Biology subjects

Chen, X.

Publications and source records attributed to Chen, X..

At least 1,567 records · Page 87Linked to original sources

bioRxiv2018

Systematic Discovery of the Functional Impact of Somatic Genome Alterations in Individual Tumors through Tumor-specific Causal Inference

We report a tumor-specific causal inference (TCI) framework, which discovers causative somatic genome alterations (SGAs) through inferring causal relationships between SGAs and molecular phenotypes (e.g., transcriptomic, proteomic, or metabolomic changes) within an individual tumor. We applied the TCI algorithm to tumors from The Cancer Genome Atlas (TCGA) and identified those SGAs that causally regulate the differentially expressed genes (DEGs) within each tumor. Overall, TCI identified 634 SGAs that cause cancer-related DEGs in a significant number of tumors, including most of the previously known drivers and many novel candidate cancer drivers. The inferred causal relationships are statistically robust and biologically sensible, and multiple lines of experimental evidence support the predicted functional impact of both well-known and novel candidate drivers. By identifying major candidate drivers and revealing their functional impact in a tumor, TCI shed light on disease mechanisms of each tumor, providing useful information for advancing cancer biology and precision oncology.\n\nSignificance statementsCancer is mainly caused by SGAs. Precision oncology involves identifying and targeting tumor-specific aberrations resulting from causative SGAs. TCI is a novel computational framework for discovering the causative SGAs and their impact on oncogenic processes, thus revealing tumor-specific disease mechanisms. This information can be used to guide precision oncology.

cancer biology↗

bioRxiv2018

Deconvolution of single-cell multi-omics layers reveals regulatory heterogeneity

Integrative analysis of multi-omics layers at single cell level is critical for accurate dissection of cell-to-cell variation within certain cell populations. Here we report scCAT-seq, a technique for simultaneously assaying chromatin accessibility and the transcriptome within the same single cell. We show that the combined single cell signatures enable accurate construction of regulatory relationships between cis-regulatory elements and the target genes at single-cell resolution, providing a new dimension of features that helps direct discovery of regulatory patterns specific to distinct cell identities. Moreover, we generated the first single cell integrated maps of chromatin accessibility and transcriptome in human pre-implantation embryos and demonstrated the robustness of scCAT-seq in the precise dissection of master transcription factors in cells of distinct states during embryo development. The ability to obtain these two layers of omics data will help provide more accurate definitions of \"single cell state\" and enable the deconvolution of regulatory heterogeneity from complex cell populations.

genomics↗

bioRxiv2018

4-hydroxyphenylpyruvate dioxygenase thermolability is responsible for temperature-dependent melanogenesis in Aeromonas salmonicida subsP salmonicida

Aeromonas salmonicida subsp. salmonicida (A.s.s) is a major pathogen affecting fisheries worldwide. It is a well-known member of the pigmented Aeromonas species, which produces melanin at [≤] 22 {degrees}C. However, melanogenesis decreases as the culture temperature increases and is completely suppressed at 30-35 {degrees}C while bacterial growth is not affected. The mechanism and biological significance of this temperature-dependent melanogenesis are not clear. Heterologous expression of an A.s.s. 4-hydroxyphenylpyruvate dioxygenase (HppD), the most crucial enzyme in the HGA-melanin synthesis pathway, results in thermosensitive pigmentation in Escherichia coli, suggesting that HppD plays a key role in this process. In the current study, we demonstrated that the extreme thermolability of HppD is responsible for the temperature-dependent melanization of A.s.s. Substitutions in three residues, Ser18, Pro103, or Leu119 of HppD from A.s.s increases the thermolability of this enzyme and results in temperature-independent melanogenesis. Moreover, replacing the corresponding residues of HppD from Aeromonas media strain WS, which forms pigment independent of temperature, with those of A.s.s HppD leads to thermosensitive melanogenesis. Structural analysis suggested that mutations at these sites, especially at position P103, can strengthen the secondary structure of HppD and greatly improve its thermal stability. In addition, we found that HppD sequences of all A.s.s isolates are identical and that two of the three residues are completely conserved within A.s.s isolates, which clearly distinguishes these from other Aeromonas strains. We suggest that this property represents an adaptive strategy to the psychrophilic lifestyle of A.s.s.\n\nImportanceAeromonas salmonicida subsp. salmonicida (A.s.s) is the causative agent of furunculosis, a bacterial septicemia of cold water fish of the Salmonidae family. As it has a well-defined host range, A.s.s has become an ideal model to investigate the co-evolution of host and pathogen. For many pathogens, melanin production is associated with virulence. Although other species of Aeromonas can produce melanin, A.s.s is the only member of this genus that has been reported to exhibit temperature-dependent melanization. Here we demonstrate that thermosensitive melanogenesis in A.s.s strains is due to the thermolability of 4-hydroxyphenylpyruvate dioxygenase (HppD). The strictly conserved hppD sequences among A.s.s and the exclusive thermosensitive pigmentation of these strains might provide insight into the role of melanin in the adaptation to a particular host, and offer a novel molecular marker to readily differentiate A.s.s strains from other A. salmonicida subspecies and Aeromonas species.

molecular biology↗

bioRxiv2018

Reduced but not Enhanced Default Mode Network Functional Connectivity in Major Depressive Disorder: Evidence from 25 Cohorts in the REST-meta-MDD Project

Major Depressive Disorder (MDD) is common and disabling, but its neural pathophysiology remains unclear. Functional brain network studies in MDD have largely had limited statistical power and data analysis approaches have varied widely. The REST-meta-MDD Project of resting-state fMRI (R-fMRI) addresses these issues. The 25 research groups in China composing the REST-meta-MDD Project contributed R-fMRI data of 1,300 patients with MDD and 1,128 normal controls (NCs). The data were preprocessed locally with a standardized protocol prior to aggregated group analyses. We focused on functional connectivity (FC) within the default mode network (DMN), frequently reported to show increased FC in MDD. We found decreased instead of increased DMN FC when comparing 848 MDDs with 794 NCs from 17 sites after data exclusion. We found FC reduction only in recurrent MDD, not in first-episode drug-naive MDD. Decreased DMN FC was associated with medication usage but not with MDD duration. DMN FC was also positively related to symptom severity but only in recurrent MDDs. Exploratory analyses also revealed alterations of local intrinsic activity in MDD. We confirmed the key role of DMN in MDD but found reduced rather than increased FC within the DMN. Future studies should test whether decreased DMN FC mediates treatment response. This manuscript announces the publicly available resting-state fMRI indices of the REST-meta-MDD consortium shared via the R-fMRI Maps Project.\n\nSIGNIFICANCE STATEMENTFunctional connectivity within the default mode network in major depressive disorder patients has been frequently reported abnormal but with contradicting directions in previous small sample size studies. By creating the REST-meta-MDD consortium containing neuroimaging data of 1,300 depressed patients and 1,128 normal controls from 25 research groups in China, we found decreased default mode network functional connectivity in depressed patients, driven by patients with recurrent depression, and associated with current medication treatment but not with disease duration. These findings suggest that default mode network functional connectivity remains a prime target for understanding the pathophysiology of depression, with particular relevance to revealing mechanisms of effective treatments.

neuroscience↗

bioRxiv2018

The Evolution and Sequence Diversity of FhuA in Salmonella and Escherichia

The fhuACDB operon, present in a number of Enterobacteriaceae, encodes components essential for the uptake of ferric hydroxamate type siderophores. FhuA acts not only as transporter for physiologically important chelated ferric iron, but also as receptor for various bacteriophages, toxins and antibiotics, which are pathogenic to bacterial cells. In this research, the fhuA gene distribution and sequence diversity were investigated in Enterobacteriaceae, especially Salmonella and Escherichia. Comparative sequence analysis resulted in a fhuA phylogenetic tree that did not match the expected phylogeny based on housekeeping sequence analysis or trees of fhuCDB genes. The fhuA sequences showed a unique mosaic-clustering pattern. On the other hand, the gene sequences showed high conservation for strains from the same serovar or serotype. In total, six clusters were identified from FhuA proteins in Salmonella and Escherichia, among which typical peptide fragment variations could be defined. Six fragmental insertions / deletions and two substitution fragments were discovered, which could well classify the different clusters. Structure modeling demonstrated that all the six featured insertions/deletions and one substitution fragment are located at the apexes of the long loops of FhuA external pocket. These frequently mutated regions are likely under high selection pressure, and bacterial strains could have escaped from phage infection or toxin / antibiotics attack via fhuA gene mutations while maintaining the siderophore uptake activity essential for bacterial survival. The unusual fhuA clustering suggests that high frequency exchange of fhuA genes has occurred between enterobacterial strains after distinctive species were established.\n\nIMPORTANCEThe enterobacterial fhuACDB operon encodes proteins which mediate the uptake of siderophores to supply the cells with iron essential for bacterial survival. Here we show different evolutionary patterns for the fhu genes within the same operon. The fhuA has a phylogenetic tree that does not match the species phylogeny, whereas the rest of the fhu genes do. The fhuA genes showed inter-species sequence convergence and conservation within specific serovars and serotypes. Nearly all of the significant sequence differences among FhuA clusters are located in potential ligand-binding sites on the extracellular surface of fhuA-encoding receptors. The unusual fhuA clustering suggests the frequent recombination and exchange of fhuA genes between enterobacterial strains in the evolutionary state after distinctive species were established.\n\nOur findings suggested either a new evolutionary mechanism or local gene recombination in fhuA that is in contrast to previous evolutionary hypotheses that have formed under the assumption of no recombination.

microbiology↗

bioRxiv2018

Epidemiology, Microbiology and Therapeutic Consequences of Chronic Osteomyelitis in Northern China: A Retrospective Analysis of 255 Patients

The study aimed to explore the epidemiology and clinical characteristics of chronic osteomyelitis observed in a northern China hospital. Clinical data of 255 patients with chronic osteomyelitis from January 2007 to January 2014 were collected and analyzed, including general information, disease data, treatment and follow-up data. Chronic osteomyelitis is more common in males and in the age group from 41-50 years of age. Common infection sites are the femur, tibiofibular, and hip joint. More g+ than g- bacterial infections were observed, with S. aureus the most commonly observed pathogenic organism. The positive detection rate from debridement bacterial culture is 75.6%. The detection rate when five samples are sent for bacterial culture is 90.6%, with pathogenic bacteria identified in 82.8% of cases. The two-stage debridement method (87.0%) has higher first curative rate than the one-stage debridement method (71.2%). To improve detection rate using bacterial culture, at least five samples are recommended. Treatment of chronic osteomyelitis with two-stage debridement, plus antibiotic-loaded polymethylmethacrylate (PMMA) beads provided good clinical results in this study and is therefore recommended.

microbiology↗

bioRxiv2018

Structural basis for transfer RNA mimicry by a bacterial Y RNA

Noncoding Y RNAs are present in both animal cells and many bacteria. In all species examined, Y RNAs tether the Ro60 protein to an effector protein to perform various cellular functions. For example, in the bacterium Deinococcus radiodurans, Y RNA tethers Ro60 to the exoribonuclease polynucleotide phosphorylase, specializing this nuclease for structured RNA degradation. Recently, a new Y RNA subfamily was identified in bacteria. Bioinformatic analyses of these YrlA (Y RNA-like A) RNAs predict that the effector-binding domain resembles tRNA. We present the structure of this domain, the overall folding of which is strikingly similar to canonical tRNAs. The tertiary interactions that are responsible for stabilizing tRNA are present in YrlA, making it a close tRNA mimic. However, YrlA lacks a free CCA end and contains a kink in the stem corresponding to the anticodon stem. Since nucleotides in the D and T stems are conserved among YrlAs, they may be an interaction site for an unknown factor. Our experiments identify YrlA RNAs as a new class of tRNA mimics.

biochemistry↗

bioRxiv2018

Integrative analysis of single cell genomics data by coupled nonnegative matrix factorizations

When different types of functional genomics data are generated on single cells from different samples of cells from the same heterogeneous population, the clustering of cells in the different samples should be coupled. We formulate this \"coupled clustering\" problem as an optimization problem, and propose the method of coupled nonnegative matrix factorizations (coupled NMF) for its solution. The method is illustrated by the integrative analysis of single cell RNA-seq and single cell ATAC-seq data.\n\nSignificance StatementsBiological samples are often heterogeneous mixtures of different types of cells. Suppose we have two single cell data sets, each providing information on a different cellular feature and generated on a different sample from this mixture. Then, the clustering of cells in the two samples should be coupled as both clusterings are reflecting the underlying cell types in the same mixture. This \"coupled clustering\" problem is a new problem not covered by existing clustering methods. In this paper we develop an approach for its solution based the coupling of two nonnegative matrix factorizations. The method should be useful for integrative single cell genomics analysis tasks such as the joint analysis of single cell RNA-seq and single cell ATAC-seq data.

bioinformatics↗

bioRxiv2018

Biogenesis of a young, 22-nt microRNA in Phaseoleae species by precursor-programmed uridylation

Phased, secondary siRNAs (phasiRNAs) represent a class of small RNAs in plants generated via distinct biogenesis pathways, predominantly dependent on the activity of 22 nt miRNAs. Most 22 nt miRNAs are processed by DCL1 from miRNA precursors containing an asymmetric bulge, yielding a 22/21 nt miRNA/miRNA* duplex. Here we show that miR1510, a soybean miRNA capable of triggering phasiRNA production from numerous NB-LRRs, previously described as 21 nt in its mature form, primarily accumulates as a 22 nt isoform via monouridylation. We demonstrate that in Arabidopsis, this uridylation is performed by HESO1. Biochemical experiments showed that the 3 terminus of miR1510 is only partially 2-O-methylated, because of the terminal mispairing in the miR1510/miR1510* duplex that inhibits HEN1 activity in soybean. miR1510 emerged in the Phaseoleae ~41 to 42 MYA with a conserved precursor structure yielding a 22 nt monouridylated form, yet a variant in mung bean is processed directly in a 22 nt mature form. This analysis of miR1510 yields two observations: (1) plants can utilize post-processing modification to generate abundant 22 nt miRNA isoforms to more efficiently regulate target mRNA abundances; (2) comparative analysis demonstrates an example of selective optimization of precursor processing of a young plant miRNA.

plant biology↗

bioRxiv2018

Asymmetric increases in the intensity of the green autofluorescence of ischemic stroke patients’ skin and fingernails: A novel diagnostic biomarker for ischemic stroke

AbstractEarly and economical diagnosis of acute ischemic stroke (AIS) is pivotal for therapeutic efficacy, particularly for the settings where medical imaging resource is deficient. We have obtained evidence supporting our hypothesis that collective properties of the green autofluorescence (AF) of the fingernails and certain skins positions may be a novel diagnostic biomarker for AIS: Both the green AF intensity and AF asymmetry of the AIS patients in their Index Fingernails and most examined skins positions were significantly higher than that of the healthy subjects and the Non-AIS subjects. ROC analyses and machine learning-based analyses on the AF properties showed that AUC was 0.93 and 0.87, respectively, for differentiating the AIS patients from the healthy subjects and for differentiating the AIS patients from the Non-AIS subjects. The AIS patients had significantly higher AF intensity and AF asymmetry at several examined positions, compared to those of the patients of Parkinsons disease, pulmonary infection and transient ischemic attack. The AUC was 0.79 - 0.88 for differentiating AIS patients from each of these diseases. There was evidence suggesting that the AF originates from keratins. Collectively, our study has indicated that the characteristic AISs Pattern of AF is a novel diagnostic biomarker for the disease. The Pattern of AF Technology holds excellent potential to become a new non-invasive, label-free and economical diagnostic approach for AIS, which is particularly valuable when MRI or CT imaging resource is deficient.

neuroscience↗

bioRxiv2018

A rapid and robust method for single cell chromatin accessibility profiling

The assay for transposase-accessible chromatin using sequencing (ATAC-seq) is widely used to identify regulatory regions throughout the genome. However, very few studies have been performed at the single cell level (scATAC-seq) due to technical challenges. Here we developed a simple and robust plate-based scATAC-seq method, combining upfront bulk Tn5 tagging with single-nuclei sorting. We demonstrated that our method worked robustly across various systems, including fresh and cryopreserved cells from primary tissues. By profiling over 3,000 splenocytes, we identify distinct immune cell types and reveal cell type-specific regulatory regions and related transcription factors.

genomics↗

bioRxiv2018

Joint single-cell DNA accessibility and protein epitope profiling reveals environmental regulation of epigenomic heterogeneity

Here we introduce Protein-indexed Assay of Transposase Accessible Chromatin with sequencing (Pi-ATAC) that combines single-cell chromatin and proteomic profiling. In conjunction with DNA transposition, the levels of multiple cell surface or intracellular protein epitopes are recorded by index flow cytometry and positions in arrayed microwells, and then subject to molecular barcoding for subsequent pooled analysis. Pi-ATAC simultaneously identifies the epigenomic and proteomic heterogeneity in individual cells. Pi-ATAC reveals a casual link between transcription factor abundance and DNA motif access, and deconvolute cell types and states in the tumor microenvironment in vivo. We identify a dominant role for hypoxia, marked by HIF1 protein, in the tumor microvenvironment for shaping the regulome in a subset of epithelial tumor cells.

genomics↗

bioRxiv2018

Epitope-based vaccine design yields fusion peptide-directed antibodies that neutralize diverse strains of HIV-1

A central goal of HIV-1-vaccine research is the elicitation of antibodies capable of neutralizing diverse primary isolates of HIV-1. Here we show that focusing the immune response to exposed N-terminal residues of the fusion peptide, a critical component of the viral entry machinery and the epitope of antibodies elicited by HIV-1 infection, through immunization with fusion peptide-coupled carriers and prefusion-stabilized envelope trimers, induces cross-clade neutralizing responses. In mice, these immunogens elicited monoclonal antibodies capable of neutralizing up to 31% of a cross-clade panel of 208 HIV-1 strains. Crystal and cryo-electron microscopy structures of these antibodies revealed fusion peptide-conformational diversity as a molecular explanation for the cross-clade neutralization. Immunization of guinea pigs and rhesus macaques induced similarly broad fusion peptide-directed neutralizing responses suggesting translatability. The N terminus of the HIV-1-fusion peptide is thus a promising target of vaccine efforts aimed at eliciting broadly neutralizing antibodies.

immunology↗

bioRxiv2018

LCA robustly reveals subtle diversity in large-scale single-cell RNA-seq data

Single-cell RNA sequencing has emerged as a powerful tool for characterizing the cell-to-cell variation and dynamics. We present Latent Cellular Analysis (LCA), a machine learning-based analytical pipeline that features a dual-space model search with inference of latent cellular states, control of technical variations, cosine similarity measurement, and spectral clustering. LCA has proved to be robust, accurate, scalable, and powerful in revealing subtle diversity in cell populations.

bioinformatics↗

bioRxiv2018

DNA local structure decreases mutation rates

BackgroundMutation rates vary across the genome. Whereas many trans factors that influence mutation rates have been identified, as have specific sequence motifs at the 1-7 bp scale, cis elements remain poorly characterized. The lack of understanding why different sequences have different mutation rates hampers our ability to identify positive selection in evolution and to identify driver mutations in tumorigenesis.\n\nResultsHere we show, using a combination of synthetic genes and sequencing of thousands of isolated yeast colonies, that intrinsic DNA curvature is the major cis determinant of mutation rate. Mutation rate negatively correlates with DNA curvature within genes, and a 10% decrease in curvature results in a 70% increase in mutation rate. Consistently, both yeast cells and human tumors accumulate mutations in regions with small curvature. We further show that this effect is due to differences in the intrinsic mutation rate, likely due to differences in mutagen sensitivity, and not due to differences in the local activity of DNA repair.\n\nConclusionsOur study establishes a framework in understanding the cis properties of DNA sequence in modulating the local mutation rate and identifies a novel causal source of non-uniform mutation rates across the genome.

genetics↗

bioRxiv2018

Spatial organization of projection neurons in the mouse auditory cortex identified by in situ barcode sequencing

Understanding neural circuits requires deciphering interactions among myriad cell types defined by spatial organization, connectivity, gene expression, and other properties. Resolving these cell types requires both single neuron resolution and high throughput, a challenging combination with conventional methods. Here we introduce BARseq, a multiplexed method based on RNA barcoding for mapping projections of thousands of spatially resolved neurons in a single brain, and relating those projections to other properties such as gene or Cre expression. Mapping the projections to 11 areas of 3579 neurons in mouse auditory cortex using BARseq confirmed the laminar organization of the three top classes (IT, PT-like and CT) of projection neurons. In depth analysis uncovered a novel projection type restricted almost exclusively to transcriptionally-defined subtypes of IT neurons. By bridging anatomical and transcriptomic approaches at cellular resolution with high throughput, BARseq can potentially uncover the organizing principles underlying the structure and formation of neural circuits.

neuroscience↗

bioRxiv2018

Astroplastic: A start-to-finish process for polyhydroxybutyrate production from solid human waste using genetically engineered bacteria to address the challenges for future manned Mars missions

Space exploration has long been a source of inspiration, challenging scientists and engineers to find innovative solutions to various problems. One of the current focuses in space exploration is to send humans to Mars. However, the challenge of transporting materials to Mars and the need for waste management processes are two major obstacles for these long-duration missions.\n\nTo address these two challenges a process called Astroplastic was developed that produces polyhydroxybutyrate (PHB) from solid human waste, which can be used to 3D print useful items for astronauts. PHB granules are naturally produced by bacteria such as Ralstonia eutropha and Pseudomonas aeruginosa for carbon and energy storage. The phaJ, phaC, and phaCBA genes were cloned from these native PHB-producing bacteria into Escherichia coli. These genes code for enzymes that aid in PHB production by converting products of glycolysis and {beta}-oxidation pathways, such as acetyl-CoA and enoyl-CoA, into PHB. To ensure a continuous PHB production system and to eliminate the need for cell lysis to extract PHB, recombinant E. coli was engineered to use the genes in its natural type I secretion system to secrete PHB. The C-terminal of the HlyA secretion tag was fused to phasin (PhaP), a protein originally from R. eutropha. Phasin-HlyA electrostatically binds PHB granules and transports them outside of the cell.\n\nIn addition to genetically engineering bacteria, a concept for start-to-finish PHB production process was designed. Integrating expert feedback and experimental results, conditions for each step of the process including the collection and storage of waste, volatile fatty acid (VFA) fermentation, VFA extraction, PHB fermentation, and PHB extraction were optimized. The optimized system will provide a sustainable and continuous PHB production system, which will address the problems of transportation costs and waste management for future space missions.\n\nFinancial DisclosureMindfuel Science Alberta Foundation Genome Alberta GenScript Polyferm Canada GeekStarter Alberta Integrated DNA Technologies University of Calgary University of Calgary Cumming School of Medicine University of Calgary Bachelor of Sciences University of Calgary Schulich School of Engineering University of Calgary OBrien Centre for the Bachelor of Health Sciences City of Calgary Alberta Innovates The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.\n\nCompeting InterestsThe authors have declared that no competing interests exist.\n\nEthics StatementN/A\n\nData AvailabilityAll data are freely available without restriction.

synthetic biology↗

bioRxiv2018

Widespread and polymorphous noncoding amino acid residues in human sperm proteome

Proteins are usually deciphered by translation of the coding genome; however, their amino acid residues are seldom determined directly across the proteome. Herein, we describe a systematic workflow for identifying all possible protein residues that differ from the coding genome, termed noncoded amino acids (ncAAs). By measuring the mass differences between the coding amino acids and the actual protein residues in human spermatozoa, over a million nonzero delta masses were detected, fallen into 424 high-quality Gaussian clusters and 571 high-confidence ncAAs spanning 29,053 protein sites. Most ncAAs are novel with unresolved side-chains and discriminative between healthy individuals and patients with oligoasthenospermia. For validation, 40 out of 98 ncAAs that matched with amino acid substitutions were confirmed by exon sequencing. This workflow revealed the widespread existence of previously unreported ncAAs in the sperm proteome, which represents a new dimension on the understanding of amino acid polymorphisms at the proteomic level.\n\nHighlightsO_LI571 ncAAs spanning 108,000 protein sites were identified in human sperm proteome.\nC_LIO_LIMost ncAAs are novel with unresolved sidechains and found at unreported protein sites.\nC_LIO_LIExon sequencing confirmed 40 of 98 ncAAs that matched with amino acid substitutions.\nC_LIO_LIMany ncAAs are linked with disease and have potential for diagnosis and targeting.\nC_LI\n\neTOC BlurbWe describe a systematic identification of all possible protein residues that were not encoded by their genomic sequences. A total of 571 high-confidence most novel noncoded amino acids were identified in human sperm proteome, corresponding to over 108,000 ncAA-containing protein sites. For validation, 40 out of 98 ncAAs that matched to amino acid substitutions were confirmed by exon sequencing. These ncAAs are discriminative between individuals and expand our understanding of amino acid polymorphisms in human proteomes and diseases.

molecular biology↗