The Zika virus (ZIKV) can be vertically transmitted, causing congenital Zika syndrome (CZS) in fetuses. ZIKV infection in early gestational trimesters increases the chances of developing CZS. This ...syndrome involves several pathologies with a complex diagnosis. In this work, we aim to identify biological processes and molecular pathways related to CZS and propose a series of putative protein and metabolite biomarkers for CZS prognosis in early pregnancy trimesters. We analyzed serum samples of healthy pregnant women and ZIKV-infected pregnant women bearing nonmicrocephalic and microcephalic fetuses. A total of 1090 proteins and 512 metabolites were identified by bottom-up proteomics and untargeted metabolomics, respectively. Univariate and multivariate statistical approaches were applied to find CZS differentially abundant proteins (DAP) and metabolites (DAM). Enrichment analysis (i.e., biological processes and molecular pathways) of the DAP and the DAM allowed us to identify the ECM organization and proteoglycans, amino acid metabolism, and arachidonic acid metabolism as CZS signatures. Five proteins and four metabolites were selected as CZS biomarker candidates. Serum multiomics analysis led us to propose nine putative biomarkers for CZS prognosis with high sensitivity and specificity.
The severe acute respiratory syndrome spread worldwide, causing a pandemic. SARS-CoV-2 mutations have arisen in the spike, a glycoprotein at the viral envelope and an antigenic candidate for vaccines ...against COVID-19. Here, we present comparative data of the glycosylated full-length ancestral and D614G spike together with three other transmissible strains classified by the World Health Organization as variants of concern: beta, gamma, and delta. By showing that D614G has less hydrophobic surface exposure and trimer persistence, we place D614G with features that support a model of temporary fitness advantage for virus spillover. Furthermore, during the SARS-CoV-2 adaptation, the spike accumulates alterations leading to less structural stability for some variants. The decreased trimer stability of the ancestral and gamma and the presence of D614G uncoupled conformations mean higher ACE-2 affinities compared to the beta and delta strains. Mapping the energetics and flexibility of variants is necessary to improve vaccine development.
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•Comparative biochemical data of the ancestral, D614G, beta, gamma, and delta spikes•D614G has less hydrophobic exposure and trimer persistence at mid temperatures•The ancestral and gamma spikes have similar glycan abundance•SARS-CoV-2 evolution alters the spike stability for some variants
Biochemistry; Virology; Structural biology; Protein structure aspects
In recent years, the use of proton pump inhibitors (PPI), especially omeprazole, has been associated with development of chronic kidney disease (CKD). These drugs are widely used worldwide. Although ...some studies have found an association between the use of PPI and the onset of acute renal failure and CKD. This study aims to analyze the association between the continuous use of omeprazole and the progression of CKD in adult and elderly individuals.
A retrospective cohort study was conducted with patients followed up at a nephrology clinic in Brazil, in 2016 and 2017. Information about clinical and sociodemographic data, health behaviors, and medication use were collected from all patients diagnosed with CKD through consultation of medical charts and the Brazilian health information system (SIS). The participants were allocated into two groups: users and non-users of omeprazole, and the progression of CKD was then evaluated for each group. In the bivariate analysis, the Mann-Whitney U test to compare the quantitative variables between groups, and the Pearson/Fisher two-tailed chi-square test to compare the categorical variables were applied. Multivariate analysis was performed using Cox regression.
A total of 199 CKD patients were attended in the polyclinic, and of these, 42.7% were omeprazole users. There was a higher percentage of CKD progression in users (70.6%) compared to non-users (10.5%). The hazard ratio was 7.34 (CI: 3.94-13.71), indicating a higher risk of progression to worse stages of CKD in omeprazole users than in non-users. As for the other variables, no statistically significant difference was found between groups (p > 0.05).
An association between omeprazole use and progression of CKD stage was identified, showing a higher risk of disease evolution among omeprazole users.
Although older adults are at a high risk of severe or critical Covid-19, there are many cases of unvaccinated centenarians who had a silent infection or recovered from mild or moderate Covid-19. We ...studied three Brazilian supercentenarians, older than 110 years, who survived Covid-19 in 2020 before being vaccinated.
Despite their advanced age, humoral immune response analysis showed that these individuals displayed robust levels of IgG and neutralizing antibodies (NAbs) against SARS-CoV-2. Enrichment of plasma proteins and metabolites related to innate immune response and host defense was also observed. None presented autoantibodies (auto-Abs) to type I interferon (IFN). Furthermore, these supercentenarians do not carry rare variants in genes underlying the known inborn errors of immunity, including particular inborn errors of type I IFN.
These observations suggest that their Covid-19 resilience might be a combination of their genetic background and their innate and adaptive immunity.
Huntington's disease (HD) is a neurodegenerative genetic disorder. Although described as a brain pathology, there is evidence suggesting that defects in other systems can contribute to disease ...progression. In line with this, cardiovascular defects are a major cause of death in HD. To date, relatively little is known about the peripheral abnormalities associated with the disease. Here, we applied a range of assays to evaluate cardiac electro‐mechanical properties in vivo, using a previously characterized mouse model of HD (BACHD), and in vitro, using cardiomyocytes isolated from the same mice. We observed conduction disturbances including QT interval prolongation in BACHD mice, indicative of cardiac dysfunction. Cardiomyocytes from these mice demonstrated cellular electro‐mechanical abnormalities, including a prolonged action potential, arrhythmic contractions, and relaxation disturbances. Cellular arrhythmia was accompanied by an increase in calcium waves and increased Ca2+/calmodulin‐dependent protein kinase II activity, suggesting that disruption of calcium homeostasis plays a key part. We also described structural abnormalities in the mitochondria of BACHD‐derived cardiomyocytes, indicative of oxidative stress. Consistent with this, imbalances in superoxide dismutase and glutathione peroxidase activities were detected. Our data provide an in vivo demonstration of cardiac abnormalities in HD together with new insights into the cellular mechanistic basis, providing a possible explanation for the higher cardiovascular risk in HD.
Huntington's disease (HD) is a neurodegenerative disorder and the main cause of patients' death is related to cardiovascular defects. Here, we investigated cardiac dysfunction and its mechanisms in 12‐month‐old BACHD mice, which correspond to the late clinical manifestation in humans. Our data provide an in vivo demonstration together with a new evidence of the cellular mechanistic basis in cardiac HD.
Esters are one of the major functional groups present in the structures of prodrugs and bioactive compounds. Their presence is often associated with hydrolytic lability. In this paper, we describe a ...comparative chemical and biological stability of homologous esters and isosteres in base media as well as in rat plasma and rat liver microsomes. Our results provided evidence for the hydrolytic structure lability relationship and demonstrated that the hydrolytic stability in plasma and liver microsome might depend on carboxylesterase activity. Molecular modelling studies were performed in order to understand the experimental data. Taken together, the data could be useful to design bioactive compounds or prodrugs based on the correct choice of the ester subunit, addressing compounds with higher or lower metabolic lability.
Caulerpin (CLP), an alkaloid from algae of the genus Caulerpa, has shown anti-inflammatory activity. Therefore, this study aimed to analyze the effect of CLP in the murine model of peritonitis and ...ulcerative colitis. Firstly, the mice were submitted to peritonitis to evaluate which dose of CLP (40, 4, or 0.4 mg/kg) could decrease the inflammatory infiltration in the peritoneum. The most effective doses were 40 and 4 mg/kg. Then, C57BL/6 mice were submitted to colitis development with 3% dextran sulfate sodium (DSS) and treated with CLP at doses of 40 and 4 mg/kg. The disease development was analyzed through the disease activity index (DAI); furthermore, colonic tissue samples were submitted to histological analysis, NFκB determination, and in vitro culture for cytokines assay. Therefore, CLP at 4 mg/kg presented the best results, triggering improvement of DAI and attenuating the colon shortening and damage. This dose was able to reduce the TNF-α, IFN-γ, IL-6, IL-17, and NFκB p65 levels, and increased the levels of IL-10 in the colon tissue. Thus, CLP mice treatment at a dose of 4 mg/kg showed promising results in ameliorating the damage observed in the ulcerative colitis.
MSH2 Loss in Primary Prostate Cancer Guedes, Liana B; Antonarakis, Emmanuel S; Schweizer, Michael T ...
Clinical cancer research,
11/2017, Letnik:
23, Številka:
22
Journal Article
Recenzirano
Odprti dostop
Inactivation of mismatch repair (MMR) genes may predict sensitivity to immunotherapy in metastatic prostate cancers. We studied primary prostate tumors with MMR defects.
A total of 1,133 primary ...prostatic adenocarcinomas and 43 prostatic small cell carcinomas (NEPC) were screened by MSH2 immunohistochemistry with confirmation by next-generation sequencing (NGS). Microsatellite instability (MSI) was assessed by PCR and NGS (mSINGS).
Of primary adenocarcinomas and NEPC, 1.2% (14/1,176) had MSH2 loss. Overall, 8% (7/91) of adenocarcinomas with primary Gleason pattern 5 (Gleason score 9-10) had MSH2 loss compared with 0.4% (5/1,042) of tumors with any other scores (
< 0.05). Five percent (2/43) of NEPC had MSH2 loss. MSH2 was generally homogenously lost, suggesting it was an early/clonal event. NGS confirmed
loss-of-function alterations in all (12/12) samples, with biallelic inactivation in 83% (10/12) and hypermutation in 83% (10/12). Overall, 61% (8/13) and 58% (7/12) of patients had definite MSI by PCR and mSINGS, respectively. Three patients (25%) had germline mutations in
Tumors with MSH2 loss had a higher density of infiltrating CD8
lymphocytes compared with grade-matched controls without MSH2 loss (390 vs. 76 cells/mm
;
= 0.008), and CD8
density was correlated with mutation burden among cases with MSH2 loss (
= 0.72,
= 0.005). T-cell receptor sequencing on a subset revealed a trend toward higher clonality in cases versus controls.
Loss of MSH2 protein is correlated with
inactivation, hypermutation, and higher tumor-infiltrating lymphocyte density, and appears most common among very high-grade primary tumors, for which routine screening may be warranted if validated in additional cohorts.
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