Rett syndrome: interferon-γ to the rescue?

Rett syndrome is a severe neurodevelopmental disorder in girls, underpinned by mutations in the X-linked gene . In their recent work (Frasca et al, 2024), Frasca and colleagues identified a novel pathway involving interferon-gamma (IFNγ) that could pave the way to potential therapies.

Ultrasound-Guided Injections of HYADD4 for Knee Osteoarthritis Improves Pain and Functional Outcomes at 3, 6, and 12 Months without Changes in Measured Synovial Fluid, Serum Collagen Biomarkers, or Most Synovial Fluid Biomarker Proteins at 3 Months.

Background: Prior studies have demonstrated improved efficacy when intra-articular (IA) therapeutics are injected using ultrasound (US) guidance. The aim of this study was to determine if clinical improvement in pain and function after IA hyaluronic acid injections using US is associated with changes in SF volumes and biomarker proteins at 3 months.

Methods: 49 subjects with symptomatic knee OA, BMI < 40, and KL radiographic grade II or III participated.

Synovial Fluid Cytokines, Chemokines and MMP Levels in Osteoarthritis Patients with Knee Pain Display a Profile Similar to Many Rheumatoid Arthritis Patients.

Background: There are currently no effective disease-modifying drugs to prevent cartilage loss in osteoarthritis and synovial fluid is a potentially valuable source of biomarkers to understand the pathogenesis of different types of arthritis and identify drug responsiveness. The aim of this study was to compare the differences between SF cytokines and other proteins in patients with OA ( = 21) to those with RA ( = 27) and normal knees ( = 3).

Methods: SF was obtained using ultrasound (US) guidance and an external pneumatic compression device.

Precision Medicine for Rheumatoid Arthritis: The Right Drug for the Right Patient-Companion Diagnostics.

Despite the growing number of biologic and JAK inhibitor therapeutic agents available to treat various systemic autoimmune illnesses, the lack of a validated companion diagnostic (CDx) to accurately predict drug responsiveness for an individual results in many patients being treated for years with expensive, ineffective, or toxic drugs. This review will focus primarily on rheumatoid arthritis (RA) therapeutics where the need is greatest due to poor patient outcomes if the optimum drug is delayed. We will review current FDA-approved biologic and small molecule drugs and why RA patients switch these medications.

A human pluripotent stem cell model for the analysis of metabolic dysfunction in hepatic steatosis.

Nonalcoholic fatty liver disease (NAFLD) is currently the most prevalent form of liver disease worldwide. This term encompasses a spectrum of pathologies, from benign hepatic steatosis to non-alcoholic steatohepatitis, which have, to date, been challenging to model in the laboratory setting. Here, we present a human pluripotent stem cell (hPSC)-derived model of hepatic steatosis, which overcomes inherent challenges of current models and provides insights into the metabolic rewiring associated with steatosis.

Multiple breath washout test data for healthy controls.

This article includes pulmonary function data collected via multiple breath nitrogen washout for 103 healthy U.S. adults recruited at National Jewish Health in Denver, Colorado.

Multiple breath washout: A noninvasive tool for identifying lung disease in symptomatic military deployers.

Rationale: Military deployments to austere environments since November 9, 2001 may put "deployers" at risk for respiratory disease. Sensitive, noninvasive tools for detecting large and small airways injury are needed to identify early disease and help inform management for this at-risk population.

Objectives: We examined multiple breath washout (MBW) as a tool for identifying deployment-related airways disease and assessed host and exposure risk factors compared to healthy controls.

Neutrophils Fuel Effective Immune Responses through Gluconeogenesis and Glycogenesis.

Neutrophils can function and survive in injured and infected tissues, where oxygen and metabolic substrates are limited. Using radioactive flux assays and LC-MS tracing with U-C glucose, glutamine, and pyruvate, we observe that neutrophils require the generation of intracellular glycogen stores by gluconeogenesis and glycogenesis for effective survival and bacterial killing. These metabolic adaptations are dynamic, with net increases in glycogen stores observed following LPS challenge or altitude-induced hypoxia.

Consensus Guidelines for Evaluation and Management of Pulmonary Disease in Sjögren's.

Background: Pulmonary disease is a potentially serious yet underdiagnosed complication of Sjögren's syndrome, the second most common autoimmune rheumatic disease. Approximately 16% of patients with Sjögren's demonstrate pulmonary involvement with higher mortality and lower quality of life.

Research Question: Clinical practice guidelines for pulmonary manifestations of Sjögren's were developed by the Sjögren's Foundation after identifying a critical need for early diagnosis and improved quality and consistency of care.

Activation of transcription factor circuity in 2i-induced ground state pluripotency is independent of repressive global epigenetic landscapes.

Mouse embryonic stem cells (mESCs) cultured with MEK/ERK and GSK3β (2i) inhibitors transition to ground state pluripotency. Gene expression changes, redistribution of histone H3K27me3 profiles and global DNA hypomethylation are hallmarks of 2i exposure, but it is unclear whether epigenetic alterations are required to achieve and maintain ground state or occur as an outcome of 2i signal induced changes. Here we show that ESCs with three epitypes, WT, constitutively methylated, or hypomethylated, all undergo comparable morphological, protein expression and transcriptome changes independently of global alterations of DNA methylation levels or changes in H3K27me3 profiles.

Bivalent promoter hypermethylation in cancer is linked to the H327me3/H3K4me3 ratio in embryonic stem cells.

Background: Thousands of mammalian promoters are defined by co-enrichment of the histone tail modifications H3K27me3 (repressive) and H3K4me3 (activating) and are thus termed bivalent. It was previously observed that bivalent genes in human ES cells (hESC) are frequent targets for hypermethylation in human cancers, and depletion of DNA methylation in mouse embryonic stem cells has a marked impact on H3K27me3 distribution at bivalent promoters. However, only a fraction of bivalent genes in stem cells are targets of hypermethylation in cancer, and it is currently unclear whether all bivalent promoters are equally sensitive to DNA hypomethylation and whether H3K4me3 levels play a role in the interplay between DNA methylation and H3K27me3.

Respiratory Diseases in Post-9/11 Military Personnel Following Southwest Asia Deployment.

Objective: Persistent respiratory symptoms following post-9/11 military deployment to Iraq and Afghanistan are well-recognized, but the spectrum of respiratory diseases remains poorly characterized. This study describes deployment-related respiratory diseases and the diagnostic utility of resting and exercise pulmonary function testing.

Methods: Between 2009 and 2017, 127 consecutive military workers ("deployers") with new-onset respiratory symptoms underwent clinical evaluation.

DNA Methylation Directs Polycomb-Dependent 3D Genome Re-organization in Naive Pluripotency.

The DNA hypomethylation that occurs when embryonic stem cells (ESCs) are directed to the ground state of naive pluripotency by culturing in two small molecule inhibitors (2i) results in redistribution of polycomb (H3K27me3) away from its target loci. Here, we demonstrate that 3D genome organization is also altered in 2i, with chromatin decompaction at polycomb target loci and a loss of long-range polycomb interactions. By preventing DNA hypomethylation during the transition to the ground state, we are able to restore to ESC in 2i the H3K27me3 distribution, as well as polycomb-mediated 3D genome organization that is characteristic of primed ESCs grown in serum.

Loss of the maintenance methyltransferase, xDnmt1, induces apoptosis in Xenopus embryos.

[Image: see text]

Military Occupational Specialty Codes: Utility in Predicting Inhalation Exposures in Post-9/11 Deployers.

Objective: The aim of this study was to examine military occupational specialty (MOS) codes to identify those at risk from inhalation exposures during Southwest Asia deployment.

Methods: Exposure intensity to diesel exhaust, sandstorms, burn pit smoke, combat dust, and occupational vapors/dusts/gases/fumes (VDGF) were scored for all Army/Marine MOS codes by an expert panel. Based on MOS code, panel-rated exposure scores were compared with questionnaire data from military personnel with postdeployment respiratory illnesses.

Ultrasound measurement of knee synovial fluid during external pneumatic compression.

Synovial fluid based biomarker research has been limited by the small volumes of synovial fluid from the knees of some patients. We used ultrasound (US) to determine if synovial fluid could be displaced into an access port during pneumatic compression to 100 mmHg. Forty knees from 37 consecutive arthritis patients with rheumatoid arthritis -25, osteoarthritis -8, psoriatic arthritis -2, and 1 each with systemic lupus erythematosus and gout were evaluated.

A Cell/Cilia Cycle Biosensor for Single-Cell Kinetics Reveals Persistence of Cilia after G1/S Transition Is a General Property in Cells and Mice.

The cilia and cell cycles are inextricably linked. Centrioles in the basal body of cilia nucleate the ciliary axoneme and sequester pericentriolar matrix (PCM) at the centrosome to organize the mitotic spindle. Cilia themselves respond to growth signals, prompting cilia resorption and cell cycle re-entry.

A reassessment of DNA-immunoprecipitation-based genomic profiling.

DNA immunoprecipitation followed by sequencing (DIP-seq) is a common enrichment method for profiling DNA modifications in mammalian genomes. However, the results of independent DIP-seq studies often show considerable variation between profiles of the same genome and between profiles obtained by alternative methods. Here we show that these differences are primarily due to the intrinsic affinity of IgG for short unmodified DNA repeats.

Modelling non-alcoholic fatty liver disease in human hepatocyte-like cells.

Non-alcoholic fatty liver disease (NAFLD) is the most common cause of liver disease in developed countries. An NAFLD model would permit mechanistic studies and enable high-throughput therapeutic screening. While hepatic cancer-derived cell lines are a convenient, renewable resource, their genomic, epigenomic and functional alterations mean their utility in NAFLD modelling is unclear.

Methyl donor deficient diets cause distinct alterations in lipid metabolism but are poorly representative of human NAFLD.

: Non-alcoholic fatty liver disease (NAFLD) is a global health issue. Dietary methyl donor restriction is used to induce a NAFLD/non-alcoholic steatohepatitis (NASH) phenotype in rodents, however the extent to which this model reflects human NAFLD remains incompletely understood. To address this, we undertook hepatic transcriptional profiling of methyl donor restricted rodents and compared these to published human NAFLD datasets.

Investigation into the role of the germline epigenome in the transmission of glucocorticoid-programmed effects across generations.

Background: Early life exposure to adverse environments affects cardiovascular and metabolic systems in the offspring. These programmed effects are transmissible to a second generation through both male and female lines, suggesting germline transmission. We have previously shown that prenatal overexposure to the synthetic glucocorticoid dexamethasone (Dex) in rats reduces birth weight in the first generation (F1), a phenotype which is transmitted to a second generation (F2), particularly through the male line.

Corrigendum: Cholangiocytes act as facultative liver stem cells during impaired hepatocyte regeneration.

This corrects the article DOI: 10.1038/nature23015.