Biology subjects

Huang, C.

Publications and source records attributed to Huang, C..

At least 235 records · Page 13Linked to original sources

bioRxiv2019

Microscaled Proteogenomic Methods for Precision Oncology

Cancer proteogenomics integrates genomics, transcriptomics and mass spectrometry (MS)-based proteomics to gain insights into cancer biology and treatment efficacy. A proteogenomics approach was therefore developed for frozen core biopsies using tissue-sparing specimen processing with a \"microscaled\" proteomics workflow. For technical proof-of-principle, biopsies from ERBB2 positive breast cancers before and 48-72 hours after the first dose of neoadjuvant trastuzumab-based chemotherapy were analyzed. ERBB2 protein and phosphosite levels, as well as mTOR target phosphosites, were significantly more suppressed upon treatment in cases associated with pathological complete response, suggesting MS-based pharmacodynamics is achievable. Furthermore, integrated analyses indicated potential causes of treatment resistance including the absence of ERBB2 amplification (false-ERBB2 positive) and insufficient ERBB2 activity for therapeutic sensitivity despite ERBB2 amplification (pseudo-ERBB2 positive). Candidate resistance features in true-ERBB2+ cases, including androgen receptor signaling, mucin expression and an inactive immune microenvironment were observed. Thus, proteogenomic analysis of needle core biopsies is feasible and clinical utility should be investigated.

cancer biology↗

bioRxiv2019

Satellite Imaging of Global Urbanicity relate to Adolescent Brain Development and Behavior

Urbanicity, the impact of living in urban areas, is among the greatest environmental challenges for mental health. While urbanicity might be distinct in different sociocultural conditions and geographic locations, there are likely to exist common features shared in different areas of the globe. Understanding these common and specific relations of urbanicity with human brain and behavior will enable to assess the impact of urbanicity on mental disorders, especially in childhood and adolescence, where prevention and early interventions are likely to be most effective.\n\nWe constructed from satellite-based remote sensing data a factor for urbanicity that was highly correlated with population density ground data. This factor, UrbanSat was utilized in the Chinese CHIMGEN sample (N=831) and the longitudinal European IMAGEN cohort (N=810) to investigate if exposure to urbanicity during childhood and adolescence is associated with differences in brain structure and function in young adults, and if these changes are linked to behavior.\n\nUrbanicity was found negatively correlated with medial prefrontal cortex volume and positively correlated with cerebellar vermis volume in young adults from both China and Europe. We found an increased correlation of urbanicity with functional network connectivity within- and between- brain networks in Chinese compared to European participants. Urbanicity was highly correlated with a measure of perceiving a situation from the perspective of others, as well as symptoms of depression in both datasets. These correlations were mediated by the structural and functional brain changes observed. Susceptibility to urbanicity was greatest in two developmental windows during mid-childhood and adolescence.\n\nUsing innovative technology, we were able to probe the relationship between urban upbringing with brain change and behavior in different sociocultural conditions and geographic locations. Our findings help to identify shared and distinct determinants of adolescent brain development and mental health in different regions of the world, thus contributing to targeted prevention and early-intervention programs for young people in their unique environment. Our approach may be relevant for public health, policy and urban planning globally.

neuroscience↗

bioRxiv2019

Comparative transcriptome analysis of the ovary and testis of the lacustrine goby (Gobiopterus lacustris)

ABSTRCTLacustrine goby (Gobiopterus lacustris) belongs to a genus of gobies that are small in size and endemic to freshwater, brackish waters or coastal environments around the Indian and Pacific oceans. To date, there are no genomic or transcriptomic studies on G. lacustris. Here, we constructed gonadal transcriptomes of G. lacustris for the first time and identified genes that may be involved in gonadal development and reproduction. In total, 60,657,644 and 52,016,136 clean reads were obtained from ovary and testis, respectively, using Illumina sequencing. Reads were assembled into 62,573 unigenes with N50 value of 3,082 bp and a mean length of 1,869 bp. A total of 47,891 (76.53%) unigenes were annotated in at least one of the seven databases that were used in this study. In addition, 38,550 SSRs (simple sequence repeat, microsatellite) were identified from 20,517 SSR containing sequences. Gene expression patterns in the testis and ovary were compared, and 10,954 DEGs (differentially expressed genes) were identified. Of these genes, 2,383 were up-regulated in the testis and 8,571 were up-regulated in the ovary. RT-qPCR analysis of 14 selected genes showed patterns consistent with the transcriptome results. Numerous DEGs involved in gonadal development and gametogenesis were identified, including foxl2, dmrt1, cyp19a1a, inha, inhb, sycp2, zglp1, tdrp, zps and esra. Using GO and KEGG enrichment analyses, pathways involving regulation of gonadal development and gametogenesis also identified. This work represents the first gonadal transcriptomic analysis of G. lacustris and provides a valuable dataset for future research on the genes involved in reproduction of G. lacustris.

molecular biology↗

bioRxiv2019

Strain-level identification of bacterial tomato pathogens directly from metagenomic sequences

Routine strain-level identification of plant pathogens directly from symptomatic tissue could significantly improve plant disease control and prevention. Here we tested the Oxford Nanopore Technologies (ONT) MinION sequencer for metagenomic sequencing of tomato plants either artificially inoculated with a known strain of the bacterial speck pathogen Pseudomonas syringae pv. tomato (Pto), or collected in the field and showing bacterial spot symptoms caused by either one of four Xanthomonas species. After species-level identification using ONTs WIMP software and the third party tools Sourmash and MetaMaps, we used Sourmash and MetaMaps with a custom database of representative genomes of bacterial tomato pathogens to attempt strain-level identification. In parallel, each metagenome was assembled and the longest contigs were used as query with the genome-based microbial identification Web service LINbase. Both the read-based and assembly-based approaches correctly identified Pto strain T1 in the artificially inoculated samples. The pathogen strain in most field samples was identified as a member of Xanthomonas perforans group 2. This result was confirmed by whole genome sequencing of colonies isolated from one of the samples. Although in our case, metagenome-based pathogen identification at the strain-level was achieved, caution still needs to be exerted when interpreting strain-level results because of the challenges inherent to assigning reads to specific strains and the error rate of nanopore sequencing.

microbiology↗

bioRxiv2019

An integrated Asian human SNV and indel benchmark combining multiple sequencing methods

Precision medicine of human requires an accurate and complete reference variant benchmark for different populations. A human standard cell line of NA12878 provides a good reference for part of the human populations, but it is still lack of a fine reference standard sample and variant benchmark for the Asians. Here, we constructed a stabilized cell line of a Chinese Han volunteer. We received about 4.16T clean data of the sample using eight sequencing strategies in different laboratories, including two BGI regular NGS platforms, three Illumina regular NGS platforms, two linked-read libraries, and PacBio CCS model. The sequencing depth and reference coverage of eight sequencing strategies have reached the saturation. We detected small variants of SNPs and Indels using the eight data sets and obtained eight variant sets by performing a series of strictly quality control. Finally, we got 3.35M SNPs and 349K indels supported by all of sequencing data, which could be considered as a high confidence standard small variant sets for the studies. Besides, we also detected 5,913 high quality SNPs located in the high homologous regions supported by both linked-reads and CCS data benefited by their long-range information, while these regions are recalcitrant to regular NGS data due to the limited mappability and read length. We compared the later SNPs against the public databases and 969 sites of them were novel SNPs, indicating these SNPs provide a vital complement for the variant database. Moreover, we also phased more than 99% heterozygous SNPs also supported by linked-reads and CCS data. This work provided an integrated Asians SNV and indel benchmark for the further basic studies and precision medicine.

genomics↗

bioRxiv2019

The Influence of Blood Collection Tubes in Biomarkers Screening by Mass Spectrometry

BackgroundMass spectrometry (MS) is one of the rapidly developing bio-analytical techniques in recent years and have found many biomarkers of variety of disease. Whereas pre-analytical process is one of most crucial procedure which would significantly influence the results of biomarkers screening. In the current study, we conducted a pilot analysis of serum to determine the effects of blood collection tubes in biomarkers screening.\n\nMethodsMagnetic bead separation and matrix-assisted laser desorption ionization time-of-flight mass spectrometry were used for qualitative analysis of healthy control and serum cancer patients. A total of 24 serum samples were analyzed in this study, of which were collected from patients or healthy control using non-additive tubes or coagulant activator tubes respectively. ClinProTools were used to compare the difference among the different groups.\n\nResultsThe results demonstrated that no matter for patients or normal people, the serum protein profile changed significantly when using coagulant tubes. We also found that the effect of coagulant on serum protein of patients was smaller than that of control group. There were significant differences among 27 peaks which were obtained in the control group and the control coagulant group. However, between patient group and patient coagulant group, only 1 differential peak were obtained. Coagulant changed the protein expression difference in the original serum, and the difference expanded, narrowed even reversed, most of which are small polypeptides (Mass<3000 Da), which significantly changed the results of biomarkers screening. The results showed that 19 potential biomarkers could be found with non-additive tubes and 16 potential biomarkers could be found with coagulate activator tubes, among which only 6 were the same.\n\nConclusionsThe choice of blood collection tube significantly influence the results of biomarkers screening by MS.

cancer biology↗

bioRxiv2019

LINbase: A Web service for genome-based identification of microbes as members of crowdsourced taxa

The development of next generation and third generation DNA sequencing technologies in combination with new efficient algorithms allows scientists to economically, quickly, and precisely identify microbes at all taxonomic levels and even attribute pathogen isolates to specific disease outbreaks. However, current taxonomic practice has not kept up with the sequencing revolution and continues to rely on cumbersome journal publications to describe new species. Here we introduce a Web service that allows any user to genomically circumscribe any monophyletic group of bacteria as a taxon and associate with each taxon a name and short description. Any other user can immediately identify their unknown microbe as a member of any of these crowdsourced taxa using gene or genome sequences. The Web service is called LINbase. It leverages the previously described concept of Life Identification Numbers (LINs), which are codes assigned to individual organisms based on genome similarity. Most genomes currently in LINbase were imported from GenBank, but users have the option to upload their own genome sequences as well. Importantly, LINbase allows users to share the precise identity of their sequenced genomes without sharing the actual genome sequences, making not yet published or private genome sequences discoverable by the scientific community stimulating collaboration between academia and industry. LINbase is available at http://www.LINbase.org.

bioinformatics↗

bioRxiv2019

Conserved CxnC motifs in Kaposi’s sarcoma-associated herpesvirus ORF66 are required for viral late gene expression and mediate its interaction with ORF34

Late gene transcription in the beta- and gammaherpesviruses depends on a set of virally-encoded transcriptional activators (vTAs) that hijack the host transcriptional machinery and direct it to a subset of viral genes that are required for completion of the viral replication cycle and capsid assembly. In Kaposis sarcoma-associated herpesvirus (KSHV), these vTAs are encoded by ORF18, ORF24, ORF30, ORF31, ORF34, ORF66. Assembly of the vTAs into a complex is critical for late gene transcription, and thus deciphering the architecture of the complex is central to understanding its transcriptional regulatory activity. Here, we generated an ORF66-null virus and confirmed that it fails to produce late genes and infectious virions. We show that ORF66 is incorporated into the vTA complex primarily through its interaction with ORF34, which is mediated by a set of four conserved cysteine-rich motifs in the C-terminal domain of ORF66. While both ORF24 and ORF66 occupy the canonical K8.1 late gene promoter, their promoter occupancy requires the presence of the other vTAs, suggesting that sequence-specific, stable binding requires assembly of the entire complex on the promoter. Additionally, we find that ORF24 expression is impaired in the absence of a stable vTA complex. This work extends our knowledge about the architecture of the KSHV vPIC and suggests that it functions as a complex to recognize late gene promoters.\n\nIMPORTANCEKaposis sarcoma-associated herpesvirus (KSHV; human herpesvirus 8) is an oncogenic gammaherpesvirus that is the causative agent of multiple human cancers. Release of infectious virions requires production of capsid proteins and other late genes, whose production are transcriptionally controlled by a complex of six virally-encoded proteins that hijack the host transcription machinery. It is poorly understood how this complex assembles or what function five of its six components play in transcription. Here, we demonstrate that ORF66 is an essential component of this complex in KSHV and that its inclusion in the complex is mediated through its C-terminal domain, which contains highly conserved cysteine-rich motifs reminiscent of zinc finger motifs. Additionally, we examine assembly of the viral pre-initiation complex at late gene promoters and find that while sequence-specific binding of late gene promoters requires ORF24, it additionally requires a fully assembled viral pre-initation complex.

molecular biology↗

bioRxiv2019

Characterizing the Emergence of Liver and Gallbladder from the Embryonic Endoderm through Single-Cell RNA-Seq

The liver and gallbladder are among the most important internal organs derived from the endoderm. Several inductive signals regulate liver development, yet the pure nascent hepatic and gallbladder cells are unable to be isolated due to limited cell markers and cell numbers. The transcriptome networks of the hepatic lineage in the endoderm, and how the gallbladder differentiates from the adjacent endoderm population, are not fully understood. Using a transgenic Foxa2eGFP reporter mouse line, we performed deep single-cell RNA sequencing on 1,966 individual cells, including nascent hepatic and gallbladder cells, isolated from the endoderm and hepatic regions from ten embryonic stages, ranging from day E7.5 to E15.5. We identified the embryonic liver developmental trajectory from primitive streak to hepatoblasts and characterized the transcriptome of the hepatic lineage. During pre-hepatogenesis (5-6 somite stage), we have identified two groups of foregut endoderm cells, one derived from visceral endoderm and the second derived from primitive streak via a mesenchymal-epithelial transition (MET). During the liver specification stages, liver primordium was identified to share both foregut and liver features. We also documented dynamic gene expression during the epithelial-hepatic transition (EHT). Six gene groups were found to switch on or off at different stages during liver specification. Importantly, we found that RXR complex signaling and newly identified transcription factors associated with liver specification. Moreover, we revealed the gallbladder primordium cells at E9.5 and found genes that transcriptionally distinguish them from the liver primordium. The present data provides a high-resolution resource and critical insights for understanding the emergence of the endoderm, liver and gallbladder development.

developmental biology↗

bioRxiv2019

In situ, fluorescence lifetime-based measurements of cell membrane micromechanics

Microscopic in situ measurements of the mechanical properties of lipid bilayers were derived from the mean and variance of the fluorescence lifetime distributions of 1-dioctadecyl-3,3,33-tetramethylindocarbocyanine perchlorate (DiI). In this method, DiI, incorporated into membranes, acts as a membrane-targeted molecular rotor whose fluorescence lifetime is sensitive to local lipid viscosity. A new model was developed in which changes in area per lipid were derived from the first and second moments of a stretched exponential distribution of fluorescence lifetimes of DiI, which were subsequently used to compute mean area per lipid and its variance, quantities directly related to bilayer compressibility and bending moduli. This method enabled molecular scale assays of surface micromechanics of membrane-bound entities, such as nanoliposomes and human red blood cells.\n\nSTATEMENT OF SIGNIFICANCEDespite the progress in cell deformability studies, and in understanding mechanical properties of purified lipid bilayers, there has not, to date, been a method to measure the mechanics of the lipid bilayer in cells in situ. The current manuscript describes such a method. Using a fluorescent molecular rotor, DiI, embedded in the membrane, along with time resolved fluorescence, we directly measure area per lipid, and its temporal and spatial variance, properties directly related to bilayer mechanical moduli. Such a method will allow investigators to start exploring the relationship between lipid bilayer mechanics and cellular health and disease.

biophysics↗

bioRxiv2019

Recombinant Expression of Aldehyde Dehydrogenase 2 (ALDH2) in Escherichia coli Nissle 1917 for Oral Delivery in ALDH2-Deficient Individuals

Turning red after consuming alcohol may seem like a mere social inconvenience. Yet, this flushing response is caused by an accumulation of acetaldehyde, a carcinogenic intermediate of alcohol metabolism. Aldehyde dehydrogenase 2 (ALDH2) deficiency, the result of a point mutation, produces a less efficient ALDH2. The resulting accumulation of acetaldehyde greatly increases the risk of developing esophageal and head and neck cancers. In this study, we produced recombinant ALDH2 in the probiotic E. coli Nissle 1917, which successfully reduces acetaldehyde levels in simulated oral conditions. Packaged in a hard candy, the ALDH2-probiotic would remain in the mouth to specifically target salivary acetaldehyde. Using mathematical modeling, we also determined how much recombinant ALDH2 is needed to reduce elevated acetaldehyde levels.\n\nFinancial DisclosureThis work was funded by Taipei American School. 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 AvailabilityYes - all data are fully available without restriction. Sequences for the plasmids used in this study are available through the Registry of Standard Biological Parts. Links to raw data are included in Supplementary Information.

synthetic biology↗

bioRxiv2019

The lncRNAs Implicated in Redox Regulation in Ybx1 Deficient Zebrafish Larvae

Ybx1 has been demonstrated as a crucial gene in embryogenesis, reproduction as well as development in various vertebrates such as mouse and zebrafish. However, the underlying lncRNA-mediated mechanisms require deep investigation. Particularly, the importance of lncRNA to vertebrate development is controversial and questionable since many studies have yielded contradictory conclusions for the same lncRNAs. In the present study, in order to disclose the lncRNAs implicated in vertebrate development, a systematic transcriptome analysis is conducted based on the RNA sequencing data derived from ybx1 homozygous mutant zebrafish on day5 (day5_ybx1-/-) as well as wild type zebrafish on day5 and day6 (day5_ybx1+/+, day6_ybx1+/+). A high-confidence dataset of zebrafish lncRNAs is detected using a stepwise filtering pipeline. Differential expression analysis and co-expression network analysis reveal that several lncRNAs probably act on duox and noxo1a, the genes related to redox (reduction-oxidation reaction) processes which are triggered by ybx1 disruption. Validation by an experimental study on three selected lncRNAs indicates that knockdown of all selected lncRNAs leads to morphological deformation of larvae. In addition, our experiments effectively support the prediction of network analysis in many interaction patterns between the selected lncRNAs and the two redox genes (duox, noxo1a). In short, our study provides new insights into the function and mechanism of lncRNAs implicated in zebrafish embryonic development and demonstrates the importance of lncRNAs in vertebrate development.\n\nAuthor SummaryLncRNAs has been emerged as key regulatory layers because of their multiple functions in diverse biological processes and pathways. However, there is disagreement about the roles of lncRNAs in vertebrate development Some cases demonstrated that lncRNAs was important to development. Others showed that lncRNAs just have feeble functions in development. On the other hand, Ybx1 processing multi-functions has been well demonstrated as a key protein to most vertebrate in development. Hence, aimed at disclosure of key lncRNAs implicated in vertebrate development as well as their possible roles, we performed a systematic transcriptome analysis based on the deep RNA sequencing data of ybx1 homozygous mutant zebrafish and wild type zebrafish. Our analysis successfully revealed several lncRNAs probably target on the redox-related genes. Furthermore, our experiments validated the importance of these lncRNAs to zebrafish embryo development. This study is the first to utilize Ybx1 as breakpoint to identify key lncRNA related to vertebrate development and provides new insights into underlying mechanisms of lncRNAs in development.

developmental biology↗

bioRxiv2019

Carbon monoxide dehydrogenases enhance bacterial survival by respiring atmospheric CO

Carbon monoxide (CO) is a ubiquitous atmospheric trace gas produced by natural and anthropogenic sources. Some aerobic bacteria can oxidize atmospheric CO and, collectively, they account for the net loss of ~250 teragrams of CO from the atmosphere each year. However, the physiological role, genetic basis, and ecological distribution of this process remain incompletely resolved. In this work, we addressed these knowledge gaps through culture-based and culture-independent work. We confirmed through shotgun proteomic and transcriptional analysis that the genetically tractable aerobic soil actinobacterium Mycobacterium smegmatis upregulates expression of a carbon monoxide dehydrogenase by 50-fold when exhausted for organic carbon substrates. Whole-cell biochemical assays in wild-type and mutant backgrounds confirmed that this organism aerobically respires CO, including at sub-atmospheric concentrations, using the enzyme. Contrary to current paradigms on CO oxidation, the enzyme did not support chemolithoautotrophic growth and was dispensable for CO detoxification. However, it significantly enhanced long-term survival, suggesting that atmospheric CO serves a supplemental energy source during organic carbon starvation. Phylogenetic analysis indicated that atmospheric CO oxidation is widespread and an ancestral trait of CO dehydrogenases. Homologous enzymes are encoded by 685 sequenced species of bacteria and archaea, including from seven dominant soil phyla, and we confirmed genes encoding this enzyme are abundant and expressed in terrestrial and marine environments. On this basis, we propose a new survival-centric model for the evolution of CO oxidation and conclude that, like atmospheric H2, atmospheric CO is a major energy source supporting persistence of aerobic heterotrophic bacteria in deprived or changeable environments.

microbiology↗

bioRxiv2019

CRISPR-Cas9-assisted native end-joining editing offers a simple strategy for efficient genetic engineering in Escherichia coli

Unlike eukaryotes, bacteria are less proficient in homologous recombination (HR) and non-homologous end joining (NHEJ). All existing genomic editing methods for Escherichia coli rely on exogenous HR or NHEJ systems to repair DNA double-strand breaks (DSBs). Although an E. coli native end-joining (ENEJ) system has been reported, its potential in chromosomal engineering has not yet been explored. Here, we present a CRISPR-Cas9-assisted native end-joining editing and show that ENEJ-dependent DNA repair can be used to conduct rapid and efficient knocking-out of E. coli genomic sequence of up to 83 kb. Moreover, the positive rate and editing efficiency is independent of high-efficiency competent cells. The method requires neither exogenous DNA repair systems nor introduced editing template. The Cas9 complex is the only foreign element in this method. This study is the first successful engineering effort to utilize ENEJ mechanism in genomic editing and provides an effective strategy for genetic engineering in bacteria that are inefficient in HR and NHEJ.\n\nSignificanceThe application in prokaryotes is difficult because of the weak homologous recombination and non-homologous end joining systems. E. coli, as the most-used prokaryote in metabolic engineering, has no NHEJ system. All existing genomic editing methods for E. coli rely on exogenous HR or NHEJ systems to repair double-strand breaks introduced by CRISPR/Cas9. In this report, we firstly demonstrate that the weak and previously ignored end-joining mechanism in E. coli can be used for efficient large-scale genetic engineering assisted by CRISPR/Cas9. Our efforts greatly simplify the genomic editing procedure of E. coli and provide an effective strategy for genetic engineering in bacteria that are inefficient in HR and NHEJ.

bioengineering↗

bioRxiv2019

Deep learning in bioinformatics: introduction, application, and perspective in big data era

Deep learning, which is especially formidable in handling big data, has achieved great success in various fields, including bioinformatics. With the advances of the big data era in biology, it is foreseeable that deep learning will become increasingly important in the field and will be incorporated in vast majorities of analysis pipelines. In this review, we provide both the exoteric introduction of deep learning, and concrete examples and implementations of its representative applications in bioinformatics. We start from the recent achievements of deep learning in the bioinformatics field, pointing out the problems which are suitable to use deep learning. After that, we introduce deep learning in an easy-to-understand fashion, from shallow neural networks to legendary convolutional neural networks, legendary recurrent neural networks, graph neural networks, generative adversarial networks, variational autoencoder, and the most recent state-of-the-art architectures. After that, we provide eight examples, covering five bioinformatics research directions and all the four kinds of data type, with the implementation written in Tensorflow and Keras. Finally, we discuss the common issues, such as overfitting and interpretability, that users will encounter when adopting deep learning methods and provide corresponding suggestions. The implementations are freely available at https://github.com/lykaust15/Deep_learning_examples.

bioinformatics↗

bioRxiv2019

A paper-filter system to investigate the real micro-environment circuiting plant roots

The micro-environment circling the plant root is an interesting topic for many researchers. Until now there is not an approach to investigate the exact density of chemicals surrounding the plant roots. here we use a simple paper filter system and gas chromatography to quantify the exact density of chemicals surrounding the plant roots. this can help solve a long-existing doubt about the real micro-environment surrounding the plant roots.

plant biology↗

bioRxiv2019

Machine-learning to Improve Prediction of Mortality following Acute Myocardial Infarction: An Assessment in the NCDR-Chest Pain-Myocardial Infarction Registry

IntroductionAccurate prediction of risk of death following acute myocardial infarction (AMI) can guide the triage of care services and shared decision-making. Contemporary machine-learning may improve risk-prediction by identifying complex relationships between predictors and outcomes. Methods and ResultsWe studied 993,905 patients in the American College of Cardiology Chest Pain-MI Registry hospitalized with AMI (mean age 64 {+/-} 13 years, 34% women) between January 2011 and December 2016. We developed and validated three machine learning models to predict in-hospital mortality and compared the performance characteristics with a logistic regression model. In an independent validation cohort, we compared logistic regression with lasso regularization (c-statistic, 0.891 [95% CI, 0.890-0.892]), gradient descent boosting (c-statistic, 0.902 [0.901-0.903]), and meta-classification that combined gradient descent boosting with a neural network (c-statistic, 0.904 [0.903-0.905]) with traditional logistic regression (c-statistic, 0.882 [0.881-0.883]). There were improvements in classification of individuals across the spectrum of patient risk with each of the three methods; the meta-classifier model - our best performing model - reclassified 20.9% of individuals deemed high-risk for mortality in logistic regression appropriately as low-to-moderate risk, and 8.2% of deemed low-risk to moderate-to-high risk based consistent with the actual event rates. ConclusionsMachine-learning methods improved the prediction of in-hospital mortality for AMI compared with logistic regression. Machine learning methods enhance the utility of risk models developed using traditional statistical approaches through additional exploration of the relationship between variables and outcomes.

bioinformatics↗

bioRxiv2018

Gating TrkB switch by methylglyoxal enables GLO1 as a target for depression

The endogenous metabolite methylglyoxal (MGO) has recently emerged as a potential mediator of psychiatric disorders, such as anxiety and depression, but its precise mechanism of action remains poorly understood. Here, we find that MGO concentrations are decreased in the prefrontal cortex and hippocampus in rats subjected to chronic stress, and low-dose MGO treatment remarkedly enhances resilience to stress and alleviates depression-like symptoms. This effect is achieved by MGOs promotion on the synaptic plasticity in prefrontal cortex and hippocampus. Both in vitro and in vivo experiments show that MGO provokes the dimerization and autophosphorylation of TrkB and the subsequent activation of downstream Akt/CREB signaling, which leads to a rapid and sustained expression of brain-derived neurotrophic factor (BDNF). We further demonstrate that MGO directly binds to the extracellular domain of TrkB, but not its intracellular domain. In addition, we also identify a natural product luteolin and its derivative lutD as potent inhibitors of Glyoxalase 1 and validate their antidepressant effects in chronic stress rat models. The antidepressant role of endogenous MGO provides a new basis for the understanding and therapeutic intervention design for stress-associated mental disorders.

neuroscience↗