Inactivation of the SLC25A1 gene during embryogenesis induces a unique senescence program controlled by p53.

Germline inactivating mutations of the SLC25A1 gene contribute to various human disorders, including Velocardiofacial (VCFS), DiGeorge (DGS) syndromes and combined D/L-2-hydroxyglutaric aciduria (D/L-2HGA), a severe systemic disease characterized by the accumulation of 2-hydroxyglutaric acid (2HG). The mechanisms by which SLC25A1 loss leads to these syndromes remain largely unclear. Here, we describe a mouse model of SLC25A1 deficiency that mimics human VCFS/DGS and D/L-2HGA.

Differential effects of intrinsic- versus extrinsic-first corrective exercise programs on morphometric outcomes and navicular drop in pediatric flatfoot.

Although the connection between muscular strength and flatfoot condition is well-established, the impact of corrective exercises on these muscles remains inadequately explored. This study aimed to assess the impact of intrinsic- versus extrinsic-first corrective exercise programs on muscle morphometry and navicular drop in boys with flexible flatfoot. Twenty-five boys aged 10-12 with flexible flatfoot participated, undergoing a 12-week corrective exercise program, with a shift in focus at six weeks.

Innate immune memory in chronic HIV and HIV-associated neurocognitive disorders (HAND): potential mechanisms and clinical implications.

Although antiretroviral therapy (ART) has dramatically improved the outlook of the HIV/AIDS pandemic, people living with HIV (PLWH) on suppressive therapy are still at higher risk for a range of comorbidities including cardiovascular disease (CVD) and HIV-associated neurocognitive disorders (HAND), among others. Chronic inflammation and immune activation are thought to be an underlying cause of these comorbidities. Many of the factors thought to drive chronic inflammation and immune activation in HIV overlap with factors known to induce trained immunity.

Volatile hydrocarbon exposures and immune-related illnesses among Deepwater Horizon oil spill workers.

Background: Despite evidence from experimental studies linking some petroleum hydrocarbons to markers of immune suppression, limited epidemiologic research exists on this topic.

Objective: The aim of this cross-sectional study was to examine associations of oil spill related chemicals (benzene, toluene, ethylbenzene, xylene, and n-hexane (BTEX-H)) and total hydrocarbons (THC) with immune-related illnesses as indicators of potential immune suppression.

Methods: Subjects comprised 8601 Deepwater Horizon (DWH) oil spill clean-up and response workers who participated in a home visit (1-3 years after the DWH spill) in the Gulf Long-term Follow-up (GuLF) Study.

Brd4 modulates metabolic endotoxemia-induced inflammation by regulating colonic macrophage infiltration in high-fat diet-fed mice.

High-fat diet (HFD) induces low-grade chronic inflammation, contributing to obesity and insulin resistance. However, the precise mechanisms triggering obesity-associated metabolic inflammation remain elusive. In this study, we identified epigenetic factor Brd4 as a key player in this process by regulating the expression of Ccr2/Ccr5 in colonic macrophage.

Identification of novel candidate genes for Ascochyta blight resistance in chickpea.

Ascochyta blight, caused by the necrotrophic fungus Ascochyta rabiei, is a major threat to chickpea production worldwide. Resistance genes with broad-spectrum protection against virulent A. rabiei strains are required to secure chickpea yield in the US Northern Great Plains.

PLK1 overexpression suppresses homologous recombination and confers cellular sensitivity to PARP inhibition.

The overexpression of Polo-like kinase 1 (PLK1) is associated with poor clinical outcomes in various malignancies, making it an attractive target for anticancer therapies. Although recent studies suggest PLK1's involvement in homologous recombination (HR), the impact of its overexpression on HR remains unclear. In this study, we investigated the effect of PLK1 overexpression on HR using bioinformatics and experimental approaches.

The role of C-reactive protein and ferritin in the diagnosis of HLH, adult-onset still's disease, and COVID-19 cytokine storm.

Cytokine storm syndromes such as hemophagocytic lymphohistiocytosis (HLH), Adult-onset Still's disease (AOSD), and COVID-19 cytokine storm (CCS) are characterized by markedly elevated inflammatory cytokines. However clinical measurement of serum cytokines is not widely available. This study examined the clinical utility of C-reactive protein (CRP) and ferritin, two inexpensive and widely available inflammatory markers, for distinguishing HLH from AOSD and CCS.

Utility of quantitative measurement of T using restriction spectrum imaging for detection of clinically significant prostate cancer.

The Restriction Spectrum Imaging restriction score (RSIrs) has been shown to improve the accuracy for diagnosis of clinically significant prostate cancer (csPCa) compared to standard DWI. Both diffusion and T properties of prostate tissue contribute to the signal measured in DWI, and studies have demonstrated that each may be valuable for distinguishing csPCa from benign tissue. The purpose of this retrospective study was to (1) determine whether prostate T varies across RSI compartments and in the presence of csPCa, and (2) evaluate whether csPCa detection with RSIrs is improved by acquiring multiple scans at different TEs to measure compartmental T (cT).

Concordance and test-retest consistency of sleep biomarker-based neurodegenerative disorder profiling.

Biomarkers that aid in early detection of neurodegeneration are needed to enable early symptomatic treatment and enable identification of people who may benefit from neuroprotective interventions. Increasing evidence suggests that sleep biomarkers may be useful, given the bi-directional relationship between sleep and neurodegeneration and the prominence of sleep disturbances and altered sleep architectural characteristics in several neurodegenerative disorders. This study aimed to demonstrate that sleep can accurately characterize specific neurodegenerative disorders (NDD).

Accelerated growth and local progression of radiorecurrent prostate cancer in an orthotopic bioluminescent mouse model.

Globally, prostate cancer is the second most common malignancy in males, with over 400 thousand men dying from the disease each year. A common treatment modality for localized prostate cancer is radiotherapy. However, up to half of high-risk patients can relapse with radiorecurrent prostate cancer, the aggressive clinical progression of which remains severely understudied.

Comprehensive Mass Spectral Libraries of Human Thyroid Tissues and Cells.

Thyroid nodules are a common endocrine condition with an increasing incidence over the decades. Data-independent acquisition has been widely utilized in discovery proteomics to identify disease biomarkers and therapeutic targets. To analyze the thyroid disease-related proteome in a high-throughput, reproducible and reliable manner, we introduce thyroid-specific peptide spectral libraries.

BMT: A Cross-Validated ThinPrep Pap Cervical Cytology Dataset for Machine Learning Model Training and Validation.

In the past several years, a few cervical Pap smear datasets have been published for use in clinical training. However, most publicly available datasets consist of pre-segmented single cell images, contain on-image annotations that must be manually edited out, or are prepared using the conventional Pap smear method. Multicellular liquid Pap image datasets are a more accurate reflection of current cervical screening techniques.

Towards a histological diagnosis of childhood small vessel CNS vasculitis.

Background: Primary small vessel CNS vasculitis (sv-cPACNS) is a challenging inflammatory brain disease in children. Brain biopsy is mandatory to confirm the diagnosis. This study aims to develop and validate a histological scoring tool for diagnosing small vessel CNS vasculitis.

Physician assistant/associate career flexibility: factors associated with specialty transitions.

Background: Physician assistants/associates (PAs), due to their broad medical education and certification, have the flexibility to change specialties throughout their careers. Prior studies suggest that between half and three-quarters exercise this option at some point in their career, and a third do so within the first decade. However, more research is needed to understand the factors associated with PAs changing vs.

Leveraging human microbiomes for disease prediction and treatment.

The human microbiome consists of diverse microorganisms that inhabit various body sites. As these microbes are increasingly recognized as key determinants of health, there is significant interest in leveraging individual microbiome profiles for early disease detection, prevention, and drug efficacy prediction. However, the complexity of microbiome data, coupled with conflicting study outcomes, has hindered its integration into clinical practice.

KRAS inhibitors: resistance drivers and combinatorial strategies.

In 1982, the RAS genes HRAS and KRAS were discovered as the first human cancer genes, with KRAS later identified as one of the most frequently mutated oncogenes. Yet, it took nearly 40 years to develop clinically effective inhibitors for RAS-mutant cancers. The discovery in 2013 by Shokat and colleagues of a druggable pocket in KRAS paved the way to FDA approval of the first covalently binding KRAS inhibitors, sotorasib and adagrasib, in 2021 and 2022, respectively.

Targeting CDK2 to circumvent treatment resistance in HR breast cancer.

Genetic and epigenetic defects of the p53 system have previously been associated with resistance to CDK4/6 inhibitors in women with HR breast cancer. Recent data from Kudo et al. demonstrate that CDK2-targeting agents may offer an effective strategy to circumvent such resistance by enforcing cellular senescence downstream of RBL2 dephosphorylation.

Targeting molecular pathways to control immune checkpoint inhibitor toxicities.

Immune checkpoint inhibitors (ICIs) have transformed cancer treatment but are frequently associated with immune-related adverse events (irAEs). This article offers a novel synthesis of findings from both preclinical and clinical studies, focusing on the molecular mechanisms driving irAEs across diverse organ systems. It examines key immune cells, such as T cell subsets and myeloid cells, which are instrumental in irAE pathogenesis, alongside an in-depth analysis of cytokine signaling [interleukin (IL)-6, IL-17, IL-4), interferon γ (IFN-γ), IL-1β, tumor necrosis factor α (TNF-α)], integrin-mediated interactions [integrin subunits αITGA)4 and ITGB7], and microbiome-related factors that contribute to irAE pathology.

Brain phosphoproteomic analysis identifies diabetes-related substrates in Alzheimer's disease pathology in older adults.

Introduction: Type 2 diabetes increases the risk of Alzheimer's disease (AD) dementia. Insulin signaling dysfunction exacerbates tau protein phosphorylation, a hallmark of AD pathology. However, the comprehensive impact of diabetes on patterns of AD-related phosphoprotein in the human brain remains underexplored.

Plasma phosphorylated tau and neuropsychiatric symptoms in dementia with Lewy bodies.

Introduction: Neuropsychiatric symptoms (NPSs) are common in dementia with Lewy bodies (DLB) but their neurobiological mechanisms are poorly understood.

Methods: NPSs and cognition were assessed annually in participants (DLB n = 222; Alzheimer's disease [AD] n = 125) from the European DLB (E-DLB) Consortium, and plasma phosphorylated tau-181 (p-tau181) and p-tau231 concentrations were measured at baseline.

Results: Hallucinations, delusions, and depression were more common in DLB than in AD and, in a subgroup with longitudinal follow-up, persistent hallucinations and NPSs were associated with lower p-tau181 and p-tau231 in DLB.

Harvey Cushing: France Military Hospital Surgical Unit Head and World War I United States Army Medical Corps Commissioner.

Background: This historical account reviews the course and lasting impact of Dr. Harvey Cushing (1869-1939) in neurosurgery.

Methods: The writing of this project was sparked by the discovery of original scientific and bibliographical information about Cushing.