The nucleolus is implicated in sensing and responding to cellular stress by stabilizing p53. The pro-apoptotic effect of p53 is associated with several neurodegenerative disorders, including ...Huntington's disease (HD), which is characterized by the progressive loss of medium spiny neurons (MSNs) in the striatum. Here we show that disruption of nucleolar integrity and function causes nucleolar stress and is an early event in MSNs of R6/2 mice, a transgenic model of HD. Targeted perturbation of nucleolar function in MSNs by conditional knockout of the RNA polymerase I-specific transcription initiation factor IA (TIF-IA) leads to late progressive striatal degeneration, HD-like motor abnormalities and molecular signatures. Significantly, p53 prolongs neuronal survival in TIF-IA-deficient MSNs by transient upregulation of phosphatase and tensin homolog deleted on chromosome 10 (PTEN), a tumor suppressor that inhibits mammalian target of rapamycin signaling and induces autophagy. The results emphasize the initial role of nucleolar stress in neurodegeneration and uncover a p53/PTEN-dependent neuroprotective response.
In this paper we introduce an hp finite element method to solve a two-dimensional fluid-structure spectral problem. This problem arises from the computation of the vibration modes of a bundle of ...parallel tubes immersed in an incompressible fluid. We prove the convergence of the method and a priori error estimates for the eigenfunctions and the eigenvalues. We define an a posteriori error estimator of the residual type which can be computed locally from the approximate eigenpair. We show its reliability and efficiency by proving that the estimator is equivalent to the energy norm of the error up to higher order terms, the equivalence constant of the efficiency estimate being suboptimal in that it depends on the polynomial degree. We present an hp adaptive algorithm and several numerical tests which show the performance of the scheme, including some numerical evidence of exponential convergence.
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New heteroaryl HIV-protease inhibitors bearing a carboxyamide spacer were synthesized in few steps and high yield, from commercially available homochiral epoxides. Different ...substitution patterns were introduced onto a given isopropanoyl-sulfonamide core modifying the type of heteroarene and the central core, with the presence of either H or benzyl group. Their in vitro inhibition activity against recombinant protease showed a general beneficial effect of carboxyamide moiety, the IC50 values ranging between 1 and 15nM. In particular benzofuryl derivatives showed IC50 values among the best for such structurally simple inhibitors. Docking analysis allowed to identify the favorable situation of such benzofuryl derivatives in terms of number of interactions in the active site, supporting the experimental results on activity.
The inhibition activity of such molecules has been also evaluated in HEK293 cells expressing the protease fused to green fluorescent protein, by western blotting analysis, fluorescence microscopy and cytofluorimetry.
Recent findings have confirmed relationships between coronavirus disease (COVID-19) and multiple organ dysfunction. The prevalence of cardiac and renal involvement in COVID-19 has been increasingly ...reported and is a marker of severe disease that not only directly or indirectly affects the organs, but may also exacerbate the underlying comorbid illness. In addition, patients affected by the new coronavirus present a systemic inflammatory condition that results in damage to several tissues, especially the heart, kidneys, and vessels. It is well known that the heart and kidneys are closely related, so that any change in one of the organs can lead to damage to the other, establishing the so-called cardiorenal syndrome. Herein, we explore some case reports of patients with COVID-19 who had heart and kidney abnormalities, consequently resulting in worse prognosis of the disease. These results highlight the importance of understanding the cause and effect between the cardiac and renal systems and the course of early SARS-CoV-2 infection.
•The anti-apoptotic protein URG7 is targeted and localized to the ER.•URG7 is glycosylated in the N-terminal region.•URG7 is inserted into the ER membrane with a single transmembrane segment.•URG7 ...mainly adapts a topology with an Nlumen–Ccytosol orientation.•The results suggest that the C-tail of URG7 could sequester a pro-apoptotic signal.
Hepatitis B x antigen up-regulates the liver expression of URG7 that contributes to sustain chronic virus infection and to increase the risk for hepatocellular carcinoma by its anti-apoptotic activity. We have investigated the subcellular localization of URG7 expressed in HepG2 cells and determined its membrane topology by glycosylation mapping in vitro. The results demonstrate that URG7 is N-glycosylated and located to the endoplasmic reticulum membrane with an Nlumen–Ccytosol orientation. The results imply that the anti-apoptotic effect of URG7 could arise from the C-terminal cytosolic tail binding a pro-apoptotic signaling factor and retaining it to the endoplasmic reticulum membrane.
Unlike non mammalian vertebrates, adult neurogenesis in mammals is detectable in highly restricted brain sites. Persistent neurogenesis is thought to depend on stem cells residing in neural stem cell ...niches which are remnants of the embryonic germinal layers. Local progenitors which retain some proliferative capacity have been identified in the mature brain parenchyma, yet they do not support a constitutive, 'actual' neurogenesis, but rather a 'potential' neurogenesis which does not extrinsecate fully and spontaneously in vivo. In contrast with such a view, genesis of neuronal and glial cells from local progenitors does occur in the peripuberal and adult rabbit cerebellum. This process is independent from persisting germinal layers and involves different cell populations.
Abstract Small ruminant lentivirus genotype E lacks the dUTPase subunit and vpr-like gene. Two strains (Roccaverano and Seui) with identical genetic organization have been described, with the env ...HV1–HV2 domains being the most divergent. Although dUTPase and vpr-like deletions have been involved in the RT fidelity in non dividing cells, both strains were able to replicate efficiently in blood derived macrophages (BDM), while virus production of E1 subtype was reduced or abrogated in replicating fibroblastic-like cells. The transcriptional activity of genotype E was similar in these two cellular populations. When viral pseudotypes were generated with the env of both viruses, Roccaverano pseudotype displayed a paranuclear localization on BDM, suggesting a different mechanism of entry. Polymorphic GAS and TAS sites in the U3 region, further suggest that a population different from classically activated macrophages can be infected by these viruses, opening new insights into lentiviruses with low or null pathogenic potential.
Nowadays, more and more users keep up with news through information streams coming from real-time micro-blogging activity offered by services such as Twitter. In these sites, information is shared ...via a followers/followees social network structure in which a follower receives all the micro-blogs from his/her followees. Recent research efforts on understanding micro-blogging as a novel form of communication and news spreading medium have identified three different categories of users in these systems: information sources, information seekers and friends. As social networks grow in the number of registered users, finding relevant and reliable users to receive interesting information becomes essential. In this paper we propose a followee recommender system based on both the analysis of the content of micro-blogs to detect users' interests and in the exploration of the topology of the network to find candidate users for recommendation. Experimental evaluation was conducted in order to determine the impact of different profiling strategies based on the text analysis of micro-blogs as well as several factors that allows the identification of users acting as good information sources. We found that user-generated content available in the network is a rich source of information for profiling users and finding like-minded people.
•We present an effective algorithm for recommending followees in Twitter.•We defined four different strategies to create content-based user profiles.•The target user's own tweets are not a good source of profiling knowledge.•Profiles based on the posts of the target user's followees give high precision values.
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