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Infection by chikungunya virus (CHIKV), a mosquito-borne alphavirus, causes severe polyarthralgia and polymyalgia, which can last in some people for months to years. Chronic CHIKV disease signs and symptoms are associated with the persistence of viral nucleic acid and antigen in tissues. Like humans and nonhuman primates, CHIKV infection in mice results in the development of robust adaptive antiviral immune responses. Despite this, joint tissue fibroblasts survive CHIKV infection and can support persistent viral replication, suggesting that they escape immune surveillance. Here, using a recombinant CHIKV strain encoding the fluorescent protein VENUS with an embedded CD8+ T cell epitope, SIINFEKL, we observed a marked loss of both MHC class I (MHC-I) surface expression and antigen presentation by CHIKV-infected joint tissue fibroblasts. Both in vivo and ex vivo infected joint tissue fibroblasts displayed reduced cell surface levels of H2-Kb and H2-Db MHC-I proteins while maintaining similar levels of other cell surface proteins. Mutations within the methyl transferase-like domain of the CHIKV nonstructural protein 2 (nsP2) increased MHC-I cell surface expression and antigen presentation efficiency by CHIKV-infected cells. Moreover, expression of WT nsP2 alone, but not nsP2 with mutations in the methyltransferase-like domain, resulted in decreased MHC-I antigen presentation efficiency. MHC-I surface expression and antigen presentation was rescued by replacing VENUS-SIINFEKL with SIINFEKL tethered to ß2-microglobulin in the CHIKV genome, which bypasses the requirement for peptide processing and TAP-mediated peptide transport into the endoplasmic reticulum. Collectively, this work suggests that CHIKV escapes the surveillance of antiviral CD8+ T cells, in part, by nsP2-mediated disruption of MHC-I antigen presentation.
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Febre de Chikungunya , Vírus Chikungunya , Humanos , Animais , Camundongos , Apresentação de Antígeno , Replicação Viral , Proteínas não Estruturais Virais/genética , Proteínas não Estruturais Virais/metabolismo , Epitopos de Linfócito T , Peptídeos/metabolismoRESUMO
The nucleolus is sensitive to stress and can orchestrate a chain of cellular events in response to stress signals. Despite being a growth factor, FGF2 has antiproliferative and tumor-suppressive functions in some cellular contexts. In this work, we investigated how the antiproliferative effect of FGF2 modulates chromatin-, nucleolus- and rDNA-associated proteins. The chromatin and nucleolar proteome indicated that FGF2 stimulation modulates proteins related to transcription, rRNA expression and chromatin-remodeling proteins. The global transcriptional rate and nucleolus area increased along with nucleolar disorganization upon 24â h of FGF2 stimulation. FGF2 stimulation induced immature rRNA accumulation by increasing rRNA transcription. The rDNA-associated protein analysis reinforced that FGF2 stimulus interferes with transcription and rRNA processing. RNA Pol I inhibition partially reversed the growth arrest induced by FGF2, indicating that changes in rRNA expression might be crucial for triggering the antiproliferative effect. Taken together, we demonstrate that the antiproliferative FGF2 stimulus triggers significant transcriptional changes and modulates the main cell transcription site, the nucleolus.
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Nucléolo Celular , Fator 2 de Crescimento de Fibroblastos , Fator 2 de Crescimento de Fibroblastos/genética , Fator 2 de Crescimento de Fibroblastos/farmacologia , Fator 2 de Crescimento de Fibroblastos/metabolismo , Nucléolo Celular/metabolismo , RNA Ribossômico/genética , RNA Ribossômico/metabolismo , Transcrição Gênica , DNA Ribossômico/genética , Cromatina/genética , Cromatina/metabolismoRESUMO
The mitochondrial electron transport chain (mETC) is a series of membrane embedded enzymatic complexes critical for energy conversion and mitochondrial metabolism. In commonly studied eukaryotes, including humans and animals, complex II, also known as succinate dehydrogenase (SDH), is an essential four-subunit enzyme that acts as an entry point to the mETC, by harvesting electrons from the TCA cycle. Apicomplexa are pathogenic parasites with significant impact on human and animal health. The phylum includes Toxoplasma gondii which can cause fatal infections in immunocompromised people. Most apicomplexans, including Toxoplasma, rely on their mETC for survival, yet SDH remains largely understudied. Previous studies pointed to a divergent apicomplexan SDH with nine subunits proposed for the Toxoplasma complex, compared to four in humans. While two of the nine are homologs of the well-studied SDHA and B, the other seven have no homologs in SDHs of other systems. Moreover, SDHC and D, that anchor SDH to the membrane and participate in substrate bindings, have no homologs in Apicomplexa. Here, we validated five of the seven proposed subunits as bona fide SDH components and demonstrated their importance for SDH assembly and activity. We further find that all five subunits are important for parasite growth, and that disruption of SDH impairs mitochondrial respiration and results in spontaneous initiation of differentiation into bradyzoites. Finally, we provide evidence that the five subunits are membrane bound, consistent with their potential role in membrane anchoring, and we demonstrate that a DY motif in one of them, SDH10, is essential for complex formation and function. Our study confirms the divergent composition of Toxoplasma SDH compared to human, and starts exploring the role of the lineage-specific subunits in SDH function, paving the way for future mechanistic studies.
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Succinato Desidrogenase , Toxoplasma , Animais , Humanos , Succinato Desidrogenase/genética , Toxoplasma/genética , Toxoplasma/metabolismo , Mitocôndrias/metabolismo , Membranas Mitocondriais/metabolismo , Ciclo do Ácido CítricoRESUMO
In response to the spread of artemisinin (ART) resistance, ART-based hybrid drugs were developed, and their activity profile was characterized against drug-sensitive and drug-resistant Plasmodium falciparum parasites. Two hybrids were found to display parasite growth reduction, stage-specificity, speed of activity, additivity of activity in drug combinations, and stability in hepatic microsomes of similar levels to those displayed by dihydroartemisinin (DHA). Conversely, the rate of chemical homolysis of the peroxide bonds is slower in hybrids than in DHA. From a mechanistic perspective, heme plays a central role in the chemical homolysis of peroxide, inhibiting heme detoxification and disrupting parasite heme redox homeostasis. The hybrid exhibiting slow homolysis of peroxide bonds was more potent in reducing the viability of ART-resistant parasites in a ring-stage survival assay than the hybrid exhibiting fast homolysis. However, both hybrids showed limited activity against ART-induced quiescent parasites in the quiescent-stage survival assay. Our findings are consistent with previous results showing that slow homolysis of peroxide-containing drugs may retain activity against proliferating ART-resistant parasites. However, our data suggest that this property does not overcome the limited activity of peroxides in killing non-proliferating parasites in a quiescent state.
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Antimaláricos , Artemisininas , Plasmodium falciparum , Artemisininas/farmacologia , Antimaláricos/farmacologia , Plasmodium falciparum/efeitos dos fármacos , Resistência a Medicamentos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Humanos , Testes de Sensibilidade Parasitária , Animais , Peróxidos/farmacologiaRESUMO
Our core timekeeping mechanism, the circadian clock, plays a vital role in immunity. Although the mechanics of circadian control over the immune response is generally explained by transcriptional activation or repression derived from this clock's transcription-translation negative-feedback loop, research suggests that some regulation occurs beyond transcriptional activity. We comprehensively profiled the transcriptome and proteome of murine bone marrow-derived macrophages and found that only 15% of the circadian proteome had corresponding oscillating mRNA, suggesting post-transcriptional regulation influences macrophage clock regulatory output to a greater extent than any other tissue previously profiled. This regulation may be explained by the robust temporal enrichment we identified for proteins involved in degradation and translation. Extensive post-transcriptional temporal-gating of metabolic pathways was also observed and further corresponded with daily variations in ATP production, mitochondrial morphology, and phagocytosis. The disruption of this circadian post-transcriptional metabolic regulation impaired immune functionality. Our results demonstrate that cell-intrinsic post-transcriptional regulation is a primary driver of circadian output in macrophages and that this regulation, particularly of metabolic pathways, plays an important role in determining their response to immune stimuli.
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The use of antimicrobials in poultry leaves residues in the litter, favoring the emergence of antimicrobial-resistant pathogens and making it a source of contamination. An in vitro 4 × 4 factorial trial was performed to investigate the influence of four treatments, consisting of antimicrobial sub-concentrations, on the transference of IncB/O-plasmid through conjugation in four groups. Each group was composed of one plasmid donor bacterium (Escherichia coli H2332) and a recipient bacterium (Escherichia coli J62 or Salmonella enterica serovars, Enteritidis, Typhimurium, or Heidelberg). Our results showed a little decrease in the conjugation frequency in almost all treatments between the two bacterial species, which varied according to each strain. The MIC test revealed an increase of up to 4096-fold in resistance to beta-lactams in Salmonella serovars after plasmid acquisition. This finding suggests that some genetic apparatus may be involved in increased antimicrobial resistance in Salmonella serovars after the acquisition of primary resistance determinants.
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Antibacterianos , Conjugação Genética , Escherichia coli , Testes de Sensibilidade Microbiana , Plasmídeos , Salmonella enterica , beta-Lactamas , Salmonella enterica/efeitos dos fármacos , Salmonella enterica/genética , Plasmídeos/genética , Escherichia coli/efeitos dos fármacos , Escherichia coli/genética , beta-Lactamas/farmacologia , Antibacterianos/farmacologiaRESUMO
Lapachol (2-hydroxy-3-(3-methylbut-2-en-1-yl)naphthalene-1,4-dione) is a 1,4-naphthoquinone-derived natural product that presents numerous bioactivities and was shown to have cytotoxic effects against several human tumor cells. Indium(III) complexes with a variety of ligands also exhibit antineoplastic activity. Indium(III) complexes [In(lap)Cl2].4H2O (1), [In(lap)2Cl(Et3N)] (2), [In(lap)3]·2H2O (3) [In(lap)(bipy)Cl2] bipy = 2,2'-bipyridine (4) and [In(lap)(phen)Cl2] phen = 1,10-phenanthroline (5) were obtained with 2-hydroxy-3-(3-methylbut-2-en-1-yl)naphthalene-1,4-dione (lapachol). Crystal structure determinations for (4) and (5) revealed that the indium(III) center is coordinated to two O atoms from lapachol, two N atoms from 1,10-phenanthroline or 2,2'-bipyridine, and two chloride anions, in a distorted octahedral geometry. Although both complexes (4) and (5) interacted with CT-DNA in vitro by an intercalative mode, only 5 exhibited cytotoxicity against MCF-7 and MDA-MB breast tumor cells. 1,10-phenanthroline and complex (5) presented cytotoxic effects against MCF-7 and MDA-MB cells, with complex (5) being threefold more active than 1,10-phenanthroline on MCF-7 cells. In addition, complex (5) significantly reduced the formation of MDA-MB-231 colonies in a clonogenicity assay. The foregoing results suggest that further studies on the cytotoxic effects and cellular targets of complex (5) are of utmost relevance.
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INTRODUCTION: It is unknown how cardiac imaging studies are used by neurologists to investigate cardioembolic sources in ischemic stroke patients. METHODS: Between August 12, 2023, and December 8, 2023, we conducted an international survey among neurologists from Europe, North America, South America, and Asia, to investigate the frequency of utilization of cardiac imaging studies for the detection of cardioembolic sources of ischemic stroke. Questions were structured into deciles of percentage utilization of transthoracic echocardiography (TTE), transesophageal echocardiography (TEE), ECG-gated cardiac computed tomography (G-CCT), and cardiac magnetic resonance imaging (CMRI). We estimated the weighted proportion (
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This cross-sectional study aims to describe and compare energy, nutrient intake and food consumption according to eating location and by age groups using data from the National Food, Nutrition and Physical Activity Survey (IAN-AF 2015/2016). Dietary intake was estimated by two non-consecutive days of food diaries (children)/24-h recalls (other age groups), and four eating location categories were defined according to the proportion of meals consumed at out-of-home locations: Home (at least 80 % of meals at home), Other Homes, School or Work and Restaurants and Other Places. The majority of meals (69·1 %) were consumed at home. Meals were also often taken at school by children and adolescents and in restaurants and similar outlets by adults and elderly. Children and adolescents in the School or Work category ate more fruit, vegetables and pulses and cereals and starchy tubers, whereas adults in this category ate more red and processed meats, sugar-sweetened beverages and sweets. Compared with Home category, Restaurants and Other Places was associated with worse diet adequacies among children (ß = -1·0; 95 % CI = -2·0, -0·04), adolescents: (ß = -2·4; 95 % CI = -3·2, -1·5) and adults (ß = -1·3; 95 % CI = -1·6, -1·0) reflecting higher intakes of energy, fat, trans-fatty acids and SFA, and Na. The elderly consumed more free sugars and fat when eating out of home in general. Overall, findings reflect important variation in nutrient profiles by eating location, with meals taken at school or work contributing to higher consumption of nutrient-dense foods and those taken in restaurants and other similar settings implying higher consumption of energy-dense foods.
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BACKGROUND: Omicron has become the dominant variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) since first reported in November 2021. From the initially detected Wuhan lineage, sublineages BA.2, BA.4, BA.5, BQ, XAG, and XBB have emerged over time and are dominant in many countries. Therefore, the aim is to evaluate which variants are circulating and the clinical characteristics of inpatients infected with the Omicron variant. METHODS: This retrospective cohort study selected hospitalized patients admitted with respiratory symptoms to a hospital in the state of Rio Grande do Sul, Brazil, between June and July 2022. SARS-CoV-2 results were analyzed together with clinical outcomes and vaccination status. A viral genome library was prepared and forwarded to the Illumina MiSeq Platform for sequencing. RESULTS: In total, 37 genomes were sequenced. Concerning the Omicron sublineages, our study detected: BA.1 (21 K), BA.2 (21 L), BA.4 (22A), BA.5 (22B), BA.2.12.1 (22C), BQ.1 (22E), XBB (22F), and XAG recombinant. Omicron BA.5 (30%), BA.2 (19%), and BQ.1 (19%) were the most frequent sublineages, respectively. In total, 38% of patients present hypertension, and the most common symptoms were coughing (62%). Analyzing the COVID-19 vaccination, 30% of patients were fully vaccinated, 49% had a partial vaccination status, and 21% were unvaccinated (no dose). CONCLUSIONS: BA.5 was the most prevalent sublineage in our study and surpassed the predominance of BA.2, as reported by the national genomic surveillance program. BQ.1 was diagnosed earlier in this study than it was officially reported in the state. Current data have demonstrated that the Omicron variant causes less severe infections, with the high rate of transmissibility and mutational landscape causing the rapid emergence of new sublineages.
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Vacinas contra COVID-19 , Pacientes Internados , Humanos , Brasil/epidemiologia , Estudos Retrospectivos , TosseRESUMO
INTRODUCTION: There is uncertainty regarding the method of mesh fixation and peritoneal closure during transabdominal preperitoneal (TAPP) repair for inguinal hernias, with no definitive guidelines to guide surgeon choice. METHODS: MEDLINE, Cochrane, Central Register of Clinical Trials, and Web of Science were searched for RCTs published until November 2023. Risk ratios (RRs) and mean differences (MD) with 95% confidence intervals (CIs) were pooled with a random-effects model. Statistical significance was defined as p < 0.05. Heterogeneity was assessed using the Cochran Q test and I2 statistics, with p values inferior to 0.10 and I2 > 25% considered significant. Statistical analyses were conducted using Review Manager version 5.4 and RStudio version 4.1.2 (R Foundation for Statistical Computing). RESULTS: Eight randomized controlled trials (RCTs) were included, comprising 624 patients, of whom 309 (49.5%) patients were submitted to TAPP with the use of tacks, and 315 (50.5%) received suture fixation. The use of tacker fixation was associated with a significant increase in postoperative pain at 24 h (MD 0.79 [VAS score]; 95% CI 0.38 to 1.19; p < 0.0002; I2 = 87%) and one week (MD 0.42 [VAS score]; 95% CI 0.05 to 0.79; p < 0.03, I2 = 84%). The use of tacks was associated with shorter operative time (MD-25.80 [min]; 95% - 34.31- - 17.28; P < 0.00001; I2 = 94%). No significant differences were found in overall complications, chronic pain, seromas, hematomas, and urinary retention rates. CONCLUSION: In patients who underwent TAPP hernia repair, tacks are associated with decreased operative time but increased postoperative pain at 24 h and one week.
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Despite its global importance as a primary source of table sugar and bioethanol, sugarcane faces a significant threat to its production due to diseases. One of these diseases, sugarcane smut, involves the emergence of a whip-like structure from the host apical shoot. The slow onset of this pathogenesis is the most substantial challenge for researchers to investigate the molecular events leading to resistance or susceptibility. In this study, we explored the early interaction between the smut fungus Sporisorium scitamineum and foliar tissues of the model plants Arabidopsis thaliana and Nicotiana benthamiana. Upon inoculation with the fungus, A. thaliana showed a compatible reaction, producing lesions during fungus colonization, whereas N. benthamiana showed signs of nonhost resistance. In addition, we propose a sugarcane detached leaf assay using plants cultivated in vitro to reveal sugarcane smut response outcomes. We used two sugarcane genotypes with known contrasting reactions to smut in the field. Although there is no evidence of sugarcane smut fungus infecting host leaves naturally, the sugarcane detached leaf assay enabled a rapid assessment of disease outcomes. Different symptoms in the detached leaves after inoculation distinguished smut-susceptible and smut-resistant sugarcane genotypes. Microscopic observations and gene expression analysis of S. scitamineum candidate effectors confirmed the fungal growth and its restriction on the compatible and incompatible interactions, respectively. These findings offer new prospects into the disease phenotyping of S. scitamineum, which could greatly expedite the comprehension of the initial stages of the pathogenesis and predict smut resistance in sugarcane genotypes.
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Arabidopsis , Nicotiana , Doenças das Plantas , Folhas de Planta , Saccharum , Doenças das Plantas/microbiologia , Saccharum/microbiologia , Folhas de Planta/microbiologia , Nicotiana/microbiologia , Arabidopsis/microbiologia , Interações Hospedeiro-Patógeno , Ustilaginales/fisiologia , Ustilaginales/patogenicidade , Ustilaginales/genética , Regulação da Expressão Gênica de Plantas , Genótipo , Resistência à Doença/genéticaRESUMO
INTRODUCTION: Interpersonal violence is a phenomenon that can occur with different people and conditions. However, people with intellectual disabilities have increased vulnerability to this problem, with potential risks to their health and well-being. The aim of this study was to identify the sociodemographic characteristics of people with disabilities who have been victims of interpersonal violence, the profile of the perpetrators and the measures taken after the victims have been cared for. METHODS: This is an exploratory, descriptive, cross-sectional study using the Interpersonal Violence Notification Forms entered into the Brazilian Ministry of Health's Notifiable Diseases Information System. The city of São Paulo was chosen as the setting because it is the largest city in Latin America and has a faster data processing system than other cities. The period covered notifications made between 2016 and 2022. The information was collected between October and November 2023 and a univariate statistical analysis was carried out. Fisher's exact test was used, with a significance level of 5% (α = 0.05). RESULTS: There were 4,603 notifications against people with intellectual disabilities in the period. The forms of physical violence, neglect/abandonment and psychological/moral violence were more frequent in the 15-19 age group, while sexual violence was more frequent in the 10-14 age group (p < 0.001). The sex most often attacked was female in all the forms investigated (p < 0.001) and the skin colors of the most victimized people were black and/or brown, except in cases of neglect/abandonment (p = 0.058). Most of the victims had little schooling (p = 0.012). The aggressions were committed by one person (p < 0.001), known or related to the victim, such as mother or father, except in cases of sexual violence, where strangers were the main perpetrators (p < 0.001). The sex of the perpetrator was male, except in cases of neglect and/or abandonment (p < 0.001), and the age was between 25 and 29 (p = 0.004). In cases of sexual violence, rape was the most frequent and the procedures carried out were blood collection followed by prophylaxis for Sexually Transmitted Infections (STIs) were the main procedures carried out by health professionals (p = 0.004). The majority of referrals made after receiving care were to the health and social assistance network, with few referrals to bodies such as the human rights reference center, guardianship council and police stations (p < 0.001). CONCLUSION: People with intellectual disabilities are highly vulnerable to the forms of violence studied, especially children and adolescents, black or brown, with low levels of education. The perpetrators are usually close people, male and older than the victims. The referrals made by health professionals did not prioritize the victim's safety and the guarantee of human rights. Lines of care for the health of victims of violence should be implemented, taking into account special aspects, such as people with intellectual disabilities, whose search for help can be difficult.
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Vítimas de Crime , Deficiência Intelectual , Humanos , Brasil/epidemiologia , Feminino , Masculino , Adulto , Deficiência Intelectual/epidemiologia , Estudos Transversais , Adolescente , Adulto Jovem , Pessoa de Meia-Idade , Vítimas de Crime/estatística & dados numéricos , Vítimas de Crime/psicologia , Criança , Violência/estatística & dados numéricos , Violência/psicologia , Encaminhamento e Consulta/estatística & dados numéricos , Pré-Escolar , IdosoRESUMO
Multiple in vitro eye irritation methods have been developed and adopted as OECD health effects test guidelines. However, for predicting the ocular irritation/damage potential of agrochemical formulations there is an applicability domain knowledge gap for most of the methods. To overcome this gap, a retrospective evaluation of 192 agrochemical formulations with in vivo (OECD TG 405) and in vitro (OECD TG 437, 438, and/or 492) data was conducted to determine if the in vitro methods could accurately assign United Nations Globally Harmonized System for Classification and Labelling of Chemicals (GHS) eye irritation hazard classifications. In addition, for each formulation the eye irritation classification was derived from the classification of the contained hazardous ingredients and their respective concentration in the product using the GHS concentration threshold (CT) approach. The results herein suggest that the three in vitro methods and the GHS CT approach were highly predictive of formulations that would not require GHS classification for eye irritation. Given most agrochemical formulations fall into this category, methods that accurately identify non-classified agrochemical formulations could significantly reduce the use of animals for this endpoint.
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Agroquímicos , Irritantes , Animais , Agroquímicos/toxicidade , Agroquímicos/química , Estudos Retrospectivos , Alternativas aos Testes com Animais , OlhoRESUMO
Electroejaculation (EE) represents the main technique for semen collection from domestic and wild animals independently of libido. However, the technique is associated with intense involuntary muscle contractions, vocalization, ataxia and lying down, caused by the electric stimulation of the nerves in the caudal epigastric region. These clinical manifestations represent important indicators of discomfort. In this context, the objective of this study was to evaluate two protocols of local anaesthetic blockade and two anatomical access for pharmacological desensitization of the caudal epigastric innervation as alternatives to promote comfort and reduce stress associated with EE in rams. For the study, four clinically healthy Dorper rams were selected. All animals were subjected to a design consisting of five semen collection treatments (n = 3 collections per treatment): T1-control, conventional EE without local anaesthetic blockade; T2, EE with ventral blockade (VB) of epigastric innervation using lidocaine hydrochloride 2%; T3, EE with VB of epigastric innervation using a combination of lidocaine hydrochloride 2% and fentanyl citrate; T4, EE with blockade of epigastric innervation through the perineal access using lidocaine hydrochloride 2%; T5, EE with blockade of epigastric innervation through the perineal access using a combination of lidocaine hydrochloride and fentanyl citrate. Seminal samples resulting from EE were subjectively evaluated for sperm motility and concentration, vigour and volume. Additionally, blood serum samples were collected for quantification of cortisol and creatine kinase (CK) enzyme. Assessments of stress and discomfort were conducted by measuring blood pressure, heart rate (HR) and respiratory rate (RR), as well as observing involuntary muscle contractions, ataxia and animal vocalization. No variations in blood pressure, sperm motility, vigour, CK, and cortisol were observed among the treatments. Individual variations were observed for the occurrence of vocalization (p = .0066), but there were no differences between the groups. Anaesthetic blockades conducted using the combination of lidocaine and fentanyl resulted in a lower incidence of ataxia during EE (p < .0001). It is concluded that the combination of fentanyl citrate and lidocaine hydrochloride results in less discomfort for animals undergoing EE, regardless of the anatomical access used for local anaesthetic blockades.
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Anestésicos Locais , Doenças dos Ovinos , Masculino , Animais , Ovinos , Anestésicos Locais/farmacologia , Hidrocortisona , Motilidade dos Espermatozoides , Dor/veterinária , Lidocaína/farmacologia , Fentanila/farmacologia , Ataxia/veterináriaRESUMO
Importance: Sodium-glucose cotransporter 2 (SGLT-2) inhibitors improve outcomes in patients with type 2 diabetes, heart failure, and chronic kidney disease, but their effect on outcomes of critically ill patients with organ failure is unknown. Objective: To determine whether the addition of dapagliflozin, an SGLT-2 inhibitor, to standard intensive care unit (ICU) care improves outcomes in a critically ill population with acute organ dysfunction. Design, Setting, and Participants: Multicenter, randomized, open-label, clinical trial conducted at 22 ICUs in Brazil. Participants with unplanned ICU admission and presenting with at least 1 organ dysfunction (respiratory, cardiovascular, or kidney) were enrolled between November 22, 2022, and August 30, 2023, with follow-up through September 27, 2023. Intervention: Participants were randomized to 10 mg of dapagliflozin (intervention, n = 248) plus standard care or to standard care alone (control, n = 259) for up to 14 days or until ICU discharge, whichever occurred first. Main Outcomes and Measures: The primary outcome was a hierarchical composite of hospital mortality, initiation of kidney replacement therapy, and ICU length of stay through 28 days, analyzed using the win ratio method. Secondary outcomes included the individual components of the hierarchical outcome, duration of organ support-free days, ICU, and hospital stay, assessed using bayesian regression models. Results: Among 507 randomized participants (mean age, 63.9 [SD, 15] years; 46.9%, women), 39.6% had an ICU admission due to suspected infection. The median time from ICU admission to randomization was 1 day (IQR, 0-1). The win ratio for dapagliflozin for the primary outcome was 1.01 (95% CI, 0.90 to 1.13; P = .89). Among all secondary outcomes, the highest probability of benefit found was 0.90 for dapagliflozin regarding use of kidney replacement therapy among 27 patients (10.9%) in the dapagliflozin group vs 39 (15.1%) in the control group. Conclusion and Relevance: The addition of dapagliflozin to standard care for critically ill patients and acute organ dysfunction did not improve clinical outcomes; however, confidence intervals were wide and could not exclude relevant benefits or harms for dapagliflozin. Trial Registration: ClinicalTrials.gov Identifier: NCT05558098.
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Compostos Benzidrílicos , Estado Terminal , Glucosídeos , Mortalidade Hospitalar , Unidades de Terapia Intensiva , Tempo de Internação , Inibidores do Transportador 2 de Sódio-Glicose , Humanos , Compostos Benzidrílicos/uso terapêutico , Feminino , Masculino , Glucosídeos/uso terapêutico , Glucosídeos/efeitos adversos , Pessoa de Meia-Idade , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos , Idoso , Terapia de Substituição Renal , Insuficiência de Múltiplos Órgãos/tratamento farmacológicoRESUMO
Milk is renowned for its nutritional richness but also serves as a remarkable reservoir of bioactive compounds, particularly milk proteins and their derived peptides. Recent studies have showcased several robust antiviral activities of these proteins, evidencing promising potential within zoonotic viral diseases. While several publications focus on milk's bioactivities, antiviral peptides remain largely neglected in reviews. This knowledge is critical for identifying novel research directions and analyzing potential nutraceuticals within the One Health context. Our review aims to gather the existing scientific information on milk-derived antiviral proteins and peptides against several zoonotic viral diseases, and their possible mechanisms. Overall, in-depth research has increasingly revealed them as a promising and novel strategy against viruses, principally for those constituting a plausible pandemic threat. The underlying mechanisms of the bioactivity of milk's proteins include inhibiting viral entry and attachment to the host cells, blocking replication, or even viral inactivation via peptide-membrane interactions. Their marked versatility and effectiveness stand out compared to other antiviral peptides and can support future research and development in the post-COVID-19 era. Overall, our review helps to emphasize the importance of potentially effective milk-derived peptides, and their significance for veterinary and human medicines, along with the pharmaceutical, nutraceutical, and dairy industry.
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Proteínas do Leite , Viroses , Animais , Humanos , Proteínas do Leite/química , Peptídeos/farmacologia , Zoonoses , Antivirais/farmacologia , Antivirais/uso terapêutico , Viroses/tratamento farmacológicoRESUMO
Escherichia coli is one of the key bacteria responsible for a variety of diseases in humans and livestock-associated infections around the globe. It is the leading cause of mortality in neonatal and weaned piglets in pig husbandry, causing diarrhea and significant harm to the industry. Furthermore, the frequent and intensive use of antimicrobials for the prevention of diseases, particularly gastrointestinal diseases, may promote the selection of multidrug-resistant (MDR) strains. These resistant genotypes can be transmitted through the excrement of animals, including swine. It is common practice to use porcine manure processed by biodigesters as fertilizer. This study aimed to examine the antimicrobial susceptibility, the presence of virulence genes frequently associated with pathotypes of intestinal pathogenic E. coli (InPEC), and antimicrobial resistance genes (ARGs) of 28 E. coli isolates collected from swine manure fertilizers. In addition, the enterobacterial repetitive intergenic consensus-PCR (ERIC-PCR) technique was used to investigate the genetic relationship among the strains. Using disk diffusion, the antimicrobial susceptibility profiles of the strains were determined. Using polymerase chain reaction (PCR), 14 distinct virulence genes associated with the most prevalent diarrhea and intestinal pathogenic E. coli (DEC/InPEC) and five ARGs were analyzed. All isolates tested positive for multidrug resistance. There was no detection of any of the 14 virulence genes associated with InPECs, indicating the presence of an avirulent commensal microbiota. Molecular classification by ERIC-PCR revealed that the majority of isolates (27 isolates) coalesced into a larger cluster with a genetic similarity of 47.7%; only one strain did not cluster in this cluster, indicating a high level of genetic diversity among the analyzed isolates. Thus, it is of the utmost importance to conduct epidemiological surveillance of animal breeding facilities in order to determine their microbiota and formulate plans to reduce the use of antimicrobials and improve animal welfare.
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Farmacorresistência Bacteriana Múltipla , Escherichia coli , Fertilizantes , Esterco , Animais , Suínos , Escherichia coli/genética , Escherichia coli/efeitos dos fármacos , Escherichia coli/isolamento & purificação , Esterco/microbiologia , Brasil , Farmacorresistência Bacteriana Múltipla/genética , Antibacterianos/farmacologiaRESUMO
Essentially all cells are covered with a dense coat of different glycan structures/sugar chains, giving rise to the so-called glycocalyx. Changes in cellular glycosylation are a hallmark of cancer, affecting most of the pathophysiological processes associated with malignant transformation, including tumour immune responses. Glycans are chief macromolecules that define T-cell development, differentiation, fate, activation and signalling. Thus, the diversity of glycans expressed at the surface of T cells constitutes a fundamental molecular interface with the microenvironment by regulating the bilateral interactions between T-cells and cancer cells, fine-tuning the anti-tumour immune response. In this review, we will introduce the power of glycans as orchestrators of T-cell-mediated immune response in physiological conditions and in cancer. We discuss how glycans modulate the glyco-metabolic landscape in the tumour microenvironment, and whether glycans can synergize with immunotherapy as a way of rewiring T-cell effector functions against cancer cells.
Assuntos
Neoplasias , Humanos , Polissacarídeos , Linfócitos T , Glicosilação , Imunidade , Microambiente TumoralRESUMO
The mitochondrial electron transport chain (mETC) and F1Fo-ATP synthase are of central importance for energy and metabolism in eukaryotic cells. The Apicomplexa, important pathogens of humans causing diseases such as toxoplasmosis and malaria, depend on their mETC in every known stage of their complicated life cycles. Here, using a complexome profiling proteomic approach, we have characterised the Toxoplasma mETC complexes and F1Fo-ATP synthase. We identified and assigned 60 proteins to complexes II, IV and F1Fo-ATP synthase of Toxoplasma, of which 16 have not been identified previously. Notably, our complexome profile elucidates the composition of the Toxoplasma complex III, the target of clinically used drugs such as atovaquone. We identified two new homologous subunits and two new parasite-specific subunits, one of which is broadly conserved in myzozoans. We demonstrate all four proteins are essential for complex III stability and parasite growth, and show their depletion leads to decreased mitochondrial potential, supporting their assignment as complex III subunits. Our study highlights the divergent subunit composition of the apicomplexan mETC and F1Fo-ATP synthase complexes and sets the stage for future structural and drug discovery studies.