U1 snRNP and RNA polymerase II interaction is predominantly mediated by Prp40 rather than U1-70K in yeast.

Transcription and splicing are coupled both temporally and physically. A previous cryo-EM structure of the human U1 snRNP and RNA polymerase pol II complex has shown that U1 snRNP uses predominantly the RRM domain of U1-70K to directly interact with the RPB2 subunit of pol II. However, residues on U1-70K involved in the interaction with pol II are not conserved in yeast U1-70K, raising the question whether yeast U1 snRNP interacts with pol II in a similar manner.

Caffeine impairs red blood cell storage quality by dual inhibition of ADORA2b signaling and G6PD activity.

Caffeine is the most widely consumed psychoactive substance globally, yet its peripheral physiological effects remain incompletely understood. Leveraging comprehensive data from 13,091 blood donors in the REDS RBC-Omics study, we identify caffeine as a significant modulator of red blood cell (RBC) storage quality and transfusion outcomes. Elevated caffeine levels were reproducible across multiple donations from 643 recalled donors, selected based on their extremes in hemolytic propensity.

Increased Exercise Tolerance in G6PD African Variant Mice Driven by Metabolic Adaptations and Erythrophagocytosis.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency, the most common enzymatic disorder, affects over 500 million people worldwide and is often linked to exercise intolerance due to oxidative stress, but its true impact on physical performance remains unclear. This study aimed to evaluate the physiological and metabolic effects of G6PD deficiency on endurance capacity. Using humanized mice carrying the African G6PD variant [V68M; N126D] (hG6PD), we show that despite reduced pentose phosphate pathway activity, these mice exhibit a 10.

Plasma lipid levels predict chemotherapy response and survival in acute myeloid leukemia.

Acute myeloid leukemia (AML) is characterized by a low five-year survival rate. Despite having many clinical metrics to assess patient prognosis, there remain opportunities to improve risk stratification. We hypothesized that an underexplored resource to examine AML patient prognosis is the plasma metabolome.

Targeting pyruvate metabolism generates distinct CD8+ T cell responses to gammaherpesvirus and B lymphoma.

T cells rely on different metabolic pathways to differentiate into effector or memory cells, and metabolic intervention is a promising strategy to optimize T cell function for immunotherapy. Pyruvate dehydrogenase (PDH) is a nexus between glycolytic and mitochondrial metabolism, regulating pyruvate conversion to either lactate or acetyl-CoA. Here, we retrovirally transduced pyruvate dehydrogenase kinase 1 (PDK1) or pyruvate dehydrogenase phosphatase 1 (PDP1), which control PDH activity, into CD8+ T cells to test effects on T cell function.

From metabolomics to transfusion-associated immunomodulation.

Purpose Of Review: This review summarizes recent advances in metabolomics that have enhanced our understanding of transfusion-related immunomodulation (TRIM), highlighting how biochemical changes in stored blood products - with a focus on packed red blood cells - affect recipient immune responses.

Recent Findings: Metabolomics has revealed critical biochemical shifts - termed storage lesions - in blood products, notably accumulation of oxidized lipids, extracellular vesicles, and hemolysis-derived molecules, such as free heme and iron. These metabolites influence recipient immunity by triggering both inflammatory and immunosuppressive pathways, mediated through mechanisms involving redox imbalance, inflammasome activation, and modulation of immune cell metabolism.

Trauma-induced dysfibrinogenemia: the von Clauss assay does not accurately measure fibrinogen levels after injury.

Trauma patients who sustain severe tissue injury and hemorrhage often receive fibrinogen repletion to avert coagulopathy and achieve hemostasis. However, fibrinogen supplementation has not shown a benefit in trauma patients with coagulopathy. The von Clauss functional fibrinogen assay is the primary indication for fibrinogen transfusion.

Metabolic Adaptation of Regenerative Hematopoiesis Depends on Docking-Independent Mitochondrial Connexin-43.

Hematopoietic stem cells (HSC) exhibit a distinctive antioxidant profile during steady-state and stress hematopoiesis. HSC and multipotential progenitors (HSC/MPP) are metabolically coupled to bone marrow (BM) mesenchymal stromal cells through mitochondrial transfer, a process dependent on hematopoietic connexin 43 (Cx43) and low AMP-activated protein kinase (AMPK) activity. However, the mechanism by which Cx43 preserves mitochondrial functionality in HSC remains elusive.

Erythrocyte Glycolytic and Redox Metabolism Affects Muscle Oxygenation and Exercise Performance: A Randomized Double-Blind Crossover Study in Men.

Background: Erythrocytes are traditionally considered passive oxygen carriers, yet their energetic and redox metabolism plays a critical role in regulating oxygen kinetics.

Objective: This study integrates experimental and computational data to provide a comprehensive analysis of erythrocyte metabolism in response to exercise-induced oxidative stress.

Methods: The study consisted of three phases: in vivo, ex vivo, and computational.

Altered branched chain ketoacids underlie shared metabolic phenotypes in type 1 diabetes and maple syrup urine disease.

Background: Diabetic ketoacidosis is an acute, potentially life-threatening, metabolic complication and often first presentation of type 1 diabetes (T1D) mellitus. Here, we investigated the metabolic and lipid profiles from pediatric patients with T1D, at initial diagnosis and after two weeks of insulin treatment, employing findings from patients affected by maple syrup urine disease (MSUD) and the Recipient Epidemiology and Donor Evaluation Study (REDS) III RBC Omics.

Methods: 27 patients with newly onset T1D were assessed at the University of Campania "L.

Post-transfusion recovery, quality and metabolism of short and long-term stored platelets during controlled inflammation.

Platelet concentrates (PCs) are frequently used to prevent and treat bleeding in patients. However, their efficacy is reduced during inflammation as well as due to platelet storage lesion, including metabolomic shifts and changes in surface markers of stored PCs. This study aims to identify disparities between short-term and long-term stored PCs during controlled inflammation, focusing on distinct metabolic pathways, alterations in surface markers and post-transfusion recovery (PTR).

Chemoresistance of TP53 mutant acute myeloid leukemia requires the mevalonate byproduct, geranylgeranyl pyrophosphate, for induction of an adaptive stress response.

Acute myeloid leukemia with mutations in TP53 (TP53 AML) is fatal with a median survival of 6 months. RNA sequencing on purified AML patient samples showed that TP53 AML had higher expression of mevalonate pathway genes. Using novel, isogenic TP53 AML cell lines and primary samples, we determined that TP53 AML resistance to AML chemotherapy cytarabine (AraC) correlated with increased mevalonate pathway activity, a lower induction of reactive oxygen species (ROS), and a mitochondrial response with increased mitochondrial mass and oxidative phosphorylation.

Blood-storage duration affects hematological and metabolic profiles in patients with sickle cell disease receiving transfusions.

BACKGROUNDPatients with sickle cell disease (SCD) frequently receive RBC units stored near the end of their permissible storage duration. We aimed to determine whether RBC storage duration influences recipient hematological, metabolic, and clinical chemistry parameters.METHODSIn a randomized, prospective, double-blind trial, 24 adults with SCD receiving chronic transfusion therapy were assigned to receive three consecutive outpatient transfusions with RBCs stored for either ≤10 days (short-stored; n = 13) or ≥30 days (long-stored; n = 11).

Obesity influences the biological response to injury: a multi-omics analysis.

Purpose: Obesity is a prevalent disease, but its influence on post-injury biology remains unclear. In this study, we aimed to characterize the independent effect of obesity on the proteomic and metabolomic signatures of trauma.

Methods: Plasma was obtained on arrival from injured patients at a Level 1 Trauma Center and analyzed with modern mass spectrometry-based proteomics and metabolomics.

The STAT3-VDAC1 axis modulates mitochondrial function and plays a critical role in the survival of acute myeloid leukemia cells.

Signal transducer and activator of transcription 3 (STAT3) is a well-described transcription factor that mediates oxidative phosphorylation and glutamine uptake in bulk acute myeloid leukemia (AML) cells and leukemic stem cells (LSCs). STAT3 has also been shown to translocate to the mitochondria in AML cells, and phosphorylation at the serine 727 (pSTAT3 S727) residue has been shown to be especially important for STAT3's mitochondrial functions. We demonstrate that inhibition of STAT3 results in impaired mitochondrial function and decreased leukemia cell viability.

Caffeine Impairs Red Blood Cell Storage Quality by Dual Inhibition of ADORA2b Signaling and G6PD Activity.

Unlabelled: Caffeine is the most widely consumed psychoactive substance globally, yet its peripheral physiological effects remain incompletely understood. Leveraging comprehensive data from 13,091 blood donors in the REDS RBC-Omics study, we identify caffeine as a significant modulator of red blood cell (RBC) storage quality and transfusion outcomes. Elevated caffeine levels were reproducible across multiple donations from 643 recalled donors, selected based on their extremes in hemolytic propensity.

TNF-α impairs platelet function by inhibiting autophagy and disrupting metabolism via syntaxin 17 downregulation.

Platelets play a dual role in hemostasis and inflammation-associated thrombosis and hemorrhage. Although the mechanisms linking inflammation to platelet dysfunction remain poorly understood, our previous work demonstrated that TNF-α alters mitochondrial mass, platelet activation, and autophagy-related pathways in megakaryocytes. Here, we hypothesized that TNF-α impairs platelet function by disrupting autophagy, a process critical for mitochondrial health and cellular metabolism.

Donor genetics and storage conditions influence mitochondrial DNA and extracellular vesicle levels in RBC units.

Mitochondrial DNA (mtDNA) shares characteristics with bacterial DNA and activates immune cells via TLR9Extracellular vesicles (EVs) and mtDNA have been found in blood products and can activate immune cells; we sought to characterize their evolution in stored blood products. From a previous study of hemolysis in 13,403 blood donors, a second blood unit was drawn from 651 donors and sampled at days 10, 21, and 42. EV counts and RBC-EVs increased with storage time, and EV levels were higher in males and in RBC units processed in AS-1 compared with AS-3.

New alleles of D-2-hydroxyglutarate dehydrogenase enable studies of oncometabolite function in Drosophila melanogaster.

D-2-hydroxyglutarate (D-2HG) is a potent oncometabolite capable of disrupting chromatin architecture, altering metabolism, and promoting cellular dedifferentiation. As a result, ectopic D-2HG accumulation induces neurometabolic disorders and promotes progression of multiple cancers. However, the disease-associated effects of ectopic D-2HG accumulation are dependent on genetic context.

Therapy resistance in AML is mediated by cytoplasmic sequestration of the transcriptional repressor IRF2BP2.

While the development of venetoclax with azacitidine (ven/aza) has improved AML therapy, drug resistance remains a major challenge. Notably, primary ven/aza-resistant AML are frequently reliant on MCL1, however, the underlying mechanisms remain unclear. Co-immunoprecipitation of MCL1 from ven/aza-resistant AML samples coupled with mass spectrometry analysis identified the transcriptional repressor Interferon Regulatory Factor 2 Binding Protein 2 (IRF2BP2) as an MCL1 binding partner.

Integrative Multi-Omics Analysis Identifies Nuclear Factor I as a Key Driver of Dysregulated Purine Metabolism in DIPG.

Diffuse intrinsic pontine glioma (DIPG) is a devastating brainstem cancer in children, with a median survival of under one year and limited treatment options. Over 80% of DIPGs possess a H3K27M mutation. To identify metabolic vulnerabilities linked to this mutation, we utilized a multi-omics approach in H3K27M-expressing cells, patient-derived cell lines, and mouse models.

Biliverdin reductase B as a new target in breast cancer.

Background: Enhanced metabolic and mitochondrial activity inherent in actively proliferating cancer cells is associated with intracellular redox imbalance that impacts cellular viability. To restore redox homeostasis cancer cells evolve to activate redox protective mechanisms. This differential activation of redox defense pathways compared to normal cells provides a therapeutic window for novel targeted therapies in cancer.

Sweeteners: erythritol, xylitol and cardiovascular risk-friend or foe?

Hyperglycaemia harms vascular health and promotes platelet aggregation. Reducing glucose concentration is crucial, and sugar alcohols may aid this effort. Used for over 50 years in food, cosmetic, and pharmaceutical industries, erythritol and xylitol minimally affect plasma glucose and insulin levels while promoting the release of beneficial gastrointestinal hormones such as e.

Metabolic insights into hypoxia adaptation in adolescent athletes at different altitudes: a cross-sectional study.

Athletes use hypoxic training methods to enhance their performance under altitude conditions. Comparative studies involving populations from low (500-2,000 m) and moderate (2,000-3,000 m) altitudes offer an opportunity to understand the mechanisms behind adaptations to hypoxia. The present study combined data from metabolomics analysis based on gas- and liquid-chromatography mass spectrometry (GC-MS and LC-MS) to compare plasma profiles from 80 adolescent athletes at moderate- or low altitudes.

Physiologic relevance of the transpulmonary metabolome in connective tissue disease-associated pulmonary vascular disease.

Pathologic implications of dysregulated pulmonary vascular metabolism to pulmonary arterial hypertension (PAH) are increasingly recognized, but their clinical applications have been limited. We hypothesized that metabolite quantification across the pulmonary vascular bed in connective tissue disease-associated (CTD-associated) PAH would identify transpulmonary gradients of pathobiologically relevant metabolites, in an exercise stage-specific manner. Sixty-three CTD patients with established or suspected PAH underwent exercise right heart catheterization.