High-Resolution Mass Spectrometry for Human Exposomics: Expanding Chemical Space Coverage

In the modern "omics" era, measurement of the human exposome is a critical missing link between genetic drivers and disease outcomes. High-resolution mass spectrometry (HRMS), routinely used in proteomics and metabolomics, has emerged as a leading technology to broadly profile chemical exposure agents and related biomolecules for accurate mass measurement, high sensitivity, rapid data acquisition, and increased resolution of chemical space. Non-targeted approaches are increasingly accessible, supporting a shift from conventional hypothesis-driven, quantitation-centric targeted analyses toward data-driven, hypothesis-generating chemical exposome-wide profiling. However, HRMS-based exposomics encounters unique challenges. New analytical and computational infrastructures are needed to expand the analysis coverage through streamlined, scalable, and harmonized workflows and data pipelines that permit longitudinal chemical exposome tracking, retrospective validation, and multi-omics integration for meaningful health-oriented inferences. In this article, we survey the literature on state-of-the-art HRMS-based technologies, review current analytical workflows and informatic pipelines, and provide an up-to-date reference on exposomic approaches for chemists, toxicologists, epidemiologists, care providers, and stakeholders in health sciences and medicine. We propose efforts to benchmark fit-for-purpose platforms for expanding coverage of chemical space, including gas/liquid chromatography-HRMS (GC-HRMS and LC-HRMS), and discuss opportunities, challenges, and strategies to advance the burgeoning field of the exposome

Correction: Expanding the clinical phenotype of individuals with a 3-bp in-frame deletion of the NF1 gene (c.2970_2972del): an update of genotype–phenotype correlation

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Genotype-Phenotype Correlation in NF1: Evidence for a More Severe Phenotype Associated with Missense Mutations Affecting NF1 Codons 844–848

Neurofibromatosis type 1 (NF1), a common genetic disorder with a birth incidence of 1:2,000–3,000, is characterized by a highly variable clinical presentation. To date, only two clinically relevant intragenic genotype-phenotype correlations have been reported for NF1 missense mutations affecting p.Arg1809 and a single amino acid deletion p.Met922del. Both variants predispose to a distinct mild NF1 phenotype with neither externally visible cutaneous/plexiform neurofibromas nor other tumors. Here, we report 162 individuals (129 unrelated probands and 33 affected relatives) heterozygous for a constitutional missense mutation affecting one of five neighboring NF1 codons—Leu844, Cys845, Ala846, Leu847, and Gly848—located in the cysteine-serine-rich domain (CSRD). Collectively, these recurrent missense mutations affect ∼0.8% of unrelated NF1 mutation-positive probands in the University of Alabama at Birmingham (UAB) cohort. Major superficial plexiform neurofibromas and symptomatic spinal neurofibromas were more prevalent in these individuals compared with classic NF1-affected cohorts (both p < 0.0001). Nearly half of the individuals had symptomatic or asymptomatic optic pathway gliomas and/or skeletal abnormalities. Additionally, variants in this region seem to confer a high predisposition to develop malignancies compared with the general NF1-affected population (p = 0.0061). Our results demonstrate that these NF1 missense mutations, although located outside the GAP-related domain, may be an important risk factor for a severe presentation. A genotype-phenotype correlation at the NF1 region 844–848 exists and will be valuable in the management and genetic counseling of a significant number of individuals

Expanding the clinical phenotype of individuals with a 3-bp in-frame deletion of the NF1 gene (c.2970_2972del): an update of genotype–phenotype correlation

Purpose: Neurofibromatosis type 1 (NF1) is characterized by a highly variable clinical presentation, but almost all NF1-affected adults present with cutaneous and/or subcutaneous neurofibromas. Exceptions are individuals heterozygous for the NF1 in-frame deletion, c.2970_2972del (p.Met992del), associated with a mild phenotype without any externally visible tumors. Methods: A total of 135 individuals from 103 unrelated families, all carrying the constitutional NF1 p.Met992del pathogenic variant and clinically assessed using the same standardized phenotypic checklist form, were included in this study. Results: None of the individuals had externally visible plexiform or histopathologically confirmed cutaneous or subcutaneous neurofibromas. We did not identify any complications, such as symptomatic optic pathway gliomas (OPGs) or symptomatic spinal neurofibromas; however, 4.8% of individuals had nonoptic brain tumors, mostly low-grade and asymptomatic, and 38.8% had cognitive impairment/learning disabilities. In an individual with the NF1 constitutional c.2970_2972del and three astrocytomas, we provided proof that all were NF1-associated tumors given loss of heterozygosity at three intragenic NF1 microsatellite markers and c.2970_297

Grain Refinement of Aluminum Weld Metal Titanium and zirconium microadditions have a strong influence on grain size, solidification rate and nucleation time

ABSTRACT. The influence of titanium and zirconium microadditions on the grain refinement in aluminum weld metal was investigated. These grain refiners significantly altered the morphology of the solidification structure. The time to nucleate the first grain in the weld metal, the weld metal solidification rate and the columnar grain size were all characterized as a function of the grain refiner content. Increasing the zirconium and titanium contents altered the weld pool shape, which increased the solidification rates, increased the nucleation rate and promoted grain refinement. A grain refinement model based on heterogeneous nucleation on second-phase particles is introduced

S-glutathionylation of the Na+-K+ pump : a novel redox mechanism in preeclampsia

Context: Reduced Na+ -K+ pump activity is widely reported in preeclampsia and may be caused by a reversible oxidative modification that is a novel pathological feature of preeclampsia. Objective: This work aims to determine whether β1 subunit (GSS-β1 ) protein glutathionylation of the Na+ -K + pump occurs in preeclampsia. Methods: The GSS-β1 of the Na+ -K+ pump and its subunit expression in human placentas were compared between women with healthy pregnancies and women with preeclampsia. Human placental samples of pregnant women with preeclampsia (n = 11, mean gestational age 36.5 weeks) were used to examine the GSS-β1 of the Na+ -K+ pump, compared to healthy pregnancies (n = 11, mean gestational age 39 weeks). The potential pathogenetic role of GSS-β1 -mediated Na+ -K+ pump dysfunction in preeclampsia was investigated. Results: Protein expression of the β1 subunit was unchanged in placentas from women with preeclampsia vs those with normotensive pregnancies. Preeclamptic placentas had a significantly increased GSS-β1 of the Na+ -K+ pump compared to those from healthy pregnancies, and this was linked to a decrease in α1 /β1 subunit coimmunoprecipitation. The cytosolic p47phox nicotinamide adenine dinucleotide phosphate hydrogen (NADPH) oxidase subunit and its coimmunoprecipitation with the α1 Na+ -K+ pump subunit was increased in preeclamptic placentas, thus implicating NADPH oxidase–dependent pump inhibition. Conclusions: The high level of β1 pump subunit glutathionylation provides new insights into the mechanism of Na+ -K+ pump dysfunction in preeclampsia

Deficiencies of secondary Fe (oxy)hydroxides associated with phyllosilicates and organic carbon limit the formation of water-stable aggregates in Fe-ore tailings

The formation of water-stable, hierarchical aggregate structure is one of the critical processes in eco-engineering iron (Fe) ore tailings into soil-like medium for sustainable rehabilitation of Fe ore mine site. Through systematically comparing physical structure and mineralogical differences between Fe ore tailings' aggregates and Fe-rich native soil aggregates at a magnetite-Fe ore mine, the present study captured the microstructure, mineralogy and organic matter composition of aggregates in aged (4 years old) tailings, in comparison with those in native soils. A suite of micro-spectroscopic methods have been employed to elucidate their physical, mineralogical and morphological characteristics, including synchrotron based Fe K edge X-ray absorption fine structure spectroscopy (XAFS), and backscattered electrons (BSE)-scanning electron microscopy/energy dispersive X-ray spectroscopy (SEM/EDS). The results revealed significant differences in physical structure of aggregates in Fe ore tailings and natural soils rich in Fe, which was attributed to their different mineralogical and organic components and characteristics. Especially, it was found that the secondary Fe (oxy)hydroxides (i.e., goethite, ferrihydrite) and their interactions with Al/Si rich secondary phyllosilicates (or aluminosilicates) were required in the formation of amorphous Fe-Si-Al rich gels that acted as cementing agents for agglomerating Si-rich particles (e.g., quartz) in soil. In contrast, tailing aggregates (rich in more crystalline primary minerals such as magnetite and biotite) lacked these gels, resulting in poor stability. Comparatively, natural soil aggregates contained more recalcitrate organic carbon groups (e.g., aromatic, carboxyl and aliphatic C) than tailing aggregates, which would have also contributed to the improvement of aggregate stability through organo-mineral associations. This study has improved our understanding of key limiting geochemical factor(s) involved in the aggregation of Fe rich soils, which would provide the basis for formulating effective eco-engineering inputs to accelerate the development of soil-like structure in the Fe ore tailings for sustainable rehabilitation