Broadening the -Associated Neurodevelopmental Phenotype.

Background: Monoallelic damaging variants in (MIM*612870), encoding the Pleckstrin Homology Domain Interacting Protein, have been associated with a novel neurodevelopmental disorder, also termed Chung-Jansen syndrome (CHUJANS, MIM#617991). Most of the described individuals show developmental delay (DD)/intellectual disability (ID), obesity/overweight, and variable congenital anomalies, so the condition can be considered as an ID-overweight syndrome.

Case Description: We evaluated a child presenting with DD/ID and a craniofacial phenotype reminiscent of a Pitt-Hopkins syndrome (PTHS)-like condition.

Privacy-Preserving Workflow for the Cross-Border Federated Analysis of Clinical Data.

The motivation behind this research is to perform a privacy-preserving analysis of data located at remote sites and in different jurisdictions with no possibility of sharing individual-level information. Here, we present key findings from requirements analysis and a resulting federated data analysis workflow built using open-source research software, where patient-level information is securely stored and never exposed during the analysis process. We present additional improvements to further strengthen the security of the workflow.

Contaminants of Concern and Spatiotemporal Metabolomic Changes in Quagga Mussels (Dreissena bugensis rostriformis) from the Milwaukee Estuary (Wisconsin, USA).

Environmental metabolomics has emerged as a promising technique in the field of biomonitoring and as an indicator of aquatic ecosystem health. In the Milwaukee Estuary (Wisconsin, USA), previous studies have used a nontargeted metabolomic approach to distinguish between zebra mussels (Dreissena polymorpha) collected from sites of varying contamination. To further elucidate the potential effects of contaminants on bivalve health in the Milwaukee Estuary, the present study adopted a caging approach to study the metabolome of quagga mussels (Dreissena bugensis rostriformis) deployed in six sites of varying contamination for 2, 5, or 55 days.

Distinct dynamical features of plasmodial and human HSP70-HSP110 highlight the divergence in their chaperone-assisted protein folding.

HSP70 and its evolutionarily diverged co-chaperone HSP110, forms an important node in protein folding cascade. How these proteins maintain the aggregation-prone proteome of malaria parasite in functional state remains underexplored, in contrast to its human orthologs. In this study, we have probed into conformational dynamics of plasmodial HSP70 and HSP110 through multiple μs MD-simulations (ATP-state) and compared with their respective human counterparts.

Conformational response to ligand binding of TMPRSS2, a protease involved in SARS-CoV-2 infection: Insights through computational modeling.

Thanks to the considerable research which has been undertaken in the last few years to improve our understanding of the biology and mechanism of action of SARS-CoV-2, we know how the virus uses its surface spike protein to infect host cells. The transmembrane prosthesis, serine 2 (TMPRSS2) protein, located on the surface of human cells, recognizes the cleavage site in the spike protein, leading to the release of the fusion peptide and entry of the virus into the host cells. Because of its role, TMPRSS2 has been proposed as a drug target to prevent infection by the virus.

PFAS in municipal landfill leachate: Occurrence, transformation, and sources.

To understand sources and processes affecting per- and polyfluoroalkyl substances (PFAS), 32 PFAS were measured in landfill leachate from 17 landfills across Washington State in both pre-and post-total oxidizable precursor (TOP) assay samples, using an analytical method that was the precursor to EPA Draft Method 1633. As in other studies, 5:3FTCA was the dominant PFAS in the leachate, suggesting that carpets, textiles, and food packaging were the main sources of PFAS. Total PFAS concentrations (ΣPFAS) ranged from 61 to 172,976 ng/L and 580-36,122 ng/L in pre-TOP and post-TOP samples, respectively, suggesting that little or no uncharacterized precursors remained in landfill leachate.

Computational Study of Helicase from SARS-CoV-2 in RNA-Free and Engaged Form.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the pandemic that broke out in 2020 and continues to be the cause of massive global upheaval. Coronaviruses are positive-strand RNA viruses with a genome of ~30 kb. The genome is replicated and transcribed by RNA-dependent RNA polymerase together with accessory factors.

Dominant ARF3 variants disrupt Golgi integrity and cause a neurodevelopmental disorder recapitulated in zebrafish.

Vesicle biogenesis, trafficking and signaling via Endoplasmic reticulum-Golgi network support essential developmental processes and their disruption lead to neurodevelopmental disorders and neurodegeneration. We report that de novo missense variants in ARF3, encoding a small GTPase regulating Golgi dynamics, cause a developmental disease in humans impairing nervous system and skeletal formation. Microcephaly-associated ARF3 variants affect residues within the guanine nucleotide binding pocket and variably perturb protein stability and GTP/GDP binding.

Consideration of metabolomics and transcriptomics data in the context of using avian embryos for toxicity testing.

Early-life stage (ELS) avian toxicity tests have been proposed as a more ethical alternative to traditional standardized tests with adult birds. At the same time, 'omics approaches are gaining traction in the field of avian toxicology, but little has been done to characterize the metabolome and transcriptome at different life stages. The present study uses 'omics data from toxicity tests of 8 environmental chemicals in ELS and adult Japanese quail (Coturnix japonica) to address this data gap.

Targeted Metabolomics to Assess Exposure to Environmental Chemicals of Concern in Japanese Quail at Two Life Stages.

This proof-of-concept study characterizes the Japanese quail () hepatic metabolome following exposure to benzo[a]pyrene, chlorpyrifos, ethinylestradiol, fluoxetine hydrochloride, hexabromocyclododecane, lead(II)nitrate, seleno-L-methionine, and trenbolone in embryos and adults. The analysis revealed effects on lipid metabolism following exposure to several chemicals at both life stages. The most pronounced effects were observed in embryos exposed to 41.

Using Transcriptomics and Metabolomics to Understand Species Differences in Sensitivity to Chlorpyrifos in Japanese Quail and Double-Crested Cormorant Embryos.

Modern 21st-century toxicity testing makes use of omics technologies to address critical questions in toxicology and chemical management. Of interest are questions relating to chemical mechanisms of toxicity, differences in species sensitivity, and translation of molecular effects to observable apical endpoints. Our study addressed these questions by comparing apical outcomes and multiple omics responses in early-life stage exposure studies with Japanese quail (Coturnix japonica) and double-crested cormorant (Phalacrocorax auritus), representing a model and ecological species, respectively.

Anterior Odontoid Screw Fixation for C2 Fractures: Surgical Nuances, Complications, and Factors Affecting Fracture Union.

Objective: Type II odontoid fractures are the commonest C2 fractures. The management of dens fractures remains controversial with various radiological and fracture morphological factors affecting the approach and outcomes.

Methods: All cases of anterior odontoid screw fixation between 2010 and 2020 were retrospectively analyzed.

Identification of Natural Products as Potential Pharmacological Chaperones for Protein Misfolding Diseases.

Defective protein folding and accumulation of misfolded proteins is associated with neurodegenerative, cardiovascular, secretory, and metabolic disorders. Efforts are being made to identify small-molecule modulators or structural-correctors for conformationally destabilized proteins implicated in various protein aggregation diseases. Using a metastable-reporter-based primary screen, we evaluated pharmacological chaperone activity of a diverse class of natural products.

Unsupervised search of low-lying conformers with spectroscopic accuracy: A two-step algorithm rooted into the island model evolutionary algorithm.

The fruitful interplay of high-resolution spectroscopy and quantum chemistry has a long history, especially in the field of small, semi-rigid molecules. However, in recent years, the targets of spectroscopic studies are shifting toward flexible molecules, characterized by a large number of closely spaced energy minima, all contributing to the overall spectrum. Here, artificial intelligence comes into play since it is at the basis of powerful unsupervised techniques for the exploration of soft degrees of freedom.

Computational Spectroscopy in Solution by Integration of Variational and Perturbative Approaches on Top of Clusterized Molecular Dynamics.

Multiscale QM/MM approaches have become the most suitable and effective methods for the investigation of spectroscopic properties of medium- or large-size chromophores in condensed phases. On these grounds, we are developing a novel workflow aimed at improving the generality, reliability, and ease of use of the available tools. In the present paper, we report the latest developments of such an approach with specific reference to a general workplan starting with the addition of acetonitrile to the panel of solvents already available in the General Liquid Optimized Boundary (GLOB) model enforcing nonperiodic boundary conditions (NPBC).

Enumeration of various Ayurvedic formulations listed in an ancient palm-leaf manuscript of Rayalaseema region in Andhra Pradesh state, India.

Ethnopharmacological Relevance: Ancient India relied on manuscripts written by scholars for storing, transferring and retrieving the information pertaining to culture, traditions, religion, geography and political issues. Similarly, Ayurveda, an ancient human health care management system in India and most of its information is available through palm-leaf manuscripts. Though each palm-leaf can persist for a fairly long time, it suffers gradual deterioration owing to physical, chemincal and biological factors, thus warranting digitiation.

Effect of Sample Storage on the Quantitative Determination of 29 PFAS: Observation of Analyte Interconversions during Storage.

In this study, we measured the effects of sample type and storage temperature on the stability of 29 per- and polyfluorinated alkyl substances (PFAS) in water. Spiked bottled water, surface water, and two types of effluent samples were stored in HDPE containers at +20, 4, and -20 °C over a period of up to 180 days. The analytes studied included C through C perfluorinated carboxylates (PFCAs); C through C and C perfluorinated sulfonates (PFSAs); 4:2, 6:2, and 8:2 fluorotelomer sulfonates (FTS); three perfluorooctane sulfonamides (PFOSA, N-MeFOSA, and N-EtFOSA); two perfluorooctane sulfonamide ethanols (N-MeFOSE and N-EtFOSE); and two perfluorooctane sulfonamide acetic acids (N-MeFOSAA and EtFOSAA).