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Introduction: To better understand the role of mucosa immunity in the development of cervical carcinoma in HIV infection, cervical lymphocyte subsets were characterized in HIV+ and HIV− women, as well as their relation to HPV-associated cervical lesions. Methods: Eighty-three (52 HIV+, 31 HIV−) cell suspensions of cervicovaginal lavage (CVL) and 52 HIV+ peripheral blood (PB) samples were assessed by flow cytometry to evaluate lymphoid populations. High-risk (HR) HPV was assessed in liquid-based cytology and HIV mRNA in PB in the same patients. Results: Cervical CD4+ T cells and CD4+/CD8+ ratio were decreased (p < 0.0001) and cervical CD8+ T cells were increased (p = 0.0080) in HIV+ women. These patients had lower CD4+ T-cell percentages in CVL compared to PB (p = 0.0257), and the opposite was true for CD8+ T cells (p = 0.0104). They also had a higher prevalence of high-grade squamous intraepithelial lesions (SILs) with an increased prevalence of HR HPV. Cervical CD8+ T cells were increased in HR HPV+ patients (p = 0.0300) and related to higher prevalence of SILs (p = 0.0001). Discussion/Conclusion: Cervical lymphoid populations can be characterized by flow cytometry, showing a distinct cervical T-cell compartment in HIV+ women. This may represent a surrogate risk marker of HPV-associated cervical lesions in this population and prompt further research on this subject, contributing to improving patients’ management.

Clonal hematopoiesis driven by somatic mutations in hematopoietic cells, frequently called clonal hematopoiesis of indeterminate potential (CHIP), has been associated with adverse cardiovascular outcomes in population-based studies and in patients with ischemic heart failure (HF) and reduced left ventricular ejection fraction (LVEF). Yet, the impact of CHIP on HF progression, including nonischemic etiology, is unknown.The purpose of this study was to assess the clinical impact of clonal hematopoiesis on HF progression irrespective of its etiology.The study cohort comprised 62 patients with HF and LVEF 45% (age 74 ± 7 years, 74% men, 52% nonischemic, and LVEF 30 ± 8%). Deep sequencing was used to detect CHIP mutations with a variant allelic fraction2% in 54 genes. Patients were followed for at least 3.5 years for various adverse events including death, HF-related death, and HF hospitalization.CHIP mutations were detected in 24 (38.7%) patients, without significant differences in all-cause mortality (p = 0.151). After adjusting for risk factors, patients with mutations in either DNA methyltransferase 3 alpha (DNMT3A) or Tet methylcytosine dioxygenase 2 (TET2) exhibited accelerated HF progression in terms of death (hazard ratio [HR]: 2.79; 95% confidence interval [CI]: 1.31 to 5.92; p = 0.008), death or HF hospitalization (HR: 3.84; 95% CI: 1.84 to 8.04; p 0.001) and HF-related death or HF hospitalization (HR: 4.41; 95% CI: 2.15 to 9.03; p 0.001). In single gene-specific analyses, somatic mutations in DNMT3A or TET2 retained prognostic significance with regard to HF-related death or HF hospitalization (HR: 4.50; 95% CI: 2.07 to 9.74; p 0.001, for DNMT3A mutations; HR: 3.18; 95% CI: 1.52 to 6.66; p = 0.002, for TET2 mutations). This association remained significant irrespective of ischemic/nonischemic etiology.Somatic mutations that drive clonal hematopoiesis are common among HF patients with reduced LVEF and are associated with accelerated HF progression regardless of etiology.

The sudden need for an adaptation of two science projects based on the changes that the COVID-19 pandemic brought to the education system in Portugal, transitioning from classroom learning to distance learning, led to a reorganization within the structure of these projects in order to implement them, maintaining the same objectives. Both projects have the main goal to develop computational thinking, with the first project having simultaneously the aim to also develop an environmental awareness through an initiation to programming by way of implementing challenges regarding the same topic, within 1st grade pupils, namely recycling and reducing single use waste. The second project constitutes the assembly and implementation of a weather station, based on the microprocessor Micro:bit, at the service of the science curricula contents within 5th grade students, with regard to abiotic factors and its influence on animals and plants.

Summary MV130 is an inactivated polybacterial mucosal vaccine that confers protection to patients against recurrent respiratory infections, including those of viral etiology. However, its mechanism of action remains poorly understood. Here, we find that intranasal prophylaxis with MV130 modulates the lung immune landscape and provides long-term heterologous protection against viral respiratory infections in mice. Intranasal administration of MV130 provides protection against systemic candidiasis in wild-type and Rag1-deficient mice lacking functional lymphocytes, indicative of innate immune-mediated protection. Moreover, pharmacological inhibition of trained immunity with metformin abrogates the protection conferred by MV130 against influenza A virus respiratory infection. MV130 induces reprogramming of both mouse bone marrow progenitor cells and in vitro human monocytes, promoting an enhanced cytokine production that relies on a metabolic shift. Our results unveil that the mucosal administration of a fully inactivated bacterial vaccine provides protection against viral infections by a mechanism associated with the induction of trained immunity., Graphical abstract, Highlights • MV130 reduces morbi-mortality in mouse models of viral respiratory infection • MV130 modulates mouse immunity complying with key features of trained immunity • MV130 promotes reprogramming of mouse bone marrow progenitors • MV130 induces trained immunity in human monocytes, Brandi et al. investigate the mechanism of action of an inactivated polybacterial mucosal immunomodulator, MV130, which confers protection in patients suffering from recurrent respiratory infections. They show that MV130 induces trained immunity both in mouse bone marrow progenitors, resulting in protection from viral infection, and in human monocytes in vitro.

An early analysis of circulating monocytes may be critical for predicting COVID-19 course and its sequelae. In 131 untreated, acute COVID-19 patients at emergency room arrival, monocytes showed decreased surface molecule expression, including low HLA-DR, in association with an inflammatory cytokine status and limited anti-SARS-CoV-2-specific T cell response. Most of these alterations had normalized in post-COVID-19 patients 6 months after discharge. Acute COVID-19 monocytes transcriptome showed upregulation of anti-inflammatory tissue repair genes such as BCL6, AREG and IL-10 and increased accessibility of chromatin. Some of these transcriptomic and epigenetic features still remained in post-COVID-19 monocytes. Importantly, a poorer expression of surface molecules and low IRF1 gene transcription in circulating monocytes at admission defined a COVID-19 patient group with impaired SARS-CoV-2-specific T cell response and increased risk of requiring intensive care or dying. An early analysis of monocytes may be useful for COVID-19 patient stratification and for designing innate immunity-focused therapies.

Relative age is a phenomenon broadly studied in sport sciences. Youth sports participants born earlier in the selection year tend to present a maturational advantage over their peers. As it is also dependent on physical performance, older physical education students may also benefit from this effect in this school subject. The main goal of this manuscript was to determine whether the relative age effect is present within physical fitness outcomes of Portuguese children and adolescents. The physical–aerobic fitness, strength, flexibility and body composition of 885 students (490 females and 395 males) were collected and compared by quarters of birth, segmented by gender and age groups (10–12, 12–14, 14–16 and 16–18 years). The results reveal a moderate to small effect in physical fitness outcomes, with a trend for children and adolescents born in the early part of the year to present higher performance levels. These differences were more evident in ages closer to the physical maturational onset (12–14 y) and more apparent in male students. This physical fitness advantage may lead to a biased assessment and development of students born earlier in the year.

Copyright © 2020. Published by Elsevier Ltd. INTRODUCTION: This study aimed to analyse cervix lymphocytic populations in HIV + and HIV- patients and correlate different cervical lesions with HIV viral load and presence of high-risk HPV types. MATERIAL AND METHODS: A total of 132 histological specimens from 40 HIV + and 72 HIV- patients were evaluated for CD4+ and CD8+ T cell distribution, presence of high-risk HPV types, peripheral blood HIV viral load and CD4+/CD8+ ratio. RESULTS: High-grade squamous intraepithelial lesions (HSIL) and squamous cell carcinoma (SCC) from HIV + patients had lower CD4+ T cell scores compared with HIV- patients. In all lesion groups, HIV + patients presented higher epithelial and stromal CD8+ T cell scores. HIV viral load was more often detectable in patients with SCC than in those with low-grade squamous intraepithelial lesion (LSIL) (p = 0.0409). HSIL HIV + patients had lower circulating CD4+ T cell counts (p = 0.0434) and CD4+/CD8+ ratio (p = 0.0378) compared with LSIL HIV + patients. High-risk HPV types other than 16 and 18/45 were more prevalent in the HIV + group. DISCUSSION: These results support an imbalance between cervical CD4+ and CD8+ T lymphocytes of HIV + patients with SIL and SCC, with increased CD8+ infiltrate density with lesion severity, even in patients with immune system recovery under cART. proof published

Introduction Somatic mutations in hematopoietic cells are associated with age and have been associated with higher mortality in apparently healthy adults, especially due to atherosclerotic disease. In animal models, somatic mutations are associated with atherosclerosis progression and myocardial dysfunction, especially when gene TET2 is affected. Preliminary clinical data, referred to ischemic heart failure (HF), have associate the presence of these acquired mutations with impaired prognosis. Purpose To study the prevalence of somatic mutations in patients with heart failure with reduced ejection fraction (HFrEF) and their impact on long-term prognosis. Methods We studied a cohort of elderly patients (more than 60 years old) hospitalized with HFrEF (LVEF Results A total of 62 patients (46 males (74.2%), age 74±7.5 years) with HFrEF (LVEF 29.7±7.8%) were enrolled in the study. The ischemic etiology was present in 54% of patients. Somatic mutations in Dnmt3a or Tet2 were present in 11 patients (17.7%). No differences existed in baseline characteristics except for a higher prevalence of atrial fibrillation in patients with somatic mutations (70% vs. 40%, p=0.007). During the follow-up period, 40 patients (64.5%) died and 38 (61.3%) had HF re-admission. The KM survival analysis for the combined event is shown in Figure 1. Compared with patients without somatic mutations and after adjusting for covariates, there was an increased risk of adverse outcomes when the somatic mutations were present (HR 3.6, 95% CI [1.6, 7.8], p=0.0014). This results remains considering death as a competing risk (Gray's test p=0.0097) and adjusting for covariates (HR = 2.21 95% CI [0.98, 5], p=0.0556). Conclusions Somatic mutation are present in patients with HFrEF and determine a higher risk of adverse events in the follow-up. Further studies are needed to assess the clinical implications of these findings. Figure 1 Funding Acknowledgement Type of funding source: None

This study aimed to analyse cervical lymphocytic populations in HIV+ and HIV- patients and correlate different cervical lesions with HIV viral load and presence of high-risk HPV types.A total of 132 histological specimens from 40 HIV+ and 72 HIV- patients were evaluated for CD4High-grade squamous intraepithelial lesions (HSIL) and squamous cell carcinoma (SCC) from HIV+ patients had lower CD4These results support an imbalance between cervical CD4

We assessed the feasibility of using a new oocyte-holding pipette (pipette without aspiration, PiWA) for intracytoplasmic sperm injection (ICSI), which prevents cytoplasmic aspiration during microinjection. A pilot experimental study in eight mature mouse oocytes to assess the feasibility of the oocyte-holding PiWA for ICSI procedure. The absence of oocyte degeneration after microinjection and the viability of correct embryo development were also evaluated. The pipette comprises a suction conduit inside an elongated cylindrical body and a funnel-shaped working end, which is dimensioned to hold the oocyte in a tight-fitting manner. Upon aspirating via the suction conduit, the oocyte remains partially trapped inside the funnel and becomes deformed changing the spherical shape of its resting state to an oval shape that tensions the surface and increases the turgor. In all ICSI procedures using the new PiWA, the oocyte membrane presented some resistance but was easily broken when exerting some pressure or small aspiration. The eight oocytes developed, six of which reached the blastocyte stage. The results obtained in this study indicate that the increase in oocyte membrane turgidity caused by PiWA prevents vigorous aspiration of the cytoplasm during spermatozoa microinjection.

This work evaluates the embodied carbon and energy of an industrial building construction with 6733 m² of built area, following a LCA methodology, on a gate-to-gate approach. For the LCI it was used primary data of electricity, water and diesel fuel, directly measured at the construction site, and information about the building materials used in the architecture and stability phases, obtained from the specialty design and construction documents, complemented with secondary data from literature. Results show an embodied carbon of 508.57 kgCO2-eq/m² and an embodied energy of 4908.68 MJ/m2 for the construction of the industrial building, being the building materials the main contributor.

African swine fever virus (ASFV) infection is characterized by a progressive decrease in cellular protein synthesis with a concomitant increase in viral protein synthesis, though the mechanism by which the virus achieves this is still unknown. Decrease of cellular mRNA is observed during ASFV infection, suggesting that inhibition of cellular proteins is due to an active mRNA degradation process. ASFV carries a gene (Ba71V D250R/Malawi g5R) that encodes a decapping protein (ASFV-DP) that has a Nudix hydrolase motif and decapping activity in vitro. Here, we show that ASFV-DP was expressed from early times and accumulated throughout the infection with a subcellular localization typical of the endoplasmic reticulum, colocalizing with the cap structure and interacting with the ribosomal protein L23a. ASFV-DP was capable of interaction with poly(A) RNA in cultured cells, primarily mediated by the N-terminal region of the protein. ASFV-DP also interacted with viral and cellular RNAs in the context of infection, and its overexpression in infected cells resulted in decreased levels of both types of transcripts. This study points to ASFV-DP as a viral decapping enzyme involved in both the degradation of cellular mRNA and the regulation of viral transcripts., Ministerio de Ciencia e Innovacion of Spain (BIO2013-46605) and the European Community’s Seventh Framework Programme (KBBE.2012.1.3-02-ASFORCE

We have studied the effect of aging and late onset caloric restriction (CR) on the expression of SIRT1 in hippocampus and cerebral cortex of the rat. Quantitative analysis showed that there is a significant reduction of SIRT1 protein levels in hippocampus with aging. Late onset, moderate CR prevented the deleterious effect of aging on SIRT1 content. Examination of SIRT1 immunoreactivity in coronal sections from hippocampus supported these results, and confirmed that old animals are able to respond to the beneficial effects of CR by regulating SIRT1 protein expression. Differences in the amounts of SIRT1 transcripts among animal groups were not found, which suggest that post-transcriptional mechanisms could be involved in the effects of aging and CR on SIRT1 expression.

Throughout a viral infection, the infected cell reprograms the gene expression pattern in order to establish a satisfactory antiviral response. African swine fever virus (ASFV), like other complex DNA viruses, sets up a number of strategies to evade the host's defense systems, such as apoptosis, inflammation and immune responses. The capability of the virus to persist in its natural hosts and in domestic pigs, which recover from infection with less virulent isolates, suggests that the virus displays effective mechanisms to escape host defense systems. ASFV has been described to regulate the activation of several transcription factors, thus regulating the activation of specific target genes during ASFV infection.Whereas some reports have concerned about anti-apoptotic ASFV genes and the molecular mechanisms by which ASFV interferes with inducible gene transcription and immune evasion, less is yet known regarding how ASFV regulates the translational machinery in infected cells, although a recent report has shown a mechanism for favored expression of viral genes based on compartmentalization of viral mRNA and ribosomes with cellular translation factors within the virus factory.The viral mechanisms involved both in the regulation of host genes transcription and in the control of cellular protein synthesis are summarized in this review. © 2012 Elsevier B.V., Spanish Ministerio de Ciencia e Innovación (BFU2007-63110/BFU2010-17794); European Community’s Seventh Framework Programme (FP7/2007–2013); KBBE-211691-ASFRISK; Fundación Ramón Areces.

African swine fever (ASF) is caused by a large and highly pathogenic DNA virus, African swine fever virus (ASFV), which provokes severe economic losses and expansion threats. Presently, no specific protection or vaccine against ASF is available, despite the high hazard that the continued occurrence of the disease in sub-Saharan Africa, the recent outbreak in the Caucasus in 2007, and the potential dissemination to neighboring countries, represents. Although virus entry is a remarkable target for the development of protection tools, knowledge of the ASFV entry mechanism is still very limited. Whereas early studies have proposed that the virus enters cells through receptor-mediated endocytosis, the specific mechanism used by ASFV remains uncertain. Here we used the ASFV virulent isolate Ba71, adapted to grow in Vero cells (Ba71V), and the virulent strain E70 to demonstrate that entry and internalization of ASFV includes most of the features of macropinocytosis. By a combination of optical and electron microscopy, we show that the virus causes cytoplasm membrane perturbation, blebbing and ruffles. We have also found that internalization of the virions depends on actin reorganization, activity of Na +/H + exchangers, and signaling events typical of the macropinocytic mechanism of endocytosis. The entry of virus into cells appears to directly stimulate dextran uptake, actin polarization and EGFR, PI3K-Akt, Pak1 and Rac1 activation. Inhibition of these key regulators of macropinocytosis, as well as treatment with the drug EIPA, results in a considerable decrease in ASFV entry and infection. In conclusion, this study identifies for the first time the whole pathway for ASFV entry, including the key cellular factors required for the uptake of the virus and the cell signaling involved. © 2012 Sánchez et al., Ministerio de Ciencia e Innovation (BFU2007-63110/BFU2010-17794); European Community’s Seventh Framework Programme (FP7/2007-2013); KBBE-211691- ASFRISK; Fundación Ramón Areces

African swine fever virus (ASFV), like other complex DNA viruses, deploys a variety of strategies to evade the host’s defence systems, such as inflammatory and immune responses and cell death. Here, we analyse the modifications in the translational machinery induced by ASFV. During ASFV infection, eIF4G and eIF4E are phosphorylated (Ser1108 and Ser209, respectively), whereas 4E-BP1 is hyperphosphorylated at early times post infection and hypophosphorylated after 18 h. Indeed, a potent increase in eIF4F assembly is observed in ASFV-infected cells, which is prevented by rapamycin treatment. Phosphorylation of eIF4E, eIF4GI and 4E-BP1 is important to enhance viral protein production, but is not essential for ASFV infection as observed in rapamycin- or CGP57380-treated cells. Nevertheless, eIF4F components are indispensable for ASFV protein synthesis and virus spread, since eIF4E or eIF4G depletion in COS-7 or Vero cells strongly prevents accumulation of viral proteins and decreases virus titre. In addition, eIF4F is not only activated but also redistributed within the viral factories at early times of infection, while eIF4G and eIF4E are surrounding these areas at late times. In fact, other components of translational machinery such as eIF2a, eIF3b, eIF4E, eEF2 and ribosomal P protein are enriched in areas surrounding ASFV factories. Notably, the mitochondrial network is polarized in ASFV-infected cells co-localizing with ribosomes. Thus, translation and ATP synthesis seem to be coupled and compartmentalized at the periphery of viral factories. At later times after ASFV infection, polyadenylated mRNAs disappear from the cytoplasm of Vero cells, except within the viral factories. The distribution of these pools of mRNAs is similar to the localization of viral late mRNAs. Therefore, degradation of cellular polyadenylated mRNAs and recruitment of the translation machinery to viral factories may contribute to the inhibition of host protein synthesis, facilitating ASFV protein production in infected cells., This work was supported by Grants from Laboratorios Esteve, Ministerio de Educacio´n y Ciencia BFU2007-63110 and BFU2006-02182, and by an Institutional grant from the Fundacio´n Ramo´n Areces. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.