Gut microbiota density influences host physiology and is shaped by host and microbial factors.

Unlabelled: To identify factors that regulate gut microbiota density and the impact of varied microbiota density on health, we assayed this fundamental ecosystem property in fecal samples across mammals, human disease, and therapeutic interventions. Physiologic features of the host (carrying capacity) and the fitness of the gut microbiota shape microbiota density. Therapeutic manipulation of microbiota density in mice altered host metabolic and immune homeostasis.

Combined Inhibition of DYRK1A, SMAD, and Trithorax Pathways Synergizes to Induce Robust Replication in Adult Human Beta Cells.

Small-molecule inhibitors of dual-specificity tyrosine-regulated kinase 1A (DYRK1A) induce human beta cells to proliferate, generating a labeling index of 1.5%-3%. Here, we demonstrate that combined pharmacologic inhibition of DYRK1A and transforming growth factor beta superfamily (TGFβSF)/SMAD signaling generates remarkable further synergistic increases in human beta cell proliferation (average labeling index, 5%-8%, and as high as 15%-18%), and increases in both mouse and human beta cell numbers.

Deciphering bacterial epigenomes using modern sequencing technologies.

Prokaryotic DNA contains three types of methylation: N6-methyladenine, N4-methylcytosine and 5-methylcytosine. The lack of tools to analyse the frequency and distribution of methylated residues in bacterial genomes has prevented a full understanding of their functions. Now, advances in DNA sequencing technology, including single-molecule, real-time sequencing and nanopore-based sequencing, have provided new opportunities for systematic detection of all three forms of methylated DNA at a genome-wide scale and offer unprecedented opportunities for achieving a more complete understanding of bacterial epigenomes.

Prostate Cancer Risk-Associated Single-Nucleotide Polymorphism Affects Prostate-Specific Antigen Glycosylation and Its Function.

Background: Genetic association studies have reported single-nucleotide polymorphisms (SNPs) at chromosome 19q13.3 to be associated with prostate cancer (PCa) risk. Recently, the rs61752561 SNP (Asp84Asn substitution) in exon 3 of the kallikrein-related peptidase 3 () gene encoding prostate-specific antigen (PSA) was reported to be strongly associated with PCa risk ( = 2.

BPLLDA: Predicting lncRNA-Disease Associations Based on Simple Paths With Limited Lengths in a Heterogeneous Network.

In recent years, it has been increasingly clear that long noncoding RNAs (lncRNAs) play critical roles in many biological processes associated with human diseases. Inferring potential lncRNA-disease associations is essential to reveal the secrets behind diseases, develop novel drugs, and optimize personalized treatments. However, biological experiments to validate lncRNA-disease associations are very time-consuming and costly.

Author Correction: Expression-based drug screening of neural progenitor cells from individuals with schizophrenia.

In the originally published version of this Article, the affiliation details for Eric E. Schadt and Radoslav Savic incorrectly omitted 'Sema4, a Mount Sinai venture, Stamford, Connecticut, USA'. This has been corrected in both the PDF and HTML versions of the Article.

Large-scale protein function prediction using heterogeneous ensembles.

Heterogeneous ensembles are an effective approach in scenarios where the ideal data type and/or individual predictor are unclear for a given problem. These ensembles have shown promise for protein function prediction (PFP), but their ability to improve PFP at a large scale is unclear. The overall goal of this study is to critically assess this ability of a variety of heterogeneous ensemble methods across a multitude of functional terms, proteins and organisms.

Functional regulatory mechanism of smooth muscle cell-restricted LMOD1 coronary artery disease locus.

Recent genome-wide association studies (GWAS) have identified multiple new loci which appear to alter coronary artery disease (CAD) risk via arterial wall-specific mechanisms. One of the annotated genes encodes LMOD1 (Leiomodin 1), a member of the actin filament nucleator family that is highly enriched in smooth muscle-containing tissues such as the artery wall. However, it is still unknown whether LMOD1 is the causal gene at this locus and also how the associated variants alter LMOD1 expression/function and CAD risk.

Rare, Pathogenic Germline Variants in Genes Increase Risk for Squamous Lung Cancer.

Purpose: Lung cancer is the leading cause of cancer deaths worldwide, with substantially better prognosis in early-stage as opposed to late-stage disease. Identifying genetic factors for lung squamous cell carcinoma (SqCC) risk will enable their use in risk stratification, and personalized intensive surveillance, early detection, and prevention strategies for high-risk individuals.

Experimental Design: We analyzed whole-exome sequencing datasets of 318 cases and 814 controls (discovery cohort) and then validated our findings in an independent cohort of 444 patients and 3,479 controls (validation cohort), all of European descent.

Predicting Influenza Antigenicity by Matrix Completion With Antigen and Antiserum Similarity.

The rapid mutation of influenza viruses especially on the two surface proteins hemagglutinin (HA) and neuraminidase (NA) has made them capable to escape from population immunity, which has become a key challenge for influenza vaccine design. Thus, it is crucial to predict influenza antigenic evolution and identify new antigenic variants in a timely manner. However, traditional experimental methods like hemagglutination inhibition (HI) assay to select vaccine strains are time and labor-intensive, while popular computational methods are less sensitive, which presents the need for more accurate algorithms.

Understanding the Hidden Complexity of Latin American Population Isolates.

Most population isolates examined to date were founded from a single ancestral population. Consequently, there is limited knowledge about the demographic history of admixed population isolates. Here we investigate genomic diversity of recently admixed population isolates from Costa Rica and Colombia and compare their diversity to a benchmark population isolate, the Finnish.

Oncogenic role of SFRP2 in p53-mutant osteosarcoma development via autocrine and paracrine mechanism.

Osteosarcoma (OS), the most common primary bone tumor, is highly metastatic with high chemotherapeutic resistance and poor survival rates. Using induced pluripotent stem cells (iPSCs) generated from Li-Fraumeni syndrome (LFS) patients, we investigate an oncogenic role of secreted frizzled-related protein 2 (SFRP2) in p53 mutation-associated OS development. Interestingly, we find that high SFRP2 expression in OS patient samples correlates with poor survival.

A crowdsourced analysis to identify ab initio molecular signatures predictive of susceptibility to viral infection.

The response to respiratory viruses varies substantially between individuals, and there are currently no known molecular predictors from the early stages of infection. Here we conduct a community-based analysis to determine whether pre- or early post-exposure molecular factors could predict physiologic responses to viral exposure. Using peripheral blood gene expression profiles collected from healthy subjects prior to exposure to one of four respiratory viruses (H1N1, H3N2, Rhinovirus, and RSV), as well as up to 24 h following exposure, we find that it is possible to construct models predictive of symptomatic response using profiles even prior to viral exposure.

Expression-based drug screening of neural progenitor cells from individuals with schizophrenia.

A lack of biologically relevant screening models hinders the discovery of better treatments for schizophrenia (SZ) and other neuropsychiatric disorders. Here we compare the transcriptional responses of 8 commonly used cancer cell lines (CCLs) directly with that of human induced pluripotent stem cell (hiPSC)-derived neural progenitor cells (NPCs) from 12 individuals with SZ and 12 controls across 135 drugs, generating 4320 unique drug-response transcriptional signatures. We identify those drugs that reverse post-mortem SZ-associated transcriptomic signatures, several of which also differentially regulate neuropsychiatric disease-associated genes in a cell type (hiPSC NPC vs.

Radiation Therapy Outcomes Models in the Era of Radiomics and Radiogenomics: Uncertainties and Validation.

Recent advances in imaging and biotechnology have tremendously improved the availability of quantitative imaging (radiomics) and molecular data (radiogenomics) for radiotherapy patients. This big data development with its comprehensive nature promises to transform outcome modeling in radiotherapy from few dose-volume metrics into utilizing more data-driven analytics. However, it also presents new profound challenges and creates new tasks for alleviating uncertainties arising from dealing with heterogeneous data and complex big data analytics.

Immunomodulatory activity of a novel polysaccharide from Lonicera japonica in immunosuppressed mice induced by cyclophosphamide.

Lonicera japonica is a typical Chinese herbal medicine. We previously reported a method to isolate polysaccharides from Lonicera japonica (LJP). In this study, we first performed a qualitative analysis of LJP using the Fourier Transform Infrared Spectrometer (FT-IR) and explored the monosaccharide composition of LJP using the pre-column derivatization high performance liquid chromatography (HPLC) method.

Genome-wide Scan Identifies Role for AOX1 in Prostate Cancer Survival.

Background: Most men diagnosed with prostate cancer have low-risk cancers. How to predict prostate cancer progression at the time of diagnosis remains challenging.

Objective: To identify single nucleotide polymorphisms (SNPs) associated with death from prostate cancer.

Analysis of chromatin accessibility uncovers TEAD1 as a regulator of migration in human glioblastoma.

The intrinsic drivers of migration in glioblastoma (GBM) are poorly understood. To better capture the native molecular imprint of GBM and its developmental context, here we isolate human stem cell populations from GBM (GSC) and germinal matrix tissues and map their chromatin accessibility via ATAC-seq. We uncover two distinct regulatory GSC signatures, a developmentally shared/proliferative and a tumor-specific/migratory one in which TEAD1/4 motifs are uniquely overrepresented.

Temporal genetic association and temporal genetic causality methods for dissecting complex networks.

A large amount of panomic data has been generated in populations for understanding causal relationships in complex biological systems. Both genetic and temporal models can be used to establish causal relationships among molecular, cellular, or phenotypical traits, but with limitations. To fully utilize high-dimension temporal and genetic data, we develop a multivariate polynomial temporal genetic association (MPTGA) approach for detecting temporal genetic loci (teQTLs) of quantitative traits monitored over time in a population and a temporal genetic causality test (TGCT) for inferring causal relationships between traits linked to the locus.

Pharmacological risk factors associated with hospital readmission rates in a psychiatric cohort identified using prescriptome data mining.

Background: Worldwide, over 14% of individuals hospitalized for psychiatric reasons have readmissions to hospitals within 30 days after discharge. Predicting patients at risk and leveraging accelerated interventions can reduce the rates of early readmission, a negative clinical outcome (i.e.

DECtp: Calling Differential Gene Expression Between Cancer and Normal Samples by Integrating Tumor Purity Information.

Identifying differentially expressed genes (DEGs) between tumor and normal samples is critical for studying tumorigenesis, and has been routinely applied to identify diagnostic, prognostic, and therapeutic biomarkers for many cancers. It is well-known that solid tumor tissue samples obtained from clinical settings are always mixtures of cancer and normal cells. However, the tumor purity information is more or less ignored in traditional differential expression analyses, which might decrease the power of differential gene identification or even bias the results.

EMT- and stroma-related gene expression and resistance to PD-1 blockade in urothelial cancer.

Cancers infiltrated with T-cells are associated with a higher likelihood of response to PD-1/PD-L1 blockade. Counterintuitively, a correlation between epithelial-mesenchymal transition (EMT)-related gene expression and T-cell infiltration has been observed across tumor types. Here we demonstrate, using The Cancer Genome Atlas (TCGA) urothelial cancer dataset, that although a gene expression-based measure of infiltrating T-cell abundance and EMT-related gene expression are positively correlated, these signatures convey disparate prognostic information.