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Biology subjects

Jin, L.

Publications and source records attributed to Jin, L..

At least 55 records · Page 3Linked to original sources

Microsurgical Cervical Lymphaticovenous Anastomosis: A Novel Mouse Model for Brain Lymphatic Outflow

BackgroundCervical lymphaticovenous bypass has recently emerged as an innovative surgical approach to enhance brain lymphatic clearance for the treatment of Alzheimers disease (AD). While early clinical findings are promising, the absence of a reproducible preclinical model has hindered mechanistic investigations and translational advancements. ObjectiveThis study aimed to establish the first rat model for cervical LVA, addressing technical challenges and providing a standardized platform for preclinical research on lymphatic clearance and its role in neurodegeneration. MethodsRats underwent bilateral cervical LNVA using high-magnification supermicrosurgical techniques. Following identification of the deep cervical lymph nodes, end-to-side lymph node-to-venous anastomosis was performed. Anastomotic patency was confirmed intraoperatively by direct visualization without leakage. Indocyanine green (ICG) lymphangiography, performed via nasal administration, demonstrated fluorescence drainage into the external jugular vein. ResultsWith progressive refinement of microsurgical skills and improved anatomical familiarity, procedural stability was achieved. In the final cohort of five rats, all LVA procedures resulted in successful anastomotic patency. ConclusionThis study is the first to establish a rat model of cervical deep lymph node-venous anastomosis (LNVA), offering a novel microsurgical platform with dual value. On one hand, it serves as a technically demanding and reproducible model for advanced training in plastic and lymphatic surgery. On the other, it provides a structurally precise, gain-of-function approach for targeted intervention of the deep cervical lymph nodes--an anatomical hub increasingly implicated in brain lymphatic clearance and neurodegeneration. As such, this model may contribute meaningfully to future mechanistic studies on glymphatic function and its modulation.

animal behavior and cognition↗

Homoharringtonine Promotes FTO Degradation to Suppress LILRB4-Mediated Immune Evasion in Acute Monocytic Leukemia

Acute monocytic leukemia (AML-M5), a subtype of acute myeloid leukemia, is a highly aggressive malignancy characterized by a poor prognosis, primarily due to the ability of leukemic cells to evade immune surveillance. In this study, we demonstrate that homoharringtonine (HHT), an FDA-approved therapeutic agent for chronic myeloid leukemia (CML), inhibits this immune evasion by targeting the FTO/m6A/LILRB4 signaling pathway in monocytic AML. Utilizing RNA sequencing (RNA-seq) and various functional assays, we reveal that HHT treatment significantly reduces LILRB4 expression at both the RNA and protein levels, suggesting that the effects of HHT on LILRB4 are distinct from its well-established role as a protein synthesis inhibitor. Mechanistically, HHT treatment markedly increases global levels of RNA m6A in THP-1 cells by promoting the degradation of FTO, which subsequently diminishes the expression of its downstream targets, MLL1 and LILRB4. Furthermore, in vitro and in vivo analyses employing monocytic AML cell lines, mouse-derived AML xenograft models, and patient samples collectively support the conclusion that HHT suppresses immune evasion in monocytic AML by reducing LILRB4 expression. Importantly, the downregulation of LILRB4 resulting from HHT treatment enhances the susceptibility of THP-1 cells to CD8+ T cell cytotoxicity, accompanied by increased markers of immune activation. Overall, our findings position HHT as a promising clinical agent for enhancing CD8+ T cell-based cancer immunotherapy by mitigating immune evasion in monocytic AML. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=147 HEIGHT=200 SRC="FIGDIR/small/643466v1_ufig1.gif" ALT="Figure 1"> View larger version (20K): org.highwire.dtl.DTLVardef@e72e5dorg.highwire.dtl.DTLVardef@19519aeorg.highwire.dtl.DTLVardef@1c8f786org.highwire.dtl.DTLVardef@f2a963_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

High-efficiency likelihood inference of shared proteomic architectures across 50 complex human traits

Advancements in genetic correlation estimation have elucidated genome-wide pleiotropys influence on phenotypic correlations among human complex traits and diseases. However, the role of proteomic domains in these correlations remains underexplored. Traditional genetic correlation analysis assumptions, including the minute effects of SNPs and their linkage disequilibrium, do not suit proteomic data. We present a novel method, Likelihood-based Estimation for Proteomic Correlation (LEAP), tailored to provide unbiased estimation of shared proteomic architectures between trait pairs. LEAP notably decreases computational demands by approximately 1000-fold compared to conventional bivariate linear mixed models. We applied LEAP to data from the UK Biobank Pharma Proteomics Project, identifying 585 significant proteomic correlations among 1,225 pairs of 50 biochemical, anthropometric, and behavioral traits. Furthermore, we quantified the distinct proteomic and genetic contributions to phenotypic correlations, highlighting significant gender differences. This study provides a comprehensive computational approach for proteomic correlation estimation, clarifying the specific roles of genomics and proteomics in complex trait correlations. Our findings not only advance the understanding of proteomic contributions to phenotypic traits but also suggest potential applications for evaluating shared omics architectures in other domains such as transcriptomics and metabolomics.

bioinformatics↗

Deletion of RSK2 kinase alleviates age-dependent hypertension

BackgroundHypertension prevalence increases with age, reaching over 70% of people over age 65. The underlying mechanisms are poorly understood. This study interrogates a new signaling pathway in vascular smooth muscle of aged mice driven by p90 ribosomal S6 kinase, RSK2, and its role in increasing peripheral vascular resistance and blood pressure (BP). MethodsBasal BP measurements were taken at 26-29 month (812-892 day) old mice with global deletion of RSK2 (Rsk2-/-) prior to and following treatment with L-NAME. Cardiac function, vessel stiffness, myogenic responses, Ca2+events, contractility, immuno-staining, histology studies and western blotting were performed. ResultsResting BP and myogenic vasoconstriction were normal in aged global Rsk2-/- mice and elevated in wild type (WT) littermates. L-NAME treatment increased BP in aged Rsk2+/+ but not aged Rsk2-/-. Vessel stiffness and glycation collagen crosslinking increased in both aged Rsk2+/+ and Rsk2-/- compared to young vessels with no remodeling or increase in collagen content, even though BP in aged Rsk2-/- arterioles was normal. Increased vessel stiffness was dissociated from increased BP. Ca2+ transients increased and sensitivity to NO-induced relaxation decreased in aged Rsk2+/+ compared to young WT arterioles. IEL structures, eNOS and Hb distribution at myoendothelial junctions were disturbed impairing vasorelaxation in aged Rsk2+/+ but not aged Rsk2-/- arterioles. ConclusionsRSK2 plays a significant role in hypertension associated with aging by downregulating prorelaxant signaling and promoting procontractile events in the vasculature, offering potential new therapeutic targets.

physiology↗

Genomic Analysis Reveals Genetic Diversity, Population Structure and Evolutionary Dynamics in Bluebunch wheatgrass (Pseudoroegneria species)

Bluebunch wheatgrass (BBWG: Pseudoroegneria species) is an outcrossing perennial grass of considerable ecological and agricultural importance due to its resilience in adverse environmental conditions. To gain a deeper understanding of the diversity, population structure, and genetic relationship within the Pseudoroegneria genus, we analyzed genomic variations of 145 genotypes representing seven species (P. spicata, P. tauri, P. geniculata, P. libanotica, P. strigosa, P. stipifolia, and P. cognata) from major global lineages, using genotyping-by-sequencing. Our results identify six distinct genetic clusters, with P. spicata (a North America species) clearly separated from the other six species underscoring its unique genetic identity. In contrast, the Eurasian species exhibit mixed ancestry, indicating intricate genetic relationships and widespread exchange of genetic material. Furthermore, no single species tree fully captures the relationships among them, implying interactions such as hybridization or gene flows between closely related species. To investigate the evolutional history of Eurasian BBWG species, we reconstructed the species tree topology based on the SNV (single nucleotide variants) matrix, which revealed potential gene flow events. Our findings suggest that the Eurasian BBWG species have undergone reticulate evolution, characterized by substantial gene flow.

genomics↗

Role of drug induced nuclear CTSL (nCTSL) in DNA damage response in cancer- therapeutic implications

ABSTRACT Background: Despite treatment advances, ovarian cancer (OC) remains the deadliest gynecological cancer, with a ~70% mortality rate. OCs initially respond to platinum chemotherapy but often develop resistance. While PARP inhibitors improve relapse-free survival in responsive cases, they do not extend overall survival. This underscores the need for effective combination therapies beyond BRCA status. The lysosomal protein cathepsin L (CTSL) can traffic to the nucleus, where it can regulate DNA repair and serve as a chromatin modifier. Here, we tested the hypothesis that nucleoside analog clofarabine (CLF) induced nuclear CTSL (nCTSL) serves as a biomarker of sensitivity to DNA-damaging agents in ovarian cancer. Methods: Role of nuclear CTSL in DNA damage, synergy with PARPis and CRM1 inhibitor, tumor regression was analyzed by 3D-spheroid culture, colony forming assay, subcellular fractions, comet assay, and IFC/ western-blotting using PARP inhibitor-sensitive and -resistant OC cell lines, ex vivo cultures of patient-derived OC ascites cells (OVA), primary OCs, and patient-derived xenografts (PDXs). Results: In OC cell lines, treatment with CLF induced nCTSL in a subset of models-designated CLF-responsive (CLF-r)-and sensitized them to the PARP inhibitors olaparib and rucaparib. In CLF-non-responsive (CLF-nr) models, nCTSL trafficking and drug synergy were achieved with the CLF+olaparib combination. Synergy was observed in 47% of CLF-r and 24% of CLF-nr OVA samples. Mechanistically, CLF monotherapy induced nuclear import of CTSL via KPNB1 in CLF-r cells, while combination treatment with CLF+olaparib was required in CLF-nr cells. CLF also downregulated the nuclear export protein CRM1 in both CLF-r and CLF-nr models. CTSL knockdown conferred resistance to CLF+olaparib in both cohorts, supporting a functional role for nCTSL in therapeutic response. Notably, in a subset of OVAs (29%) classified as CLF-resistant (CLF-Res), CLF failed to downregulate CRM1; however, pharmacological inhibition of CRM1 with KPT8602 restored sensitivity to CLF+PARP inhibitor treatment. In vivo, CLF+olaparib treatment in CLF-r and CLF-nr PDX models led to enhanced DNA damage, reduced tumor burden, and prolonged survival. Conclusion: Collectively, these findings identify nCTSL as a predictive marker of response to DNA-damaging therapies and support the CLF+olaparib combination as a promising strategy for overcoming drug resistance in OC via CTSL-mediated DNA damage.

cancer biology↗

Bovine Formative Embryonic Stem Cell Plasticity in Embryonic and Extraembryonic Differentiation

Bovine embryonic stem cells (bESCs) can greatly enhance understanding of bovine embryonic development and applications for disease-resistance, biomedical and zoonotic pre-clinical models. However, formative bESCs with distinct morphology and complete differentiation capacity are still unreported. We document here the generation of bESCs which are pluripotent both in vitro and in vivo, and efficiently converted into neural progenitor cells (NPCs) and primordial germ cell-like cells (PGCLCs) by direct differentiation. These cells exhibited distinct metabolic features from human and mouse ESCs and early embryos. Formative bESCs contributed to a wide range of cell types within embryonic and extraembryonic tissues after aggregating with mouse and bovine embryos. The establishment of bovine formative ESCs with dual developmental plasticity represents a milestone for agricultural biotechnology and decoding the underlying mechanism of bona fide bovine pluripotency. Summary statementGenerating bovine ESCs would greatly enhance understanding of bovine embryonic development and bioengineering of cattle for disease-resistance, biomedical and zoonotic pre-clinical models.

developmental biology↗

A Novel Efficient Algorithm for Common Variants Genotyping from Low-Coverage Sequencing Data

Low-coverage whole-genome sequencing (LC-WGS) combined with imputation represents a cost-effective genotyping strategy for genome-wide association studies (GWAS) in population genetics. In this study, the Limpute algorithm was developed specifically for genotyping from low-coverage sequencing data, it extracts variant information from low-coverage sequencing data by the novel virtual probes and subsequently performs imputation through cross-reference between samples. Compared to the currently dominant algorithm for low-coverage sequencing data, GLIMPSE2, Limpute achieved similar imputation performance within common variants (r2>0.87) while the GLIMPSE2 has a runtime approximately five times longer than that of the Limpute. Furthermore, to fully evaluate the accuracy of genotype imputation by Limpute, we utilized high-coverage whole-genome sequencing data (30x), microarray data, and high-coverage whole-exome sequencing data (30x) as validation sets respectively. The results demonstrated that Limpute has a good imputation performance for common variants using low-coverage sequencing data (1x: r2 > 0.87; 3x: r2 > 0.92; 5x: r2 > 0.93). In summary, we present a highly efficient, low-cost algorithm for genotyping from low-coverage sequencing data, offering substantial support for genetic research.

bioinformatics↗

Deep Learning Unravels Potential Antibiotic-Resistance Drugs against Klebsiella Pneumoniae

BackgroundKlebsiella pneumoniae (KP) is a critical pathogen recognized by the World Health Organization due to its high mortality rates and resistance to antibiotics. Developing effective treatments for KP is essential to mitigate the growing threat of multidrug-resistant infections. This study leverages deep learning techniques to identify and validate potential drug candidates against KP, accelerating the drug discovery process and reducing associated risks. ResultsA comprehensive dataset was constructed, comprising 3,475 drugs selected from the DrugBank database, filtered for their potential efficacy and safety. Using convolutional neural networks (CNNs) for drug-drug interaction analysis, a prediction accuracy of 72% was achieved. Evolutionary Scale Modeling (ESM) was employed to calculate molecular similarities between drugs and KP strains, identifying five promising candidates with structural similarities exceeding 85% to known KP targets. A drug repurposing knowledge graph (DRKG) further validated these findings, with the PairRE model outperforming other approaches in ranking potential drug candidates. ConclusionsThis study presents a scalable and efficient framework for identifying and validating drug candidates to combat antibiotic-resistant KP. By integrating deep learning models, molecular similarity analysis, and knowledge graph techniques, this approach shortens the drug discovery timeline from years to months. The identified candidates hold significant promise for preclinical and clinical testing, offering a pathway to effective therapies against KP and other multidrug-resistant pathogens.

bioinformatics↗

Deep Learning with Evolutionary Scale Modeling to discover Antibiotic-Resistance Drug against Klebsiella Pneumoniae

The development of effective antibiotics is crucial in combating antibiotic-resistant pathogens such as Klebsiella pneumoniae (KP). This study utilizes deep learning, specifically Evolutionary Scale Modeling (ESM), to identify potential drug candidates. By analyzing molecular similarities between known drugs and KP strains, we aim to accelerate the discovery of new treatments and reduce the risks associated with clinical trials. This approach may shed new lights in the field of drug repositioning.

bioinformatics↗

Retrospective Attention Can Trigger Visual Perception Without Dependence on Either Cue Awareness or Target Reporting

Whether retrospective attention changes a target representation relevant to conscious perception, rather than only later report processes, remains unresolved. Across three experiments, we traced a progression from retroperception to attentional selection and to a consciousness-linked target representation. Experiments 1 and 2 showed that post-target cues altered orientation discrimination despite strongly reduced cue-location discrimination; Experiment 2 additionally revealed an N2pc modulation, a lateralized event-related potential (ERP) signature consistent with attentional selection. Experiment 3 combined parallel Report and No-report sessions with cue-controlled EEG and validity-neutral decoding. During Report, stronger target evidence predicted visibility and orientation discrimination, and Valid cues enhanced this evidence at medium contrast. Under No-report, Valid cues enhanced high-contrast target evidence. Crucially, target evidence learned entirely under No-report predicted visibility and orientation discrimination in an independent Report session, and target-present codes generalized between Report and No-report in both directions. In contrast, validity transfer was reliable only from Report to No-report. These results support the conclusion that retrospective attention can strengthen a target representation linked to conscious visibility and discrimination without requiring an explicit target report.

neuroscience↗

Stacked Human Arterial Endothelial Cells Generate Atherosclerotic Fatty Streaks and Release Proinflammatory Cytokines

Fatty streaks are the first sign of atherosclerosis. They consist of lipid-containing foam cells, which were believed to be derived from the monocytes in the blood through the leaky endothelium, and from the vascular smooth muscle cells migrating into the intima from the media. Here, we showed that fatty streaks can also be formed by the stacked human arterial endothelial cells (HAECs) cultured in vitro. Via SEM we revealed a novel cell phenotype (coralthelial) that forms a streak/coral-like structure. We observed accumulation of lipids in the coralthelial cell and increased Golgi and coat protein II markers in its nucleus. Additionally, proinflammatory cytokines were upregulated in these cells, likely due to Golgi nuclear translocation and subsequently increased expression of the ribosomal protein RPL23 in the nucleus. We demonstrated, for the first time, that the atherosclerotic fatty streak-like structure can be generated from the stacked HAECs, which also create a proinflammatory microenvironment. Significance StatementOur work presents a novel perspective on atherosclerotic fatty streak formation, a critical early event in atherosclerosis development. We demonstrate, for the first time, that human arterial endothelial cells (HAECs) can transform into a novel phenotype, termed "coralthelial cells". These cells contribute to fatty streak formation, and produce proinflammatory cytokines through the relocation of RPL23 with the Golgi apparatus to the nucleus. This finding provides a new cellular mechanism by which endothelial cells initiate atherosclerosis, independent of traditional monocyte-derived foam cells. By enriching established paradigms, our research not only opens new avenues for therapeutic intervention targeting endothelial cells but also enhances understanding of vascular diseases and provides potential diagnostic and prognostic markers for atherosclerosis.

cell biology↗

Exploring The Genome of The Oribatid Mite, Oppia Nitens: Environmental Stress Response and Toxicity Adaptation

Oribatid mites are one of the most abundant groups of microarthropods in soil. Oppia nitens, belonging to the family Oppiidae, one of the largest and most diverse families of oribatid mites, has been developed as a standardized model test organism for assessing soil contamination. However, the limited availability of genomic information for this species hinders our understanding of its physiological adaptation and sensitivity to chemical and environmental stressors in soil. Hence, we present the annotated O. nitens draft genome assembled using both Oxford Nanopore Technologies and Illumina sequencing platforms as a basis to identify potential genes that can be linked to adaptation to chemical and environmental stressors. The sequences were assembled into 65 scaffolds spanning 125.4Mb with a 24.5% GC content and an N50 length of 4.41Mb. Genome quality and completeness were checked using arthropod Benchmarking Universal Single-Copy Orthologs (BUSCO) analysis, which identified 93.5 % complete single-copy orthologs, 3.4% complete but duplicated orthologs, 0.5% fragmented, and 2.6% missing orthologs (n=2934). The NCBI Eukaryotic Genome Annotation Pipeline annotated 15,291 genes, 16,969 mRNAs, and 14,938 proteins. Here, we describe the O. nitens complete draft genome and discuss its utility as a genetic basis for further investigations and understanding of the molecular mechanisms and physiological functions in adaptations to environmental change, especially tolerance to metal stress.

genomics↗

α-Synuclein Strain Dynamics Correlate with Cognitive Shifts in Parkinson's Disease

-Synuclein (-syn) strains can serve as discriminators between Parkinsons disease (PD) and related -synucleinopathies. The relationship between -syn strain dynamics and clinical performance as patients transition from normal cognition (NC) to cognitive impairment (CI) is not known. Here, we show that the biophysical properties and neurotoxicity of -syn strains change as PD cognitive status transitions from NC to mild cognitive impairment (PD-MCI) and dementia (PD-D). Both cross-sectional and longitudinal analyses reveal distinct -syn strains in PD patients correlating to their level of cognitive impairment. Machine learning (ML) was employed to achieve high classification accuracy. The combination of thioflavin T (ThT) maximal fluorescence intensity (mfi), max slope of rise curve (forming rate), lag time (tlag), 20% time (t20), and half-time (t50), dynamic light scattering (DLS) (peak number, [1/2] peak size, [1/2] peak intensity) and neurotoxicity together with demographic variables for model training yielded superior performance (89[~]99% accuracy in the 4- and 2- classification schema) compared to individual features alone in classifying cognitive status. For the longitudinal study, DLS peak number emerged as the strongest predictor of cognitive transition (HR = 0.12, P = 0.002), with the optimal predictive model combining DLS peak number, sex, education, DLS peak 1 size, and DLS peak 2 polydispersity achieving high accuracy (C-index of [~]93%). This study presents evidence that individuals with PD have different -syn strains correlating to their cognitive status and highlights the potential of -syn strain dynamics to guide future diagnosis, management, and stratification of PD patients. One Sentence SummaryDistinct features of -syn strains change with cognitive decline in Parkinsons disease and AI-based analysis incorporating these combined characteristics serves as a powerful tool for PD clinical stratification.

neuroscience↗

Distinct gene regulatory networks govern hematopoietic and leukemia stem cells

The underlying gene regulatory networks (GRN) that govern leukemia stem cells (LSC) in acute myeloid leukemia (AML) and hematopoietic stem cells (HSC) are not well understood. Here, we identified GRNs by integrating gene expression (GE) and chromatin accessibility data derived from functionally defined cell populations enriched for HSC and LSC. We analyzed n=32 LSC+ and n=32 LSC-cell fractions from n=22 AML patients, along with n=7 stem and n=10 progenitor enriched cell populations sorted from human umbilical cord blood (hUCB), producing a database of n{approx}17,000 transcription factor (TF) regulatory interactions for hUCB-HSPC and AML. We developed an iterative algorithm that associates the degree of chromatin openness with TF binding preferences, and the GE of candidate TF and target genes within 100kb upstream of transcription start sites. A putative regulatory structure was found to be enriched in HSC-enriched cell populations, comprising TF-target gene interactions between ETS1, EGR1, RUNX2, and ZNF683 oriented in a self-reinforcing configuration. A regulatory loop comprising FOXK1 and MEIS1, rather than the 4-factor HSC subnetwork, was detected in the LSC-specific GRN. The core HSC and LSC TF networks were extended using protein-protein interaction (PPI) data to determine connectivity with interacting genes whose expression strongly associated with LSC/HSC frequency estimates, producing a database of n=103,516 PPI target pathways. The effect of perturbing genes along the identified pathways on functional HSC and LSC frequency was predicted based on statistical regression analyses. To validate GRN predictions, we used pharmacologic and CRISPR targeting, in addition to re-examining published functional data associated with several network nodes that were predicted to impact stemness. Notably, we found that inhibition of CDK6 in AML samples markedly reduced LSC numbers as assessed in de novo serial xenotransplantation studies (fold change {approx} 10), as predicted by the LSC GRN model. Additionally, in-house CRISPR-based knockdown of ETS1 resulted in a significant decrease in HSC quiescence-associated microRNA-126 expression, and increased HSC frequency. Taken together, our models provide a comprehensive view of the underlying regulatory structures governing functional human HSC and LSC. This approach has translational potential as it can be used as a high-throughput in-silico screening tool for the systematic identification of gene targets for LSC elimination and HSC expansion.

bioinformatics↗

Hematopoietic Tet2 inactivation enhances the response to checkpoint blockade immunotherapy

Somatic mutations inactivating TET2 are among the most common drivers of clonal hematopoiesis (CH). While TET2 inactivation is associated with monocyte-derived inflammation and improved chimeric antigen-receptor-T cell function, its impact on immunotherapy response is unknown. In our mouse model, hematopoietic Tet2 mutation enhanced immune checkpoint blockade (ICB) response. Enhanced ICB response with Tet2 mutation required phagocytes, CD4 and CD8 T cells. Mechanistically, in Tet2-mutant tumor-infiltrating leukocytes (TILs), ICB preferentially induced anti-tumor states and restricted cell states linked to tumor progression. Tet2-mutant monocytes activated costimulatory programs, while Tet2-mutant T cells showed enhanced T cell memory signatures, lesser exhaustion and decreased regulatory phenotype. Our murine data was clinically relevant, since we found that melanomas from patients with TET2 driver mutation-CH (TET2-CH) showed enhanced immune infiltration, T cell activation, and T cell memory programs. In melanoma patients treated with ICB, TET2-CH was associated with 6-fold greater odds of clinical benefit. Collectively, our data establishes that hematopoietic Tet2 inactivation primes leukocytes for anti-tumor states associated with immunotherapy response and provides a potential biomarker for personalized therapy.

cancer biology↗

Legume genome structures and histories inferred from Cercis canadensis and Chamaecrista fasciculata genomes

O_LIThe legume family originated ca. 70 million years ago and soon diversified into at least six lineages (now extant subfamilies). The signal of whole genome duplications (WGD) is apparent in species sampled from all six subfamilies. The early diversification has posed difficulties for resolving the legume backbone structure and the timing of WGDs. C_LIO_LIIn this study, we report the genome sequences and annotations for Cercis canadensis (Cercidoideae) and Chamaecrista fasciculata (Caesalpinoideae) to help resolve the relative taxonomic placements along the legume backbone, the timings of WGDs relative to subfamily origins, and the ancestral legume karyotype. C_LIO_LIAnalyses of genome assemblies from four subfamilies within Fabaceae show that the last common ancestor of all legumes likely had seven chromosomes, with a genome structure similar to the extant Cercis genome. Our analysis supports an allopolyploid origin of the subfamily Caesalpinoideae, with progenitors involving lineages along the backbone of the legume phylogeny. C_LIO_LIA probable allopolyploid origin of Caesalpinoideae subfamily provides a partial explanation for the difficulty in resolving the structure of the legume backbone. The retained karyotype structure and lack of a WGD in the last 100+ Mya, underscore the utility of the Cercis genome as an ancestral reference for the legume family. C_LI

genomics↗

Inhibition on neutrophil extracellular traps by oligomeric procyanidins alleviate chemotherapy-induced chronic kidney injury via gut-kidney axis

Cisplatin is one of the most widely used chemotherapeutic agents for various solid tumors in the clinic, but its use is limited by adverse effects in normal tissues. In particular, cisplatin administration often damages the kidneys. However, little is known about how to alleviate cisplatin-induced chronic kidney disease (CKD) specifically. Here, we found that repeated low-dose cisplatin (RLDC) recruited susceptible neutrophils to the proximal tubule, thereby promoting the progression of CKD in the mouse model. Mechanically, cisplatin destroyed the intestinal epithelium, which induced dysregulation of gut flora and intestinal leakage. Under the dual stimulation of intestinal bacteria and cisplatin, neutrophils become extremely susceptible to form Neutrophil extracellular traps (NETs), accumulating in the proximal tubule and promoted chronic inflammation, fibrosis, and chronic hypoxia, leading to poor regeneration that promoted CKD progression. NETs provided a scaffold for tissue factors (TF) adhesion and metalloid-matrix protease 9 (MMP-9) activation, which triggered local ischemia and hypoxia. In addition, NETs promoted inflammasome construction through NOD-like receptor thermal protein domain associated protein 3 (NLRP3) shear and secretion of mature interleukin-18 (IL18), which subsequently released interferon- {gamma} (IFN-{gamma}), contributing to renal interstitial fibrosis. We proposed that oligomeric procyanidins (OPCs) ameliorated RLDC-induced CKD through multi-targeting damage induced by NETs. OPCs ameliorated microcirculatory disorders and inhibited inflammation by protecting the intestinal mucosa barrier and subsequent bacterial endotoxin translocation. Furthermore, we found that OPCs altered the susceptibility of neutrophils to form NETs. In summary, OPC alleviates CKD by inhibiting NETs production via TF/MMP-9 and IL-18-NLRP3 pathways. OPCs protect the kidney through anti-inflammatory and antioxidant activities, and restore the balance of the intestinal flora.

immunology↗