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Remodeling of the cellular endomembrane system by viruses allows for efficient and coordinated replication of the viral genome in distinct subcellular compartments termed replication organelles. As a critical step in the viral life cycle, replication organelle formation is an attractive target for therapeutic intervention, but factors central to this process are only partially understood. In this study, we corroborate that two viral proteins, nsp3 and nsp4, are the major drivers of membrane remodeling in SARS-CoV-2 infection. We further report a number of host cell factors interacting with these viral proteins and supporting the viral replication cycle, some of them by contributing to the formation of the SARS-CoV-2 replication organelle.

Background. Transplant glomerulopathy (TG) is the hallmark of chronic antibody-mediated rejection but often occurs without anti-HLA donor-specific antibodies (DSAs) in the assumption that other DSAs may be the effectors of the tissue injury. Recently, we reported a positive effect of interleukin-6 (IL-6) receptor blocker tocilizumab (TCZ) in TG/DSA+. In the present study, we investigate the effect of TCZ in a cohort of TG cases without detectable anti-HLA DSAs. Methods. Single-center retrospective analysis of TG cases without anti-HLA DSAs (TG/DSA) treated with TCZ for chronic antibody-mediated rejection as first-line therapy evaluated through clinical, protocol biopsies, and gene expression analyses was included. Results. Differently from TG/DSA+, TG/DSA– showed a progressive reduction in the estimated glomerular filtration rate at 12 mo and after that with no significant modification in microvascular inflammation or C4d+. No upregulation in tight junction protein-1, aldo-keto reductase family 1 member C3, and calcium/calmodulin-dependent serine protein kinase, documented in TG/DSA+, was noted in post-TCZ biopsies. The reduction of microvascular inflammation was associated with natural killer-cell reduction in TG/DSA+, whereas TG/DSA– tends to maintain or increase periglomerular/interstitial infiltration. Conclusions. In the absence of anti-HLA DSAs, TG behavior seems not to be modified by IL-6 receptor blockade. These results are at variance with observational studies and previous trials with IL-6 inhibitors in TG associated with anti-HLA DSAs. These data may fuel the hypothesis of different mechanisms underlying TGs (including the potentially different roles of natural killer cells) and suggest carefully selecting patients with TG for clinical trials or off-label treatment based on their antidonor serologic status.

Most launcher networks are based on proprietary buses such as MIL-STD-1553B whose low bandwidth limits the introduction of new services of suitable characteristics. Ethernet technology, because of its low cost and high performance, has been considered an excellent candidate for its use in launcher networks. The real time Ethernet solutions based on the Time Sensitive Networking (TSN) standards seem the most suitable because of its multi-vendor product characteristics. In this paper we propose a real time Ethernet solution for aerospace applications in which negligible jitter services has to be guaranteed. The proposed solution is based on the following TSN standards: IEEE 802.1AS/ASrev as synchronization protocol and 802.1Qbv-2015 for deterministic traffic scheduling. To improve both the bandwidth effective and the frame delay the solution is also based on a change in the management of the Priority Code Point field in IEEE 802.1Q standard. The optimal scheduling problem is formulated so as to minimize the makespan, defined as the time needed to deliver all of the messages of an elementary cycle. The problem has been resolved with the CPLEX solver and the proposed solution has been evaluated in terms of both delay and bandwidth effective by comparing its performance with the TTEthernet, FTTEthernet benchmark solutions. The obtained results in a real traffic scenario characterized by the set of messages of the VEGA launcher show how the proposed solution allows for the same performance of TTEthernet, i.e., the solution of proprietary and real-time Ethernet with better performance.

Intensively developed mobile systems and networks 5G [...]

Abstract For successful infection of host cells and virion production, enveloped viruses, including Zika virus (ZIKV), extensively rely on cellular lipids. However, how virus protein–lipid interactions contribute to the viral life cycle remains unclear. Here, we employ a chemo-proteomics approach with a bifunctional cholesterol probe and show that cholesterol is closely associated with the ZIKV structural protein prM. Bioinformatic analyses, reverse genetics alongside with photoaffinity labeling assays, and atomistic molecular dynamics simulations identified two functional cholesterol binding motifs within the prM transmembrane domain. Loss of prM–cholesterol association has a bipartite effect reducing ZIKV entry and leading to assembly defects. We propose a model in which membrane-resident M facilitates cholesterol-supported lipid exchange during endosomal entry and, together with cholesterol, creates a platform promoting virion assembly. In summary, we identify a bifunctional role of prM in the ZIKV life cycle by mediating viral entry and virus assembly in a cholesterol-dependent manner.

The article discusses the importance of optical and photonic technologies in supporting 5G and future 6G mobile networks. These advanced technologies are necessary for the construction and implementation of these networks, particularly in the core networks, backhaul, midhaul, and fronthaul components. Optical technologies such as DWDM, CWDM, OTN, EON, and PON are used in these networks, and Li-Fi optical wireless connectivity is also expected to be utilized in 6G networks. The article highlights the need for efficient management of optical resources and the potential use of machine learning and artificial intelligence in optimizing future optical networks. The article also provides a summary of five contributions in the field of optics and photonics for telecommunications systems, including research on passive optical networks, advanced optical modulations, optical path analysis, and software management for optical converters. [Extracted from the article]

Whether there are conserved nucleic acid (NA) binding proteins across species is not fully known. Using data from human, mouse and fly, the authors identify common binders, implicate TAOKs and show that these kinases bind NAs across species and promote virus defence in mammalian cells.

Abstract Background Rare diseases (RDs) encompass many difficult-to-treat conditions with different characteristics often associated with end-stage renal disease (ESRD). However, data about transplant outcomes in adult patients are still lacking and limited to case reports/case series without differentiation between immunological/non-immunological RDs. Methods Retrospective analysis among all adult kidney transplanted patients (KTs) with RDs (RDsKT group) performed in our high-volume transplantation center between 2005 and 2016. RDs were classified according to the Orphanet code system differentiating between immunological and non-immunological diseases, also comparing clinical outcomes and temporal trends to a control population without RDs (nRDsKT). Results Among 1381 KTs, 350 patients (25.3%) were affected by RDs (RDsKTs). During a f/up > 5 years [median 7.9 years (4.8–11.1)], kidney function and graft/patient survival did not differ from nRDsKTs. Considering all post-transplant complications, RDsKTs (including, by definition, patients with primary glomerulopathy except on IgA nephropathy) have more recurrent and de-novo glomerulonephritis (14.6% vs. 9.6% in nRDsKTs; p = 0.05), similar rates of de-novo cancers, post-transplant diabetes, dysmetabolism, hematologic disorders, urologic/vascular problems, and lower infectious episodes than nRDsKTs (63.7% vs 72.7%; p = 0.013). Additional stratification for immunological and non-immunological RDsKTs or transplantation periods (before/after 2010) showed no differences or temporal trends between groups. Conclusions Kidney transplant centers are deeply involved in RDs management. Despite their high-complex profile, both immunological and non-immunological RDsKTs experienced favorable patients’ and graft survival.

The emergence and global spread of SARS-CoV-2 has resulted in the urgent need for an in-depth understanding of molecular functions of viral proteins and their interactions with the host proteome. Several individual omics studies have extended our knowledge of COVID-19 pathophysiology.sup.1-10. Integration of such datasets to obtain a holistic view of virus-host interactions and to define the pathogenic properties of SARS-CoV-2 is limited by the heterogeneity of the experimental systems. Here we report a concurrent multi-omics study of SARS-CoV-2 and SARS-CoV. Using state-of-the-art proteomics, we profiled the interactomes of both viruses, as well as their influence on the transcriptome, proteome, ubiquitinome and phosphoproteome of a lung-derived human cell line. Projecting these data onto the global network of cellular interactions revealed crosstalk between the perturbations taking place upon infection with SARS-CoV-2 and SARS-CoV at different levels and enabled identification of distinct and common molecular mechanisms of these closely related coronaviruses. The TGF-[beta] pathway, known for its involvement in tissue fibrosis, was specifically dysregulated by SARS-CoV-2 ORF8 and autophagy was specifically dysregulated by SARS-CoV-2 ORF3. The extensive dataset (available at https://covinet.innatelab.org) highlights many hotspots that could be targeted by existing drugs and may be used to guide rational design of virus- and host-directed therapies, which we exemplify by identifying inhibitors of kinases and matrix metalloproteases with potent antiviral effects against SARS-CoV-2. Multi-omics profiling of effects of SARS-CoV-2 and SARS-CoV on A549, a lung-derived human cell line, produces a dataset enabling identification of common and virus-specific mechanisms of infection., Author(s): Alexey Stukalov [sup.1] , Virginie Girault [sup.1] , Vincent Grass [sup.1] , Ozge Karayel [sup.2] , Valter Bergant [sup.1] , Christian Urban [sup.1] , Darya A. Haas [sup.1] , [...]

Introduction: Broad national or international programs contribute to mitigating the expected longer waiting list (WL) time for sensitized patients but with minor benefits for highly sensitized subjects. Therefore, strategies to prevent high sensitization are urgently required. In this study, we investigated the risk of developing highly sensitized patients with different immunosuppressive (IS) handling after kidney allograft failure (KAF). Methods: Data from 185 patients with KAF, retransplanted/relisted from 2010 to 2020 in two regions of Italy that share the same regional WL, were analyzed. Patients were categorized according to IS management at 12 months after KAF as follows: patients maintaining IS with calcineurin inhibitors (CNI) (late withdrawal group [LWG], n = 58) and those who withdrew all IS therapy or were on steroids only (early withdrawal group [EWG], n = 127). Results: Patients in the LWG showed lower panel reactive antibodies (PRA) at 12 (29.0% vs. 85.5%, p < 0.001) and 24 months (61.0% vs. 91.0%, p = 0.001), reduced risk of high sensitization (PRA ≥90%) at 12 (9.4% vs. 40.7%, p < 0.001, OR = 0.15) and 24 months (25.6% vs. 57.3%, p = 0.001, OR = 0.26) and almost no very high sensitization (PRA ≥ 98%) at 12 months (1.9% vs. 18.6%, p = 0.003, OR = 0.08) after KAF. In the LWG subgroup analysis, patients who maintained IS for up to 24 months after KAF did not show very high sensitization. The LWG showed shorter active WL times (406 vs. 813 days, p = 0.001) without an increased risk of complications. Conclusions: CNI maintenance for at least 12 months after KAF could be a useful approach to prevent high sensitization and reduce WL times in patients who are offered retransplantation, without a higher burden of complications. [ABSTRACT FROM AUTHOR]

Abstract Despite type 2 diabetes mellitus (T2D) is commonly considered a detrimental factor in dialysis, its clear effect on morbidity and mortality on waitlisted patients for kidney transplant (KT) has never been completely elucidated. We performed a retrospective analysis on 714 patients admitted to wait-list (WL) for their first kidney transplant from 2005 to 2010. Clinical characteristics at registration in WL (age, body mass index -BMI-, duration and modality of dialysis, underlying nephropathy, coronary artery -CAD- and/or peripheral vascular disease), mortality rates, and effective time on WL were investigated and compared according to T2D status (presence/absence). Data about therapy and management of T2D were also considered. At the time of WL registration T2D patients (n = 86) were older than non-T2D (n = 628) (58.7 ± 8.6 years vs 51.3 ± 12.9) with higher BMI (26.2 ± 3.8 kg/m2 vs 23.8 ± 3.6), more frequent history of CAD (33.3% vs 9.8%) and peripheral vascular disease (25.3% vs 5.8%) (p

The high time required for the deployment of cloud resources in Network Function Virtualization network architectures has led to the proposal and investigation of algorithms for predicting traffic or the necessary processing and memory resources. However, it is well known that whatever approach is taken, a prediction error is inevitable. Two types of prediction errors can occur that have a different impact on the increase in network operational costs. In case the predicted values are higher than the real ones, the resource allocation algorithms will allocate more resources than necessary with the consequent introduction of an over-provisioning cost. Conversely, when the predicted values are lower than the real values, the allocation of fewer resources will lead to a degradation of QoS and the introduction of an under-provisioning cost. When over-provisioning and under-provisioning costs are different, most of the prediction algorithms proposed in the literature are not adequate because they are based on minimizing the mean square error or symmetric cost functions. For this reason we propose and investigate a forecasting methodology in which it is introduced an asymmetric cost function capable of weighing the costs of over-provisioning and under-provisioning differently. We have applied the proposed forecasting methodology for resource allocation in a Network Function Virtualization architectures where the Network Function Virtualization Infrastructure Point-of-Presences are interconnected by an elastic optical network. We have verified a cost savings of 40% compared to solutions that provide a minimization of the mean square error.

Objectives: To explore the Cytomegalovirus (CMV) burden on the long-term post-transplant course in different donor ages, we evaluated the incidence and risk factors for CMV in our kidney-transplanted patients (KTs) with extensive adoption of expanded-criteria donors (ECDs). Methods: Retrospective evaluation of 929 consecutive first KTs (49.5% receiving an organ from a donor ≥ 60 years) performed between 01-2003 and 12-2013. Overall survival was estimated using Kaplan–Meier curves; cumulative incidence function was additionally analyzed to consider the potential role of death with a functioning graft as a competitive event with graft dysfunction and to avoid overestimation. Apart from regular DNAemia monitoring in all patients, prophylaxis was adopted in high-risk groups (D+/R− or recipients of anti-thymocyte globulin induction), with pre-emptive therapy in the remaining groups. Results: CMV incidence was 19.5% (4–34.9% according to serostatus combination: D−/R−, D−/R+, D+/R+, D+/R−). Donor and recipient age, recipient pre-transplant hypertension, DR antigen compatibility, cold ischemia time, and post-transplant early complications, including rejection, urologic and renal artery stenosis, and lower renal function and proteinuria ≥ 0.5 g/day at one year after KT were associated with CMV. CMV determined lower death-censored graft survival (DCGS) (p < 0.01), with a prominent effect in R+ (p < 0.01) and without impact in R− (p = 0.32 in D−/R− and p = 0.006 in D+/R−). Interestingly, CMV occurrence influenced DCGS only in KTs who received grafts from donors < 50 or 50–69 years old (p < 0.01), while it was not significant with older donors (p = 0.07). The analysis of the cumulative incidence of graft loss accounting for death as a competing risk confirmed all these findings. In multivariate analysis, CMV replication/disease in the first year was an independent predictor for DCGS (HR 1.73 [1.3–2.3]). Conclusions: In a large population with extensive ECD adoption, CMV viremia in the first year demonstrates its harmful effect with an independent role for graft loss and significant impact among R+ recipients and KTs with donors < 70 years.

Abstract We present the analytic calculation of the Master Integrals for the twoloop, non-planar topologies that enter the calculation of the amplitude for top-quark pair hadroproduction in the quark-annihilation channel. Using the method of differential equations, we expand the integrals in powers of the dimensional regulator ϵ and determine the expansion coefficients in terms of generalized harmonic polylogarithms of two dimensionless variables through to weight four.