Three mutations in SASH1 cause the pathogenesis of dyschromatosis universalis hereditaria (DUH)

Dyschromatosis universalis hereditaria (DUH) is a rare genodermatosis characterized by hyper- and hypopigmented macules which form a reticulate or mottled pattern. The causal gene and the precise pathogenesis of DUH have been unclear since the disease was initially reported in 1933. However, we found three heterozygous mutations encoding amino acid substitutions in SASH1 in each of three nonconsanguineous DUH families. Immunohistochemistry and melanin staining showed distribution heterogenicity of melanocytes, predominantly melanized melanocytes in the epidermal tissues of a DUH patient. Specifically, we identified that mutations of SASH1 can up-regulate resident melanogenic proteins, transport proteins of melanosome, and induce increased mobility of melanocytes in vitro and in vivo. Furthermore, SASH1 was shown to interact with several proteins associated with melanogenesis in the MAPK signaling pathway and the endothelin signaling pathway, indicating an additional melanogenesis signaling pathway in the regulation of melanin biosynthesis. Collectively, these observations suggest that DUH is a heterogeneous disorder of increased production and transport of melanosomes caused by SASH1 mutation together with melanocyte maldistribution

Determinants that control the specific interactions between TAB1 and p38α

Previous studies have revealed that transforming growth factor-beta-activated protein kinase 1 (TAB1) interacts with p38 alpha and induces p38 alpha autophosphorylation. Here, we examine the sequence requirements in TAB1 and p38 alpha that drive their interaction. Deletion and point mutations in TAB1 reveal that a proline residue in the C terminus of TAB1 (Pro412) is necessary for its interaction with p38 alpha. Furthermore, a cryptic D-domain-like docking site was identified adjacent to the N terminus of Pro412, putting Pro412 in the (phi(B)+3 position of the docking site. Through mutational analysis, we found that the previously identified hydrophobic docking groove in p38 alpha is involved in this interaction, whereas the CD domain and ED domain are not. Furthermore, chimeric analysis with p38 beta (which does not bind to TAB1) revealed a previously unidentified locus of p38 alpha comprising Thr218 and Ile275 that is essential for specific binding of p38 alpha to TAB1. Converting either of these residues to the corresponding amino acid of p380 abolishes p38 alpha interaction with TAB1. These p38a mutants still can be fully activated by p38 alpha upstream activating kinase mitogen-activated protein kinase kinase 6, but their basal activity and activation in response to some extracellular stimuli are reduced. Adjacent to Thr218 and Ile275 is a site where large conformational changes occur in the presence of docking-site peptides derived from p38 alpha substrates and activators. This suggests that TAB1-induced autophosphorylation of p38 alpha results from conformational changes that are similar but unique to those seen in p38 alpha interactions with its substrates and activating kinases

Transient Receptor Potential V Channels Are Essential for Glucose Sensing by Aldolase and AMPK

Fructose-1,6-bisphosphate (FBP) aldolase links sensing of declining glucose availability to AMPK activation via the lysosomal pathway. However, how aldolase transmits lack of occupancy by FBP to AMPK activation remains unclear. Here, we show that FBP-unoccupied aldolase interacts with and inhibits endoplasmic reticulum (ER)-localized transient receptor potential channel subfamily V, inhibiting calcium release in low glucose. The decrease of calcium at contact sites between ER and lysosome renders the inhibited TRPV accessible to bind the lysosomal v-ATPase that then recruits AXIN:LKB1 to activate AMPK independently of AMP. Genetic depletion of TRPVs blocks glucose starvation-induced AMPK activation in cells and liver of mice, and in nematodes, indicative of physical requirement of TRPVs. Pharmacological inhibition of TRPVs activates AMPK and elevates NAD(+) levels in aged muscles, rejuvenating the animals' running capacity. Our study elucidates that TRPVs relay the FBP-free status of aldolase to the reconfiguration of v-ATPase, leading to AMPK activation in low glucose

Beyond Control: Exploring Novel File System Objects for Data-Only Attacks on Linux Systems

The widespread deployment of control-flow integrity has propelled non-control data attacks into the mainstream. In the domain of OS kernel exploits, by corrupting critical non-control data, local attackers can directly gain root access or privilege escalation without hijacking the control flow. As a result, OS kernels have been restricting the availability of such non-control data. This forces attackers to continue to search for more exploitable non-control data in OS kernels. However, discovering unknown non-control data can be daunting because they are often tied heavily to semantics and lack universal patterns. We make two contributions in this paper: (1) discover critical non-control objects in the file subsystem and (2) analyze their exploitability. This work represents the first study, with minimal domain knowledge, to semi-automatically discover and evaluate exploitable non-control data within the file subsystem of the Linux kernel. Our solution utilizes a custom analysis and testing framework that statically and dynamically identifies promising candidate objects. Furthermore, we categorize these discovered objects into types that are suitable for various exploit strategies, including a novel strategy necessary to overcome the defense that isolates many of these objects. These objects have the advantage of being exploitable without requiring KASLR, thus making the exploits simpler and more reliable. We use 18 real-world CVEs to evaluate the exploitability of the file system objects using various exploit strategies. We develop 10 end-to-end exploits using a subset of CVEs against the kernel with all state-of-the-art mitigations enabled.Comment: 14 pages, in submission of the 31th ACM Conference on Computer and Communications Security (CCS), 202

Response of the nosZ-type denitrifying microbial community and metabolic characteristics to precipitation changes in the alpine wetland

The impact of climate change on the global hydrological cycle is becoming increasingly significant, with changes in precipitation patterns emerging as a key factor influencing the carbon and nitrogen cycling processes in alpine wetland ecosystems. However, the response of the nosZ-type denitrifying microbial community and its metabolic characteristics in the source wetland to precipitation changes remains unclear. In this study, high-throughput sequencing of the nosZ gene and LC-MS-based metabolomics were used to investigate the response of the nosZ-type denitrifying microbial community and its metabolic characteristics to precipitation changes (4 years) in the source wetland of Qinghai Lake. The results showed that Microvirga was the key bacterial group in the source wetland of Qinghai Lake, and Azospirillum was sensitive to changes in precipitation (P < 0.05). The 50% rainfall enhancement treatment significantly increased soil moisture, and the total carbon content showed an increasing trend with the increase in precipitation (P < 0.05). pH was the most important explanatory factor for community structure, while total nitrogen content was the key explanatory factor for community diversity. Deterministic processes dominated the assemblage of the nosZ-type denitrifying microbial community in the source wetland of Qinghai Lake. Soil metabolomics analysis showed that the differential metabolites in the Source Wetland mostly exhibited significant positive correlations. Precipitation changes significantly affected the relative abundance of N-Acetylaspartic acid. In summary, lower precipitation is more favorable for maintaining carbon storage in the source wetlands of Qinghai Lake. Precipitation variation disrupted the existing nitrogen balance within the ecosystem and altered the structure of the nosZ-type denitrifying microbial community and soil metabolic characteristics. These findings imply that climate change-driven shifts in precipitation patterns may impact carbon and nitrogen dynamics in alpine wetlands, alter ecosystem stability, and have profound effects on microbial communities and biogeochemical cycles

Basalt-polypropylene fiber reinforced concrete for durable and sustainable pipe production. Part 1: experimental program

This is the peer reviewed version of the following article: [ Deng, Z, Liu, X, Chen, P, et al. Basalt-polypropylene fiber reinforced concrete for durable and sustainable pipe production. Part 1: Experimental program. Structural Concrete. 2022; 23: 311– 327. https://doi.org/10.1002/suco.202000759], which has been published in final form at https://onlinelibrary.wiley.com/doi/abs/10.1002/suco.202000759. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving.An experimental program consisting in producing and testing reinforced concrete pipes (RCPs) under the three-edge bearing tests considering different types of reinforcement was carried out. Four types of RCPs were produced, these reinforced with: (1) polypropylene macrofibers; (2) basalt microfibers; (3) combination of both (hybrid reinforcement); and (4) plain concrete. The analysis of the crack patterns and both service and ultimate mechanical responses allowed concluding that the use of fibers do not lead to an effective increase of the first cracking load; however, both types of fibers allowed a better crack width control respect to the standard RCP. In this regard, basalt microfiber reinforced concrete led to a better response caused by concentrated loads (jacketing) whilst polypropylene macrofibers increased the concrete pipe performance in terms of bearing capacity and flexural crack control. The hybrid fiber reinforced concrete was found to be the most suitable alternative for increasing the load bearing capacity and the crack width control for service loads. These incipient experimental results permit to conclude that this type of hybrid basalt-polypropylene fiber reinforced concretes are an interesting alternative to traditional steel-cage RCPs.This work is supported by the National Key Research and Development Program of China (2018YFC1504802), Natural Science Foundation Project of Chongqing, Chongqing Science and Technology Commission (cstc2018jscxmszdX0071), Postgraduate Research Innovation Project of Chongqing (CYS19005, CYS18026). In addition, Prof. Albert de la Fuente also wants to express his gratitude to the Spanish Ministry of Science and Innovation for the financial support received under the scope of the project CREEF (PID2019-108978RB-C32).Peer ReviewedPostprint (author's final draft

Survival analysis of patients with hepatocellular carcinoma based on the ratio of platelet count to spleen diameter

BackgroundIn China, 80% of Hepatocellular Carcinoma (HCC) is associated with cirrhosis. Portal hypertension, the most common outcome of cirrhosis progression, has a high incidence. Platelet count/spleen diameter ratio (PSL) with a cut-off value of 909 can predict the presence of esophagogastric varices and thus portal hypertension, which is also an independent risk factor for early recurrence and late recurrence of hepatocellular carcinoma after resection. Therefore, the effect of PSL on the overall survival (OS) of patients with HCC is necessary. The aim of this study was to apply a new method to establish and validate a model for predicting the prognosis of patients based on PSL with HCC.MethodsA total of 1,104 patients with clinical diagnosed with HCC following non-surgical therapy randomly divided the patients into a primary cohort and a validation cohort in a ratio of 7:3, in which 772 HCC patients were in the primary cohort and a total of 332 HCC patients were in the validation cohort. Through Lasso-Cox analysis, the independent predictors of OS of training cohort were included in nomogram1, and the independent predictors of Cox regression analysis were included in nomogram2. Nomogram1 and nomogram2 used consistency index (C-index), AUC and time-dependent ROC curves in the training cohort, respectively, and the calibration curves were plotted. All suggest that nomogram1 is better than nomogram2. We get similar results in the validation cohort.ResultsThe C-index of nomogram1was 0.792 (95%CI: 0.772–0.812), which was superior to nomogram2 (0.788) and traditional modes (0.631–0.712). The AUC of nomogram1 was 0.866 (95%CI: 0.840–0.889). In the validation cohort, the nomogram1 still gave good discrimination (C-index: 0.769, 95%CI: 0.740–0.798; AUC: 0.867, 95%CI: 0.826–0.902). Calibration plots for 3-year OS probabilities showed the good agreement between nomogram1 predictions and actual observations. In addition, we found that the decision curve analysis of nomogram1 and nomogram2 was also meaningful.ConclusionNovel nomogram containing PSL, based on LASSO Cox regression, had higher predictive efficacy for 3-year overall survival in patients with HCC