Biology subjects

Li, Z.

Publications and source records attributed to Li, Z..

At least 559 records · Page 31Linked to original sources

bioRxiv2024

MuMu: a sample multiplexing protocol for droplet-based simultaneous single nuclei RNA- and ATAC-seq systems

Sample multiplexing is a common approach to reduce experimental cost and technical batch effect. Here, we present a protocol that for the first time allows the pooling of single nuclei from multiple biological samples prior to performing simultaneous single nuclei RNA-seq and ATAC-seq, which we term Multiplexed Multiome (MuMu). We describe steps for assembling the custom Tn5 transposome, performing the transposition reaction, nuclei pooling, sequencing library preparation, and sequencing data pre-processing. This protocol will greatly reduce the cost of sn-Multiome. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=163 HEIGHT=200 SRC="FIGDIR/small/625728v2_ufig1.gif" ALT="Figure 1"> View larger version (40K): org.highwire.dtl.DTLVardef@19d7962org.highwire.dtl.DTLVardef@18c1c04org.highwire.dtl.DTLVardef@18355a9org.highwire.dtl.DTLVardef@16cdb6f_HPS_FORMAT_FIGEXP M_FIG C_FIG

molecular biology↗

bioRxiv2024

Cardiac Reprogramming with Drug Resistance Alleviates Doxorubicin-induced Cardiotoxicity in Mice and Pigs

Doxorubicin (Dox)-induced cardiotoxicity represents a significant clinical adverse effect associated with cancer chemotherapy treatment. The systematic toxicity associated with the currently available drug dexrazoxane has limited its clinical utility. Inspired by cancer drug resistance mechanisms, we propose a novel strategy termed Transient overexpression of p-glycoprotein (P-gp) for Cardiac reprogramming (TopCare) to induce cardiac drug resistance as a treatment for cardiotoxicity. This approach involves reprogramming cardiomyocytes by delivering lipid nanoparticles (LNPs)-based mRNA therapeutics to induce temporary P-gp overexpression, which in turn reduces intracellular Dox levels and suppresses cytotoxic effects. Our results demonstrated that LNPs with P-gp mRNAs (P-gp LNPs) enhance P-gp expression in H9c2 cells, significantly lowering the cytotoxicity of both Dox and paclitaxel (PTX). In a mouse model with Dox-induced cardiotoxicity, it was observed that P-gp LNPs effectively promoted P-gp overexpression in cardiomyocytes, with a time-dependent decline in P-gp protein levels. This TopCare strategy resulted in improved survival rates, restored cardiac function, and reduced myocardial fibrosis and structural cardiac alterations. Furthermore, studies in large animals have shown that intrapericardial (iPC) injection of P-gp LNPs effectively mitigates adverse effects and restores cardiac function in pig models of Dox-induced cardiotoxicity. The significant cardioprotective effects achieved through cardiac drug resistance highlight the safety, efficacy, and clinical potential of the TopCare strategy for alleviating doxorubicin-induced cardiotoxicity.

bioengineering↗

bioRxiv2024

VIACOT: a web server for interactive visualization and comparison of cell lineage trees

The cell lineage tree (CLT) records some or all cell division events during the development of multicellular organisms, as well as the functional characteristics of terminal cells, and is therefore commonly considered one of the most fundamental types of biological data. The combining of single-cell RNA sequencing with DNA barcoding has recently led to the rapid accumulation of CLT datasets. Unlike biological sequence data, web-based analysis and visualization tools for CLT data are currently lacking. In order to facilitate studies surrounding CLT, we built a webserver named VIACOT (Visualize Interactively And COmpare Trees). VIACOT is not only a comprehensive repository of published CLT datasets, but also a web tool that enables three preliminary analyses of preprocessed CLT datasets, including. (i) interactive visualization of CLT allowing fine-grain or coarse-grain exploration. (ii) calculations of correlations among single-cell metrics, such as gene expression levels, either using the original metrics or their phylogenetic independent contrasts. (iii) comparison among different CLTs to identify differences in cell fate. We anticipate that VIACOT will be a useful tool for exploration and biological interpretation of CLTs.

bioinformatics↗

bioRxiv2024

Versatile Stain Transfer in Histopathology Using a Unified Diffusion Framework

Histological staining is vital in clinical pathology for visualizing tissue structures. However, these techniques are laborious and time-consuming. Digital virtual staining offers a promising solution, but existing methods typically rely on Generative Adversarial Networks (GANs), which may suffer from artifacts and mode collapse. Motivated by the success of diffusion models, we present DUST, a novel Diffusion-based Unified framework for versatile Stain Transfer in histopathology. To enhance domain awareness and task-specific performance, we propose a dual encoding strategy that integrates the stain types of both the source and target domains. Additionally, we introduce a dynamic dual-output head to address the unstable intensity issue encountered with conventional DDPM implementations. Validated on a curated fourstain kidney histopathological dataset (H&E, MT, PAS, and PASM), DUST demonstrates superior versatile stain transfer capabilities. Our research highlights the potential of diffusion models to advance virtual staining, paving the way for more efficient digital pathology analyses.

pathology↗

bioRxiv2024

Cardiolipin-mimic lipid nanoparticles without antibody modification delivered senolytic in-vivo CAR-T therapy for inflamm-aging

mRNA-based in vivo CAR T cell engineering offers advantages over ex vivo therapies, including streamlined manufacturing and transient expression. However, current delivery requires antibody-modified vehicles with manufacturing challenges. In this study, inspired by cardiolipin, we identified a cardiolipin-like di-phosphoramide lipid that improved T cell transfection without targeting ligands, both in vivo and in vitro. The T cell-favored tropism is likely due to the lipids packing, shape, and rigidity. Encapsulating circular RNA further prolonged mRNA expression in the spleen and T cells. Using PL40 lipid nanoparticles, we delivered mRNA encoding a CAR targeting the senolytic and inflammatory antigen urokinase-type plasminogen activator receptor (uPAR), alleviating uPAR-related liver fibrosis and rheumatoid arthritis (RA). Single cell sequencing in humans confirmed uPARs relevance to senescence and inflammation in RA. To further enhance clinical translation, we screened and humanized scFvs against uPAR, establishing PL40 mRNA encoding a circular human uPAR CAR, with potential for treating aging-inflamed disorders. One Sentence SummaryWeve developed a unique class of Cardiolipin-mimic lipids that facilitate mRNA delivery to T cells in vivo without the need for antibody modification, enhancing the treatment of liver fibrosis and rheumatoid arthritis through circular CAR uPAR RNA and propelling the clinical application of humanized CAR against human uPAR.

bioengineering↗

bioRxiv2024

Exploring the Hypothetical Role of Bacteroides Species in Depression Progression: Insights from Metagenomic Analysis

Depression, a psychiatric disorder with significant morbidity and mortality, has a complex etiology. Recent advances in microbiome research have highlighted the potential role of gut microbiota in depression pathogenesis. This study utilized shotgun metagenomic sequencing to compare the fecal microbiota of 28 depression patients and 26 healthy individuals. Significant differences in gut microbiota composition were observed between the two groups. We generated 350 non-redundant high-quality metagenome-assembled Genomes (MAGs) by binning and conducted comparisons between the depression and control groups. Notably, we found that the MAGs enriched in people with depression mostly belonged to Bactendicating a close link between Bacteroides abundance and the development of depression, suggesting that Bacteroides might be a potential culprit for deroides, ipression. In the depression group, we found that the module of nitric oxide synthesis was remarkably enriched, and all Bacteroides MAGs were annotated to nitric oxide synthase, suggesting that increased levels of Bacteroides may contribute to elevated nitric oxide synthesis. Specifically, the mean relative abundance about the genomes of Bacteroides xylanisolvens, Bacteroides caccae, Bacteroides fragilis, Bacteroides stercoris and Bacteroides ovatus showed strong discriminatory power in distinguishing depressed patients from healthy individuals (AUC=0.834). This research shed light on the potential role of gut microbiota in depression and highlights specific metabolic pathways and microbial markers for further investigation. ImprotanceThis research highlighted significant differences in the composition and function of gut microbiota between individuals with depression and healthy individuals, particularly the enrichment of Bacteroides MAGs in depression patients. The upregulation of the nitric oxide synthesis pathway associated with these MAGs belong to Bacteroides in the gut of depression patients had also been observed. The mean relative abundance of a specific set of Bacteroides MAGs had been identified, which could accurately classify individuals with depression from healthy individuals (AUC=0.834). Our results suggest the importance of exploring microbial markers as potential diagnostic and therapeutic targets in managing depression.

genomics↗

bioRxiv2024

Restoration of PKM1 improves functional maturation of human stem-cell derived-β cell by regulating PEP metabolism

Human stem cell-derived {beta} (SC-{beta}) cells still exhibit limited glucose response required for insulin secretion due to glycolytic bottlenecks, yet how these metabolic abnormalities impact glucose response and functional maturation of SC-{beta} cells remains unclear. In this study, we identified a metabolic checkpoint located at PEP accumulation that impeded the functional maturation, which was rescued by restoration of pyruvate kinase 1 (PKM1). Glucose-tracing metabolomics in human stem cell-derived islets revealed abnormal glycolytic PEP accumulation at resting condition, resulting in impaired calcium response and insulin secretion upon high glucose or glycolytic metabolite stimulation. Mechanistically, elevated PEP significantly raised intracellular basal calcium levels, leading to downregulated expression of genes involved in TCA cycle elucidated by single cell transcriptomics. Furthermore, the activity of pyruvate kinase, which metabolizes PEP, was notably reduced due to low PKM1 expression. By overexpressing PKM1, the impairment of TCA-related genes caused by PEP accumulation was reversed via modulating PEP metabolism, resulting in enhanced calcium responses and insulin secretion upon high glucose stimulation. Together, we discovered a novel role of PKM1-regulated PEP metabolism in mediating the functional maturation of human SC-{beta} cells. This study highlights the importance of metabolic reprogramming in human SC-{beta} cell maturation, advancing cell therapy approaches for diabetes treatment.

cell biology↗

bioRxiv2024

A reconstruction of the mammalian secretory pathway identifies mechanisms regulating antibody production

The secretory pathway processes >30% of mammalian proteins, orchestrating their synthesis, modification, trafficking, and quality control. However, its complexity-- spanning multiple organelles and dependent on coordinated protein interactions--limits our ability to decipher how protein secretion is controlled in biomedical and biotechnological applications. To advance such research, we present secRecon--a comprehensive reconstruction of the mammalian secretory pathway, comprising 1,127 manually curated genes organized within an ontology of 77 secretory process terms, annotated with functional roles, subcellular localization, protein interactions, and complex composition. Using secRecon to integrate multi-omics data, we identified distinct secretory topologies in antibody-producing plasma cells compared to CHO cells. Genes within proteostasis, translocation, and N-glycosylation are deficient in CHO cells, highlighting them as potential engineering targets to boost secretion capacity. Applying secRecon to single-cell transcriptomics and SEC-seq data, we uncovered secretory pathway signatures underlying secretion diversity among IgG-secreting plasma cells. Different transcriptomic clusters had unique secretory phenotypes characterized by variations in the unfolded protein response (UPR), endoplasmic reticulum-associated degradation (ERAD), and vesicle trafficking pathways. Additionally, we discovered specific secretory machinery genes as new markers for plasma cell differentiation. These findings demonstrate secRecon can identify mechanisms regulating protein secretion and guide diverse studies in biomedical research and biotechnology. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=73 SRC="FIGDIR/small/623668v1_ufig1.gif" ALT="Figure 1"> View larger version (24K): org.highwire.dtl.DTLVardef@f9f865org.highwire.dtl.DTLVardef@122db7forg.highwire.dtl.DTLVardef@1788a1aorg.highwire.dtl.DTLVardef@b2b2bd_HPS_FORMAT_FIGEXP M_FIG C_FIG

systems biology↗

bioRxiv2024

Systematic identification and characterization of virus lncRNAs suggests extensive structural mimicry of host lncRNAs

Virus long non-coding RNAs (vlncRNAs) play crucial roles in viral infections, yet their identification and characterization remain limited. This study identified 5,053 novel vlncRNAs across 25 viral species using third-generation sequencing, with two from Influenza A virus and Vesicular stomatitis virus validated by RT-qPCR. Most vlncRNAs originated from dsDNA viruses. Only 1% having annotated RNA families, suggesting many novel RNA structures. Although only seven vlncRNAs shared sequence similarities with human lncRNAs (hlncRNAs), 772 vlncRNAs from 15 human viruses structurally mimicked hlncRNAs. These vlncRNA and hlncRNAs bound to similar miRNAs, potentially acting as miRNA sponges to promote essential life process. Splicing analysis showed vlncRNAs had a prevalence of alternative first exon. Finally, we developed vlncRNAbase (http://computationalbiology.cn/vlncRNAbase/#/) to store and organize the newly identified and known vlncRNAs. Overall, the study provides a valuable resource for further investigation into vlncRNAs and deepens our understanding of the diversity, structure and function of the molecule.

bioinformatics↗

bioRxiv2024

Machine learning reveals novel targets for both glioblastoma and osteosarcoma

Glioblastoma and osteosarcoma originate from the same lineage, yet patients with these two tumour types show significant differences in survival outcomes. Transcriptomic analysis comparing these tumours reveals that over 65% genes show similar expression patterns. Principal component analysis further demonstrates substantial similarities between these two tumour types, albeit with discernible differences. Deep learning analysis employing an autoencoder unveils nuanced distinctions and similarities of these two tumours at a high resolution. A classification model, leveraging gradient boosting with eXtreme Gradient Boosting (XGBoost), achieves high accuracy in distinguishing between these two tumour types. Identification of key contributors to the models performance is facilitated by SHapley Additive exPlanations (SHAP), yielding two lists of top target genes with and without considering gender. Notably, these SHAP targets tend to cluster within one or two networks of signalling pathways. Remarkably, gene expression levels of many of these SHAP targets alone can recapitulate survival differences solely based on clinical data between glioblastoma and osteosarcoma patients. Of particular interest, C2ORF72 emerges as a common target from both lists, representing an uncharacterised protein with promising potential as a novel target for diagnostic, prognostic, and therapeutic target for both glioblastoma and osteosarcoma.

genomics↗

bioRxiv2024

Hope for Others: Research Results from the University of Pittsburgh Rapid Autopsy Program for Breast Cancer

Breast cancer affects 1/8 of women throughout their lifetimes, with over 90% of cancer deaths being caused by metastasis. However, metastasis poses unique challenges to research, as complex changes in the microenvironment in different metastatic sites and difficulty obtaining tissue for study hinder the ability to examine in depth the changes that occur during metastasis. Rapid autopsy programs thus fill a unique need in advancing metastasis research. Here, we describe our protocol and processes for establishing and improving the US-based Hope for OTHERS (Our Tissue Helping Enhance Research and Science) program for organ donation in metastatic breast cancer. As of August 2024, we consented 114 patients and performed 37 autopsies, from which we collected 551 unique metastatic frozen tumor samples, 1244 FFPE blocks, 90 longitudinal liquid biopsy samples and developed 14 patient-derived organoid and 8 patient-derived xenograft models. We report in-depth clinical and histopathological information and discuss extensive new research and novel findings in patient outcomes, metastatic phylogeny, and factors in successful living model development. Our results reveal key logistical and protocol improvements that are uniquely beneficial to certain programs based on identifiable features, such as working closely with patient advocates, methods to rescue RNA quality in cases where tissue quality may degrade due to time delays, as well as guidelines and future expansions of our program. Statement of SignificanceRapid autopsy programs are unique research settings with huge potential for studying metastatic cancer, however, they have complex research challenges. Our work provides a valuable resource in advancing this field of research.

cancer biology↗

bioRxiv2024

Interplay between autophagy, the unfolded protein response and the cytoplasmic heat stress response during heat stress in maize

High temperatures can substantially reduce plant survival and reproduction, and therefore decrease crop productivity. Plants activate several pathways in response to high temperatures, including the endoplasmic reticulum (ER) unfolded protein response (UPR), the cytoplasmic heat stress response, and autophagy, which together aid in stress tolerance by refolding or degrading misfolded and unfolded proteins. The relationship between the UPR and autophagy is known, as ER stress activates the UPR, and a key activator of the UPR, Inositol-requiring enzyme type 1 (IRE1B), upregulates autophagy. To assess the relationship between the distinct responses to heat stress in maize, we analyzed the effect of disruption of the UPR, via a bzip60 mutant, on autophagy. We found that genes related to autophagy are upregulated in the bzip60 mutant, and that autophagy is activated in this mutant even in the absence of stress. We in turn analyzed the effect of loss of autophagy on the UPR. The bZIP60 mRNA spliced form, a marker for the UPR, was increased in mutants in ATG10, a core component of the autophagy machinery, during ER stress. By contrast, bZIP60 splicing was unaffected in atg10 mutants in response to heat, whereas cytoplasmic heat stress components were increased. Loss of autophagy therefore differentially affects other heat stress response pathways, depending on the specific stress conditions leading to the activation of the pathways.

plant biology↗

bioRxiv2024

A fast, muscle-actuated biohybrid swimming robot

The integration of biological actuators with soft scaffolds has led to biohybrid robots including microscale flagellate-like swimmers which generate thrust by waving their flagella-like tails. However, they achieve swimming speeds of only 0.014 body lengths per minute, Reynolds number (Re) [~] 10-3, which is much slower than natural flagellates (O(102 - 103) body lengths per minute). To investigate this, we applied theoretical and experimental methods, including fabrication of a swimmer that converts muscle contractions into large angular tail displacements, reaching swimming speeds of 86.8 m/s (0.58 body lengths per minute), surpassing low-Re predictions. Swimming dynamics sharply transition from a low-Re ([~] 10-3) to an intermediate-Re ([~] 0.1) regime when the actuation angle exceeded 4{degrees}. We used the swimmer to study the ability of muscle to adapt to mechanical stiffness and the beneficial effects of neuromuscular coculture on muscle development. These insights into mechanical and chemical cues will help optimize future biobots. TeaserHow are biological flagellate swimmers like E. coli and sperm cells so fast? We have built a new biohybrid robot to explore the theory.

bioengineering↗

bioRxiv2024

Detecting Special Genes in Marine Symbionts: A Phylogeny-Deviation Approach Identifies Recombination-Enhancing Variants

Different microbes possess special traits that enable adaptation to their specific niches, often through specialized genes. Identifying such species-special genes provides insights into microbial physiology and offers new tools for bioengineering. However, beyond the search for orphan genes, there are few methods for detecting genes that are homologous to those in other species yet contain unusual functional regions. In investigating the extreme recombination frequency of the marine symbiont bacterium Ca. E. kahalalidifaciens, we developed a computational approach to identify vairants that substantially deviate from phylogenetic expectations. This unbiased strategy successfully identified multiple Holliday junctions-related genes in Ca. E. kahalalidifaciens as candidates responsible for its exceptional recombination capacity. Heterologous expression of these gene variants in Escherichia coli significantly enhanced recombination efficiency. These high-efficient variants offer insights into improving tools for genetic manipulations, and our gene-identification approach can be applied broadly for microbial genome mining.

bioinformatics↗

bioRxiv2024

CILP from Cartilage Intermediate Zone Inhibits Hyaline Cartilage Fibrosis and Chondrocyte Ferroptosis via Keap1-Nrf2 Axis in Early Osteoarthritis Exercise Therapy

By analyzing the single-cell RNA-Seq libraries, the roles of cartilage intermediate layer protein (CILP) and the cartilage intermediate zone in early osteoarthritis (OA) exercise therapy were explored. An early OA rat model was established via a 4-week anterior cruciate ligament transection. The effect of moderate exercise was confirmed using histology, the open-field test, and gait analysis. The response of the cartilage intermediate zone to mechanical stimulation was explored using multiplex fluorescent immunohistochemical staining. Radiomics was used to evaluate the relatively damaged and undamaged areas in the cartilage of patients with OA. CILP was OE and KD in early OA chondrocytes, and quantitative proteomics, yeast one-hybrid, co-immunoprecipitation, Nrf2 and ubiquitination assays were used to investigate its mechanism. We found that moderate exercise upregulates CILP in the cartilage intermediate zone. CILP recovers the type II/I collagen, Sox9, and -SMA expression ratios, and reduces Keap1-Nrf2 dimer stability, inhibiting Nrf2 ubiquitination and promoting Nrf2 nuclear translocation. Nrf2 nuclear translocation activates SLC7A11, HO-1, GPX4, and SOD-1 expression, decreases MDA content, and increases GSH content, inhibiting chondrocyte ferroptosis and promoting fibrocartilage hyalinization. In conclusion, the exercise-induced cartilage intermediate zone and CILP-Keap1-Nrf2 axis inhibit hyaline cartilage fibrosis and chondrocyte ferroptosis to alleviate early OA.

cell biology↗

bioRxiv2024

Genome-wide investigation of outer membrane protein families under mosaic evolution in Escherichia coli

Several genes in Gram-negative bacteria encoding outer membrane proteins (OMPs) have been reported to show patterns of mosaic evolution featured by mixture of negative selection and local recombination. Here, we proposed a strategy, and applied it to screen OMPs under mosaic evolution in Escherichia coli in the genome level. In total, 21 OMP families, including 16 new ones, were detected with the typical patterns of mosaic evolution. An abosolute majority of the protein families are conserved in E. coli for the composition, genomic loci and the overall structures. Highly Variable Regions (HVRs) can be recognized, which are frequently located extracellularly within the protruding loops. There are only limited number of major HVR sequence types, within which positively selected sites can be detected ocassionally. Based on the simulated results of multiple models, the OMPs under mosaic evolution are often with good antigenicity, with HVRs of various sequence types coinciding with the B-cell epitopes of the strongest immunogenicity. The study futher broadened our understanding of the characteristics of mosaic evolution and the functions of OMPs in Gram-negative bacteria, laying an important foundation for their potential translational applications. ImportanceIt is important to understand the evolutionary mechanisms of bacterial OMP-encoding genes, which would facilitate the development of anti-bacterial reagents. This study made the first genome-wide screening of bacterial OMPs under mosaic evolution, and increased the list of candidate OMP families by 3 folds in E. coli, far more than we expected. The study further confirmed the hypothesis about the evolutionary, micro-evolutionary and structural features of these OMPs, and facilitated the functional theory of mosaic evolution. Moreover, the findings of limited HVR sequence types and strong immunogenicity of HVRs paved important foundation for application of these OMPs and their HVRs in development of antibodies or other anti-bacterial treatment.

microbiology↗

bioRxiv2024

Phage CRISPR-like regulatory RNAs silence bacterial adaptive and innate immunity

CRISPR RNAs (crRNAs) encoded by CRISPR arrays direct Cas nucleases against viruses. Some CRISPR-Cas loci also contain mini-arrays encoding crRNA-like RNAs (crlRNAs), which modulate transcription of cas or associated toxin genes that safeguard CRISPR-Cas activity. Here, we report that phages hijack these host crlRNA regulatory circuits to suppress bacterial immunity. Viral crlRNAs compete with host crRNAs for Cas protein binding and reprogram Cas proteins to silence their own expression or suppress transcription of CRISPR-safeguarding toxins. These anti-defense crlRNAs are found across diverse phages and plasmids, frequently organized into multiplexed transcriptional units resembling CRISPR arrays, and often synergize with co-encoded anti-CRISPR proteins to disable hierarchical host immune responses. Furthermore, we demonstrate that these compact viral crlRNA architectures can be harnessed for efficient mammalian genome editing. Our findings uncover widespread viral hijacking of host Cas proteins via crlRNAs, highlighting the recurrent exaptation of CRISPR-Cas regulatory functions to counter multilayered bacterial immune defenses.

microbiology↗

bioRxiv2024

Label-Free Optical Biopsy Reveals Biomolecular and Morphological Features of Diabetic Kidney Tissue in 2D and 3D

Kidney disease, the ninth leading cause of death in the United States, has one of the poorest diagnostic efficiencies of only 10%1. Conventional diagnostic methods often rely on light microscopy analysis of 2D fixed tissue sections with limited molecular insight compared to omics studies. Targeting multiple features in a biopsy using molecular or chemical reagents can enhance molecular phenotyping but are limited by overlap of their spatial and chromatic properties, variations in quality of the products, limited multimodal nature and need additional tissue processing. To overcome these limitations and increase the breadth of molecular information available from tissue without an impact on routine diagnostic workup, we implemented label-free imaging modalities including stimulated Raman scattering (SRS) microscopy, second harmonic generation (SHG), and two photon fluorescence (TPF) into a single microscopy setup. We visualized and identified morphological, structural, lipidomic, and metabolic biomarkers of control and diabetic human kidney biopsy samples in 2D and 3D at a subcellular resolution. The label-free biomarkers, including collagen fiber morphology, mesangial-glomerular fractional volume, lipid saturation, redox status, and relative lipid and protein concentrations in the form of Stimulated Raman Histology (SRH), illustrate distinct features in kidney disease tissues not previously appreciated. The same tissue section can be used for routine diagnostic work up thus enhancing the power of cliniopathological insights obtainable without compromising already limited tissue. The additional multimodal biomarkers and metrics are broadly applicable and deepen our understanding of the progression of kidney diseases by integrating lipidomic, fibrotic, and metabolic data. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=125 SRC="FIGDIR/small/620507v1_ufig1.gif" ALT="Figure 1"> View larger version (76K): org.highwire.dtl.DTLVardef@116edb1org.highwire.dtl.DTLVardef@4f010corg.highwire.dtl.DTLVardef@cde718org.highwire.dtl.DTLVardef@1ff0841_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical AbstractC_FLOATNO Label-free indicators of diabetic nephropathies. C_FIG

bioengineering↗