Transgelin 2 guards T cell lipid metabolism and antitumour function.

Mounting effective immunity against pathogens and tumours relies on the successful metabolic programming of T cells by extracellular fatty acids. Fatty-acid-binding protein 5 (FABP5) has a key role in this process by coordinating the efficient import and trafficking of lipids that fuel mitochondrial respiration to sustain the bioenergetic requirements of protective CD8 T cells. However, the mechanisms that govern this immunometabolic axis remain unexplored.

High-grade serous ovarian cancer development and anti-PD-1 resistance is driven by IRE1α activity in neutrophils.

High-grade serious ovarian cancer (HGSOC) is an aggressive malignancy that remains refractory to current immunotherapies. While advanced stage disease has been extensively studied, the cellular and molecular mechanisms that promote early immune escape in HGSOC remain largely unexplored. Here, we report that primary HGSO tumors program neutrophils to inhibit T cell anti-tumor function by activating the endoplasmic reticulum (ER) stress sensor IRE1α.

Deficiency of metabolic regulator PKM2 activates the pentose phosphate pathway and generates TCF1 progenitor CD8 T cells to improve immunotherapy.

TCF1 progenitor CD8 T cells mediate the efficacy of immunotherapy; however, the mechanisms that govern their generation and maintenance are poorly understood. Here, we show that targeting glycolysis through deletion of pyruvate kinase muscle 2 (PKM2) results in elevated pentose phosphate pathway (PPP) activity, leading to enrichment of a TCF1 progenitor-exhausted-like phenotype and increased responsiveness to PD-1 blockade in vivo. PKM2 CD8 T cells showed reduced glycolytic flux, accumulation of glycolytic intermediates and PPP metabolites and increased PPP cycling as determined by 1,2-C glucose carbon tracing.

High-grade serous ovarian cancer development and anti-PD-1 resistance is driven by IRE1α activity in neutrophils.

High-grade serous ovarian cancer (HGSOC) is an aggressive malignancy that remains refractory to current immunotherapies. While advanced stage disease has been extensively studied, the cellular and molecular mechanisms that promote early immune escape in HGSOC remain largely unexplored. Here we report that primary HGSO tumors program neutrophils to inhibit T cell anti-tumor function by activating the endoplasmic reticulum (ER) stress sensor IRE1α.

Iron Chelation Therapy Elicits Innate Immune Control of Metastatic Ovarian Cancer.

Iron accumulation in tumors contributes to disease progression and chemoresistance. Although targeting this process can influence various hallmarks of cancer, the immunomodulatory effects of iron chelation in the tumor microenvironment are unknown. Here, we report that treatment with deferiprone, an FDA-approved iron chelator, unleashes innate immune responses that restrain ovarian cancer.

The Consequences of Random Sequential Adsorption for the Precursor Packing and Growth-Per-Cycle of Atomic Layer Deposition Processes.

Atomic layer deposition (ALD) processes are known to deposit submonolayers of material per cycle, primarily attributed to steric hindrance and a limited number of surface sites. However, an often-overlooked factor is the random sequential adsorption (RSA) mechanism, where precursor molecules arrive one-by-one and adsorb at random surface sites. Consequently, the saturation coverage of precursors significantly deviates from ideal closed packing.

In situ formation of inhibitor species through catalytic surface reactions during area-selective atomic layer deposition of TaN.

Small molecule inhibitors (SMIs) have been gaining attention in the field of area-selective atomic layer deposition (ALD) because they can be applied in the vapor-phase. A major challenge for SMIs is that vapor-phase application leads to a disordered inhibitor layer with lower coverage as compared to self-assembled monolayers, SAMs. A lower coverage of SMIs makes achieving high selectivity for area-selective ALD more challenging.

DO seniors and IMGs have lower match probabilities than MD seniors after adjusting for specialty choice and USMLE Step 1 score.

Context: It is unknown if US residency applicants of different educational backgrounds (US allopathic [MD], Doctor of Osteopathic Medicine [DO], and international medical graduates [IMG]) but comparable academic performance have similar match success.

Objectives: Our objective was to compare match probabilities between applicant types after adjusting for specialty choice and United States Medical Licensing Examination (USMLE) Step 1 scores.

Methods: We performed a secondary analysis of published data in National Resident Matching Program (NRMP) reports from 2016, 2018, 2020, and 2022 for US MD seniors, DO seniors, and IMGs (US citizens and non-US citizens).

Transgelin 2 guards T cell lipid metabolic programming and anti-tumor function.

Mounting effective immunity against pathogens and tumors relies on the successful metabolic programming of T cells by extracellular fatty acids. During this process, fatty-acid-binding protein 5 (FABP5) imports lipids that fuel mitochondrial respiration and sustain the bioenergetic requirements of protective CD8 T cells. Importantly, however, the mechanisms governing this crucial immunometabolic axis remain unexplored.

Innate IRE1α-XBP1 activation by viral single-stranded RNA and its influence on lung cytokine production during SARS-CoV-2 pneumonia.

The utilization of host-cell machinery during SARS-CoV-2 infection can overwhelm the protein-folding capacity of the endoplasmic reticulum and activate the unfolded protein response (UPR). The IRE1α-XBP1 arm of the UPR could also be activated by viral RNA via Toll-like receptors. Based on these premises, a study to gain insight into the pathogenesis of COVID-19 disease was conducted using nasopharyngeal exudates and bronchioloalveolar aspirates.

Spatial and single-cell profiling of the metabolome, transcriptome and epigenome of the aging mouse liver.

Tissues within an organism and even cell types within a tissue can age with different velocities. However, it is unclear whether cells of one type experience different aging trajectories within a tissue depending on their spatial location. Here, we used spatial transcriptomics in combination with single-cell ATAC-seq and RNA-seq, lipidomics and functional assays to address how cells in the male murine liver are affected by age-related changes in the microenvironment.

Deficiency of metabolic regulator PKM2 activates the pentose phosphate pathway and generates TCF1+ progenitor CD8+ T cells to improve checkpoint blockade.

TCF1 progenitor CD8+ T cells mediate the efficacy of PD-1 blockade, however the mechanisms that govern their generation and maintenance are poorly understood. Here, we show that targeting glycolysis through deletion of pyruvate kinase muscle 2 (PKM2) results in elevated pentose phosphate pathway (PPP) activity, leading to enrichment of a TCF1 central memory-like phenotype and increased responsiveness to PD-1 blockade . PKM2 CD8+ T cells showed reduced glycolytic flux, accumulation of glycolytic intermediates and PPP metabolites, and increased PPP cycling as determined by 1,2 C glucose carbon tracing.

Piper nigrum extract suppresses tumor growth and enhances the antitumor immune response in murine models of breast cancer and melanoma.

Although the antitumor effect of P. nigrum has been widely studied, research related to its possible immunomodulatory effects is relatively scarce. Here, the antitumor and immunomodulatory activity of an ethanolic extract of P.

Inflammatory ER stress responses dictate the immunopathogenic progression of systemic candidiasis.

Recognition of pathogen-associated molecular patterns can trigger the inositol-requiring enzyme 1 α (IRE1α) arm of the endoplasmic reticulum (ER) stress response in innate immune cells. This process maintains ER homeostasis and also coordinates diverse immunomodulatory programs during bacterial and viral infections. However, the role of innate IRE1α signaling in response to fungal pathogens remains elusive.

Computational Investigation of Precursor Blocking during Area-Selective Atomic Layer Deposition Using Aniline as a Small-Molecule Inhibitor.

Area-selective atomic layer deposition using small-molecule inhibitors (SMIs) involves vapor-phase dosing of inhibitor molecules, resulting in an industry-compatible approach. However, the identification of suitable SMIs that yield a high selectivity remains a challenging task. Recently, aniline (CHNH) was shown to be an effective SMI during the area-selective deposition (ASD) of TiN, giving 6 nm of selective growth on SiO in the presence of Ru and Co non-growth areas.

Increased Pitch Velocity Is Associated With Throwing Arm Kinetics, Injury Risk, and Ulnar Collateral Ligament Reconstruction in Adolescent, Collegiate, and Professional Baseball Pitchers: A Qualitative Systematic Review.

Purpose: To assess the relationship between pitch velocity and throwing arm kinetics, injury, and ulnar collateral ligament reconstruction (UCLr) among high school, collegiate, and professional baseball pitchers.

Methods: The Cochrane Database of Systematic Reviews, the Cochrane Central Register of Controlled Trials, PubMed (2008-2019), and OVID/MEDLINE (2008-2019) were queried for articles that reported on pitch velocity predicting throwing arm kinetics, injury, or UCLr. The Methodological Index for Non-randomized Studies checklist was used to evaluate the quality of all included studies.

Tumor-intrinsic IRE1α signaling controls protective immunity in lung cancer.

IRE1α-XBP1 signaling is emerging as a central orchestrator of malignant progression and immunosuppression in various cancer types. Employing a computational XBP1s detection method applied to TCGA datasets, we demonstrate that expression of the XBP1s mRNA isoform predicts poor survival in non-small cell lung cancer (NSCLC) patients. Ablation of IRE1α in malignant cells delays tumor progression and extends survival in mouse models of NSCLC.

The impact of COVID-19 and masking practices on pertussis cases at a large academic medical center (2019-2021).

We reviewed cases of Bordatella pertussis (B. pertussis) cases in ambulatory clinics at a large academic health care institution in Los Angeles from 2019-2021. Public health prevention measures during the Coronavirus disease 19 (COVID-19) pandemic impacted the number of pertussis cases identified.

Remodeling of the Enterococcal Cell Envelope during Surface Penetration Promotes Intrinsic Resistance to Stress.

Enterococcus faecalis is a normal commensal of the human gastrointestinal tract (GIT). However, upon disruption of gut homeostasis, this nonmotile bacterium can egress from its natural niche and spread to distal organs. While this translocation process can lead to life-threatening systemic infections, the underlying mechanisms remain largely unexplored.

Hypoxia promotes osteogenesis by facilitating acetyl-CoA-mediated mitochondrial-nuclear communication.

Bone-derived mesenchymal stem cells (MSCs) reside in a hypoxic niche that maintains their differentiation potential. While hypoxia (low oxygen concentration) was reported to critically support stem cell function and osteogenesis, the molecular events triggering changes in stem cell fate decisions in response to normoxia (high oxygen concentration) remain elusive. Here, we study the impact of normoxia on mitochondrial-nuclear communication during stem cell differentiation.

Insulin settings and their association with time in range in patients with type 1 diabetes users of predictive low glucose suspend (PLGS) augmented insulin pumps in Santiago, Chile.

Aims: Sensor augmented insulin pumps have become a powerful tool for managing type 1 diabetes (T1D). This study aimed to analyze the insulin pump configuration in users of predictive insulin suspension technology (PLGS).

Methods: T1D patients on insulin pumps with PLGS (Medtronic 640G®) were enrolled.

Fungal Patterns Induce Cytokine Expression through Fluxes of Metabolic Intermediates That Support Glycolysis and Oxidative Phosphorylation.

Cytokine expression is fine-tuned by metabolic intermediates, which makes research on immunometabolism suitable to yield drugs with a wider prospect of application than the biological therapies that block proinflammatory cytokines. Switch from oxidative phosphorylation (OXPHOS) to glycolysis has been considered a characteristic feature of activated immune cells. However, some stimuli might enhance both routes concomitantly.

Elucidating the Reaction Mechanism of Atomic Layer Deposition of AlO with a Series of Al(CH)Cl and Al(CH) Precursors.

The adsorption of metalorganic and metal halide precursors on the SiO surface plays an essential role in thin-film deposition processes such as atomic layer deposition (ALD). In the case of aluminum oxide (AlO) films, the growth characteristics are influenced by the precursor structure, which controls both chemical reactivity and the geometrical constraints during deposition. In this work, a systematic study using a series of Al(CH)Cl ( = 0, 1, 2, and 3) and Al(CH) ( = 1, 2, and 3) precursors is carried out using a combination of experimental spectroscopic techniques together with density functional theory calculations and Monte Carlo simulations to analyze differences across precursor molecules.

Tumor-Derived Lysophosphatidic Acid Blunts Protective Type I Interferon Responses in Ovarian Cancer.

Unlabelled: Lysophosphatidic acid (LPA) is a bioactive lipid enriched in the tumor microenvironment of immunosuppressive malignancies such as ovarian cancer. Although LPA enhances the tumorigenic attributes of cancer cells, the immunomodulatory activity of this phospholipid messenger remains largely unexplored. Here, we report that LPA operates as a negative regulator of type I interferon (IFN) responses in ovarian cancer.

Relation between Reactive Surface Sites and Precursor Choice for Area-Selective Atomic Layer Deposition Using Small Molecule Inhibitors.

Implementation of vapor/phase dosing of small molecule inhibitors (SMIs) in advanced atomic layer deposition (ALD) cycles is currently being considered for bottom-up fabrication by area-selective ALD. When SMIs are used, it can be challenging to completely block precursor adsorption due to the inhibitor size and the relatively short vapor/phase exposures. Two strategies for precursor blocking are explored: (i) physically covering precursor adsorption sites, i.