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Trichomoniasis, caused by Trichomonas vaginalis (T. vaginalis), is the most common non-viral sexually transmitted disease worldwide. As current trichomoniasis chemotherapies have many side effects, we examined the Anti-Trichomonas effects of nano-liposomal metronidazole (NLMTZ) compared to metronidazole (MTZ) in vitro. Liposomes were produced using the thin film hydration-sonication technique with a slight modification coated with MTZ. The average hydrodynamic diameter of monodispersed NLMTZ was evaluated by DLS and the morphological measurements were performed by scanning electron microscopy (SEM). The effects of NLMTZ and MTZ (5, 10, 20 and 40 µg/mL) on T. vaginalis trophozoites (105 cells/mL) in trypticase-yeast extract-maltose (TYM) medium were evaluated in different exposure times. Then, cell viability, IC50, SEM analysis and the expression of the metacaspase gene were assessed by qRT-PCR. Growth inhibition of MTZ in a concentration of 40 μg/mL was 39.34% after 3 h, whereas NLMTZ caused 51% growth inhibition after 3 h and lysed Trichomonas completely after 12 h. The IC50 values were estimated at 31.51 and 15.90 μg/mL after a 6 h exposure for MTZ and NLMTZ, respectively. Moreover, both T. vaginalis treated with MTZ and NLMTZ had high levels of metacaspase mRNA expression relative to the control groups (P less then 0.05). A significant difference was observed between the apoptotic intensities of T. vaginalis treated with MTZ and NLMTZ (P less then 0.05). This study showed that nano-liposomal MTZ is a potentially excellent approach for the treatment of trichomoniasis in vitro, although further studies are needed before consideration of clinical trials.The epidemiological scenario in central Argentinian Chaco region shows persistence of Triatoma infestans domestic populations in endemic areas, with control interventions historically affected by the economic instability of the region. Considering this situation, we aimed to (i) update the information regarding to the diversity of triatomines present in domestic, peridomestic and sylvatic environments in departments historically endemic of the Chaco region, (ii) to report the occurrence of secondary vectors of Chagas disease invading domestic environments and (iii) to discuss the possible sources of dispersal of these sylvatic species towards anthropic habitats. Between November 2017 and March 2020, we visited fourteen rural communities of northwest Córdoba province (central Argentina). Entomological data were collected through community vector surveillance in domiciles, active search in peridomiciles and the use of light and yeast traps in sylvatic environments. Seven Triatominae species were captured invading domiciles (T. guasayana, T. garciabesi, T. platensis, T. delpontei, T. breyeri, Panstrongylus guentheri and T. infestans). T. guasayana and T. garciabesi were the species with the highest number of captures. The 32% of the peridomiciles registered infestation with T. infestans (n = 355), mostly in chicken coops and goat pens. In sylvatic environments, T. garciabesi, T. guasayana, T. infestans and P. guentheri were collected. Only one adult specimen of T. https://www.selleckchem.com/products/polyethylenimine.html infestans was positive for the presence of Trypanosoma cruzi. Our results suggest that the persistence of T. infestans populations in peridomiciles continues to be a serious challenge for control programs, whereas the finding of secondary vectors of Chagas disease actively invading domiciles emphasizes the need to implement new strategies for entomological surveillance.Escaping the complement system is an important step in the establishment of infections. Some pathogens have acquired the ability to inactivate the complement system to ensure successful infection. This has been observed in parasites from the genus Leishmania, which inactivate C3b molecules deposited on their surface through the membrane protease GP63. In the present study, we describe a new mechanism that also acts through C3b inactivation. This mechanism involves the binding of the complement regulatory molecule factor H from serum. Factor H signals a plasma protease (factor I) to inactivate C3b molecules deposited on the surface of the parasites. According to our results, Leishmania infantum, L. amazonensis, and L. braziliensis recruit factor H from human serum. The absorption of factor H by L. infantum was studied in detail to better understand how it works. L. infantum binds factor H from human serum and factor H-like proteins from dog serum. When exposed to purified factor H, promastigotes bind this regulatory molecule and inactivate C3b in the presence of factor I. This indicates the existence of an as yet unidentified factor H-binding outer surface molecule functioning as a receptor. The two mechanisms (GP63 and factor H binding) work independently, as Leishmania promastigotes with inhibited GP63 can easily inactivate C3b molecules on the surface of the parasite. The identification of the factor H receptor could lead to the development of a vaccine target for leishmaniasis control, as blocking antibodies to factor H binding could impair the mechanism of C3b inactivation, making the parasite more susceptible to the complement system.Individuals infected with SARS-CoV-2 who also display hyperglycemia suffer from longer hospital stays, higher risk of developing acute respiratory distress syndrome (ARDS), and increased mortality. Nevertheless, the pathophysiological mechanism of hyperglycemia in COVID-19 remains poorly characterized. Here, we show that hyperglycemia is similarly prevalent among patients with ARDS independent of COVID-19 status. Yet among patients with ARDS and COVID-19, insulin resistance is the prevalent cause of hyperglycemia, independent of glucocorticoid treatment, which is unlike patients with ARDS but without COVID-19, where pancreatic beta cell failure predominates. A screen of glucoregulatory hormones revealed lower levels of adiponectin in patients with COVID-19. Hamsters infected with SARS-CoV-2 demonstrated a strong antiviral gene expression program in the adipose tissue and diminished expression of adiponectin. Moreover, we show that SARS-CoV-2 can infect adipocytes. Together these data suggest that SARS-CoV-2 may trigger adipose tissue dysfunction to drive insulin resistance and adverse outcomes in acute COVID-19.Influenza causes significant morbidity and mortality among adults with cardiovascular disease (CVD). In nationally representative surveys of 101,210 individuals with CVD conducted in 2018 and 2019, the self-reported rate of vaccination was only 50%, with significant disparities by race and education. We advocate that cardiologists not only routinely emphasize vaccination but capitalize on the opportunity to vaccinate patients at office visits to improve overall rates of vaccination and their associated racial disparities.SARS-CoV-2 virions are surrounded by a lipid bilayer that contains membrane proteins such as spike, responsible for target-cell binding and virus fusion. We found that during SARS-CoV-2 infection, spike becomes lipid modified, through the sequential action of the S-acyltransferases ZDHHC20 and 9. Particularly striking is the rapid acylation of spike on 10 cytosolic cysteines within the ER and Golgi. Using a combination of computational, lipidomics, and biochemical approaches, we show that this massive lipidation controls spike biogenesis and degradation, and drives the formation of localized ordered cholesterol and sphingolipid-rich lipid nanodomains in the early Golgi, where viral budding occurs. Finally, S-acylation of spike allows the formation of viruses with enhanced fusion capacity. Our study points toward S-acylating enzymes and lipid biosynthesis enzymes as novel therapeutic anti-viral targets.Severe COVID-19 infection increases the risk of myocardial injury that contributes to mortality. We used multiparameter immunofluorescence to examine extensively heart autopsy tissue of 7 patients who died of COVID-19 compared to 12 control specimens, some with and some without cardiovascular disease. Consistent with prior reports, we found no evidence of viral infection or lymphocytic infiltration indicative of myocarditis but did observe frequent and extensive thrombosis in large and small vessels in the hearts of the COVID cohort, findings that were infrequent in controls. The endothelial lining of thrombosed vessels typically lacked evidence of cytokine-mediated endothelial activation, assessed as nuclear expression of transcription factors p65 (RelA), pSTAT1, or pSTAT3 or evidence of inflammatory activation assessed by expression of intracellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), tissue factor, or von Willebrand factor (VWF). Intimal EC lining was also generally preserved with little evidence of cell death or desquamation. In contrast, there were frequent markers of neutrophil activation within myocardial thrombi of COVID-infected patients including neutrophil-platelet aggregates, neutrophil-rich clusters within macrothrombi, and evidence of neutrophil extracellular trap (NET) formation. These findings point to alterations in circulating neutrophils rather than the endothelium as contributors to the increased thrombotic diathesis in the hearts of COVID-19 patients.N6-methyladenosine (m6A), the most abundant internal modification of mRNAs and is installed by METTL3 at the (G/A)(m6A)C motif, plays a critical role in gene expression regulation. METTL3 is essential for embryonic development, and its dysregulation is linked to various diseases. However, the role of METTL3 in liver biology is largely unknown, and, here, METTL3 function was unraveled in mice depleted of Mettl3 in neonatal livers (Mettl3fl/fl; Alb-Cre, "M3LKO"). M3LKO livers exhibited global decrease in m6A on polyadenylated RNAs, and pathological features associated with nonalcoholic fatty liver disease e.g., hepatocyte ballooning, ductular reaction, microsteatosis, pleomorphic nuclei, DNA damage, foci of altered hepatocytes, focal lobular and portal inflammation, and elevated serum ALT/ALP levels. Mettl3-depleted hepatocytes were highly proliferative, with decreased numbers of binucleate hepatocytes and increased nuclear polyploidy. M3LKO livers were characterized by reduced m6A and expression of several key metabolic transcripts regulated by circadian rhythm, and nuclear protein levels of core clock transcription factors, BMAL1 and CLOCK, were also decreased. Significant decrease in total Bmal1 and Clock mRNAs but increase in their nuclear levels were observed in M3LKO livers, suggesting impaired nuclear export. Consistent with the phenotype, meRIP-seq and RNA-seq revealed transcriptome-wide loss of m6A marks and alterations in abundance of mRNAs involved in metabolism in M3LKO. Collectively, METTL3 and m6A modifications are critical regulators of liver homeostasis and function. Embryonal tumours with multi-layered rosettes (ETMRs) are a newly recognised, rare paediatric brain tumour with alterations of the C19MC microRNA locus. Due to varied diagnostic practices and scarce clinical data, disease features and determinants of outcomes for these tumours are poorly defined. We did an integrated clinicopathological and molecular analysis of primary ETMRs to define clinical phenotypes, and to identify prognostic factors of survival and key treatment modalities for this orphan disease. Paediatric patients with primary ETMRs and tissue available for analyses were identified from the Rare Brain Tumor Consortium global registry. The institutional histopathological diagnoses were centrally re-reviewed as per the current WHO CNS tumour guidelines, using histopathological and molecular assays. Only patients with complete clinical, treatment, and survival data on Nov 30, 2019, were included in clinicopathological analyses. Among patients who received primary multi-modal curative regimens, event-free survival and overall survival were determined using Cox proportional hazard and log-rank analyses.
