Coincidence site modules in 3-space

The coincidence site lattice (CSL) problem and its generalization to Z-modules in Euclidean 3-space is revisited, and various results and conjectures are proved in a unified way, by using maximal orders in quaternion algebras of class number 1 over real algebraic number fields.Comment: 25 page

Polarity-Specific Cortical Effects of Transcranial Direct Current Stimulation in Primary Somatosensory Cortex of Healthy Humans

Transcranial direct current stimulation (tDCS) is a noninvasive stimulation method that has been shown to modulate the excitability of the motor and visual cortices in human subjects in a polarity dependent manner in previous studies. The aim of our study was to investigate whether anodal and cathodal tDCS can also be used to modulate the excitability of the human primary somatosensory cortex (S1). We measured paired-pulse suppression (PPS) of somatosensory evoked potentials in 36 right-handed volunteers before and after anodal, cathodal or sham stimulation over the right non-dominant S1. Paired-pulse stimulation of the median nerve was performed at the dominant and non-dominant hand. After anodal tDCS, PPS was reduced in the ipsilateral S1 compared to sham stimulation, indicating an excitatory effect of anodal tDCS. In contrast, PPS in the stimulated left hemisphere was increased after cathodal tDCS, indicating an inhibitory effect of cathodal tDCS. Sham stimulation induced no pre-post differences. Thus, tDCS can be used to modulate the excitability of S1 in polarity-dependent manner, which can be assessed by paired-pulse suppression. An interesting topic for further studies could be the investigation of direct correlations between sensory changes and excitability changes induced by tDCS

Remediation and Recycling of Linde FUSRAP Materials

During World War II, the Manhattan Engineering District (MED) utilized facilities in the Buffalo, New York area to extract natural uranium from uranium-bearing ores. The Linde property is one of several properties within the Tonawanda, New York Formerly Utilized Sites Remedial Action Program (FUSRAP) site, which includes Linde, Ashland 1, Ashland 2, and Seaway. Union Carbide Corporation's Linde Division was placed under contract with the Manhattan Engineering District (MED) from 1942 to 1946 to extract uranium from seven different ore sources: four African pitchblende ores and three domestic ores. Over the years, erosion and weathering have spread contamination from the residuals handled and disposed of at Linde to adjacent soils. The U.S. Department of Energy (DOE) and the U.S. Environmental Protection Agency (EPA) negotiated a Federal Facilities Agreement (FFA) governing remediation of the Linde property. In Fiscal Year (FY) 1998, Congress transferred cleanup management responsibility for the sites in the FUSRAP program, including the Linde Site, from the DOE to the U.S. Army Corps of Engineers (USACE), with the charge to commence cleanup promptly. All actions by the USACE at the Linde Site are being conducted subject to the administrative, procedural, and regulatory provisions of the Comprehensive Environmental Response Compensation and Liability Act (CERCLA) and the existing FFA. USACE issued a Proposed Plan for the Linde Property in 1999 and a Final Record of Decision (ROD) in 2000. USACE worked with the local community near the Tonawanda site, and after considering public comment, selected the remedy calling for removing soils that exceed the site-specific cleanup standard, and transporting the contaminated material to off-site locations. The selected remedy is protective of human health and the environment, complies with Federal and State requirements, and meets commitments to the community

De Novo Heterozygous POLR2A Variants Cause a Neurodevelopmental Syndrome with Profound Infantile-Onset Hypotonia

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Imaging flow cytometry-based cellular screening elucidates pathophysiology in individuals with Variants of Uncertain Significance

Background: Deciphering variants of uncertain significance (VUS) represents a major diagnostic challenge, partially due to the lack of easy-to-use and versatile cellular readouts that aid the interpretation of pathogenicity and pathophysiology. To address this challenge, we propose a high-throughput screening of cellular functionality through an imaging flow cytometry (IFC)-based platform. Methods: Six assays to evaluate autophagic-, lysosomal-, Golgi- health, mitochondrial function, ER stress, and NF-κβ activity were developed in fibroblasts. Assay sensitivity was verified with compounds (N = 5) and positive control patients (N = 6). Eight healthy controls and 20 individuals with VUS were screened. Results: All molecular compounds and positive controls showed significant changes on their cognate assays, confirming assay sensitivity. Simultaneous screening of positive control patients on all six assays revealed distinct phenotypic profiles. In addition, individuals with VUS(es) in well-known disease genes showed distinct – but similar—phenotypic profiles compared to patients with pathogenic variants in the same gene. For all individuals with VUSes in Genes of Uncertain Significance (GUS), we found one or more of six assays were significantly altered. Broadening the screening to an untargeted approach led to the identification of two clusters that allowed for the recognition of altered cell cycle dynamics and DNA damage repair defects. Experimental follow-up of the ‘DNA damage repair defect cluster’ led to the discovery of highly specific defects in top2cc release from double-strand DNA breaks in one of these individuals, harboring a VUS in the RAD54L2 gene. Conclusions: Our high-throughput IFC-based platform simplifies the process of identifying VUS pathogenicity through six assays and allows for the recognition of useful pathophysiological markers that structure follow-up experiments, thereby representing a novel valuable tool for precise functional diagnostics in genomics.</p

Accessible, realistic genome simulation with selection using stdpopsim

Selection is a fundamental evolutionary force that shapes patterns of genetic variation across species. However, simulations incorporating realistic selection along heterogeneous genomes in complex demographic histories are challenging, limiting our ability to benchmark statistical methods aimed at detecting selection and to explore theoretical predictions. stdpopsim is a community-maintained simulation library that already provides an extensive catalog of species-specific population genetic models. Here we present a major extension to the stdpopsim framework that enables simulation of various modes of selection, including background selection, selective sweeps, and arbitrary distributions of fitness effects (DFE) acting on annotated subsets of the genome (for instance, exons). This extension maintains stdpopsim's core principles of reproducibility and accessibility while adding support for species-specific genomic annotations and published DFE estimates. We demonstrate the utility of this framework by comparing methods for demographic inference, DFE estimation, and selective sweep detection across several species and scenarios. Our results demonstrate the robustness of demographic inference methods to selection on linked sites, reveal the sensitivity of DFE-inference methods to model assumptions, and show how genomic features, like recombination rate and functional sequence density, influence power to detect selective sweeps. This extension to stdpopsim provides a powerful new resource for the population genetics community to explore the interplay between selection and other evolutionary forces in a reproducible, user-friendly framework.</p

A second case of glutaminase hyperactivity: Expanding the phenotype with epilepsy

Glutaminase (GLS) hyperactivity was first described in 2019 in a patient with profound developmental delay and infantile cataract. Here, we describe a 4-year-old boy with GLS hyperactivity due to a de novo heterozygous missense variant in GLS, detected by trio whole exome sequencing. This boy also exhibits developmental delay without dysmorphic features, but does not have cataract. Additionally, he suffers from epilepsy with tonic clonic seizures. In line with the findings in the previously described patient with GLS hyperactivity, in vivo 3 T magnetic resonance spectroscopy (MRS) of the brain revealed an increased glutamate/glutamine ratio. This increased ratio was also found in urine with UPLC-MS/MS, however, inconsistently. This case indicates that the phenotypic spectrum evoked by GLS hyperactivity may include epilepsy. Clarifying this phenotypic spectrum is of importance for the prognosis and identification of these patients. The combination of phenotyping, genetic testing, and metabolic diagnostics with brain MRS and in urine is essential to identify new patients with GLS hyperactivity and to further extend the phenotypic spectrum of this disease

Bi-allelic variants in NAE1 cause intellectual disability, ischiopubic hypoplasia, stress-mediated lymphopenia and neurodegeneration

Neddylation has been implicated in various cellular pathways and in the pathophysiology of numerous diseases. We identified four individuals with bi-allelic variants in NAE1, which encodes the neddylation E1 enzyme. Pathogenicity was supported by decreased NAE1 abundance and overlapping clinical and cellular phenotypes. To delineate how cellular consequences of NAE1 deficiency would lead to the clinical phenotype, we focused primarily on the rarest phenotypic features, based on the assumption that these would best reflect the pathophysiology at stake. Two of the rarest features, neuronal loss and lymphopenia worsening during infections, suggest that NAE1 is required during cellular stress caused by infections to protect against cell death. In support, we found that stressing the proteasome system with MG132—requiring upregulation of neddylation to restore proteasomal function and proteasomal stress—led to increased cell death in fibroblasts of individuals with NAE1 genetic variants. Additionally, we found decreased lymphocyte counts after CD3/CD28 stimulation and decreased NF-κB translocation in individuals with NAE1 variants. The rarest phenotypic feature—delayed closure of the ischiopubic rami—correlated with significant downregulation of RUN2X and SOX9 expression in transcriptomic data of fibroblasts. Both genes are involved in the pathophysiology of ischiopubic hypoplasia. Thus, we show that NAE1 plays a major role in (skeletal) development and cellular homeostasis during stress. Our approach suggests that a focus on rare phenotypic features is able to provide significant pathophysiological insights in diseases caused by mutations in genes with pleiotropic effects.</p