A plasma proteomics-based candidate biomarker panel predictive of amyotrophic lateral sclerosis.

Identifying a reliable biomarker for amyotrophic lateral sclerosis (ALS) is crucial for clinical practice. Here, in this cross-sectional study, we used the Olink Explore 3072 platform to investigate plasma proteomics as a biomarker tool for this neurodegenerative condition. Thirty-three proteins were differentially abundant in the plasma of patients with ALS (n = 183) versus controls (n = 309).

Proteogenomic characterization of invasive breast tumors in young women.

Breast cancer in women <40, accounting for ~5% of all breast cancer cases diagnosed in the U.S., is more aggressive and associated with worse outcomes compared to breast cancer in older women.

Well-differentiated systemic mastocytosis: genetics, mast cell immunophenotypes, and KIT autophosphorylation.

Background: Well-differentiated systemic mastocytosis (WDSM) is a rare myeloid neoplasm where the genetic etiology is often unknown.

Objective: We aimed to assess WDSM patients for novel KIT variants, mast cell (MC) aberrant immunophenotypes, and KIT autophosphorylation patterns.

Methods: Next-generation sequencing (NGS), MC immunophenotyping, and KIT autophosphorylation studies were performed.

Comparative cohort study of post-acute COVID-19 infection with a nested, randomized controlled trial of ivabradine for those with postural orthostatic tachycardia syndrome (the COVIVA study).

Background: Significant clinical similarities have been observed between the recently described "Long-Haul" COVID-19 (LHC) syndrome, Postural Orthostatic Tachycardia Syndrome (POTS) and Inappropriate Sinus Tachycardia (IST). Shared symptoms include light-headedness, palpitations, tremulousness, generalized weakness, blurred vision, chest pain, dyspnea, "brain-fog," and fatigue. Ivabradine is a selective sinoatrial node blocker FDA-approved for management of tachycardia associated with stable angina and heart failure not fully managed by beta blockers.

Biological Age and Age Acceleration Predict Alzheimer's Disease Plasma Biomarker Levels.

Epigenetic clocks can predict pathological aging associated with Alzheimer's disease (AD) risk, albeit findings are mixed regarding if clocks are predictive in blood and in non-European populations. We constructed epigenetic clocks from blood methylation data in 704 older Hispanic adults and tested the association with a clinical diagnosis of AD and plasma biomarker levels. Biological age and age acceleration, the rate of biological aging, were significantly associated with sex, clinical diagnosis, and levels of eight plasma biomarkers, including P-Tau217 levels.

Severe Chronic Traumatic Encephalopathy in a US Naval Special Warfare Combatant Crewman.

Importance: Chronic traumatic encephalopathy (CTE) is a tauopathy mostly observed following a history of repeated impact-type head injury, usually from contact sports. The overwhelming majority of published, high-stage CTE cases are in older, former high-level contact sport athletes. CTE was infrequent in a large case series of brains donated by military service members, wherein it was most often of minimal severity, while being unanimously present in former contact sport participants.

A single valine to leucine switch disrupts AP2-G DNA binding and reveals GDV1's role in activation.

Sexual commitment in parasites is essential for malaria transmission, yet much remains unknown about the underlying signaling events initiating sexual conversion in a subpopulation of parasites. We discovered a single valine (V) to leucine (L) mutation in an Apetala 2 (AP2) transcription factor required for gametocytogenesis, that abrogates sexual differentiation and confirmed this with forward and reverse mutation editing. Mutated AP2-G.

Transferability of European-derived Alzheimer's disease polygenic risk scores across multiancestry populations.

A polygenic score (PGS) for Alzheimer's disease (AD) was derived recently from data on genome-wide significant loci in European ancestry populations. We applied this PGS to populations in 17 European countries and observed a consistent association with the AD risk, age at onset and cerebrospinal fluid levels of AD biomarkers, independently of apolipoprotein E locus (APOE). This PGS was also associated with the AD risk in many other populations of diverse ancestries.

Next generation sequencing analysis reveals complex genetic architecture of childhood-onset systemic lupus erythematosus.

Objectives: Our current understanding of the genetic architecture of childhood-onset SLE (cSLE) is limited by a dearth of comprehensive genomic studies in cSLE. We have quantified the number of known rare and common SLE risk variants in a diverse cSLE cohort. We characterised type I interferon (IFN) gene expression scores along with genomic data.

Alzheimer's Disease Sequencing Project release 4 whole genome sequencing dataset.

Introduction: The Alzheimer's Disease Sequencing Project (ADSP) is a national initiative to understand the genetic architecture of Alzheimer's disease and related dementias (ADRD) by integrating whole genome sequencing (WGS) with other genetic, phenotypic, and harmonized datasets from diverse populations.

Methods: The Genome Center for Alzheimer's Disease (GCAD) uniformly processed WGS from 36,361 ADSP samples, including 35,014 genetically unique participants of which 45% are from non-European ancestry, across 17 cohorts in 14 countries in this fourth release (R4).

Results: This sequencing effort identified 387 million bi-allelic variants, 42 million short insertions/deletions, and 6.

Transcriptional reprogramming in SMA mouse hearts reveals signatures of early heart failure and dysregulated calcium signaling.

Spinal muscular atrophy (SMA) is an inherited neurodegenerative disease that leads to loss of motor neurons in the anterior horn of the spinal cord with consequent muscle atrophy. SMA results from the functional deletions of the SMN1 gene, resulting in insufficient production of the survival motor neuron (SMN) protein. It is not known why lower motor neurons are particularly sensitive to the loss of SMN function, but it is increasingly apparent that extraneuronal tissues, such as cardiac and skeletal muscle, are also affected by SMN deficiency.

Deciphering distinct genetic risk factors for FTLD-TDP pathological subtypes via whole-genome sequencing.

Frontotemporal lobar degeneration with neuronal inclusions of the TAR DNA-binding protein 43 (FTLD-TDP) is a fatal neurodegenerative disorder with only a limited number of risk loci identified. We report our comprehensive genome-wide association study as part of the International FTLD-TDP Whole-Genome Sequencing Consortium, including 985 patients and 3,153 controls compiled from 26 institutions/brain banks in North America, Europe and Australia, and meta-analysis with the Dementia-seq cohort. We confirm UNC13A as the strongest overall FTLD-TDP risk factor and identify TNIP1 as a novel FTLD-TDP risk factor.

Dominant interfering CARD11 variants disrupt JNK signaling to promote GATA3 expression in T cells.

Several "primary atopic disorders" are linked to monogenic defects that attenuate TCR signaling, favoring T helper type 2 (TH2) cell differentiation. Patients with CARD11-associated atopy with dominant interference of NF-κB signaling (CADINS) disease suffer from severe atopy, caused by germline loss-of-function/dominant interfering (LOF/DI) CARD11 variants. The CARD11 scaffold enables TCR-induced activation of NF-κB, mTORC1, and JNK signaling, yet the function of CARD11-dependent JNK signaling in T cells remains nebulous.

Genetic Regulation of the Metabolome Differs by Sex, Alzheimer's Disease Stage, and Plasma Biomarker Status.

We investigated genetic regulators of circulating plasma metabolites to identify pathways underlying biochemical changes in clinical and biomarker-assisted diagnosis of Alzheimer's disease (AD). We computed metabolite quantitative trait loci by using whole genome sequencing and small molecule plasma metabolites from 229 older adults with clinical AD and 322 age-matched healthy controls. Unbiased associations between 6,881 metabolites and 332,772 common genetic variants were tested, adjusted for age, sex, and both metabolomic and genomic principal components.

SOS1 Inhibition Enhances the Efficacy of KRASG12C Inhibitors and Delays Resistance in Lung Adenocarcinoma.

The clinical effectiveness of KRASG12C inhibitors (G12Ci) is limited both by intrinsic and acquired resistance, necessitating the development of combination approaches. Here, we identified targeting proximal receptor tyrosine kinase signaling using the SOS1 inhibitor (SOS1i) BI-3406 as a strategy to improve responses to G12Ci treatment. SOS1i enhanced the efficacy of G12Ci and limited rebound receptor tyrosine kinase/ERK signaling to overcome intrinsic/adaptive resistance, but this effect was modulated by SOS2 protein levels.

A Baseline Model of PTSD From the ACES Cohort.

Introduction: Post-traumatic stress disorder (PTSD) is a primary military psychiatric condition with complex etiology including strong genetic and/or environmental influences. Environmental influences and demographics can play a role in supporting underlying genetic traits for clinical utility evaluation as risk modifying factors. We are undertaking an IRB approved study to evaluate polygenic scores of PTSD risk in the adverse childhood experience and serotonin (ACES) transporter cohort.

Multiomic analysis of uterine leiomyomas in self-described Black and White women: molecular insights into health disparities.

Background: Black women are at an increased risk of developing uterine leiomyomas and experiencing worse disease prognosis than White women. Epidemiologic and molecular factors have been identified as underlying these disparities, but there remains a paucity of deep, multiomic analysis investigating molecular differences in uterine leiomyomas from Black and White patients.

Objective: To identify molecular alterations within uterine leiomyoma tissues correlating with patient race by multiomic analyses of uterine leiomyomas collected from cohorts of Black and White women.

Lack of association between classical HLA genes and asymptomatic SARS-CoV-2 infection.

Human genetic studies of critical COVID-19 pneumonia have revealed the essential role of type I interferon-dependent innate immunity to SARS-CoV-2 infection. Conversely, an association between the HLA-B∗15:01 allele and asymptomatic SARS-CoV-2 infection in unvaccinated individuals was recently reported, suggesting a contribution of pre-existing T cell-dependent adaptive immunity. We report a lack of association of classical HLA alleles, including HLA-B∗15:01, with pre-omicron asymptomatic SARS-CoV-2 infection in unvaccinated participants in a prospective population-based study in the United States (191 asymptomatic vs.

Rare genetic variation in fibronectin 1 (FN1) protects against APOEε4 in Alzheimer's disease.

The risk of developing Alzheimer's disease (AD) significantly increases in individuals carrying the APOEε4 allele. Elderly cognitively healthy individuals with APOEε4 also exist, suggesting the presence of cellular mechanisms that counteract the pathological effects of APOEε4; however, these mechanisms are unknown. We hypothesized that APOEε4 carriers without dementia might carry genetic variations that could protect them from developing APOEε4-mediated AD pathology.