Inferring causal cell types of human diseases and risk variants from candidate regulatory elements.

The heritability of human diseases is extremely enriched in candidate regulatory elements (cRE) from disease-relevant cell types. Critical next steps are to infer which and how many cell types are truly causal for a disease (after accounting for co-regulation across cell types), and to understand how individual variants impact disease risk through single or multiple causal cell types. Here, we propose CT-FM and CT-FM-SNP, two methods that leverage cell-type-specific cREs to fine-map causal cell types for a trait and for its candidate causal variants, respectively.

Improved multi-ancestry fine-mapping identifies -regulatory variants underlying molecular traits and disease risk.

Multi-ancestry statistical fine-mapping of -molecular quantitative trait loci (-molQTL) aims to improve the precision of distinguishing causal -molQTLs from tagging variants. However, existing approaches fail to reflect shared genetic architectures. To solve this limitation, we present the Sum of Shared Single Effects (SuShiE) model, which leverages LD heterogeneity to improve fine-mapping precision, infer cross-ancestry effect size correlations, and estimate ancestry-specific expression prediction weights.

DISP1 deficiency: Monoallelic and biallelic variants cause a spectrum of midline craniofacial malformations.

Purpose: DISP1 encodes a transmembrane protein that regulates the secretion of the morphogen, Sonic hedgehog, a deficiency of which is a major cause of holoprosencephaly (HPE). This disorder covers a spectrum of brain and midline craniofacial malformations. The objective of the present study was to better delineate the clinical phenotypes associated with division transporter dispatched-1 (DISP1) variants.

Structure and Properties of High-Entropy Boride Ceramics Synthesized by Mechanical Alloying and Spark Plasma Sintering.

This manuscript shows the study of the structure, mechanical, and chemical properties of high-entropy borides MeB (Me = Ti, Ta, Nb, Hf, Zr). High-entropy borides were synthesized by mechanical alloying and spark plasma sintering. A chemically homogeneous powder with a low iron content (0.

A scalable approach to characterize pleiotropy across thousands of human diseases and complex traits using GWAS summary statistics.

Genome-wide association studies (GWASs) across thousands of traits have revealed the pervasive pleiotropy of trait-associated genetic variants. While methods have been proposed to characterize pleiotropic components across groups of phenotypes, scaling these approaches to ultra-large-scale biobanks has been challenging. Here, we propose FactorGo, a scalable variational factor analysis model to identify and characterize pleiotropic components using biobank GWAS summary data.

A scalable variational approach to characterize pleiotropic components across thousands of human diseases and complex traits using GWAS summary statistics.

Genome-wide association studies (GWAS) across thousands of traits have revealed the pervasive pleiotropy of trait-associated genetic variants. While methods have been proposed to characterize pleiotropic components across groups of phenotypes, scaling these approaches to ultra large-scale biobanks has been challenging. Here, we propose FactorGo, a scalable variational factor analysis model to identify and characterize pleiotropic components using biobank GWAS summary data.

Structural, Electrical, and Mechanical Properties Investigation of Open-Cell Aluminum Foams Obtained by Spark Plasma Sintering and Replication on Polyurethane Template.

The present paper illustrates a comparison of open-cell aluminum foams. The foams were fabricated by two different methods: spark plasma sintering and replication on a polyurethane template. The influence of pressure, temperature, and diameter of space holding material on foam obtained by the spark plasma sintering method was investigated.

Influence of Alloying Elements on the Mechanical Properties of Anodized Aluminum and on the Adhesion of Copper Metallization.

The active development of the power electronics market and a constant increase in the prices of components require new materials and approaches, including a power module packaging technology. The use of aluminum instead of copper in the power module baseplate is an interesting and promising solution. The insulated metal baseplate is one of the most extensively developed technologies nowadays.

Refractory CrMoNbWV High-Entropy Alloy Manufactured by Mechanical Alloying and Spark Plasma Sintering: Evolution of Microstructure and Properties.

In this study, bulk samples of a CrMoNbWV high-entropy alloy (HEA) were obtained for the first time by spark plasma sintering (SPS) of mechanically alloyed (MA) powders at 1200 °C, 1300 °C, and 1400 °C. Microstructure evolution, phase formation as well as wear and corrosion behavior were investigated. The MA powders' phase composition was found to be represented by body-centered-cubic (BCC) solid solution.

Synonymous variants in holoprosencephaly alter codon usage and impact the Sonic Hedgehog protein.

Synonymous single nucleotide variants (sSNVs) have been implicated in various genetic disorders through alterations of pre-mRNA splicing, mRNA structure and miRNA regulation. However, their impact on synonymous codon usage and protein translation remains to be elucidated in clinical context. Here, we explore the functional impact of sSNVs in the Sonic Hedgehog (SHH) gene, identified in patients affected by holoprosencephaly, a congenital brain defect resulting from incomplete forebrain cleavage.

Disrupted Hypothalamo-Pituitary Axis in Association With Reduced SHH Underlies the Pathogenesis of NOTCH-Deficiency.

Context: In human, Sonic hedgehog (SHH) haploinsufficiency is the predominant cause of holoprosencephaly, a structural malformation of the forebrain midline characterized by phenotypic heterogeneity and incomplete penetrance. The NOTCH signaling pathway has recently been associated with holoprosencephaly in humans, but the precise mechanism involving NOTCH signaling during early brain development remains unknown.

Objective: The aim of this study was to evaluate the relationship between SHH and NOTCH signaling to determine the mechanism by which NOTCH dysfunction could cause midline malformations of the forebrain.

Depicting the genetic architecture of pediatric cancers through an integrative gene network approach.

The genetic etiology of childhood cancers still remains largely unknown. It is therefore essential to develop novel strategies to unravel the spectrum of pediatric cancer genes. Statistical network modeling techniques have emerged as powerful methodologies for enabling the inference of gene-disease relationship and have been performed on adult but not pediatric cancers.