Identification of PPAR-related differentially expressed genes liver hepatocellular carcinoma and construction of a prognostic model based on data analysis and molecular docking.

Liver hepatocellular carcinoma (LIHC) is a significant global health issue with limited treatment options. In this study, single-cell RNA sequencing (scRNA-seq) data were used to explore the molecular mechanisms of LIHC development and identify potential targets for therapy. The expression of peroxisome proliferator-activated receptors (PPAR)-related genes was analysed in LIHC samples, and primary cell populations, including natural killer cells, T cells, B cells, myeloid cells, endothelial cells, fibroblasts and hepatocytes, were identified. Analysis of the differentially expressed genes (DEGs) between normal and tumour tissues revealed significant changes in gene expression in various cell populations. PPAR activity was evaluated using the 'AUCell' R software, which indicated higher scores in the normal versus the malignant hepatocytes. Furthermore, the DEGs showed significant enrichment of pathways related to lipid and glucose metabolism, cell development, differentiation and inflammation. A prognostic model was then constructed using 8 PPARs-related genes, including FABP5, LPL, ACAA1, PPARD, FABP4, PLIN1, HMGCS2 and CYP7A1, identified using least absolute shrinkage and selection operator-Cox regression analysis, and validated in the TCGA-LIHC, ICGI-LIRI and GSE14520 datasets. Patients with low-risk scores had better prognosis in all cohorts. Based on the expression of the eight model genes, two clusters of patients were identified by ConsensusCluster analysis. We also predicted small-molecule drugs targeting the model genes, and identified perfluorohexanesulfonic acid, triflumizole and perfluorononanoic acid as potential candidates. Finally, wound healing assay confirmed that PPARD can promote the migration of liver cancer cells. Overall, our study offers novel perspectives on the molecular mechanisms of LIHC and potential areas for therapeutic intervention, which may facilitate the development of more effective treatment regimens.

Challenges and Breakthroughs in Enhancing Temperature Tolerance of Sodium-Ion Batteries.

Lithium-based batteries (LBBs) are highly researched and recognized as a mature electrochemical energy storage (EES) system in recent years. However, their stability and effectiveness are primarily confined to room temperature conditions. At temperatures significantly below 0 °C or above 60 °C, LBBs experience substantial performance degradation. Under such challenging extreme contexts, sodium-ion batteries (SIBs) emerge as a promising complementary technology, distinguished by their fast dynamics at low temperature region and superior safety under elevated temperatures. Notably, developing SIBs suitable for wide-temperature usage still presents significant challenges, particularly for specific applications such as electric vehicles, renewable energy storage, and deep-space/polar explorations, which requires a thorough understanding of how SIBs perform under different temperature conditions. By reviewing the development of wide-temperature SIBs, we systematically and comprehensively analyze the influence of temperature on the parameters related to battery performance, such as reaction constant, charge transfer resistance, etc. The review emphasizes challenges encountered by SIBs in both low and high temperatures while exploring recent advancements in SIB materials, specifically focusing on strategies to enhance battery performance across diverse temperature ranges. Overall, insights gained from these studies will drive the development of SIBs that can handle the challenges posed by diverse and harsh climates. This article is protected by copyright. All rights reserved.

T cell activation contributes to purifying selection against the MELAS-associated m.3243A>G pathogenic variant in blood.

T cells have been shown to maintain a lower percentage (heteroplasmy) of the pathogenic m.3243A>G variant (MT-TL1, associated with maternally inherited diabetes and deafness [MIDD] and mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes [MELAS]). The mechanism(s) underlying this purifying selection, however, remain unknown. Here we report that purified patient memory CD4+ T cells have lower bulk m.3243A>G heteroplasmy compared to naïve CD4+ T cells. In vitro activation of naïve CD4+ m.3243A>G patient T cells results in lower bulk m.3243A>G heteroplasmy after proliferation. Finally, m.3243A>G patient T cell receptor repertoire sequencing reveals relative oligoclonality compared to controls. These data support a role for T cell activation in peripheral, purifying selection against high m.3243A>G heteroplasmy T cells at the level of the cell, in a likely cell-autonomous fashion.

Eleven species of jumping spiders from Sichuan, Xizang, and Yunnan, China (Araneae, Salticidae).

Ten new species of jumping spiders are described from China, including Attulusjimanisp. nov. (♂♀) from Yunnan, Colaxescibagousp. nov. (♂♀), Epeuspengisp. nov. (♂♀), Evarchazayusp. nov. (♂♀), Iciuszangsp. nov. (♂♀), Pancoriusnyingchisp. nov. (♂♀), Stertiniusliqingaesp. nov. (♂♀), and Synagelidesmedogsp. nov. (♀) from Xizang, S.tianquansp. nov. (♂♀), and Yaginumaellaerlangsp. nov. (♂♀) from Sichuan. The hitherto unknown female of Phintellalongapophysis Lei & Peng, 2013 is described for the first time. Diagnostic photos and the distributional maps for all species are provided. Four new combinations are proposed: Epeusdilucidus (Próchniewicz, 1990), comb. nov., and E.guangxi (Peng & Li, 2002), comb. nov. transferred from Plexippoides Prószynski, 1984, Phintellasufflava (Jastrzebski, 2009), comb. nov. transferred from Carrhotus Thorell, 1891, and Yaginumaellaarmata (Jastrzebski, 2011), comb. nov. transferred from Pancorius Simon, 1902.

Coordinated Immune Cell Networks in the Bone Marrow Microenvironment Define the Graft versus Leukemia Response with Adoptive Cellular Therapy.

Understanding how intra-tumoral immune populations coordinate to generate anti-tumor responses following therapy can guide precise treatment prioritization. We performed systematic dissection of an established adoptive cellular therapy, donor lymphocyte infusion (DLI), by analyzing 348,905 single-cell transcriptomes from 74 longitudinal bone-marrow samples of 25 patients with relapsed myeloid leukemia; a subset was evaluated by protein-based spatial analysis. In acute myelogenous leukemia (AML) responders, diverse immune cell types within the bone-marrow microenvironment (BME) were predicted to interact with a clonally expanded population of ZNF683 + GZMB + CD8+ cytotoxic T lymphocytes (CTLs) which demonstrated in vitro specificity for autologous leukemia. This population, originating predominantly from the DLI product, expanded concurrently with NK and B cells. AML nonresponder BME revealed a paucity of crosstalk and elevated TIGIT expression in CD8+ CTLs. Our study highlights recipient BME differences as a key determinant of effective anti-leukemia response and opens new opportunities to modulate cell-based leukemia-directed therapy.

Deep convolutional network-based chest radiographs screening model for pneumoconiosis.

Background: Pneumoconiosis is the most important occupational disease all over the world, with high prevalence and mortality. At present, the monitoring of workers exposed to dust and the diagnosis of pneumoconiosis rely on manual interpretation of chest radiographs, which is subjective and low efficiency. With the development of artificial intelligence technology, a more objective and efficient computer aided system for pneumoconiosis diagnosis can be realized. Therefore, the present study reported a novel deep learning (DL) artificial intelligence (AI) system for detecting pneumoconiosis in digital frontal chest radiographs, based on which we aimed to provide references for radiologists. Methods: We annotated 49,872 chest radiographs from patients with pneumoconiosis and workers exposed to dust using a self-developed tool. Next, we used the labeled images to train a convolutional neural network (CNN) algorithm developed for pneumoconiosis screening. Finally, the performance of the trained pneumoconiosis screening model was validated using a validation set containing 495 chest radiographs. Results: Approximately, 51% (25,435/49,872) of the chest radiographs were labeled as normal. Pneumoconiosis was detected in 49% (24,437/49,872) of the labeled radiographs, among which category-1, category-2, and category-3 pneumoconiosis accounted for 53.1% (12,967/24,437), 20.4% (4,987/24,437), and 26.5% (6,483/24,437) of the patients, respectively. The CNN DL algorithm was trained using these data. The validation set of 495 digital radiography chest radiographs included 261 cases of pneumoconiosis and 234 cases of non-pneumoconiosis. As a result, the accuracy of the AI system for pneumoconiosis identification was 95%, the area under the curve was 94.7%, and the sensitivity was 100%. Conclusion: DL algorithm based on CNN helped screen pneumoconiosis in the chest radiographs with high performance; thus, it could be suitable for diagnosing pneumoconiosis automatically and improve the efficiency of radiologists.

Integrative genotyping of cancer and immune phenotypes by long-read sequencing.

Single-cell transcriptomics has become the definitive method for classifying cell types and states, and can be augmented with genotype information to improve cell lineage identification. Due to constraints of short-read sequencing, current methods to detect natural genetic barcodes often require cumbersome primer panels and early commitment to targets. Here we devise a flexible long-read sequencing workflow and analysis pipeline, termed nanoranger, that starts from intermediate single-cell cDNA libraries to detect cell lineage-defining features, including single-nucleotide variants, fusion genes, isoforms, sequences of chimeric antigen and TCRs. Through systematic analysis of these classes of natural 'barcodes', we define the optimal targets for nanoranger, namely those loci close to the 5' end of highly expressed genes with transcript lengths shorter than 4 kB. As proof-of-concept, we apply nanoranger to longitudinal tracking of subclones of acute myeloid leukemia (AML) and describe the heterogeneous isoform landscape of thousands of marrow-infiltrating immune cells. We propose that enhanced cellular genotyping using nanoranger can improve the tracking of single-cell tumor and immune cell co-evolution.

Two new species of Amaurobius C. L. Koch, 1837 (Araneae, Amaurobiidae) from Sichuan Province, China.

In this paper, two new species of the genus Amaurobius C. L. Koch, 1837 of the family Amaurobiidae Thorell, 1869 are reported from Sichuan Province, China: A. danba Lin & Li, sp. nov. () and A. yaan Lin & Li, sp. nov. (). Photos and morphological descriptions of the new species are presented; the type specimens of the new species are deposited in the Institute of Zoology, Chinese Academy of Sciences (IZCAS), Beijing.

Indian monsoon drove the dispersal of the thoracica group of Scytodes spitting spiders.

We examined the global biogeography of the Scytodes thoracica group of spitting spiders based on 23 years of sampling at the species level (61 species in the thoracica group and 84 species of Scytodes) using DNA data from six loci. Our results indicated that the thoracica group initially dispersed from Southeast Asia to East Africa between 46.5 and 33.0 million years ago, and dispersal events intensified between Southeast/South Asia and East/South Africa from the early to late Miocene. The timing of these events indicates that Asian-African faunal exchange of the thoracica group was driven by the Indian monsoon, and the pattern of dispersal suggests that colonialization took root when the Indian monsoon shifted from a North-South direction to an East-West direction from the middle Eocene.

Dictionary of immune responses to cytokines at single-cell resolution.

Cytokines mediate cell-cell communication in the immune system and represent important therapeutic targets1-3. A myriad of studies have highlighted their central role in immune function4-13, yet we lack a global view of the cellular responses of each immune cell type to each cytokine. To address this gap, we created the Immune Dictionary, a compendium of single-cell transcriptomic profiles of more than 17 immune cell types in response to each of 86 cytokines (>1,400 cytokine-cell type combinations) in mouse lymph nodes in vivo. A cytokine-centric view of the dictionary revealed that most cytokines induce highly cell-type-specific responses. For example, the inflammatory cytokine interleukin-1ß induces distinct gene programmes in almost every cell type. A cell-type-centric view of the dictionary identified more than 66 cytokine-driven cellular polarization states across immune cell types, including previously uncharacterized states such as an interleukin-18-induced polyfunctional natural killer cell state. Based on this dictionary, we developed companion software, Immune Response Enrichment Analysis, for assessing cytokine activities and immune cell polarization from gene expression data, and applied it to reveal cytokine networks in tumours following immune checkpoint blockade therapy. Our dictionary generates new hypotheses for cytokine functions, illuminates pleiotropic effects of cytokines, expands our knowledge of activation states of each immune cell type, and provides a framework to deduce the roles of specific cytokines and cell-cell communication networks in any immune response.

Multi-Ion Engineering Strategies toward High Performance Aqueous Zinc-Based Batteries.

As alternatives to batteries with organic electrolytes, aqueous zinc-based batteries (AZBs) have been intensively studied. However, the sluggish kinetics, side reactions, structural collapse, and dissolution of the cathode severely compromise the commercialization of AZBs. Among various strategies to accelerate their practical applications, multi-ion engineering shows great feasibility to maintain the original structure of the cathode and provide sufficient energy density for high-performance AZBs. Though multi-ion engineering strategies could solve most of the problems encountered by AZBs and show great potential in achieving practical AZBs, the comprehensive summaries of the batteries undergo electrochemical reactions involving more than one charge carrier is still in deficiency. The ambiguous nomenclature and classification are becoming the fountainhead of confusion and chaos. In this circumstance, this review overviews all the battery configurations and the corresponding reaction mechanisms are investigated in the multi-ion engineering of aqueous zinc-based batteries. By combing through all the reported works, this is the first to nomenclate the different configurations according to the reaction mechanisms of the additional ions, laying the foundation for future unified discussions. The performance enhancement, fundamental challenges, and future developing direction of multi-ion strategies are accordingly proposed, aiming to further accelerate the pace to achieve the commercialization of AZBs with high performance.

Multilevel Gradient-Ordered Silicon Anode with Unprecedented Sodium Storage.

While cost-effective sodium-ion batteries (SIBs) with crystalline silicon anodes promise high theoretical capacities, they perform poorly because silicon stores sodium ineffectively (capacity <40 mAh g-1 ). To address this issue, herein an atomic-order structural-design tactic is adopted for obtaining unique multilevel gradient-ordered silicon (MGO-Si) by simple electrochemical reconstruction. In situ-formed short-range-, medium-range-, and long-range-ordered structures construct a stable MGO-Si, which contributes to favorable Na-Si interaction and fast ion diffusion channels. These characteristics afford a high reversible capacity (352.7 mAh g-1 at 50 mA g-1 ) and stable cycling performance (95.2% capacity retention after 4000 cycles), exhibiting record values among those reported for pure silicon electrodes. Sodium storage of MGO-Si involves an adsorption-intercalation mechanism, and a stepwise construction strategy of gradient-ordered structure further improves the specific capacity (339.5 mAh g-1 at 100 mA g-1 ). Reconstructed Si/C composites show a high reversible capacity of 449.5 mAh g-1 , significantly better than most carbonaceous anodes. The universality of this design principle is demonstrated for other inert or low-capacity materials (micro-Si, SiO2 , SiC, graphite, and TiO2 ), boosting their capacities by 1.5-6 times that of pristine materials, thereby providing new solutions to facilitate sodium storage capability for better-performing battery designs.

Description of the unknown male of Vappolotestianjiayu Li, Zhao & Li, 2023 (Araneae, Agelenidae, Coelotinae) from China.

Background: Vappolotes Zhao & Li, 2019 is one of the troglophilous genera, with five known species. The previous description of V.tianjiayu from China was based solely on female specimens collected from caves in the Wuling Mountains in southern China without any males. New information: The present study, deals with the first record of the male of V.tianjiayu from its type locality: Guluo Cave. The validation of species is based on the morphological characteristics of both male and female.

[Advances in revision surgery after primary total hip arthroplasty for Crowe type â £ developmental dysplasia of the hip].

Objective: To review research advances of revision surgery after primary total hip arthroplasty (THA) for patients with Crowe type Ⅳ developmental dysplasia of the hip (DDH). Methods: The recent literature on revision surgery after primary THA in patients with Crowe type Ⅳ DDH was reviewed. The reasons for revision surgery were analyzed and the difficulties of revision surgery, the management methods, and the related prosthesis choices were summarized. Results: Patients with Crowe type Ⅳ DDH have small anteroposterior diameter of the acetabulum, large variation in acetabular and femoral anteversion angles, severe soft tissue contractures, which make both THA and revision surgery more difficult. There are many reasons for patients undergoing revision surgery after primary THA, mainly due to aseptic loosening of the prosthesis. Therefore, it is necessary to restore anatomical structures in primary THA, as much as possible and reduce the generation of wear particles to avoid postoperative loosening of the prosthesis. Due to the anatomical characteristics of Crowe type Ⅳ DDH, the patients have acetabular and femoral bone defects, and the repair and reconstruction of bone defects become the key to revision surgery. The acetabular side is usually reconstructed with the appropriate acetabular cup or combined metal block, Cage, or custom component depending on the extent of the bone defect, while the femoral side is preferred to the S-ROM prosthesis. In addition, the prosthetic interface should be ceramic-ceramic or ceramic-highly cross-linked polyethylene wherever possible. Conclusion: The reasons leading to revision surgery after primary THA in patients with Crowe type Ⅳ DDH and the surgical difficulties have been clarified, and a large number of clinical studies have proposed corresponding revision modalities based on which good early- and mid-term outcomes have been obtained, but further follow-up is needed to clarify the long-term outcomes. With technological advances and the development of new materials, personalized prostheses for these patients are expected to become a reality.

Single-cell transcriptomics reveals the brain evolution of web-building spiders.

Spiders are renowned for their efficient capture of flying insects using intricate aerial webs. How the spider nervous systems evolved to cope with this specialized hunting strategy and various environmental clues in an aerial space remains unknown. Here we report a brain-cell atlas of >30,000 single-cell transcriptomes from a web-building spider (Hylyphantes graminicola). Our analysis revealed the preservation of ancestral neuron types in spiders, including the potential coexistence of noradrenergic and octopaminergic neurons, and many peptidergic neuronal types that are lost in insects. By comparing the genome of two newly sequenced plesiomorphic burrowing spiders with three aerial web-building spiders, we found that the positively selected genes in the ancestral branch of web-building spiders were preferentially expressed (42%) in the brain, especially in the three mushroom body-like neuronal types. By gene enrichment analysis and RNAi experiments, these genes were suggested to be involved in the learning and memory pathway and may influence the spiders' web-building and hunting behaviour. Our results provide key sources for understanding the evolution of behaviour in spiders and reveal how molecular evolution drives neuron innovation and the diversification of associated complex behaviours.

Na+ Preintercalated MoO3 Microrods for Aqueous Zinc/Sodium Batteries with Enhanced Performance.

Layered molybdenum trioxide (MoO3) is being investigated as a cathode material with high theoretical capacity and holds promise for aqueous secondary batteries. Unfortunately, the severe structural degradation of MoO3 and insufficient intrinsic properties hinder its practical application. Herein, a Na+ preintercalation strategy is reported as an effective method to construct cathodes with high performance for aqueous zinc/sodium batteries (AZSBs). Compared with pristine MoO3, the Na+ preintercalated Na0.25MoO3 cathode delivers a reversible capacity of 251.1 mAh g-1 at 1 A g-1, achieves a capacity retention of 79.2% after 500 cycles, and exhibits a high rate capability (121.5 mAh g-1 at 20 A g-1), which is superior to that in most of the previous reports. Through the experimental measurements and density functional theory (DFT) calculations, the preintercalation method could shorten the forbidden band gap and modulate the electronic structure and hence effectively inhibit the structural collapse of MoO3 microrods, induce reversible Na+ insertion, and enhance the discharge potential. This work is of significance for further research on molybdenum-based compounds as cathode materials for aqueous secondary batteries.

Aurora A kinase inhibition induces accumulation of SCLC tumor cells in mitosis with restored interferon signaling to increase response to PD-L1.

Despite small cell lung cancers (SCLCs) having a high mutational burden, programmed death-ligand 1 (PD-L1) immunotherapy only modestly increases survival. A subset of SCLCs that lose their ASCL1 neuroendocrine phenotype and restore innate immune signaling (termed the "inflammatory" subtype) have durable responses to PD-L1. Some SCLCs are highly sensitive to Aurora kinase inhibitors, but early-phase trials show short-lived responses, suggesting effective therapeutic combinations are needed to increase their durability. Using immunocompetent SCLC genetically engineered mouse models (GEMMs) and syngeneic xenografts, we show durable efficacy with the combination of a highly specific Aurora A kinase inhibitor (LSN3321213) and PD-L1. LSN3321213 causes accumulation of tumor cells in mitosis with lower ASCL1 expression and higher expression of interferon target genes and antigen-presentation genes mimicking the inflammatory subtype in a cell-cycle-dependent manner. These data demonstrate that inflammatory gene expression is restored in mitosis in SCLC, which can be exploited by Aurora A kinase inhibition.

Latent human herpesvirus 6 is reactivated in CAR T cells.

Cell therapies have yielded durable clinical benefits for patients with cancer, but the risks associated with the development of therapies from manipulated human cells are understudied. For example, we lack a comprehensive understanding of the mechanisms of toxicities observed in patients receiving T cell therapies, including recent reports of encephalitis caused by reactivation of human herpesvirus 6 (HHV-6)1. Here, through petabase-scale viral genomics mining, we examine the landscape of human latent viral reactivation and demonstrate that HHV-6B can become reactivated in cultures of human CD4+ T cells. Using single-cell sequencing, we identify a rare population of HHV-6 'super-expressors' (about 1 in 300-10,000 cells) that possess high viral transcriptional activity, among research-grade allogeneic chimeric antigen receptor (CAR) T cells. By analysing single-cell sequencing data from patients receiving cell therapy products that are approved by the US Food and Drug Administration2 or are in clinical studies3-5, we identify the presence of HHV-6-super-expressor CAR T cells in patients in vivo. Together, the findings of our study demonstrate the utility of comprehensive genomics analyses in implicating cell therapy products as a potential source contributing to the lytic HHV-6 infection that has been reported in clinical trials1,6-8 and may influence the design and production of autologous and allogeneic cell therapies.

DIISCO: A Bayesian framework for inferring dynamic intercellular interactions from time-series single-cell data.

Characterizing cell-cell communication and tracking its variability over time is essential for understanding the coordination of biological processes mediating normal development, progression of disease, or responses to perturbations such as therapies. Existing tools lack the ability to capture time-dependent intercellular interactions, such as those influenced by therapy, and primarily rely on existing databases compiled from limited contexts. We present DIISCO, a Bayesian framework for characterizing the temporal dynamics of cellular interactions using single-cell RNA-sequencing data from multiple time points. Our method uses structured Gaussian process regression to unveil time-resolved interactions among diverse cell types according to their co-evolution and incorporates prior knowledge of receptor-ligand complexes. We show the interpretability of DIISCO in simulated data and new data collected from CAR-T cells co-cultured with lymphoma cells, demonstrating its potential to uncover dynamic cell-cell crosstalk.

Differentiation of BCMA-specific induced pluripotent stem cells into CD8αß+ T cells targeting multiple myeloma.

A major hurdle in adoptive T cell therapy is cell exhaustion and failure to maintain anti-tumor responses. Here, we introduce an induced pluripotent stem cell (iPSC) strategy for reprogramming and revitalization of precursor exhausted BCMA-specific T cells to effectively target multiple myeloma (MM). Heteroclitic BCMA72-80 (YLMFLLRKI)-specific CD8+ memory cytotoxic T lymphocytes (CTL) were epigenetically reprogrammed to a pluripotent state, developed into hematopoietic progenitor cells (HPC: CD34+ CD43+/CD14- CD235a-), differentiated into the T cell lineage and evaluated for their poly-functional activities against MM. The final T cell products demonstrated; 1) mature CD8αß+ memory phenotype, 2) high expression of activation/costimulatory molecules (CD38, CD28, 41BB), 3) no expression of immune checkpoint and senescence markers (CTLA4, PD1, LAG3, TIM3; CD57), and 4) robust proliferation and poly-functional immune responses to MM. The BCMC-specific iPSC-T cells possessed a single T cell receptor clonotype with cognate BCMA peptide recognition and specificity for targeting MM. RNAseq analyses revealed distinct genome-wide shifts and a distinctive transcriptional profile in selected iPSC clones, which can develop CD8αß+ memory T cells. This includes a repertoire of gene regulators promoting T cell lineage-development, memory CTL activation, and immune response regulation [LCK, IL7R; 4-1BB, TRAIL, GZMB, FOXF1, ITGA1]. This study highlights the potential application of iPSC technology to an adaptive T cell therapy protocol and identifies specific transcriptional patterns that could serve as a biomarker for selection of suitable iPSC clones for successful development of antigen-specific CD8αß+ memory T cells to improve MM patient outcome.