IN VIVO CELL-TYPE AND BRAIN REGION CLASSIFICATION VIA MULTIMODAL CONTRASTIVE LEARNING.

Current electrophysiological approaches can track the activity of many neurons, yet it is usually unknown which cell-types or brain areas are being recorded without further molecular or histological analysis. Developing accurate and scalable algorithms for identifying the cell-type and brain region of recorded neurons is thus crucial for improving our understanding of neural computation. In this work, we develop a multimodal contrastive learning approach for neural data that can be fine-tuned for different downstream tasks, including inference of cell-type and brain location.

Preclinical safety and biodistribution of CRISPR targeting SIV in non-human primates.

In this study, we demonstrate the safety and utility of CRISPR-Cas9 gene editing technology for in vivo editing of proviral DNA in ART-treated, virally controlled simian immunodeficiency virus (SIV) infected rhesus macaques, an established model for HIV infection. EBT-001 is an AAV9-based vector delivering SaCas9 and dual guide RNAs designed to target multiple regions of the SIV genome: the viral LTRs, and the Gag gene. The results presented here demonstrate that a single IV inoculation of EBT-001 at each of 3 dose levels (1.

Molecular Features and Stages of Pulmonary Fibrosis Driven by Type 2 Inflammation.

Systemic sclerosis (SSc) is a progressive, multiorgan disease with limited treatment options. Although a recent proof-of-concept study using romilkimab or SAR156597, a bispecific IL-4/IL-13 antibody, suggests a direct role of these cytokines in the pathophysiology of SSc, their contributions to the balance between inflammation and fibrosis are unclear. Here, we determine the roles of type 2 inflammation in fibrogenesis using FRA2-Tg (Fos-related antigen 2-overexpressing transgenic) mice, which develop spontaneous, age-dependent progressive lung fibrosis.

Anti-microRNA-21 Therapy on Top of ACE Inhibition Delays Renal Failure in Alport Syndrome Mouse Models.

Alport mice serve as an animal model for renal fibrosis. MicroRNA-21 (miR-21) expression has been shown to be increased in the kidneys of Alport syndrome patients. Here, we investigated the nephroprotective effects of Lademirsen anti-miR-21 therapy.

Blood phenylalanine reduction reverses gene expression changes observed in a mouse model of phenylketonuria.

Phenylketonuria (PKU) is a genetic deficiency of phenylalanine hydroxylase (PAH) in liver resulting in blood phenylalanine (Phe) elevation and neurotoxicity. A pegylated phenylalanine ammonia lyase (PEG-PAL) metabolizing Phe into cinnamic acid was recently approved as treatment for PKU patients. A potentially one-time rAAV-based delivery of PAH gene into liver to convert Phe into tyrosine (Tyr), a normal way of Phe metabolism, has now also entered the clinic.

Small RNA sequencing evaluation of renal microRNA biomarkers in dogs with X-linked hereditary nephropathy.

Dogs with X-linked hereditary nephropathy (XLHN) are an animal model for Alport syndrome in humans and progressive chronic kidney disease (CKD). Using mRNA sequencing (mRNA-seq), we have characterized the gene expression profile affecting the progression of XLHN; however, the microRNA (miRNA, miR) expression remains unknown. With small RNA-seq and quantitative RT-PCR (qRT-PCR), we used 3 small RNA-seq analysis tools (QIAGEN OmicSoft Studio, miRDeep2, and CPSS 2.

Elevated protein synthesis in microglia causes autism-like synaptic and behavioral aberrations.

Mutations that inactivate negative translation regulators cause autism spectrum disorders (ASD), which predominantly affect males and exhibit social interaction and communication deficits and repetitive behaviors. However, the cells that cause ASD through elevated protein synthesis resulting from these mutations remain unknown. Here we employ conditional overexpression of translation initiation factor eIF4E to increase protein synthesis in specific brain cells.

ZIAQ: a quantile regression method for differential expression analysis of single-cell RNA-seq data.

Motivation: Single-cell RNA sequencing (scRNA-seq) has enabled the simultaneous transcriptomic profiling of individual cells under different biological conditions. scRNA-seq data have two unique challenges that can affect the sensitivity and specificity of single-cell differential expression analysis: a large proportion of expressed genes with zero or low read counts ('dropout' events) and multimodal data distributions.

Results: We have developed a zero-inflation-adjusted quantile (ZIAQ) algorithm, which is the first method to account for both dropout rates and complex scRNA-seq data distributions in the same model.

Dysregulated Expression of microRNA-21 and Disease-Related Genes in Human Patients and in a Mouse Model of Alport Syndrome.

Alport syndrome is a genetic disease caused by mutations in type IV collagen and is characterized by progressive kidney disease. The mouse model recapitulates the main features of human Alport syndrome. Previously, it was reported that kidney microRNA-21 (miR-21) expression is significantly increased in mice, and administration of anti-miR-21 oligonucleotides (anti-miR-21) attenuates kidney disease progression in mice, indicating that miR-21 is a viable therapeutic target for Alport syndrome.

An integrated hierarchical Bayesian approach to normalizing left-censored microRNA microarray data.

Background: MicroRNAs (miRNAs) are small endogenous ssRNAs that regulate target gene expression post-transcriptionally through the RNAi pathway. A critical pre-processing procedure for detecting differentially expressed miRNAs is normalization, aiming at removing the between-array systematic bias. Most normalization methods adopted for miRNA data are the same methods used to normalize mRNA data; but miRNA data are very different from mRNA data mainly because of possibly larger proportion of differentially expressed miRNA probes, and much larger percentage of left-censored miRNA probes below detection limit (DL).

Stitching together multiple data dimensions reveals interacting metabolomic and transcriptomic networks that modulate cell regulation.

Cells employ multiple levels of regulation, including transcriptional and translational regulation, that drive core biological processes and enable cells to respond to genetic and environmental changes. Small-molecule metabolites are one category of critical cellular intermediates that can influence as well as be a target of cellular regulations. Because metabolites represent the direct output of protein-mediated cellular processes, endogenous metabolite concentrations can closely reflect cellular physiological states, especially when integrated with other molecular-profiling data.

Metabolomics in pharmaceutical research and development: metabolites, mechanisms and pathways.

In recent years, quantitative metabolomics has played increasingly important roles in pharmaceutical research and development. Metabolic profiling of biofluids and tissues can provide a panoramic view of abundance changes in endogenous metabolites to complement transcriptomics and proteomics in monitoring cellular responses to perturbations such as diseases and drug treatments. Precise identification and accurate quantification of metabolites facilitate downstream pathway and network analysis using software tools for the discovery of clinically accessible and minimally invasive biomarkers of drug efficacy and toxicity.

Integrated pathway analysis of rat urine metabolic profiles and kidney transcriptomic profiles to elucidate the systems toxicology of model nephrotoxicants.

In this study, approximately 40 endogenous metabolites were identified and quantified by (1)H NMR in urine samples from male rats dosed with two proximal tubule toxicants, cisplatin and gentamicin. The excreted amount of a majority of those metabolites in urine was found to be dose-dependent and exhibited a strong correlation with histopathology scores of overall proximal tubule damage. MetaCore pathway analysis software (GeneGo Inc.