RNF168, a new RING finger, MIU-containing protein that modifies chromatin by ubiquitination of histones H2A and H2AX

<p>Abstract</p> <p>Background</p> <p>Modulation of chromatin structure has emerged as a critical molecular device to control gene expression. Histones undergo different post-translational modifications that increase chromatin accessibility to a number of regulatory factors. Among them, histone ubiquitination appears relevant in nuclear processes that govern gene silencing, either by inhibiting or activating transcription, and maintain genome stability, acting as scaffold to properly organize the DNA damage response. Thus, it is of paramount importance the identification and the characterization of new ubiquitin ligases that address histones.</p> <p>Results</p> <p>We identified and characterized RNF168, a new chromatin-associated RING finger protein. We demonstrated that RNF168 is endowed with ubiquitin ligase activity both <it>in vitro </it>and <it>in vivo</it>, which targets histones H2A and H2AX, but not H2B, forming K63 polyubiquitin chains. We previously described the presence within RNF168 sequence of two MIU domains, responsible for the binding to ubiquitinated proteins. Here we showed that inactivation of the MIUs impairs ubiquitin binding ability <it>in vitro </it>and reduces chromatin association of RNF168 <it>in vivo</it>. Moreover, upon formation of DNA double strand breaks induced by chemical and physical agents, RNF168 is recruited to the DNA damage foci, where it co-localizes with γH2AX and 53BP1. The localization of RNF168 at the site of damage highly increases the local concentration of ubiquitinated proteins and determines the prolonged ubiquitination signal.</p> <p>Conclusion</p> <p>The RING finger protein RNF168 is a new ubiquitin ligase that functions as chromatin modifier, through histone ubiquitination. We hypothesize a dual function for RNF168. In normal condition RNF168 modifies chromatin structure by modulating ubiquitination of histone H2A. Upon DNA lesions, RNF168 is recruited to DNA damage response foci where it contributes to increase the amount of ubiquitinated proteins, thereby facilitating the downstream signalling cascade.</p

Composite Y internal thoracic artery–saphenous vein grafts: short-term angiographic results and vasoreactive profile

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Measuring the experience of remote home workers: A scoping review

Introduction: Working from home (WFH) remotely is a modality of working that requires the careful design of systems of rules and tools to enable people to exchange information and perform actions. WFH is expected to expand after the COVID-19 pandemic, and how best to reliably assess and compare the experience of workers with different (sociotechnical) systems of WFH is central to the diffusion of acceptable modalities of remote working. However, the concept of experience and how it can be measured in the domain in WFH is yet to be clearly characterized. Methods: Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) methodology for scoping reviews, we systematically map the approaches used by researchers to assess WFH, identify which aspects are usually investigated, and examine how such aspects are usually measured in terms of questions and tools. Literature is collected using Scopus and Web of Science. Results: Thirty-four records out of 323 focusing either on validating a scale, presenting theoretically the experience of workers or testing this empirically are included in the qualitative synthesis. The results highlight a lack of unified terminology and tools, with assessments of workers’ experience mainly characterized by survey approaches and qualitative questions. Conclusion: Clustering together the most investigated aspects in the literature and reviewing how these aspects are assessed, we propose a list of 10 relevant overarching dimensions and attempt to define workers’ experience in the domain of WFH remotely. This definition can be used as a tool by researchers aiming to assess the experience of workers in order to inform the design or redesign of the sociotechnical systems that enable WFH

Standard model anomalies: Lepton flavour non-universality and lepton g-2

We critically analyze the body of results that hints to the existence of New Physics from possible violations of lepton universality observed by the LHCb experiment in the $\mu/e$ ratios $R_{K}$ and $R_{K^*}$ to the $g-2$ lepton anomalies. The analysis begins with a theoretical, in depth, study of the $\mu/e$ ratios $R_{K}$ and $R_{K^*}$ as well as the process $B_s \rightarrow \mu^+ \mu^-$. Here we consider the impact of complex Wilson coefficients and derive constraints on their imaginary and real parts. We then move to a comprehensive comparison with experimental results. We show that, by fitting a single Wilson coefficient, the deviations from the Standard Model are at the $4.7\sigma$ level when including only the hadronic insensitive observables while it increases to $6.1\sigma$ when including also the hadronic sensitive ones. When switching on all relevant Wilson coefficients and combining both hadronic sensitive and insensitive data into the fit, the deviation from the Standard Model peaks at 7.2$\sigma$ and decreases at the $4.9\sigma$ level if we assume that the central values of $R_K$ and $R_K^{\ast}$ are taken to be unity. We further estimate the non-perturbative long distance hadronic contributions and show that their inclusion still requires New Physics to fit the data. We then introduce the $g-2$ lepton anomalies results. Different theoretical models are considered that can explain the discrepancies from the Standard Model. In the final part of our work we estimate the impact of the forthcoming data from LHCb (coming from LHC Run3) and Belle II, when it will have accumulated about $5~ab^{-1}$

Thorax support vest to prevent sternal wound infections in cardiac surgery patients—a systematic review and meta-analysis

OBJECTIVES: Midline sternotomy is the main surgical access for cardiac surgeries. The most prominent complication of sternotomy is sternal wound infection (SWI). The use of a thorax support vest (TSV) that limits thorax movement and ensures sternal stability has been suggested to prevent postoperative SWI. METHODS: We performed a meta-analysis to evaluate differences in clinical outcomes with and without the use of TSV after cardiac surgery in randomized trials. The primary outcome was deep SWI (DSWI). Secondary outcomes were superficial SWI, sternal wound dehiscence, and hospital length of stay (LOS). A trial sequential analysis was performed. Fixed (F) and random effects (R) models were calculated. RESULTS: A total of 4 studies (3820 patients) were included. Patients who wore the TSV had lower incidence of DSWI [odds ratio (OR) = F: 0.24, 95% confidence interval (CI), 0.13–0.43, P < 0.01; R: 0.24, 0.04–1.59, P = 0.08], sternal wound dehiscence (OR = F: 0.08, 95% CI, 0.02–0.27, P < 0.01; R: 0.10, 0.00–2.20, P = 0.08) and shorter hospital LOS (standardized mean difference = F: −0.30, −0.37 to −0.24, P < 0.01; R: −0.63, −1.29 to 0.02, P = 0.15). There was no difference regarding the incidence of superficial SWI (OR = F: 0.71, 95% CI, 0.34–1.47, P = 0.35; R: 0.64, 0.10, 4.26, P = 0.42). The trial sequential analysis, however, showed that the observed decrease in DSWI in the TSV arm cannot be considered conclusive based on the existing evidence. CONCLUSIONS: This meta-analysis suggests that the use of a TSV after cardiac surgery could potentially be associated with a reduction in sternal wound complications. However, despite the significant treatment effect in the available studies, the evidence is not solid enough to provide strong practice recommendations

FTY720 inhibits mesothelioma growth in vitro and in a syngeneic mouse model

Background: Malignant mesothelioma (MM) is a very aggressive type of cancer, with a dismal prognosis and inherent resistance to chemotherapeutics. Development and evaluation of new therapeutic approaches is highly needed. Immunosuppressant FTY720, approved for multiple sclerosis treatment, has recently raised attention for its anti-tumor activity in a variety of cancers. However, its therapeutic potential in MM has not been evaluated yet. Methods: Cell viability and anchorage-independent growth were evaluated in a panel of MM cell lines and human mesothelial cells (HM) upon FTY720 treatment to assess in vitro anti-tumor efficacy. The mechanism of action of FTY720 in MM was assessed by measuring the activity of phosphatase protein 2A (PP2A)-a major target of FTY720. The binding of the endogenous inhibitor SET to PP2A in presence of FTY720 was evaluated by immunoblotting and immunoprecipitation. Signaling and activation of programmed cell death were evaluated by immunoblotting and flow cytometry. A syngeneic mouse model was used to evaluate anti-tumor efficacy and toxicity profile of FTY720 in vivo. Results: We show that FTY720 significantly suppressed MM cell viability and anchorage-independent growth without affecting normal HM cells. FTY720 inhibited the phosphatase activity of PP2A by displacement of SET protein, which appeared overexpressed in MM, as compared to HM cells. FTY720 promoted AKT dephosphorylation and Bcl-2 degradation, leading to induction of programmed cell death, as demonstrated by caspase-3 and PARP activation, as well as by cytochrome c and AIF intracellular translocation. Moreover, FTY720 administration in vivo effectively reduced tumor burden in mice without apparent toxicity. Conclusions: Our preclinical data indicate that FTY720 is a potentially promising therapeutic agent for MM treatment