Beta Human Papillomavirus 8E6 Attenuates Non-Homologous End Joining by Hindering DNA-PKcs Activity

Cutaneous viral infections occur in a background of near continual exposure to environmental genotoxins, like UV radiation in sunlight. Failure to repair damaged DNA is an established driver of tumorigenesis and substantial cellular resources are devoted to repairing DNA lesions. Beta-human papillomaviruses (β-HPVs) attenuate DNA repair signaling. However, their role in human disease is unclear. Some have proposed that β-HPV promotes tumorigenesis, while others suggest that β-HPV protects against skin cancer. Most of the molecular evidence that β-HPV impairs DNA repair has been gained via characterization of the E6 protein from β-HPV 8 (β-HPV 8E6). Moreover, β-HPV 8E6 hinders DNA repair by binding and destabilizing p300, a transcription factor for multiple DNA repair genes. By reducing p300 availability, β-HPV 8E6 attenuates a major double strand DNA break (DSB) repair pathway, homologous recombination. Here, β-HPV 8E6 impairs another DSB repair pathway, non-homologous end joining (NHEJ). Specifically, β-HPV 8E6 acts by attenuating DNA-dependent protein kinase (DNA-PK) activity, a critical NHEJ kinase. This includes DNA-PK activation and the downstream of steps in the pathway associated with DNA-PK activity. Notably, β-HPV 8E6 inhibits NHEJ through p300 dependent and independent means. Together, these data expand the known genome destabilizing capabilities of β-HPV 8E6

Disposiciones sanitarias establecidas por el Covid-19 y su impacto en la rentabilidad de la Empresa Alfacorp Perú E.I.R.L. Trujillo, 2020-2021

Esta investigación tiene como objetivo general, determinar cómo las disposiciones sanitarias establecidas por el Covid-19 impactaron en la rentabilidad de La Empresa Alfacorp Perú E.I.R.L Trujillo 2020-2021. El enfoque de nuestra investigación es cuantitativa, de tipo aplicada, con un diseño no experimental – descriptiva la población fue compuesta por la empresa Alfacorp Perú E.I.R.L .Para la recopilación de la información se empleó la técnica de la entrevista, que fue aplicado al Gerente general y Contador de la empresa Alfacorp Perú E.I.R.L , así mismo, se empleó la técnica de análisis documental que fue aplicado a sus estados financieros. Por lo que se concluyó que dichas disposiciones sanitarias que emitió el estado peruano por la Covid-19, tuvo una repercusión negativa en la rentabilidad de dicha empresa, por lo que hubo una interrupción de sus actividades diarias, disminuyendo así su demanda debido a la inmovilización obligatoria que dictaminaba el gobierno, causando una reducción en sus ventas. En base a dicha problemática en la empresa Alfacorp Perú E.I.R.L es necesario implementar ciertas estrategias el cual les permita estar preparados ante alguna situación similar como la del Covid-19, para saber cómo actuar frente a dicha situación y evitar pérdidas económicas como las del 2020

Association of myostatin, a cytokine released by muscle, with inflammation in rheumatoid arthritis

Instituto Mexicano del Seguro Social, Fondo de Investigacion en Salud, FIS/IMSS/PROT/MD16/1565Supplemental Digital Content is available in the text Myostatin is a cytokine produced and released by myocytes that might have an outstanding role not only in muscle wasting during cachexia but also in inflammation. Herein we explore the association between myostatin levels and inflammatory parameters in rheumatoid arthritis (RA). One hundred twenty-seven women without rheumatic diseases and 84 women with a diagnosis of RA were assessed in a cross-sectional study. Outcomes reflecting the activity of the arthritis including Disease Activity Score (DAS28-ESR) and impairment in functioning by the Health Assessment Questionnaire-Disability Index were assessed in RA. We obtained Skeletal muscle mass index (SMI), fat-free mass index (FFMI), and fat mass index using dual-energy x-ray absorptiometry. Serum myostatin was determined by enzyme-linked immunosorbent assay. Myostatin levels were correlated with disease activity and parameters of muscle mass. The SMI was lower and concentration of myostatin was higher in RA patients than in controls (P = .008 and P < .001, respectively). Myostatin significantly positively correlated with C-reactive protein (rho = 0.48, P < .001), erythrocyte sedimentation rate (rho = 0.28, P = .009), and DAS28-ESR (rho = 0.22, P = .04), and negatively correlated with SMI (rho = −0.29, P = .008), (FFMI) (rho = −0.24, P = .027). In the multivariate logistic regression analysis, levels of myostatin remained associated with disease activity in RA (P = .027). In our study, myostatin was associated with disease activity in RA patients, suggesting a mechanistic link between myostatin, muscle wasting and inflammation in RA

Endothelial Cell Autonomous Role of Akt1

© 2018 American Heart Association, Inc. Objective - The importance of PI3K/Akt signaling in the vasculature has been demonstrated in several models, as global loss of Akt1 results in impaired postnatal ischemia- and VEGF-induced angiogenesis. The ubiquitous expression of Akt1, however, raises the possibility of cell-type-dependent Akt1-driven actions, thereby necessitating tissue-specific characterization. Approach and Results - Herein, we used an inducible, endothelial-specific Akt1-deleted adult mouse model (Akt1iECKO) to characterize the endothelial cell autonomous functions of Akt1 in the vascular system. Endothelial-targeted ablation of Akt1 reduces eNOS (endothelial nitric oxide synthase) phosphorylation and promotes both increased vascular contractility in isolated vessels and elevated diastolic blood pressures throughout the diurnal cycle in vivo. Furthermore, Akt1iECKO mice subject to the hindlimb ischemia model display impaired blood flow and decreased arteriogenesis. Conclusions - Endothelial Akt1 signaling is necessary for ischemic resolution post-injury and likely reflects the consequence of NO insufficiency critical for vascular repair

Adiponectin reduces glomerular endothelial glycocalyx disruption and restores glomerular barrier function in a mouse model of type 2 diabetes

Adiponectin has vascular anti-inflammatory and protective effects. Although adiponectin protects against the development of albuminuria, historically, the focus has been on podocyte protection within the glomerular filtration barrier (GFB). The first barrier to albumin in the GFB is the endothelial glycocalyx (eGlx), a surface gel-like barrier covering glomerular endothelial cells (GEnCs). In diabetes, eGlx dysfunction occurs before podocyte damage; hence, we hypothesized that adiponectin could protect from eGlx damage to prevent early vascular damage in diabetic kidney disease (DKD). Globular adiponectin (gAd) activated AMPK signaling in human GEnCs through AdipoR1. It significantly reduced eGlx shedding and the TNF-α–mediated increase in syndecan-4 (SDC4) and MMP2 mRNA expression in GEnCs in vitro. It protected against increased TNF-α mRNA expression in glomeruli isolated from db/db mice and against expression of genes associated with glycocalyx shedding (namely, SDC4, MMP2, and MMP9). In addition, gAd protected against increased glomerular albumin permeability (Ps’alb) in glomeruli isolated from db/db mice when administered intraperitoneally and when applied directly to glomeruli (ex vivo). Ps’alb was inversely correlated with eGlx depth in vivo. In summary, adiponectin restored eGlx depth, which was correlated with improved glomerular barrier function, in diabetes

The SARS-CoV-2 Spike protein disrupts human cardiac pericytes function through CD147-receptor-mediated signalling:a potential non-infective mechanism of COVID-19 microvascular disease

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes a broad range of clinical responses including prominent microvascular damage. The capacity of SARS-CoV-2 to infect vascular cells is still debated. Additionally, the SARS-CoV-2 Spike (S) protein may act as a ligand to induce non-infective cellular stress. We tested this hypothesis in pericytes (PCs), which are reportedly reduced in the heart of patients with severe coronavirus disease-2019 (COVID-19). Here we newly show that the in vitro exposure of primary human cardiac PCs to the SARS-CoV-2 wildtype strain or the α and δ variants caused rare infection events. Exposure to the recombinant S protein alone elicited signalling and functional alterations, including: (1) increased migration, (2) reduced ability to support endothelial cell (EC) network formation on Matrigel, (3) secretion of pro-inflammatory molecules typically involved in the cytokine storm, and (4) production of pro-apoptotic factors causing EC death. Next, adopting a blocking strategy against the S protein receptors angiotensin-converting enzyme 2 (ACE2) and CD147, we discovered that the S protein stimulates the phosphorylation/activation of the extracellular signal-regulated kinase 1/2 (ERK1/2) through the CD147 receptor, but not ACE2, in PCs. The neutralisation of CD147, either using a blocking antibody or mRNA silencing, reduced ERK1/2 activation, and rescued PC function in the presence of the S protein. Immunoreactive S protein was detected in the peripheral blood of infected patients. In conclusion, our findings suggest that the S protein may prompt PC dysfunction, potentially contributing to microvascular injury. This mechanism may have clinical and therapeutic implications

Massive star formation and tidal structures in HCG 31

We present new broad-band optical and near-infrared CCD imaging together with deep optical intermediate-resolution spectroscopy of the Hickson Compact Group 31. We analyze the morphology and colors of the stellar populations of the galaxies, as well as the kinematics, physical conditions and chemical composition of the ionized gas in order to get a more complete view on the origin and evolution of the system. We estimate the ages of the most recent star formation bursts of the system, finding an excellent consistency among the values obtained with different indicators and starburst models. We find that member F hosts the youngest starburst of the group, showing a substantial population of Wolf-Rayet stars. The chemical abundances are fairly similar in all the members of the group despite their very different absolute magnitudes. We argue that the use of traditional metallicity-luminosity relations based on the absolute $B$-magnitude is not appropriate for dwarf starburst galaxies, because their luminosity is dominated by the transient contribution of the starburst to the blue luminosity. We think that members E and F of the group are candidate tidal dwarf galaxies because of their high metallicity, their kinematics, and the absence of underlying old stellar populations. Finally, we propose that HCG~31 is suffering several almost simultaneous interaction processes. The most relevant of these processes are: (a) the merging of members A and C, that would have produced two optical tidal tails; and (b) a fly-by encounter between G and the A+C complex, that would have produced an \ion{H}{1} tidal tail from the stripping of the external gas of A+C, from which members F and E have originated.Comment: Accepted for publication in ApJS, 41 pages, 15 figures, 9 table