Background Both elemental metals and particulate air pollution have been reported to influence adult blood pressure (BP). The aim of this study is to examine which elemental components of particle ...mass with diameter ≤2.5 μm (PM
) are responsible for previously reported associations between PM
and neonatal BP. Methods and Results We studied 1131 mother-infant pairs in Project Viva, a Boston-area prebirth cohort. We measured systolic BP (SBP) and diastolic BP (DBP) at a mean age of 30 hours. We calculated average exposures during the 2 to 7 days before birth for the PM
components-aluminum, arsenic, bromine, sulfur, copper, iron, zinc, nickel, vanadium, titanium, magnesium, potassium, silicon, sodium, chlorine, calcium, and lead-measured at the Harvard supersite. Adjusting for covariates and PM
, we applied regression models to examine associations between PM
components and median SBP and DBP, and used variable selection methods to select which components were more strongly associated with each BP outcome. We found consistent results with higher nickel associated with significantly higher SBP and DBP, and higher zinc associated with lower SBP and DBP. For an interquartile range increase in the log Z score (1.4) of nickel, we found a 1.78 mm Hg (95% CI, 0.72-2.84) increase in SBP and a 1.30 (95% CI, 0.54-2.06) increase in DBP. Increased zinc (interquartile range log Z score 1.2) was associated with decreased SBP (-1.29 mm Hg; 95% CI, -2.09 to -0.50) and DBP (-0.85 mm Hg; 95% CI: -1.42 to -0.29). Conclusions Our findings suggest that prenatal exposures to particulate matter components, and particularly nickel, may increase newborn BP.
Human bone marrow (BM) plasma cells are heterogeneous, ranging from newly arrived antibody-secreting cells (ASCs) to long-lived plasma cells (LLPCs). We provide single-cell transcriptional resolution ...of 17,347 BM ASCs from five healthy adults. Fifteen clusters are identified ranging from newly minted ASCs (cluster 1) expressing MKI67 and high major histocompatibility complex (MHC) class II that progress to late clusters 5–8 through intermediate clusters 2–4. Additional ASC clusters include the following: immunoglobulin (Ig) M predominant (likely of extra-follicular origin), interferon responsive, and high mitochondrial activity. Late ASCs are distinguished by G2M checkpoints, mammalian target of rapamycin (mTOR) signaling, distinct metabolic pathways, CD38 expression, utilization of tumor necrosis factor (TNF)-receptor superfamily members, and two distinct maturation pathways involving TNF signaling through nuclear factor κB (NF-κB). This study provides a single-cell atlas and molecular roadmap of LLPC maturation trajectories essential in the BM microniche. Altogether, understanding BM ASC heterogeneity in health and disease enables development of new strategies to enhance protective ASCs and to deplete pathogenic ones.
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•Early BM ASCs contain clusters with high class I and II, IgM, IFN, and mitochondrial genes•Late BM ASCs are distinguished by G2M checkpoints, mTOR signaling, and TNFRSF members•Early ASCs have higher CD38 expression and are selectively depleted with anti-CD38 antibodies•There is heterogeneity of late BM ASCs by degree of TNF signaling through NF-κB
Although long-lived plasma cells (LLPCs) have been identified in human bone marrow (BM), the heterogeneity and mechanistic maturation trajectories have not been clearly defined. Duan et al. demonstrate the heterogeneity of the human BM plasma cells by providing a single-cell transcriptional atlas with a roadmap to LLPC maturation.
Several common and rare genetic variants have been associated with idiopathic pulmonary fibrosis, a progressive fibrotic condition that is localized to the lung.
To develop an integrated ...understanding of the rare and common variants located in multiple loci that have been reported to contribute to the risk of disease.
We performed deep targeted resequencing (3.69 Mb of DNA) in cases (
= 3,624) and control subjects (
= 4,442) across genes and regions previously associated with disease. We tested for associations between disease and
) individual common variants via logistic regression and
) groups of rare variants via sequence kernel association tests.
Statistically significant common variant association signals occurred in all 10 of the regions chosen based on genome-wide association studies. The strongest risk variant is the
promoter variant rs35705950, with an odds ratio of 5.45 (95% confidence interval, 4.91-6.06) for one copy of the risk allele and 18.68 (95% confidence interval, 13.34-26.17) for two copies of the risk allele (
= 9.60 × 10
). In addition to identifying for the first time that rare variation in
is associated with disease, we confirmed the role of rare variation in the
and
gene regions in the risk of IPF, and found that the
and
regions have independent common and rare variant signals.
A limited number of common and rare variants contribute to the risk of idiopathic pulmonary fibrosis in each of the resequencing regions, and these genetic variants focus on biological mechanisms of host defense and cell senescence.
Despite the record-breaking discovery, development and approval of vaccines and antiviral therapeutics such as Paxlovid, coronavirus disease 2019 (COVID-19) remained the fourth leading cause of death ...in the world and third highest in the United States in 2022. Here, we report the discovery and characterization of PF-07817883, a second-generation, orally bioavailable, SARS-CoV-2 main protease inhibitor with improved metabolic stability versus nirmatrelvir, the antiviral component of the ritonavir-boosted therapy Paxlovid. We demonstrate the
pan-human coronavirus antiviral activity and off-target selectivity profile of PF-07817883. PF-07817883 also demonstrated oral efficacy in a mouse-adapted SARS-CoV-2 model at plasma concentrations equivalent to nirmatrelvir. The preclinical
pharmacokinetics and metabolism studies in human matrices are suggestive of improved oral pharmacokinetics for PF-07817883 in humans, relative to nirmatrelvir.
inhibition/induction studies against major human drug metabolizing enzymes/transporters suggest a low potential for perpetrator drug-drug interactions upon single-agent use of PF-07817883.
Alport syndrome is the commonest inherited kidney disease and nearly half the pathogenic variants in the COL4A3-COL4A5 genes that cause Alport syndrome result in Gly substitutions. This study ...examined the molecular characteristics of Gly substitutions that determine the severity of clinical features. Pathogenic COL4A5 variants affecting Gly in the Leiden Open Variation Database in males with X-linked Alport syndrome were correlated with age at kidney failure (n = 157) and hearing loss diagnosis (n = 80). Heterozygous pathogenic COL4A3 and COL4A4 variants affecting Gly (n = 304) in autosomal dominant Alport syndrome were correlated with the risk of haematuria in the UK 100,000 Genomes Project. Gly substitutions were stratified by exon location (1 to 20 or 21 to carboxyl terminus), being adjacent to a non-collagenous region (interruption or terminus), and the degree of instability caused by the replacement residue. Pathogenic COL4A5 variants that resulted in a Gly substitution with a highly destabilising residue reduced the median age at kidney failure by 7 years (p = 0.002), and age at hearing loss diagnosis by 21 years (p = 0.004). Substitutions adjacent to a non-collagenous region delayed kidney failure by 19 years (p = 0.014). Heterozygous pathogenic COL4A3 and COL4A4 variants that resulted in a Gly substitution with a highly destabilising residue (Arg, Val, Glu, Asp, Trp) were associated with an increased risk of haematuria (p = 0.018), and those adjacent to a non-collagenous region were associated with a reduced risk (p = 0.046). Exon location had no effect. In addition, COL4A5 variants adjacent to non-collagenous regions were over-represented in the normal population in gnomAD (p < 0.001). The nature of the substitution and of nearby residues determine the risk of haematuria, early onset kidney failure and hearing loss for Gly substitutions in X-linked and autosomal dominant Alport syndrome.
X-linked Alport syndrome is a genetic kidney disease caused by pathogenic COL4A5 variants, but little is known of the consequences of missense variants affecting the NC1 domain of the corresponding ...collagen IV α5 chain. This study examined these variants in a normal (gnomAD) and other databases (LOVD, Clin Var and 100,000 Genomes Project) to determine their pathogenicity and clinical significance. Males with Cys substitutions in the collagen IV α5 NC1 domain reported in LOVD (n = 25) were examined for typical Alport features, including age at kidney failure. All NC1 variants in LOVD (n = 86) were then assessed for structural damage using an online computational tool, Missense3D. Variants in the ClinVar, gnomAD and 100,000 Genomes Project databases were also examined for structural effects. Predicted damage associated with NC1 substitutions was then correlated with the level of conservation of the affected residues. Cys substitutions in males were associated with the typical features of X-linked Alport syndrome, with a median age at kidney failure of 31 years. NC1 substitutions predicted to cause structural damage were overrepresented in LOVD (p < 0.001), and those affecting Cys residues or 'buried' Gly residues were more common than expected (both p < 0.001). Most NC1 substitutions in gnomAD (88%) were predicted to be structurally-neutral. Substitutions affecting conserved residues resulted in more structural damage than those affecting non-conserved residues (p < 0.001). Many pathogenic missense variants affecting the collagen IV α5 NC1 domain have their effect through molecular structural damage and 3D modelling is a useful tool in their assessment.
Interferon-γ (IFN-γ) signaling mediates host responses to infection, inflammation and anti-tumor immunity. Mutations in the IFN-γ signaling pathway cause immunological disorders, hematological ...malignancies, and resistance to immune checkpoint blockade (ICB) in cancer; however, the function of most clinically observed variants remains unknown. Here, we systematically investigate the genetic determinants of IFN-γ response in colorectal cancer cells using CRISPR-Cas9 screens and base editing mutagenesis. Deep mutagenesis of JAK1 with cytidine and adenine base editors, combined with pathway-wide screens, reveal loss-of-function and gain-of-function mutations, including causal variants in hematological malignancies and mutations detected in patients refractory to ICB. We functionally validate variants of uncertain significance in primary tumor organoids, where engineering missense mutations in JAK1 enhanced or reduced sensitivity to autologous tumor-reactive T cells. We identify more than 300 predicted missense mutations altering IFN-γ pathway activity, generating a valuable resource for interpreting gene variant function.
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•Systematic base editing mutagenesis of the IFN-γ pathway in colorectal cancer cells•Functional assessment of variants relevant to cancer and immune disorders•Mutagenesis highlights functional protein domains and interaction interfaces•Missense mutations in JAK1 alter sensitivity of tumor organoids to T cells
Coelho et al. use functional genomics to systematically analyze the genetic determinants of IFN-γ response in colorectal cancer cells. Base editing mutagenesis of key signaling components facilitates the parallel assessment of gene variant function at scale, relevant for understanding IFN-γ signaling in cancer immune surveillance and immune disorders.
Abstract
The Alliance of Genome Resources (the Alliance) is a combined effort of 7 knowledgebase projects: Saccharomyces Genome Database, WormBase, FlyBase, Mouse Genome Database, the Zebrafish ...Information Network, Rat Genome Database, and the Gene Ontology Resource. The Alliance seeks to provide several benefits: better service to the various communities served by these projects; a harmonized view of data for all biomedical researchers, bioinformaticians, clinicians, and students; and a more sustainable infrastructure. The Alliance has harmonized cross-organism data to provide useful comparative views of gene function, gene expression, and human disease relevance. The basis of the comparative views is shared calls of orthology relationships and the use of common ontologies. The key types of data are alleles and variants, gene function based on gene ontology annotations, phenotypes, association to human disease, gene expression, protein–protein and genetic interactions, and participation in pathways. The information is presented on uniform gene pages that allow facile summarization of information about each gene in each of the 7 organisms covered (budding yeast, roundworm Caenorhabditis elegans, fruit fly, house mouse, zebrafish, brown rat, and human). The harmonized knowledge is freely available on the alliancegenome.org portal, as downloadable files, and by APIs. We expect other existing and emerging knowledge bases to join in the effort to provide the union of useful data and features that each knowledge base currently provides.
Open-access publishing promotes accessibility to scholarly research at no cost to the reader. The emergence of predatory publishers, which exploit the author-pay model by charging substantial ...publication fees for publication in journals with questionable publishing processes, is on the rise. Authors are solicited through aggressive marketing tactics, though who is targeted is not well described. The purpose of this study was to identify characteristics associated with critical care pharmacists that make them targets of unsolicited invitations to publish. A prospective, observational study of critical care pharmacists was performed. Participants archived emails received by their professional email that were unsolicited invitations to submit their original work for publication in a journal (unsolicited journals). Variables were evaluated to determine which were associated with unsolicited invitations; these were compared to legitimate journals, defined as all PubMed-indexed journals in which the participants were previously published. Twenty-three pharmacist participants were included, all of whom were residency and/or fellowship trained and practicing in an academic medical center. Participants had a median of 7 years of experience since their post-graduate training, 6 years since their last change in professional email address, and 2 years since their first PubMed-indexed publication. From these participants, 136 unsolicited and 59 legitimate journals were included. The average number of invitations increased 1.04 (95% CI, 1.02–1.05) times for every additional PubMed-indexed publication (P < .001). Most unsolicited journals were considered predatory. Legitimate and unsolicited journals differed significantly. The number of previous PubMed-indexed publications strongly correlates with the likelihood of critical care pharmacists receiving unsolicited publication invitations, often from predatory journal.
The authors evaluated the association between ventricular arrhythmias detected by implantable cardioverter defibrillators and ambient air pollution concentrations in the hours immediately before the ...arrhythmia. Patients given implantable cardioverter defibrillators at the New England Medical Center in Boston, Massachusetts, between mid-1995 and 1999 who lived within 40 km of a central monitoring site (n = 203) were followed until July 2002. The authors used a case-crossover design to study the association between ambient air pollution and up to 798 confirmed ventricular arrhythmias among 84 subjects. The authors found that interquartile range increases in 24-hour moving average particulate matter less than 2.5 μm in aerodynamic diameter and ozone were associated with 19% and 21% increased risks of ventricular arrhythmia, respectively. For each, there was evidence of a linear exposure response, and the associations appeared independent. These associations were stronger than associations with mean concentrations on the same calendar day and previous calendar days. The authors did not find associations with pollutant concentrations less than 24 hours before the arrhythmia. Cases with a prior ventricular arrhythmia within 72 hours had greater risk associated with air pollutants than did cases without a recent arrhythmia. These results confirm previous findings and suggest that matching of pollution periods to arrhythmias is important in detecting such associations.
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