent advances on mitophagy and secretory autophagy involvement in BRAF-mutant CM will be also discussed. Finally, since a number of autophagy-related non-coding RNAs (ncRNAs) have been identified so far, we will briefly discussed recent advances linking ncRNAs to autophagy regulation in BRAF-mutant CM.

Chronic obstructive pulmonary disease (COPD) is an independent risk factor for the development of lung cancer. Several pathogenic pathways such as oxidative stress and chronic inflammation of the lower airways are shared by these two diseases. The RNA-binding proteins (RBPs) can modulate the post-transcriptional expression of genes involved in several biological processes, such as cell cycle, cell proliferation and injury/stress responses. The bonding between RBPs and targeted transcripts regulates mRNA turnover, subcellular localization, splicing and translation, through the formation of ribonucleoproteins (RNPs) complexes. Several pro-inflammatory mediators, that induce and maintain chronic lung inflammation and carcinogenesis, are modulate by RBPs. RBPs can have a key role in lung cancer onset in COPD patients, sharing several common pathogenic processes, including oxidative stress, inflammation of lower airways, DNA damage and impaired DNA-repair mechanisms. Further studies are mandatory to clarify the application of RBPs as novel biomarkers and potential therapeutic targets. This review will investigate recent evidences showing the role of RBPs in the pathogenic mechanisms sharing by lung cancer and COPD

IntroductionThe RNA-binding protein AU-rich-element factor-1 (AUF-1) participates to posttranscriptional regulation of genes involved in inflammation and cellular senescence, two pathogenic mechanisms of chronic obstructive pulmonary disease (COPD). Decreased AUF-1 expression was described in bronchiolar epithelium of COPD patients versus controls and in vitro cytokine- and cigarette smoke-challenged human airway epithelial cells, prompting the identification of epithelial AUF-1-targeted transcripts and function, and investigation on the mechanism of its loss.ResultsRNA immunoprecipitation-sequencing (RIP-Seq) identified, in the human airway epithelial cell line BEAS-2B, 494 AUF-1-bound mRNAs enriched in their 3’-untranslated regions for a Guanine-Cytosine (GC)-rich binding motif. AUF-1 association with selected transcripts and with a synthetic GC-rich motif were validated by biotin pulldown. AUF-1-targets’ steady-state levels were equally affected by partial or near-total AUF-1 loss induced by cytomix (TNFα/IL1β/IFNγ/10 nM each) and siRNA, respectively, with differential transcript decay rates. Cytomix-mediated decrease in AUF-1 levels in BEAS-2B and primary human small-airways epithelium (HSAEC) was replicated by treatment with the senescence- inducer compound etoposide and associated with readouts of cell-cycle arrest, increase in lysosomal damage and senescence-associated secretory phenotype (SASP) factors, and with AUF-1 transfer in extracellular vesicles, detected by transmission electron microscopy and immunoblotting. Extensive in-silico and genome ontology analysis found, consistent with AUF-1 functions, enriched RIP-Seq-derived AUF-1-targets in COPD-related pathways involved in inflammation, senescence, gene regulation and also in the public SASP proteome atlas; AUF-1 target signature was also significantly represented in multiple transcriptomic COPD databases generated from primary HSAEC, from lung tissue and from single-cell RNA-sequencing, displaying a predominant downregulation of expression.DiscussionLoss of intracellular AUF-1 may alter posttranscriptional regulation of targets particularly relevant for protection of genomic integrity and gene regulation, thus concurring to airway epithelial inflammatory responses related to oxidative stress and accelerated aging. Exosomal-associated AUF-1 may in turn preserve bound RNA targets and sustain their function, participating to spreading of inflammation and senescence to neighbouring cells.

Abstract Phospholipid scramblase 1 (PLSCR1) is the most studied protein of the scramblase family. Originally, it was identified as a membrane protein involved in maintaining plasma membrane asymmetry. However, studies conducted over the past few years have shown the involvement of PLSCR1 in several other cellular pathways. Indeed, PLSCR1 is not only embedded in the plasma membrane but is also expressed in several intracellular compartments where it interacts with a diverse repertoire of effectors, mediators, and regulators contributing to distinct cellular processes. Although most PLSCR1 interactors are thought to be cell-type specific, PLSCR1 often exerts its regulatory functions through shared mechanisms, including the trafficking of different molecules within intracellular vesicles such as endosomes, liposomes, and phagosomes. Intriguingly, besides endogenous proteins, PLSCR1 was also reported to interact with exogenous viral proteins, thereby regulating viral uptake and spread. This review aims to summarize the current knowledge about the multiple roles of PLSCR1 in distinct cellular pathways. Video Abstract

Abstract Introduction Paracoccidioidomycosis is a systemic mycosis endemic to Latin America, with frequent reports of poor treatment adherence resulting in worse clinical outcomes. The present study evaluated factors related to treatment adherence in patients with paracoccidioidomycosis. Methods This cross‐sectional study included data from medical records of patients with paracoccidioidomycosis treated between 2005 and 2018 in a reference hospital in southeastern Brazil. Clinical variables, demographic characteristics, and smoking and alcohol consumption were collected and analyzed. Results Of the 198 cases included, most were adults (median age = 51 years), males (93.4%), presented chronic paracoccidioidomycosis (83.8%), reported smoking (90.4%) and alcohol consumption (84.8%), and 56.6% adhered to treatment. Treatment adherence was associated with the discontinuation of alcohol consumption (odds ratios (OR) = 5.227; 95% confidence interval (CI) = 2.697–10.129) and smoking (OR = 3.365; 95% CI = 1.781–6.358) during therapy. Conclusions Patients' continued consumption of alcohol and tobacco was associated with non‐adherence to treatment, suggesting that a joint therapeutic approach that addresses alcohol and tobacco use alongside paracoccidioidomycosis treatment may hold promise for improving adherence and patients' quality of life.

Strawberry (Fragaria × ananassa Duch.) production can be evaluated as repeated measurements, since the same plant is harvested multiple times during the production season. The objectives were to evaluate the production of fresh mass and fruit number in successive harvests and compare three strawberry clones in two cultivation conditions. Two experiments were carried out in two environmental cultivations: the rural property and the experimental area of the Plant Science Department, Federal University of Santa Maria, Brazil. The parameters of the nonlinear logistic model and their critical points were estimated via bootstrap for each condition and clone for fresh mass and fruit number with accumulated values, depending on the thermal sum accumulated during the production season. For nonlinear regression analysis, the ordinary least squares method was used with the Gauss–Newton algorithm. Confidence intervals were obtained for each parameter and estimated critical points, and they did not cross; the treatments were considered different. There were significant differences between clones and cultivation conditions for fruit mass and number. The nonlinear logistic models, adjusted for mass and number of strawberry fruits, detailed the production season, highlighting the main differences between cultivation conditions and clones. [ABSTRACT FROM AUTHOR]

Purpose: Current World Health Organization/International Society of Urological Pathology (2004 WHO/ISUP) grading of bladder urothelial carcinoma relies on the highest pathologic grade of the specimen and does not reflect the inherent qualitative and quantitative heterogeneity of disease. Materials and Methods: We retrospectively studied consecutive urothelial high-grade cT1 (cT1HG) carcinomas submitted to adjuvant bacille Calmette–Guérin between 2008 and 2015 to evaluate the prognostic potential of grade 3 (presence or predominance) according to the 1973 WHO system concerning disease progression and cancer-specific death. Results: Among 253 patients, grading distribution was 34.4% 1+2, 7.5% 2+1, 20.2% 2+2, 19.0% 2+3, 5.1% 3+2, and 13.8% 3+3. Recurrence was diagnosed in 115 (45.5%), progression in 83 (32.8%), and cancer-specific death in 50 patients (19.8%). Mean time to recurrence, progression, and death from disease were 35.9±31.7, 47.6±44.5, and 51.2±50.4 months, respectively. Grade 3 presence (2+3, 3+2, or 3+3) occurred in 96 (37.9%) and independently predicted time to progression (p

Vascular aging is linked to reduce NO bioavailability, endothelial dysfunction, oxidative stress, and inflammation. We previously showed that a 4-week treatment of middle-aged Wistar rats (MAWRs, 46 weeks old) with Moringa oleifera seed powder (MOI, 750 mg/kg/day) improved vascular function. Here, we investigated the involvement of SIRT1 in MOI-induced vascular improvement. MAWRs were treated with a standard or MOI-containing diet. Young rats (YWR, 16 weeks old) were the controls and received a standard diet. The hearts and aortas were harvested to evaluate SIRT1 and FOXO1 expression via Western blot and/or immunostaining, SIRT1 activity via a fluorometric assay, and oxidative stress using the DHE fluorescent probe. In the hearts and aortas, SIRT1 expression, reduced in MAWRs compared to YWRs, was enhanced in MOI MAWRs. In the hearts, SIRT1 activity did not differ between YWRs and MAWRs, whereas it was increased in MOI MAWRs compared with them. In the aortas, SIRT1 activity decreased in MAWRs, and it was similar in the MOI MAWRs and YWRs. FOXO1 expression increased in the nuclei of MAWR aortas compared to YWR and was reversed in MOI MAWRs. Interestingly, MOI treatment normalized oxidative stress enhanced in MAWRs, in both the heart and aorta. These results demonstrate the protective role of MOI against cardiovascular dysfunction due to aging via enhanced SIRT1 function and subsequently reduced oxidative stress.

Simple Summary: This study investigates the impact of the BRAFV600E mutation, present in half of melanoma cases, on immune microenvironment and therapeutic response. Analyzing the Cancer Genome Atlas data, we uncover that the mutation correlates with reduced tumor mutation burden, indicating a lower generation of immune-stimulating neopeptides. Examination of immune subtypes reveal heightened immunosuppression in BRAFV600E-mutated tumors. Using melanoma cell lines harboring different genomic profiles, we observed an enhanced response to immunogenic cell death (ICD)—a crucial process eliciting anti-tumor immune responses—mediated by photodynamic therapy (PDT). Transcriptomic analysis highlights upregulation of IFNAR1, IFNAR2, and CXCL10 genes in BRAFV600E-mutated cells, suggesting their role in ICD. Our results describe the intricate relationship between the BRAFV600E mutation and immune responses, hinting at a potential link between this mutation and responsiveness to ICD-inducing therapies, particularly PDT, putatively linked to increased IFN-1 pathway activation. The BRAFV600E mutation, found in approximately 50% of melanoma cases, plays a crucial role in the activation of the MAPK/ERK signaling pathway, which promotes tumor cell proliferation. This study aimed to evaluate its impact on the melanoma immune microenvironment and therapeutic responses, particularly focusing on immunogenic cell death (ICD), a pivotal cytotoxic process triggering anti-tumor immune responses. Through comprehensive in silico analysis of the Cancer Genome Atlas data, we explored the association between the BRAFV600E mutation, immune subtype dynamics, and tumor mutation burden (TMB). Our findings revealed that the mutation correlated with a lower TMB, indicating a reduced generation of immunogenic neoantigens. Investigation into immune subtypes reveals an exacerbation of immunosuppression mechanisms in BRAFV600E-mutated tumors. To assess the response to ICD inducers, including doxorubicin and Me-ALA-based photodynamic therapy (PDT), compared to the non-ICD inducer cisplatin, we used distinct melanoma cell lines with wild-type BRAF (SK-MEL-2) and BRAFV600E mutation (SK-MEL-28, A375). We demonstrated a differential response to PDT between the WT and BRAFV600E cell lines. Further transcriptomic analysis revealed upregulation of IFNAR1, IFNAR2, and CXCL10 genes associated with the BRAFV600E mutation, suggesting their involvement in ICD. Using a gene reporter assay, we showed that PDT robustly activated the IFN-1 pathway through cGAS-STING signaling. Collectively, our results underscore the complex interplay between the BRAFV600E mutation and immune responses, suggesting a putative correlation between tumors carrying the mutation and their responsiveness to therapies inducing the IFN-1 pathway, such as the ICD inducer PDT, possibly mediated by the elevated expression of IFNAR1/2 receptors [ABSTRACT FROM AUTHOR]

The article presents a brief historiography of choral dances in the light of Rudolf Laban's ideological premises in comparison with the National Socialism ideology in Germany in the 1920s and 1930s. Laban choral dances were a form of collective dance that the choreographer proposed as a means of recovering a sense of community, and which occupied an essential place in his project of propagation of dance. Considering the background of choral dances and, more specifically, the episode of the choreography that Laban created for the 1936 Olympic games activities, the article deals with the approximations and distances between Laban's cultural projects and National Socialism. The article shows how the collective power contained in choral dances, which were part of the cultural policy instituted in the early years of the Nazi regime in Germany, ended up being a key point for both Laban's rise and fall within the German government. Finally, the text seeks to reflect on the responsibilities and consequences of concessions in the relations between art, politics and ethics that arose in this specific relationship between Laban and Nazism. Keywords Rudolf Laban. Choral Dance. Dance History. Nazism.