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We conducted a systematic review and meta-analysis of studies assessing HCV infection rates in haemodialysis patients in Brazil (Prospero CRD #42021275068). We included studies on patients under haemodialysis, comprising both convenience samples and exhaustive information from selected services. Patients underwent HCV serological testing with or without confirmation by HCV RNA PCR. Exclusion criteria were the following: absence of primary empirical information and studies without information on their respective settings, study year, accurate infection rates, or full specification of diagnostic tests. Studies with samples ≤ 30 and serial assessments with repeated information were also excluded. Reference databases included PubMed, LILACS, Scopus, and Web of Science for the period 1989-2019. A systematic review was carried out, followed by two independent meta-analyses: (i) studies with data on HCV prevalence and (ii) studies with a confirmatory PCR (i.e., active infection), respectively. A comprehensive set of different methods and procedures were used: forest plots and respective statistics, polynomial regression, meta-regression, subgroup influence, quality assessment, and trim-and-fill analysis. 29 studies and 11,290 individuals were assessed. The average time patients were in haemodialysis varied from 23.5 to 56.3 months. Prevalence of HCV infection was highly heterogeneous, with a pronounced decrease from 1992 to 2001, followed by a plateau and a slight decrease in recent years. The summary measure for HCV prevalence was 34% (95% CI 26-43%) for studies implemented before 2001. For studies implemented after 2001, the corresponding summary measure was 11% (95% CI 8-15%). Estimates for prevalence of active HCV infection were also highly heterogeneous. There was a marked decline from 1996 to 2001, followed by a plateau and a slight increase after 2010. The summary measure for active HCV infection was 19% (95% CI 15-25%) in studies carried out before 2001. For studies implemented after 2001, the corresponding summary measure was 9% (95% CI 6-13%). Heterogeneity was pervasive, but different analyses helped to identify its underlying sources. Besides the year each study was conducted, the findings differed markedly between geographic regions and were heavily influenced by the size of the studies and publication biases. Our systematic review and meta-analysis documented a substantial decline in HCV prevalence among Brazilian haemodialysis patients from 1992 to 2015. CKD should be targeted with specific interventions to prevent HCV infection, and if prevention fails, prompt diagnosis and treatment. Although the goal of HCV elimination by 2030 in Brazil remains elusive, it is necessary to adopt measures to achieve micro-elimination and to launch initiatives towards targeted interventions to curb the spread of HCV in people with CKD, among other high-risk groups. This is of particular concern in the context of a protracted COVID-19 pandemic and a major economic and political crisis., (© 2022. The Author(s).)

Intradialytic exercise (ID) programs are effective and safe for hemodialysis (HD) patients to avoid functional deterioration. However, exercise is not routinely undertaken in most HD units, and we do not know if home-based (HB) programs are as effective as ID programs. The purpose of this study was to compare the effects of 16 weeks of ID exercise versus a HB exercise program for HD patients. A total of 46 patients were randomly assigned to the ID group (n = 24) or HB group (n = 22). They completed a 16-week combined exercise program 3 times/week. We measured physical activity level, physical functioning, depression level, and health-related quality of life at baseline and after 16 weeks. A significant time effect was found in both groups for the physical activity level (p = 0.012). There was also a significant group-time interaction effect for the one-leg standing test (OLST) (p = 0.049) and a significant time effect for the Short Physical Performance Battery (p = 0.013), timed up-and-go test (p = 0.005), sit-to-stand-10 (p = 0.027), right and left hand handgrip (p = 0.044, p < 0.001), one-heel left leg raise (p = 0.019), and 6-minute walking (p = 0.006), depression (p = 0.017). HRQoL remained unchanged. There was no difference between the two interventions on the tested outcomes (besides OLST). Both interventions were associated with positive changes of the physical activity levels and physical function.

Patients with acute myeloid leukemia frequently present translocations of MLL gene. Rearrangements of MLL protein (MLL-r) in complexes that contain the histone methyltransferase DOT1L are common, which elicit abnormal methylation of lysine 79 of histone H3 at MLL target genes. Phase 1 clinical studies with pinometostat (EPZ-5676), an inhibitor of DOT1L activity, demonstrated the therapeutic potential for targeting DOT1L in MLL-r leukemia patients. We previously reported that down-regulation of DOT1L increases influenza and vesicular stomatitis virus replication and decreases the antiviral response. Here we show that DOT1L inhibition also reduces Sendai virus-induced innate response and its overexpression decreases influenza virus multiplication, reinforcing the notion of DOT1L controlling viral replication. Accordingly, genes involved in the host innate response against pathogens (RUBICON, TRIM25, BCL3) are deregulated in human lung epithelial cells treated with pinometostat. Concomitantly, deregulation of some of these genes together with that of the MicroRNA let-7B, may account for the beneficial effects of pinometostat treatment in patients with MLL-r involving DOT1L. These results support a possible increased vulnerability to infection in MLL-r leukemia patients undergoing pinometostat treatment. Close follow up of infection should be considered in pinometostat therapy to reduce some severe side effects during the treatment.

Microbial activity is highly dependent on climatic factors (moisture and temperature) and edaphic characteristics in temperate ecosystems. Moreover, soil microbial community composition in high mountain areas is less known when compared to plant communities. In this study we investigated the soil microbial community from a functional perspective using PLFA (phospholipid fatty acid) methods in the four aspects of four summits (2,242 - 3,012 m above sea level) in the Spanish Central Pyrenees. Soil organic carbon (C), microbial biomass and nutrient dynamics ([Formula: see text] + [Formula: see text], N mineralization and nitrification potential) were also determined. Microbial biomass C was highest in the lowermost summit and decreased by approximately 50, 14 and 12% with increasing altitude. In each summit soil [Formula: see text] and [Formula: see text] concentrations differed significantly among summits and aspects. Soil nitrification potential varied significantly between the factors summit and aspects, e.g., southerly vs. northerly, easterly vs. westerly aspects. Gram negative bacteria and Actinobacteria functional groups dominated the microbial community, with almost 40% of the total PLFA. Non-metric multidimensional scale (NMS) analysis showed that most of the PLFA functional groups were present in all summits and aspects, although with specific biomarkers. A high abundance of biomarkers 16:1ω9c and 16:0 2OH (gram negative bacteria) were obtained in the lowermost summit, while the biomarkers 16.1ω7cDMA (anaerobes) and 19:3ω6c (Eukaryote) were only found in the uppermost summit. Linear mixed model (lmm) analysis was used with summit as fixed effect and aspect as random effect. In general, our results demonstrate a fundamental role for environment, principally moisture, temperature and organic matter in explaining the pattern observed for soil PLFA biomarkers. Under a global change scenario, we need to shed light on the relationships between soil microbial functional groups and soil nutrient-related variables in order to identify the associated patterns of decomposition rates and soil processes driven by microbial communities in mountain areas. The results could thus be used in global predictive models on climate change impact on C or N cycles in these environments.

Influenza virus stablishes a network of virus-host functional interactions, which depends on chromatin dynamic and therefore on epigenetic modifications. Using an unbiased search, we analyzed the epigenetic changes at DNA methylation and post-translational histone modification levels induced by the infection. DNA methylation was unaltered, while we found a general decrease on histone acetylation, which correlates with transcriptional inactivation and may cooperate with the impairment of cellular transcription that causes influenza virus infection. A particular increase in H3K79 methylation was observed and the use of an inhibitor of the specific H3K79 methylase, Dot1L enzyme, or its silencing, increased influenza virus replication. The antiviral response was reduced in conditions of Dot1L downregulation, since decreased nuclear translocation of NF-kB complex, and IFN-β, Mx1 and ISG56 expression was detected. The data suggested a control of antiviral signaling by methylation of H3K79 and consequently, influenza virus replication was unaffected in IFN pathway-compromised, Dot1L-inhibited cells. H3K79 methylation also controlled replication of another potent interferon-inducing virus such as vesicular stomatitis virus, but did not modify amplification of respiratory syncytial virus that poorly induces interferon signaling. Epigenetic methylation of H3K79 might have an important role in controlling interferon-induced signaling against viral pathogens.

Although the recent Zika virus (ZIKV) epidemic in the Americas and its link to birth defects have attracted a great deal of attention, much remains unknown about ZIKV disease epidemiology and ZIKV evolution, in part owing to a lack of genomic data. Here we address this gap in knowledge by using multiple sequencing approaches to generate 110 ZIKV genomes from clinical and mosquito samples from 10 countries and territories, greatly expanding the observed viral genetic diversity from this outbreak. We analysed the timing and patterns of introductions into distinct geographic regions; our phylogenetic evidence suggests rapid expansion of the outbreak in Brazil and multiple introductions of outbreak strains into Puerto Rico, Honduras, Colombia, other Caribbean islands, and the continental United States. We find that ZIKV circulated undetected in multiple regions for many months before the first locally transmitted cases were confirmed, highlighting the importance of surveillance of viral infections. We identify mutations with possible functional implications for ZIKV biology and pathogenesis, as well as those that might be relevant to the effectiveness of diagnostic tests.

The proportion of multiple myeloma patients in long-term complete response (LTCR-MM) for more than 6 years after autologous stem cell transplantation (ASCT) is small. To evaluate whether this LTCR is associated with a particular immune signature, peripheral blood samples from 13 LTCR-MM after ASCT and healthy blood donors (HBD) were analysed. Subpopulations of T-cells (naïve, effector, central memory and regulatory), B-cells (naïve, marginal zone-like, class-switched memory, transitional and plasmablasts) and NK-cells expressing inhibitory and activating receptors were quantified by multiparametric flow cytometry (MFC). Heavy/light chains (HLC) were quantified by nephelometry. The percentage of CD4 + T-cells was lower in patients, whereas an increment in the percentage of CD4 + and CD8 + effector memory T-cells was associated with the LTCR. Regulatory T-cells and NK-cells were similar in both groups but a particular redistribution of inhibitory and activating receptors in NK-cells were found in patients. Regarding B-cells, an increase in naïve cells and a corresponding reduction in marginal zone-like and class-switched memory B-cells was observed. The HLC values were normal. Our results suggest that LTCR-MM patients express a particular immune signature, which probably reflects a 'high quality' immune reconstitution that could exert a competent anti-tumor immunological surveillance along with a recovery of the humoral immunity.

Recent studies have begun to point out the contribution of microbiota to multiple sclerosis (MS) pathogenesis. Theiler's murine encephalomyelitis virus induced demyelinating disease (TMEV-IDD) is a model of progressive MS. Here, we first analyze the effect of intracerebral infection with TMEV on commensal microbiota and secondly, whether the early microbiota depletion influences the immune responses to TMEV on the acute phase (14 dpi) and its impact on the chronic phase (85 dpi). The intracranial inoculation of TMEV was associated with a moderate dysbiosis. The oral administration of antibiotics (ABX) of broad spectrum modified neuroimmune responses to TMEV dampening brain CD4 + and CD8 + T infiltration during the acute phase. The expression of cytokines, chemokines and VP2 capsid protein was enhanced and accompanied by clusters of activated microglia disseminated throughout the brain. Furthermore, ABX treated mice displayed lower levels of CD4 + and CD8 + T cells in cervical and mesenteric lymph nodes. Increased mortality to TMEV was observed after ABX cessation at day 28pi. On the chronic phase, mice that survived after ABX withdrawal and recovered microbiota diversity showed subtle changes in brain cell infiltrates, microglia and gene expression of cytokines. Accordingly, the surviving mice of the group ABX-TMEV displayed similar disease severity than TMEV mice.

The influenza A virus polymerase associates with a number of cellular transcription-related factors, including the RNA polymerase II (RNAP II). We previously described that the cellular protein hCLE/C14orf166 interacts with and stimulates influenza virus polymerase as well as RNAP II activities. Here we show that, despite the considerable cellular shut-off observed in infected cells, which includes RNAP II degradation, hCLE protein levels increase throughout infection in a virus replication-dependent manner. Human and avian influenza viruses of various subtypes increase hCLE levels, but other RNA or DNA viruses do not. hCLE colocalises and interacts with viral ribonucleoproteins (vRNP) in the nucleus, as well as in the cytoplasm late in infection. Furthermore, biochemical analysis of purified virus particles and immunoelectron microscopy of infected cells show hCLE in virions, in close association with viral vRNP. These findings indicate that hCLE, a cellular protein important for viral replication, is one of the very few examples of transcription factors that are incorporated into particles of an RNA-containing virus.

Serine threonine kinase AKT has a central role in the cell, controlling survival, proliferation, metabolism and angiogenesis. Deregulation of its activity underlies a wide range of pathological situations, including cancer. Here we show that AKT is post-translationally modified by the small ubiquitin-like modifier (SUMO) protein. Interestingly, neither SUMO conjugation nor activation of SUMOylated AKT is regulated by the classical AKT targeting to the cell membrane or by the phosphoinositide 3-kinase pathway. We demonstrate that SUMO induces the activation of AKT, whereas, conversely, down-modulation of the SUMO machinery diminishes AKT activation and cell proliferation. Furthermore, an AKT SUMOylation mutant shows reduced activation, and decreased anti-apoptotic and pro-tumoral activities in comparison with the wild-type protein. These results identify SUMO as a novel key regulator of AKT phosphorylation and activity.

The pocket proteins retinoblastoma protein (pRb), p107 and p130 are the key targets of oncoproteins expressed by DNA tumor viruses. Some of these viral proteins contain an LXCXE motif that mediates the interaction with the three pocket proteins and the inhibition of the pRb SUMOylation. Kaposi's sarcoma herpesvirus (KSHV) contains at least two proteins that can regulate pRb function but, so far, a KSHV-encoded protein targeting p107 and p130 has not been identified. Here, we show that the KSHV latent protein LANA2 binds to pRb, p107 and p130. LANA2 contains an LXCXE motif that is required for bypassing pRb-mediated cell-cycle arrest and for inhibiting pRb SUMOylation. Finally, we demonstrate that, in addition to pRb, both p107 and p130 can be SUMOylated, and this modification is also inhibited by LANA2 in an LXCXE-dependent manner. These results demonstrate, for the first time, the SUMOylation of p107 or p130 and, so far, they represent the first example of a KSHV protein able to interact with the three pocket proteins and to inhibit their conjugation to SUMO.

SIRT1, the closest mammalian homolog of yeast Sir2, is an NAD(+)-dependent deacetylase with relevant functions in cancer, aging, and metabolism among other processes. SIRT1 has a diffuse nuclear localization but is recruited to the PML nuclear bodies (PML-NBs) after PML upregulation. However, the functions of SIRT1 in the PML-NBs are unknown. In this study we show that primary mouse embryo fibroblasts lacking SIRT1 contain reduced PML protein levels that are increased after reintroduction of SIRT1. In addition, overexpression of SIRT1 in HEK-293 cells increases the amount of PML protein whereas knockdown of SIRT1 reduces the size and number of PML-NBs and the levels of PML protein in HeLa cells. SIRT1 stimulates PML sumoylation in vitro and in vivo in a deacetylase-independent manner. Importantly, the absence of SIRT1 reduces the apoptotic response of vesicular stomatitis virus-infected cells and favors the extent of this PML-sensitive virus replication. These results show a novel function of SIRT1 in the control of PML and PML-NBs.