An unfolded protein-induced conformational switch activates mammalian IRE1.

The unfolded protein response (UPR) adjusts the cell's protein folding capacity in the endoplasmic reticulum (ER) according to need. IRE1 is the most conserved UPR sensor in eukaryotic cells. It has remained controversial, however, whether mammalian and yeast IRE1 use a common mechanism for ER stress sensing. Here, we show that similar to yeast, human IRE1α's ER-lumenal domain (hIRE1α LD) binds peptides with a characteristic amino acid bias. Peptides and unfolded proteins bind to hIRE1α LD's MHC-like groove and induce allosteric changes that lead to its oligomerization. Mutation of a hydrophobic patch at the oligomerization interface decoupled peptide binding to hIRE1α LD from its oligomerization, yet retained peptide-induced allosteric coupling within the domain. Importantly, impairing oligomerization of hIRE1α LD abolished IRE1's activity in living cells. Our results provide evidence for a unifying mechanism of IRE1 activation that relies on unfolded protein binding-induced oligomerization

Joint UAV Placement and IRS Phase Shift Optimization in Downlink Networks

This study investigates the integration of an intelligent reflecting surface (IRS) into an unmanned aerial vehicle (UAV) platform to utilize the advantages of these leading technologies for sixth-generation communications, e.g., improved spectral and energy efficiency, extended network coverage, and flexible deployment. In particular, we investigate a downlink IRS-UAV system, wherein single-antenna ground users (UEs) are served by a multi-antenna base station (BS). To assist the communication between UEs and the BS, an IRS mounted on a UAV is deployed, in which the direct links are obstructed owing to the complex urban channel characteristics. The beamforming at the BS, phase shift at the IRS, and the 3D placement of the UAV are jointly optimized to maximize the sum rate. Because the optimization variables, particularly the beamforming and IRS phase shift, are highly coupled with each other, the optimization problem is naturally non-convex. To effectively solve the formulated problem, we propose an iterative algorithm that employs block coordinate descent and inner approximation methods. Numerical results demonstrate the effectiveness of our proposed approach for a UAV-mounted IRS system on the sum rate performance over the state-of-the-art technology using the terrestrial counterpart

EFFICIENCY AND RADIATIVE RECOMBINATION RATE ENHANCEMENT IN GAN/ALGAN MULTI-QUANTUM WELL-BASED ELECTRON BLOCKING LAYER FREE UV-LED FOR IMPROVED LUMINESCENCE

In this paper, an electron blocking layer (EBL) free GaN/AlGaN light emitting diode (LED) is designed using Atlas TCAD with graded composition in the quantum barriers of the active region. The device has a GaN buffer layer incorporated in a c-plane for better carrier transportation and low efficiency droop. The proposed LED has quantum barriers with aluminium composition graded from 20% to ~2% per triangular, whereas the conventional has square barriers. The resulted structures exhibit significantly reduced electron leakage and improved hole injection into the active region, thus generating higher radiative recombination. The simulation outcomes exhibit the highest internal quantum efficiency (IQE) (48.4%) indicating a significant rise compared to the conventional LED. The designed EBL free LED with graded quantum barrier structure acquires substantially minimized efficiency droop of ~7.72% at 60 mA. Our study shows that the proposed structure has improved radiative recombination by ~136.7%, reduced electron leakage, and enhanced optical power by ~8.084% at 60 mA injected current as compared to conventional GaN/AlGaN EBL LED structure

Optimal User Pairing Approach for NOMA-based Cell-free Massive MIMO Systems

This study investigates a non-orthogonal multiple access (NOMA)-assisted cell-free massive multiple-input multiple-output (MIMO) system, considering the impact of both individual and linear-combination channel estimations. To make the best use of NOMA as an enabler for cell-free massive MIMO systems, user pairing should be employed effectively. Random user pairing naturally leads to a non-optimal solution, whereas an exhaustive search approach is unfavorable for practical systems owing to the high complexity. In this study, we propose an optimal user pairing strategy to group users that jointly optimize the minimum downlink rate per user and power allocation at an acceptable cost of complexity. To address this problem, we first relax the binary variables to continuous variables and then develop an iterative algorithm based on the inner approximation method, yielding at least one locally optimal solution. Numerical results show that the proposed user pairing algorithm outperforms existing counterparts, such as conventional beamforming, random pairing, far pairing, and close-pairing strategies, while it can be performed dynamically, that is, two arbitrary users satisfying the formulated problem can be paired regardless of geographical distance. Finally, our approach demonstrates that the combination channel estimation-based NOMA-assisted cell-free massive MIMO achieves the best result in terms of the downlink rate per user when associated with the proposed algorithm

Effects of salinity and alkalinity on growth and survival of all-male giant freshwater prawn (Macrobrachium rosenbergii De Man, 1879) juveniles

All-male giant freshwater prawns (AMGFPs) have been a popular crop cultivated in the Mekong Delta, Vietnam, due to their proven production efficiency compared to all-female or mixed-sex prawn cultures. However, the crucial water quality factors impacting AMGFP aquaculture efficiency have yet to be elaborately investigated. Two separate experiments were randomly arranged with three replicates to evaluate the effects of salinity or alkalinity on the growth and survival of AMGFP juveniles during the grow-out period. The results show that the prawn survival rate in the salinity range of 0–15‰ varied from 66.1 to 74.8％ and in a salinity range of 0–5‰ was relatively low compared to the range of 10-15‰; however, the difference was not significant among salinities after 90 days of culture (p > 0.05). All the prawn growth performance parameters significantly decreased with increasing salinities of 0, 5, 10, and 15‰ after 30, 60, and 90 days of culture (p 0.05), and both were significantly higher than those at salinities of 10 and 15‰ (p < 0.05) after 90 days of culture. In addition, the survival rate reached 82.5–84.4％ and did not significantly differ among alkalinities of 80, 100, 120, 140, and 160 mgCaCO3 L−1. However, the growth performance parameters and yield of AMGFPs at an alkalinity of 160 mg L−1 were significantly higher than those at lower alkalinities (80, 100, 120, and 140 mg CaCO3 L−1) after 90 days of culture. Therefore, it is recommended that a salinity range of 0–5‰ and alkalinity of 160 mgCaCO3 L−1 is optimal for the growth-out culture of AMGFP juveniles

Caspase-11 Activation in Response to Bacterial Secretion Systems That Access the Host Cytosol

Inflammasome activation is important for antimicrobial defense because it induces cell death and regulates the secretion of IL-1 family cytokines, which play a critical role in inflammatory responses. The inflammasome activates caspase-1 to process and secrete IL-1β. However, the mechanisms governing IL-1α release are less clear. Recently, a non-canonical inflammasome was described that activates caspase-11 and mediates pyroptosis and release of IL-1α and IL-1β. Caspase-11 activation in response to Gram-negative bacteria requires Toll-like receptor 4 (TLR4) and TIR-domain-containing adaptor-inducing interferon-β (TRIF)-dependent interferon production. Whether additional bacterial signals trigger caspase-11 activation is unknown. Many bacterial pathogens use specialized secretion systems to translocate effector proteins into the cytosol of host cells. These secretion systems can also deliver flagellin into the cytosol, which triggers caspase-1 activation and pyroptosis. However, even in the absence of flagellin, these secretion systems induce inflammasome activation and the release of IL-1α and IL-1β, but the inflammasome pathways that mediate this response are unclear. We observe rapid IL-1α and IL-1β release and cell death in response to the type IV or type III secretion systems of Legionella pneumophila and Yersinia pseudotuberculosis. Unlike IL-1β, IL-1α secretion does not require caspase-1. Instead, caspase-11 activation is required for both IL-1α secretion and cell death in response to the activity of these secretion systems. Interestingly, whereas caspase-11 promotes IL-1β release in response to the type IV secretion system through the NLRP3/ASC inflammasome, caspase-11-dependent release of IL-1α is independent of both the NAIP5/NLRC4 and NLRP3/ASC inflammasomes as well as TRIF and type I interferon signaling. Furthermore, we find both overlapping and non-redundant roles for IL-1α and IL-1β in mediating neutrophil recruitment and bacterial clearance in response to pulmonary infection by L. pneumophila. Our findings demonstrate that virulent, but not avirulent, bacteria trigger a rapid caspase-11-dependent innate immune response important for host defense

GPX8 regulates clear cell renal cell carcinoma tumorigenesis through promoting lipogenesis by NNMT

Background Clear cell renal cell carcinoma (ccRCC), with its hallmark phenotype of high cytosolic lipid content, is considered a metabolic cancer. Despite the implication of this lipid-rich phenotype in ccRCC tumorigenesis, the roles and regulators of de novo lipid synthesis (DNL) in ccRCC remain largely unexplained. Methods Our bioinformatic screening focused on ccRCC-lipid phenotypes identified glutathione peroxidase 8 (GPX8), as a clinically relevant upstream regulator of DNL. GPX8 genetic silencing was performed with CRISPR-Cas9 or shRNA in ccRCC cell lines to dissect its roles. Untargeted metabolomics, RNA-seq analyses, and other biochemical assays (e.g., lipid droplets staining, fatty acid uptake, cell proliferation, xenograft, etc.) were carried out to investigate the GPX8s involvement in lipid metabolism and tumorigenesis in ccRCC. The lipid metabolic function of GPX8 and its downstream were also measured by isotope-tracing-based DNL flux measurement. Results GPX8 knockout or downregulation substantially reduced lipid droplet levels (independent of lipid uptake), fatty acid de novo synthesis, triglyceride esterification in vitro, and tumor growth in vivo. The downstream regulator was identified as nicotinamide N-methyltransferase (NNMT): its knockdown phenocopied, and its expression rescued, GPX8 silencing both in vitro and in vivo. Mechanically, GPX8 regulated NNMT via IL6-STAT3 signaling, and blocking this axis suppressed ccRCC survival by activating AMPK. Notably, neither the GPX8-NNMT axis nor the DNL flux was affected by the von Hippel Lindau (VHL) status, the conventional regulator of ccRCC high lipid content. Conclusions Taken together, our findings unravel the roles of the VHL-independent GPX8-NNMT axis in ccRCC lipid metabolism as related to the phenotypes and growth of ccRCC, which may be targeted for therapeutic purposes. Graphical abstractThe research was supported by the Basic Science Research Program (grant NRF-2018R1A3B1052328 to S.P.) funded by the Ministry of Science, Information and Communication Technology, by Future Planning through the National Research Foundation, and by the Basic Science Research Program through the National Research Foundation (NRF-2020R1I1A1A01073124 to J-M.K.) funded by the Ministry of Education of Korea

Mutations in TUBG1, DYNC1H1, KIF5C and KIF2A cause malformations of cortical development and microcephaly

The genetic causes of malformations of cortical development (MCD) remain largely unknown. Here we report the discovery of multiple pathogenic missense mutations in TUBG1, DYNC1H1 and KIF2A, as well as a single germline mosaic mutation in KIF5C, in subjects with MCD. We found a frequent recurrence of mutations in DYNC1H1, implying that this gene is a major locus for unexplained MCD. We further show that the mutations in KIF5C, KIF2A and DYNC1H1 affect ATP hydrolysis, productive protein folding and microtubule binding, respectively. In addition, we show that suppression of mouse Tubg1 expression in vivo interferes with proper neuronal migration, whereas expression of altered gamma-tubulin proteins in Saccharomyces cerevisiae disrupts normal microtubule behavior. Our data reinforce the importance of centrosomal and microtubule-related proteins in cortical development and strongly suggest that microtubule-dependent mitotic and postmitotic processes are major contributors to the pathogenesis of MCD

High Throughput, Multiplexed Pathogen Detection Authenticates Plague Waves in Medieval Venice, Italy

Background: Historical records suggest that multiple burial sites from the 14th-16(th) centuries in Venice, Italy, were used during the Black Death and subsequent plague epidemics.Methodology/Principal Findings: High throughput, multiplexed real-time PCR detected DNA of seven highly transmissible pathogens in 173 dental pulp specimens collected from 46 graves. Bartonella quintana DNA was identified in five (2.9%) samples, including three from the 16th century and two from the 15th century, and Yersinia pestis DNA was detected in three (1.7%) samples, including two from the 14th century and one from the 16th century. Partial glpD gene sequencing indicated that the detected Y. pestis was the Orientalis biotype.Conclusions: These data document for the first time successive plague epidemics in the medieval European city where quarantine was first instituted in the 14th century