Affected cell types for hundreds of Mendelian diseases revealed by analysis of human and mouse single-cell data.

Mendelian diseases tend to manifest clinically in certain tissues, yet their affected cell types typically remain elusive. Single-cell expression studies showed that overexpression of disease-associated genes may point to the affected cell types. Here, we developed a method that infers disease-affected cell types from the preferential expression of disease-associated genes in cell types (PrEDiCT).

Predicting molecular mechanisms of hereditary diseases by using their tissue-selective manifestation.

How do aberrations in widely expressed genes lead to tissue-selective hereditary diseases? Previous attempts to answer this question were limited to testing a few candidate mechanisms. To answer this question at a larger scale, we developed "Tissue Risk Assessment of Causality by Expression" (TRACE), a machine learning approach to predict genes that underlie tissue-selective diseases and selectivity-related features. TRACE utilized 4,744 biologically interpretable tissue-specific gene features that were inferred from heterogeneous omics datasets.

Fractional exhaled Nitric Oxide (FeNO) level as a predictor of COVID-19 disease severity.

Objective: To assess the feasibility of Fractional exhaled Nitric Oxide (FeNO) as a simple, non-invasive, cost-effective and portable biomarker and decision support tool for risk stratification of COVID-19 patients.

Methods: We conducted a single-center prospective cohort study of COVID-19 patients whose FeNO levels were measured upon ward admission by the Vivatmo-me handheld device. Demographics, COVID-19 symptoms, and relevant hospitalization details were retrieved from the hospital databases.

The Organ-Disease Annotations (ODiseA) Database of Hereditary Diseases and Inflicted Tissues.

Hereditary diseases tend to manifest clinically in few selected tissues. Knowledge of those tissues is important for better understanding of disease mechanisms, which often remain elusive. However, information on the tissues inflicted by each disease is not easily obtainable.

The differential activity of biological processes in tissues and cell subsets can illuminate disease-related processes and cell-type identities.

Motivation: The distinct functionalities of human tissues and cell types underlie complex phenotype-genotype relationships, yet often remain elusive. Harnessing the multitude of bulk and single-cell human transcriptomes while focusing on processes can help reveal these distinct functionalities.

Results: The Tissue-Process Activity (TiPA) method aims to identify processes that are preferentially active or under-expressed in specific contexts, by comparing the expression levels of process genes between contexts.

The landscape of molecular chaperones across human tissues reveals a layered architecture of core and variable chaperones.

The sensitivity of the protein-folding environment to chaperone disruption can be highly tissue-specific. Yet, the organization of the chaperone system across physiological human tissues has received little attention. Through computational analyses of large-scale tissue transcriptomes, we unveil that the chaperone system is composed of core elements that are uniformly expressed across tissues, and variable elements that are differentially expressed to fit with tissue-specific requirements.

Cost containment by peer prior authorization program for second line treatment in patients with retinal disease.

Background: High and increasing drug prices have prompted the establishment of a broad range of cost-containment treatment policies in health systems globally. In 2012, the supplemental insurance program of a large Israeli health maintenance organization (Clalit Health Services) introduced a prior authorization process for second-line use of ranibizumab in patients with retinal disease for whom treatment with bevacizumab proved to be ineffective. A Clalit steering committee established authorization criteria based on cost and periodically updated clinical considerations, while a team of ophthalmic specialists evaluated their colleagues' individual patient subsidization requests, based on the funding criteria.

Dosage-sensitive molecular mechanisms are associated with the tissue-specificity of traits and diseases.

Hereditary diseases and complex traits often manifest in specific tissues, whereas their causal genes are expressed in many tissues that remain unaffected. Among the mechanisms that have been suggested for this enigmatic phenomenon is dosage-sensitive compensation by paralogs of causal genes. Accordingly, tissue-selectivity stems from dosage imbalance between causal genes and paralogs that occurs particularly in disease-susceptible tissues.

Differential network analysis of multiple human tissue interactomes highlights tissue-selective processes and genetic disorder genes.

Motivation: Differential network analysis, designed to highlight network changes between conditions, is an important paradigm in network biology. However, differential network analysis methods have been typically designed to compare between two conditions and were rarely applied to multiple protein interaction networks (interactomes). Importantly, large-scale benchmarks for their evaluation have been lacking.

Mechanisms of tissue and cell-type specificity in heritable traits and diseases.

Hundreds of heritable traits and diseases that are caused by germline aberrations in ubiquitously expressed genes manifest in a remarkably limited number of cell types and tissues across the body. Unravelling mechanisms that govern their tissue-specific manifestations is critical for our understanding of disease aetiologies and may direct efforts to develop treatments. Owing to recent advances in high-throughput technologies and open resources, data and tools are now available to approach this enigmatic phenomenon at large scales, both computationally and experimentally.

Aging promotes reorganization of the CD4 T cell landscape toward extreme regulatory and effector phenotypes.

Age-associated changes in CD4 T-cell functionality have been linked to chronic inflammation and decreased immunity. However, a detailed characterization of CD4 T cell phenotypes that could explain these dysregulated functional properties is lacking. We used single-cell RNA sequencing and multidimensional protein analyses to profile thousands of CD4 T cells obtained from young and old mice.

Role of duplicate genes in determining the tissue-selectivity of hereditary diseases.

A longstanding puzzle in human genetics is what limits the clinical manifestation of hundreds of hereditary diseases to certain tissues, while their causal genes are expressed throughout the human body. A general conception is that tissue-selective disease phenotypes emerge when masking factors operate in unaffected tissues, but are specifically absent or insufficient in disease-manifesting tissues. Although this conception has critical impact on the understanding of disease manifestation, it was never challenged in a systematic manner across a variety of hereditary diseases and affected tissues.

The TissueNet v.2 database: A quantitative view of protein-protein interactions across human tissues.

Knowledge of the molecular interactions of human proteins within tissues is important for identifying their tissue-specific roles and for shedding light on tissue phenotypes. However, many protein-protein interactions (PPIs) have no tissue-contexts. The TissueNet database bridges this gap by associating experimentally-identified PPIs with human tissues that were shown to express both pair-mates.