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Enquanto George senta em seu suporte de árvore, ele pensa sobre as coisas e, em seguida sua mente se questiona a cada movimento que vê e associa a pessoas e situações em sua própria vida.Sua esposa, seus filhos, seu casamento, seus amigos, seu trabalho, todos estão inclusos na reflexão.O que aconteceu com minha vida?.

In contrast to the many reports of successful real-world cases of personalized bacteriophage therapy (BT), randomized controlled trials of non-personalized bacteriophage products have not produced the expected results. Here we present the outcomes of a retrospective observational analysis of the first 100 consecutive cases of personalized BT of difficult-to-treat infections facilitated by a Belgian consortium in 35 hospitals, 29 cities and 12 countries during the period from 1 January 2008 to 30 April 2022. We assessed how often personalized BT produced a positive clinical outcome (general efficacy) and performed a regression analysis to identify functional relationships. The most common indications were lower respiratory tract, skin and soft tissue, and bone infections, and involved combinations of 26 bacteriophages and 6 defined bacteriophage cocktails, individually selected and sometimes pre-adapted to target the causative bacterial pathogens. Clinical improvement and eradication of the targeted bacteria were reported for 77.2% and 61.3% of infections, respectively. In our dataset of 100 cases, eradication was 70% less probable when no concomitant antibiotics were used (odds ratio = 0.3; 95% confidence interval = 0.127–0.749). In vivo selection of bacteriophage resistance and in vitro bacteriophage–antibiotic synergy were documented in 43.8% (7/16 patients) and 90% (9/10) of evaluated patients, respectively. We observed a combination of antibiotic re-sensitization and reduced virulence in bacteriophage-resistant bacterial isolates that emerged during BT. Bacteriophage immune neutralization was observed in 38.5% (5/13) of screened patients. Fifteen adverse events were reported, including seven non-serious adverse drug reactions suspected to be linked to BT. While our analysis is limited by the uncontrolled nature of these data, it indicates that BT can be effective in combination with antibiotics and can inform the design of future controlled clinical trials. BT100 study, ClinicalTrials.gov registration: NCT05498363 . Analysis of 100 consecutive personalized bacteriophage therapy cases supports the use of personalized and sometimes pre-adapted, bacteriophage preparations, often in combination with antibiotics.

BackgroundZika fever gained importance in Brazil in 2015 due to its association with congenital syndrome. Although Zika virus (ZIKV) crosses the placenta and infects the fetus, its pathogenesis remains incompletely understood. This study investigated the effects of ZIKV infection in HTR-8/SVneo trophoblast cells.MethodsCells were infected with ZIKV (MOI 0.1, 0.2, or 1) or Mock control for 24 or 48 hours. Infection rate and viability were assessed by immunofluorescence and flow cytometry. Ultrastructural changes were analyzed by transmission electron microscopy. Mitochondrial membrane potential was evaluated by flow cytometry. Gene expression related to mitochondrial dynamics, antioxidant response (sod, cat, nrf2), was analyzed by RT-qPCR. Protein expression (SOD, CAT, NRF2), enzymatic activities (SOD, CAT), and oxidative damage markers (8-OHdG, MDA, NO) were assessed by immunofluorescence and/or colorimetric assays.ResultsMOI 1 for 24 hours produced the highest NS1 expression and infection rate (62.53%) and higher viability (89% vs. 28.1%), establishing this as the optimal condition. Infected cells exhibited mitochondrial damage, including ruptured membranes and loss of cristae, dilated endoplasmic reticulum, clusters of virus-like particles, and vesicle secretion. Mitochondrial membrane potential was reduced, along with decreased transcripts of genes involved in mitochondrial dynamics. Although sod, cat, and nrf2 transcripts were reduced, protein immunolabeling and SOD activity were increased, whereas CAT activity was decreased. Elevated levels of 8-OHdG, MDA, and NO confirmed oxidative stress.ConclusionZIKV infection induces mitochondrial dysfunction, oxidative stress, and impaired mitophagy in HTR-8/SVneo trophoblast cells, highlighting mitochondrial dysfunction as a major component of the cellular response to ZIKV infection in trophoblast cells.

Bone marrow cells (BMC) migrate to the injured liver after transplantation, contributing to regeneration through multiple pathways, but mechanisms involved are unclear. This work aimed to study BMC migration, characterize cytokine profile, cell populations and proliferation in mice with liver fibrosis transplanted with GFP+ BMC. Confocal microscopy analysis showed GFP+ BMC near regions expressing HGF and SDF-1 in the fibrotic liver. Impaired liver cell proliferation in fibrotic groups was restored after BMC transplantation. Regarding total cell populations, there was a significant reduction in CD68+ cells and increased Ly6G+ cells in transplanted fibrotic group. BMC contributed to the total populations of CD144, CD11b and Ly6G cells in the fibrotic liver, related to an increment of anti-fibrotic cytokines (IL-10, IL-13, IFN-γ and HGF) and reduction of pro-inflammatory cytokines (IL-17A and IL-6). Therefore, HGF and SDF-1 may represent important chemoattractants for transplanted BMC in the injured liver, where these cells can give rise to populations of extrahepatic macrophages, neutrophils and endothelial progenitor cells that can interact synergistically with other liver cells towards the modulation of an anti-fibrotic cytokine profile promoting the onset of liver regeneration.

Most patients with Parkinson's disease, Parkinson's disease dementia, and dementia with Lewy bodies do not carry mutations in known disease-causing genes. The aim of this study was to identify a novel gene implicated in the development of these disorders. Our study was done in three stages. First, we did genome-wide linkage analysis of an Italian family with dominantly inherited Parkinson's disease to identify the disease locus. Second, we sequenced the candidate gene in an international multicentre series of unrelated probands who were diagnosed either clinically or pathologically with Parkinson's disease, Parkinson's disease dementia, or dementia with Lewy bodies. As a control, we used gene sequencing data from individuals with abdominal aortic aneurysms (who were not examined neurologically). Third, we enrolled an independent series of patients diagnosed clinically with Parkinson's disease and controls with no signs or family history of Parkinson's disease, Parkinson's disease dementia, or dementia with Lewy bodies from centres in Portugal, Sardinia, and Taiwan, and screened them for specific variants. We also did mRNA and brain pathology studies in three patients from the international multicentre series carrying disease-associated variants, and we did functional protein studies in in-vitro models, including neurons from induced pluripotent stem-like cells. Molecular studies were done between Jan 1, 2008, and Dec 31, 2017. In the initial kindred of ten affected Italian individuals (mean age of disease onset 59·8 years [SD 8·7]), we detected significant linkage of Parkinson's disease to chromosome 14 and nominated LRP10 as the disease-causing gene. Among the international series of 660 probands, we identified eight individuals (four with Parkinson's disease, two with Parkinson's disease dementia, and two with dementia with Lewy bodies) who carried different, rare, potentially pathogenic LRP10 variants; one carrier was found among 645 controls with abdominal aortic aneurysms. In the independent series, two of these eight variants were detected in three additional Parkinson's disease probands (two from Sardinia and one from Taiwan) but in none of the controls. Of the 11 probands from the international and independent cohorts with LRP10 variants, ten had a positive family history of disease and DNA was available from ten affected relatives (in seven of these families). The LRP10 variants were present in nine of these ten relatives, providing independent—albeit limited—evidence of co-segregation with disease. Post-mortem studies in three patients carrying distinct LRP10 variants showed severe Lewy body pathology. Of nine variants identified in total (one in the initial family and eight in stage 2), three severely affected LRP10 expression and mRNA stability (1424+5delG, 1424+5G→A, and Ala212Serfs*17, shown by cDNA analysis), four affected protein stability (Tyr307Asn, Gly603Arg, Arg235Cys, and Pro699Ser, shown by cycloheximide-chase experiments), and two affected protein localisation (Asn517del and Arg533Leu; shown by immunocytochemistry), pointing to loss of LRP10 function as a common pathogenic mechanism. Our findings implicate LRP10 gene defects in the development of inherited forms of α-synucleinopathies. Future elucidation of the function of the LRP10 protein and pathways could offer novel insights into mechanisms, biomarkers, and therapeutic targets. Stichting ParkinsonFonds, Dorpmans-Wigmans Stichting, Erasmus Medical Center, ZonMw—Memorabel programme, EU Joint Programme Neurodegenerative Disease Research (JPND), Parkinson's UK, Avtal om Läkarutbildning och Forskning (ALF) and Parkinsonfonden (Sweden), Lijf and Leven foundation, and cross-border grant of Alzheimer Netherlands–Ligue Européene Contre la Maladie d'Alzheimer (LECMA).

Na Região Metropolitana de São Paulo, poucos são os casos de investigação ambiental em aquíferos cristalinos; em geral, os estudos limitam-se à porção sedimentar, rasa. Este é o caso do Canal do Jurubatuba, uma área reconhecidamente complexa não apenas geologicamente, mas inclusive do ponto de vista do gerenciamento ambiental, em que o aquífero fraturado se encontra contaminado por etenos clorados provenientes de fontes multipontuais. Nessa região, sedimentos aluviais da Bacia de São Paulo estão sobrepostos a uma expressiva camada de manto inconsolidado e ao embasamento gnáissico de rochas do Complexo Embu. Este estudo visa, através da aplicação do método Discrete Fracture Network (DFN), contribuir com subsídios técnicos para o poder público realizar o gerenciamento ambiental de áreas hidrogeologicamente similares. O método DFN, inédito no Brasil e em aquíferos de rochas cristalinas fraturadas, compreende o uso de tecnologias avançadas de investigação de estruturas rúpteis e de monitoramento de água subterrânea. Em um perfil vertical de detalhe, são objetos de estudo deste trabalho: (i) caracterização estrutural e hidráulica do aquífero fraturado, (ii) caracterização do perfil de contaminação e difusão de contaminantesna matriz, (iii) e potencial de microorganismos na degradação natural de organoclorados.