CETSA-MS-based target profiling of anti-aging natural compound quercetin.

BACKGROUND: Quercetin is widely distributed in nature and abundant in the human diet, which exhibits diverse biological activities and potential medical benefits. However, there remains a lack of comprehensive understanding about its cellular targets, impeding its in-depth mechanistic studies and clinical applications. PURPOSE: This study aimed to profile protein targets of quercetin at the proteome level. METHODS: A label-free CETSA-MS proteomics technique was employed for target enrichment and identification. The R package Inflect was used for melting curve fitting and target selection. D3Pocket and LiBiSco tools were used for binding pocket prediction and binding pocket analysis. Western blotting, molecular docking, site-directed mutagenesis and pull-down assays were used for target verification and validation. RESULTS: We curated a library of direct binding targets of quercetin in cells. This library comprises 37 proteins that show increased thermal stability upon quercetin binding and 33 proteins that display decreased thermal stability. Through Western blotting, molecular docking, site-directed mutagenesis and pull-down assays, we validated CBR1 and GSK3A from the stabilized protein group and MAPK1 from the destabilized group as direct binding targets of quercetin. Moreover, we characterized the shared chemical properties of the binding pockets of quercetin with targets. CONCLUSION: Our findings deepen our understanding of the proteins pivotal to the bioactivity of quercetin and lay the groundwork for further exploration into its mechanisms of action and potential clinical applications.

Position-based anchor optimization for point supervised dense nuclei detection.

Nuclei detection is one of the most fundamental and challenging problems in histopathological image analysis, which can localize nuclei to provide effective computer-aided cancer diagnosis, treatment decision, and prognosis. The fully-supervised nuclei detector requires a large number of nuclei annotations on high-resolution digital images, which is time-consuming and needs human annotators with professional knowledge. In recent years, weakly-supervised learning has attracted significant attention in reducing the labeling burden. However, detecting dense nuclei of complex crowded distribution and diverse appearances remains a challenge. To solve this problem, we propose a novel point-supervised dense nuclei detection framework that introduces position-based anchor optimization to complete morphology-based pseudo-label supervision. Specifically, we first generate cellular-level pseudo labels (CPL) for the detection head via a morphology-based mechanism, which can help to build a baseline point-supervised detection network. Then, considering the crowded distribution of the dense nuclei, we propose a mechanism called Position-based Anchor-quality Estimation (PAE), which utilizes the positional deviation between an anchor and its corresponding point label to suppress low-quality detections far from each nucleus. Finally, to better handle the diverse appearances of nuclei, an Adaptive Anchor Selector (AAS) operation is proposed to automatically select positive and negative anchors according to morphological and positional statistical characteristics of nuclei. We conduct comprehensive experiments on two widely used benchmarks, MO and Lizard, using ResNet50 and PVTv2 as backbones. The results demonstrate that the proposed approach has superior capacity compared with other state-of-the-art methods. In particularly, in dense nuclei scenarios, our method can achieve 95.1% performance of the fully-supervised approach. The code is available at https://github.com/NucleiDet/DenseNucleiDet.

Shared metabolic shifts in endothelial cells in stroke and Alzheimer's disease revealed by integrated analysis.

Since metabolic dysregulation is a hallmark of both stroke and Alzheimer's disease (AD), mining shared metabolic patterns in these diseases will help to identify their possible pathogenic mechanisms and potential intervention targets. However, a systematic integration analysis of the metabolic networks of the these diseases is still lacking. In this study, we integrated single-cell RNA sequencing datasets of ischemic stroke (IS), hemorrhagic stroke (HS) and AD models to construct metabolic flux profiles at the single-cell level. We discovered that the three disorders cause shared metabolic shifts in endothelial cells. These altered metabolic modules were mainly enriched in the transporter-related pathways and were predicted to potentially lead to a decrease in metabolites such as pyruvate and fumarate. We further found that Lef1, Elk3 and Fosl1 may be upstream transcriptional regulators causing metabolic shifts and may be possible targets for interventions that halt the course of neurodegeneration.

Integrating single-nucleus sequence profiling to reveal the transcriptional dynamics of Alzheimer's disease, Parkinson's disease, and multiple sclerosis.

BACKGROUND: Alzheimer's disease (AD), Parkinson's disease (PD), and multiple sclerosis (MS) are three nervous system diseases that partially overlap clinically and genetically. However, bulk RNA-sequencing did not accurately detect the core pathogenic molecules in them. The availability of high-quality single cell RNA-sequencing data of post-mortem brain collections permits the generation of a large-scale gene expression in different cells in human brain, focusing on the molecular features and relationships between diseases and genes. We integrated single-nucleus RNA-sequencing (snRNA-seq) datasets of human brains with AD, PD, and MS to identify transcriptomic commonalities and distinctions among them. METHODS: The snRNA-seq datasets were downloaded from Gene Expression Omnibus (GEO) database. The Seurat package was used for snRNA-seq data processing. The uniform manifold approximation and projection (UMAP) were utilized for cluster identification. The FindMarker function in Seurat was used to identify the differently expressed genes. Functional enrichment analysis was carried out using the Gene Set Enrichment Analysis (GSEA) and Gene ontology (GO). The protein-protein interaction (PPI) analysis of differentially expressed genes (DEGs) was analyzed using STRING database ( http://string-db.org ). SCENIC analysis was performed using utilizing pySCENIC (v0.10.0) based on the hg19-tss-centered-10 kb-10species databases. The analysis of potential therapeutic drugs was analyzed on Connectivity Map ( https://clue.io ). RESULTS: The gene regulatory network analysis identified several hub genes regulated in AD, PD, and MS, in which HSPB1 and HSPA1A were key molecules. These upregulated HSP family genes interact with ribosome genes in AD and MS, and with immunomodulatory genes in PD. We further identified several transcriptional regulators (SPI1, CEBPA, TFE3, GRHPR, and TP53) of the hub genes, which has important implications for uncovering the molecular crosstalk among AD, PD, and MS. Arctigenin was identified as a potential therapeutic drug for AD, PD, and MS. CONCLUSIONS: Together, the integrated snRNA-seq data and findings have significant implications for unraveling the shared and unique molecular crosstalk among AD, PD, and MS. HSPB1 and HSPA1A as promising targets involved in the pathological mechanisms of neurodegenerative diseases. Additionally, the identification of arctigenin as a potential therapeutic drug for AD, PD, and MS further highlights its potential in treating these neurological disorders. These discoveries lay the groundwork for future research and interventions to enhance our understanding and treatment of AD, PD, and MS.

CircLDLRAD3 inhibits Oral squamous cell carcinoma progression by regulating miR-558/Smad4/TGF-ß.

Oral squamous cell carcinoma (OSCC) is a malignant neoplasm with high mortality and morbidity. The role of circRNA and its molecular mechanism in OSCC remains largely unknown. The study aims to explore the role of a novel circular RNA (circLDLRAD3) in OSCC and its underlying mechanism. PCR and fluorescence in situ hybridization were used to explore the expression features of circLDLRAD3 in OSCC. The effects of circLDLRAD3 on the behaviour of OSCC were investigated using CCK-8, colony formation assay, transwell and animal experiments. Bioinformatics analysis along with dual luciferase reporter assay and RIP assay were used to reveal the interaction between circLDLRAD3, miR-558 and Smad4. It was revealed that circLDLRAD3 exhibited low expression status in OSCC. CircLDLRAD3 inhibits proliferation, migration, and invasion of OSCC cells both in vitro and in vivo. Mechanistically, circLDLRAD3 could bind with miR-558 to positively regulate its target gene Smad4 expression. Rescue experiments further confirmed both miR-558 overexpression and Smad4 knockdown could reverse the influence of circLDLRAD3 on OSCC phenotypes. Moreover, circLDLRAD3 regulate the TGF-ß signalling pathways to influence EMT through miR-558/Smad4 axis. Our study found that circLDLRAD3 is downregulated in OSCC and verified its tumour suppressor function and mechanism in OSCC through sponging miR-558 to regulate miR-558/Smad4/TGF-ß axis. The characterization of such regulating network uncovers an important mechanism underlying OSCC progression, which could provide promising targets targeted therapy strategies for OSCC in the future.

Hybrid topological photonic crystals.

Topologically protected photonic edge states offer unprecedented robust propagation of photons that are promising for waveguiding, lasing, and quantum information processing. Here, we report on the discovery of a class of hybrid topological photonic crystals that host simultaneously quantum anomalous Hall and valley Hall phases in different photonic band gaps. The underlying hybrid topology manifests itself in the edge channels as the coexistence of the dual-band chiral edge states and unbalanced valley Hall edge states. We experimentally realize the hybrid topological photonic crystal, unveil its unique topological transitions, and verify its unconventional dual-band gap topological edge states using pump-probe techniques. Furthermore, we demonstrate that the dual-band photonic topological edge channels can serve as frequency-multiplexing devices that function as both beam splitters and combiners. Our study unveils hybrid topological insulators as an exotic topological state of photons as well as a promising route toward future applications in topological photonics.

Integration of microbiome and Koch's postulates to reveal multiple bacterial pathogens of whitish muscle syndrome in mud crab, Scylla paramamosain.

BACKGROUND: For more than a century, the Koch's postulates have been the golden rule for determining the causative agents in diseases. However, in cases of multiple pathogens-one disease, in which different pathogens can cause the same disease, the selection of microorganisms that regress infection is hard when Koch's postulates are applied. Microbiome approaches can obtain relatively complete information about disease-related microorganisms and can guide the selection of target microorganisms for regression infection. In the present study, whitish muscle syndrome (WMS) of Scylla paramamosain, which has typical symptoms with whitish muscle and blackened hemolymph was used as an example to establish a new research strategy that integrates microbiome approaches and Koch's postulates to determinate causative agents of multiple pathogens-one disease. RESULTS: Microbiome results revealed that Aeromonas, Acinetobacter, Shewanella, Chryseomicrobium, Exiguobacterium, Vibrio and Flavobacterium, and Kurtzmaniella in hemolymph were bacterial and fungal indicators for WMS. A total of 23 bacteria and 14 fungi were isolated from hemolymph and muscle tissues, and among the bacteria, Shewanella chilikensis, S. xiamenensis, Vibrio alginolyticus, S. putrefaciens, V. fluvialis, and V. parahaemolyticus were present in hemolymph and/or muscle tissues in each WMS crab, and the last three species were also present in three Healthy crabs. The target bacteria and fungi were further screened to regression infections based on two criteria: whether they belonged to the indicator genera for WMS, whether they were isolated from both hemolymph and muscle tissues in most WMS crabs. Only S. chilikensis, S. putrefaciens, S. xiamenensis, V. alginolyticus, V. fluvialis, and V. parahaemolyticus met both two criteria. The six bacteria that met both two criteria and six fungi and another bacterium that unmatched any of two criteria were used to perform regression infection experiments based on Koch's postulates. S. chilikensis, S. putrefaciens, S. xiamenensis, V. alginolyticus, V. fluvialis, and V. parahaemolyticus met both two criteria, and the results indicate that they cause WMS in crabs independently. CONCLUSIONS: This study fully demonstrated that our research strategy that integrates the microbiome and Koch's postulates can maximize the ability to catch pathogens in one net for the situation of multiple pathogens-one disease. Video Abstract.

Virome Analysis Provides an Insight into the Viral Community of Chinese Mitten Crab Eriocheir sinensis.

Recent advances in viromics have led to the discovery of a great diversity of RNA viruses and the identification of a large number of viral pathogens. A systematic exploration of viruses in Chinese mitten crab (Eriocheir sinensis), one of the most important aquatic commercial species, is still lacking. Here, we characterized the RNA viromes of asymptomatic, milky disease (MD)-affected, and hepatopancreatic necrosis syndrome (HPNS)-affected Chinese mitten crabs collected from 3 regions in China. In total, we identified 31 RNA viruses belonging to 11 orders, 22 of which were first reported here. By comparing viral composition between samples, we observed high variation in viral communities across regions, with most of the viral species being region-specific. We proposed to establish several novel viral families or genera based on the phylogenetic relationships and genome structures of viruses discovered in this study, expanding our knowledge of viral diversity in brachyuran crustaceans. IMPORTANCE High-throughput sequencing and meta-transcriptomic analysis provide us with an efficient tool to discover unknown viruses and explore the composition of viral communities in specific species. In this study, we investigated viromes in asymptomatic and diseased Chinese mitten crabs collected from three distant locations. We observed high regional variation in the composition of viral species, highlighting the importance of multi-location sampling. In addition, we classified several novel and ICTV-unclassified viruses based on their genome structures and phylogenetic relationships, providing a new perspective on current viral taxa.

Time-Reversal-Even Nonlinear Current Induced Spin Polarization.

We propose a time-reversal-even spin generation in second order of electric fields, which dominates the current induced spin polarization in a wide class of centrosymmetric nonmagnetic materials, and leads to a novel nonlinear spin-orbit torque in magnets. We reveal a quantum origin of this effect from the momentum space dipole of the anomalous spin polarizability. First-principles calculations predict sizable spin generations in several nonmagnetic hcp metals, in monolayer TiTe_{2}, and in ferromagnetic monolayer MnSe_{2}, which can be detected in experiment. Our work opens up the broad vista of nonlinear spintronics in both nonmagnetic and magnetic systems.

Meningeal immunity and neurological diseases: new approaches, new insights.

The meninges, membranes surrounding the central nervous system (CNS) boundary, harbor a diverse array of immunocompetent immune cells, and therefore, serve as an immunologically active site. Meningeal immunity has emerged as a key factor in modulating proper brain function and social behavior, performing constant immune surveillance of the CNS, and participating in several neurological diseases. However, it remains to be determined how meningeal immunity contributes to CNS physiology and pathophysiology. With the advances in single-cell omics, new approaches, such as single-cell technologies, unveiled the details of cellular and molecular mechanisms underlying meningeal immunity in CNS homeostasis and dysfunction. These new findings contradict some previous dogmas and shed new light on new possible therapeutic targets. In this review, we focus on the complicated multi-components, powerful meningeal immunosurveillance capability, and its crucial involvement in physiological and neuropathological conditions, as recently revealed by single-cell technologies.

Single-cell transcriptional profiling of hearts during cardiac hypertrophy reveals the role of MAMs in cardiomyocyte subtype switching.

Pathological cardiac hypertrophy is the main predecessor of heart failure. Its pathology is sophisticated, and its progression is associated with multiple cellular processes. To explore new therapeutic approaches, more precise examination of cardiomyocyte subtypes and involved biological processes is required in response to hypertrophic stimuli. Mitochondria and the endoplasmic reticulum (ER) are two crucial organelles associated with the progression of cardiac hypertrophy and are connected through junctions known as mitochondria-associated endoplasmic reticulum membranes (MAMs). Although MAM genes are altered in cardiac hypertrophy, the importance of MAMs in cardiac hypertrophy and the expression pattern of MAMs in certain cardiac cell types require a comprehensive analysis. In this study, we analyzed the temporal expression of MAM proteins in the process of cardiac hypertrophy and observed that MAM-related proteins preferentially accumulated in cardiomyocytes at the initial stage of cardiac hypertrophy and underwent a gradual decline, which was synchronized with the proportion of two cardiomyocyte subtypes (CM2 and CM3). Meanwhile, these subtypes went through a functional switch during cardiac hypertrophy. Trajectory analysis suggested that there was a differentiation trajectory of cardiomyocyte subtypes from high to low MAM protein expression. Distinct regulon modules across different cardiomyocyte cell types were revealed by transcriptional regulatory network analysis. Furthermore, scWGCNA revealed that MAM-related genes were clustered into a module that correlated with diabetic cardiomyopathy. Altogether, we identified cardiomyocyte subtype transformation and the potential critical transcription factors involved, which may serve as therapeutic targets in combating cardiac hypertrophy.

Single-nucleus transcriptional profiling uncovers the reprogrammed metabolism of astrocytes in Alzheimer's disease.

Astrocytes play an important role in the pathogenesis of Alzheimer's disease (AD). It is widely involved in energy metabolism in the brain by providing nutritional and metabolic support to neurons; however, the alteration in the metabolism of astrocytes in AD remains unknown. Through integrative analysis of single-nucleus sequencing datasets, we revealed metabolic changes in various cell types in the prefrontal cortex of patients with AD. We found the depletion of some important metabolites (acetyl-coenzyme A, aspartate, pyruvate, 2-oxoglutarate, glutamine, and others), as well as the inhibition of some metabolic fluxes (glycolysis and tricarbocylic acid cycle, glutamate metabolism) in astrocytes of AD. The abnormality of glutamate metabolism in astrocytes is unique and important. Downregulation of GLUL (GS) and GLUD1 (GDH) may be the cause of glutamate alterations in astrocytes in AD. These results provide a basis for understanding the characteristic changes in astrocytes in AD and provide ideas for the study of AD pathogenesis.

GGC repeat expansion in NOTCH2NLC induces dysfunction in ribosome biogenesis and translation.

GGC repeat expansion in the 5' untranslated region (UTR) of NOTCH2NLC is associated with a broad spectrum of neurological disorders, especially neuronal intranuclear inclusion disease (NIID). Studies have found that GGC repeat expansion in NOTCH2NLC induces the formation of polyglycine (polyG)-containing protein, which is involved in the formation of neuronal intranuclear inclusions. However, the mechanism of neurotoxicity induced by NOTCH2NLC GGC repeats is unclear. Here, we used NIID patient-specific induced pluripotent stem cell (iPSC)-derived 3D cerebral organoids (3DCOs) and cellular models to investigate the pathophysiological mechanisms of NOTCH2NLC GGC repeat expansion. IPSC-derived 3DCOs and cellular models showed the deposition of polyG-containing intranuclear inclusions. The NOTCH2NLC GGC repeats could induce the upregulation of autophagic flux, enhance integrated stress response and activate EIF2α phosphorylation. Bulk RNA sequencing for iPSC-derived neurons and single-cell RNA sequencing (scRNA-seq) for iPSC-derived 3DCOs revealed that NOTCH2NLC GGC repeats may be associated with dysfunctions in ribosome biogenesis and translation. Moreover, NOTCH2NLC GGC repeats could induce the NPM1 nucleoplasm translocation, increase nucleolar stress, impair ribosome biogenesis and induce ribosomal RNA sequestration, suggesting dysfunction of membraneless organelles in the NIID cellular model. Dysfunctions in ribosome biogenesis and phosphorylated EIF2α and the resulting increase in the formation of G3BP1-positive stress granules may together lead to whole-cell translational inhibition, which may eventually cause cell death. Interestingly, scRNA-seq revealed that NOTCH2NLC GGC repeats may be associated with a significantly decreased proportion of immature neurons while 3DCOs were developing. Together, our results underscore the value of patient-specific iPSC-derived 3DCOs in investigating the mechanisms of polyG diseases, especially those caused by repeats in human-specific genes.

Homocysteine impedes neurite outgrowth recovery after intracerebral haemorrhage by downregulating pCAMK2A.

Hyperhomocysteinemia (HHcy) is independently associated with poorer long-term prognosis in patients with intracerebral haemorrhage (ICH); however, the effect and mechanisms of HHcy on ICH are still unclear. Here, we evaluated neurite outgrowth and neurological functional recovery using simulated models of ICH with HHcy in vitro and in vivo. We found that the neurite outgrowth velocity and motor functional recovery in the ICH plus HHcy group were significantly slower than that in the control group, indicating that homocysteine (Hcy) significantly impedes the neurite outgrowth recovery after ICH. Furthermore, phosphoproteomic data and signalome analysis of perihematomal brain tissues suggested that calmodulin-dependent protein kinases 2 (CAMK2A) kinase substrate pairs were significantly downregulated in ICH with HHcy compared with autologous blood injection only, both western blot and immunofluorescence staining confirmed this finding. Additionally, upregulation of pCAMK2A significantly increased neurite outgrowth recovery in ICH with HHcy. Collectively, we clarify the mechanism of HHcy-hindered neurite outgrowth recovery, and pCAMK2A may serve as a therapeutic strategy for promoting neurological recovery after ICH.

Virome Analysis of Normal and Growth Retardation Disease-Affected Macrobrachium rosenbergii.

The giant freshwater prawn, Macrobrachium rosenbergii, is an important aquaculture species in China. Growth retardation disease (GRD) is a common contagious disease in M. rosenbergii, resulting in slow growth and precocious puberty in prawns, and has caused growing economic losses in the M. rosenbergii industry. To investigate the viral diversity of M. rosenbergii and identify potentially high-risk viruses linked to GRD, virome analysis of the GRD-affected and normal M. rosenbergii was carried out using next-generation sequencing (NGS). A total of 327 contigs (>500 bp) were related to viral sequences belonging to 23 families/orders and a group of unclassified viruses. The majority of the viral contigs in M. rosenbergii belonged to the order Picornavirales, with the Solinviviridae family being the most abundant in both the diseased and normal groups. Furthermore, 16 RNA viral sequences with nearly complete genomes were characterized and phylogenetically analyzed, belonging to the families Solinviviridae, Flaviviridae, Polycipiviridae, Marnaviridae, and Dicistroviridae as well as three new clades of the order Picornavirales. Notably, the cross-species transmission of a picorna-like virus was observed between M. rosenbergii and plants. The "core virome" seemed to be present in the diseased and normal prawns. Still, a clear difference in viral abundance was observed between the two groups. These results showed that the broad diversity of viruses is present in M. rosenbergii and that the association between viruses and disease of M. rosenbergii needs to be further investigated. IMPORTANCE Growth retardation disease (GRD) has seriously affected the development and economic growth of the M. rosenbergii aquaculture industry. Our virome analysis showed that diverse viral sequences were present in M. rosenbergii, significantly expanding our knowledge of viral diversity in M. rosenbergii. Some differences in viral composition were noted between the diseased and normal prawns, indicating that some viruses become more abundant in occurrences or outbreaks of diseases. In the future, more research will be needed to determine which viruses pose a risk for M. rosenbergii. Our study provides important baseline information contributing to disease surveillance and risk assessment in M. rosenbergii aquaculture.

Possible realization of optical Dirac points in woodpile photonic crystals.

The simulation of fermionic relativistic physics, e.g., Dirac and Weyl physics, has led to the discovery of many unprecedented phenomena in photonics, of which the optical-frequency realization is, however, still challenging. Here, surprisingly, we discover that the woodpile photonic crystals commonly used for optical frequency applications host exotic fermion-like relativistic degeneracies: a Dirac nodal line and a fourfold quadratic point, as protected by the nonsymmorphic crystalline symmetry. Deforming the woodpile photonic crystal leads to the emergence of type-II Dirac points from the fourfold quadratic point. Such type-II Dirac points can be detected by its anomalous refraction property which is manifested as a giant birefringence in a slab setup. Our findings provide a promising route towards 3D optical Dirac physics in all-dielectric photonic crystals.

Generalized Weakly Supervised Object Localization.

With the goal of learning to localize specific object semantics using the low-cost image-level annotation, weakly supervised object localization (WSOL) has been receiving increasing attention in recent years. Although existing literatures have studied a number of major issues in this field, one important yet challenging scenario, where the test object semantics may appear in the training phase (seen categories) or never been observed before (unseen categories), is still beyond the exploration of the existing works. We define this scenario as the generalized WSOL (GWSOL) and make a pioneering effort to study it in this article. By leveraging attribute vectors to associate seen and unseen categories, we involve threefold modeling components, i.e., the class-sensitive modeling, semantic-agnostic modeling, and content-aware modeling, into a unified end-to-end learning framework. Such design enables our model to recognize and localize unconstrained object semantics, learn compact and discriminative features that could represent the potential unseen categories, and customize content-aware attribute weights to avoid localizing on misleading attribute elements. To advance this research direction, we contribute the bounding-box manual annotations to the widely used AwA2 dataset and benchmark the GWSOL methods. Comprehensive experiments demonstrate the effectiveness of our proposed learning framework and each of the considered modeling components.

The microbiome and its association with antibiotic resistance genes in the hadal biosphere at the Yap Trench.

The hadal biosphere, the deepest part of the ocean, is known as the least-explored aquatic environment and hosts taxonomically diverse microbial communities. However, the microbiome and its association with antibiotic resistance genes (ARGs) in the hadal ecosystem remain unknown. Here, we profiled the microbiome diversity and ARG occurrence in seawater and sediments of the Yap Trench (YT) using metagenomic sequencing. Within the prokaryote (bacteria and archaea) lineages, the main components of bacteria were Gammaproteobacteria (77.76 %), Firmicutes (8.36 %), and Alphaproteobacteria (2.25 %), whereas the major components of archaea were Nitrososphaeria (6.51 %), Nanoarchaeia (0.42 %), and Thermoplasmata (0.25 %), respectively. Taxonomy of viral contigs showed that the classified viral communities in YT seawater and sediments were dominated by Podoviridae (45.96 %), Siphoviridae (29.41 %), and Myoviridae (24.63 %). A large majority of viral contigs remained uncharacterized and exhibited endemicity. A total of 48 ARGs encoding resistance to 12 antibiotic classes were identified and their hosts were bacteria and viruses. Novel ARG subtypes mexFYTV-1, mexFYTV-2, mexFYTV-3, vanRYTV-1, vanSYTV-1 (carried by unclassified viruses), and bacAYTB-1 (carried by phylum Firmicutes) were detected in seawater samples. Overall, our findings imply that the hadal environment of the YT is a repository of viral and ARG diversity.

Open Search-Based Proteomics Reveals Widespread Tryptophan Modifications Associated with Hypoxia in Lung Cancer.

The tryptophan residue has a large hydrophobic surface that plays a unique role in the folded protein conformation and functions. Tryptophan modifications are presumably to be readily detected in proteins due to the vulnerability of the indole structure to electrophilic attacks. In this study, we report a systematic identification of sequence variations at tryptophan, termed tryptophan variants, from the proteome of patients with nonsmall cell lung cancer (NSCLC). Using shotgun proteomics and a modified open search algorithm, 25 tryptophan variants on 2481 sites in over 858 proteins were identified. Among these, 6 tryptophan variants are previously identified, 15 are newly annotated, and 4 are still unknown, most of which are involved in the cascade of oxidation in the blood microparticle. Remarkably, Trp313 of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) was up-oxidized whereas Trp16 and Trp38 of hemoglobin (HBB) were down-oxidized in NCSLC tissues. The results were further supported by an independent cohort of 103 lung adenocarcinoma samples, reflecting a negative feedback and potential detoxification mechanism against tumor glycolysis and hypoxia. Overall, the study reports a quick approach to explore tryptophan variants at the proteomic scale. Our findings highlight the predominant role of tryptophan oxidation in regulating the redox balance of cancer cells and its potential role as prognostic biomarker for patients with NSCLC.

Enhancing the Photoelectrochemical Hydrogen Evolution Reaction through Nanoscrolling of Two-Dimensional Material Heterojunctions.

The clean production of hydrogen from water using sunlight has emerged as a sustainable alternative toward large-scale energy generation and storage. However, designing photoactive semiconductors that are suitable for both light harvesting and water splitting is a pivotal challenge. Atomically thin transition metal dichalcogenides (TMD) are considered as promising photocatalysts because of their wide range of available electronic properties and compositional variability. However, trade-offs between carrier transport efficiency, light absorption, and electrochemical reactivity have limited their prospects. We here combine two approaches that synergistically enhance the efficiency of photocarrier generation and electrocatalytic efficiency of two-dimensional (2D) TMDs. The arrangement of monolayer WS2 and MoS2 into a heterojunction and subsequent nanostructuring into a nanoscroll (NS) yields significant modifications of fundamental properties from its constituents. Spectroscopic characterization and ab initio simulation demonstrate the beneficial effects of straining and wall interactions on the band structure of such a heterojunction-NS that enhance the electrochemical reaction rate by an order of magnitude compared to planar heterojunctions. Phototrapping in this NS further increases the light-matter interaction and yields superior photocatalytic performance compared to previously reported 2D material catalysts and is comparable to noble-metal catalyst systems in the photoelectrochemical hydrogen evolution reaction (PEC-HER) process. Our approach highlights the potential of morphologically varied TMD-based catalysts for PEC-HER.