The progressively exhausted T cell response to a poorly immunogenic model of HCC can be partially rescued by immune checkpoint blockade and is heavily suppressed by T cell responses to oncolytic virotherapy.

Currently, the benefits of Immune Checkpoint Blockade (ICB) for Hepatocellular carcinoma (HCC) are restricted to a subset of patients. We hypothesized that co-treatment with the inflammatory oncolytic virus (OV) Vesicular Stomatitis Virus (VSV-IFNβ) would reprogram the highly immunosuppressive Tumor Microenvironment (TME) to enhance ICB. However, VSV-IFNβ inhibited the efficacy of ICB.

Exploiting viral infection/vaccination to focus high-affinity T cell populations into tumors using oncolytic viro-immunotherapy.

Immune tolerance restricts the number of T cells with significant affinity for self-tumor-associated antigens (TAAs), thereby limiting successful cancer immunotherapy through an inability to generate populations of high-affinity anti-tumor T cells. In contrast, viral infection/vaccination primes and expands high-affinity effector and memory T cells against viral antigens. We show here that it is possible to exploit population-wide preexisting, anti-viral memory recall responses against SARS-CoV-2 antigens to focus a high-affinity, immunodominant T cell response into tumors by oncolytic virus (OV)-mediated or chimeric antigen receptor (CAR)-mediated delivery of viral antigens that are not themselves related to TAAs.

Adaptation invariant concentration discrimination in an insect olfactory system.

Neural responses evoked by a stimulus reduce upon repetition. While this adaptation allows the sensory system to attend to novel cues, does information about the recurring stimulus, particularly its intensity, get compromised? We explored this issue in the locust olfactory system. We found that locusts' innate behavioral response to odorants varied with repetition and stimulus intensity.

An Aberrant Resurgence of Endogenous Retroviruses Prompts Myocarditis and Heart Failure.

Background: Endogenous retroviruses (ERVs) occupy >8% of the human genome. Aberrant resurgence of ERVs has been implicated recently in several critical pathologies. However, the possible incidence and role of ERV resurgence in heart failure (HF), a leading cause of global morbidity and mortality, remain unexplored.

Physician-guided deep learning model for assessing thymic epithelial tumor volume.

Purpose: The Response Evaluation Criteria in Solid Tumors (RECIST) relies solely on one-dimensional measurements to evaluate tumor response to treatments. However, thymic epithelial tumors (TETs), which frequently metastasize to the pleural cavity, exhibit a curvilinear morphology that complicates accurate measurement. To address this, we developed a physician-guided deep learning model and performed a retrospective study based on a patient cohort derived from clinical trials, aiming at efficient and reproducible volumetric assessments of TETs.

PACS2 initiates foam cell formation in macrophages through the ROS-PPARγ-CD36 positive feedback loop.

Disrupted mitochondria-associated endoplasmic reticulum membrane (MAM) homeostasis is closely linked to obesity-related diseases and insulin resistance pathogenesis. The formation of foam cells with classically activated lipid uptake by macrophages is an important mechanism in the progression of atherosclerosis. This study investigated the effects of the MAM interface anchor protein, phosphofurin acidic cluster sorting protein 2 (PACS2), on atherosclerosis.

Clinical decision support using pseudo-notes from multiple streams of EHR data.

Electronic health records (EHR) contain data from disparate sources, spanning various biological and temporal scales. In this work, we introduce the Multiple Embedding Model for EHR (MEME), a deep learning framework for clinical decision support that operates over heterogeneous EHR. MEME first converts tabular EHR into "pseudo-notes", reducing the need for concept harmonization across EHR systems and allowing the use of any state-of-the-art, open source language foundation models.

β Cell Gαs signaling is critical for physiological and pharmacological enhancement of insulin secretion.

The incretin peptides glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptors coordinate β cell secretion that is proportional to nutrient intake. This effect permits consistent and restricted glucose excursions across a range of carbohydrate intake. The canonical signaling downstream of ligand-activated incretin receptors involves coupling to Gαs protein and generation of intracellular cAMP.

Dual Role of NRF2 in Pancreatic Precursor Lesions.

Unlabelled: Pancreatic ductal adenocarcinoma (PDA) arises from distinct precursor lesions, primarily pancreatic intraepithelial neoplasia (PanIN) and intraductal papillary mucinous neoplasm (IPMN). Unlike PanIN, IPMN is a cystic lesion detectable by imaging, providing an opportunity for early intervention. However, the molecular determinants guiding the formation of PanIN versus IPMN remain poorly understood.

Division of labor among H3K4 methyltransferases defines distinct facets of homeostatic plasticity.

Heterozygous mutations in any of the six H3K4 methyltransferases (KMT2s) result in monogenic neurodevelopmental disorders, indicating non-redundant yet poorly understood roles of this enzyme family in neurodevelopment. However, the specific cellular role of KMT2 enzymes in the brain remains poorly understood, owing to the clear non-catalytic functions of each family member and the potential for functional redundancy in installing H3K4 methylation (H3K4me). Here, we identify an instructive role for H3K4me in controlling synapse function and a division of labor among the six KMT2 enzymes in regulating homeostatic synaptic scaling.

Norepinephrine changes behavioral state through astroglial purinergic signaling.

Both neurons and glia communicate through diffusible neuromodulators; however, how neuron-glial interactions in such neuromodulatory networks influence circuit computation and behavior is unclear. During futility-induced behavioral transitions in the larval zebrafish, the neuromodulator norepinephrine (NE) drives fast excitation and delayed inhibition of behavior and circuit activity. We found that astroglial purinergic signaling implements the inhibitory arm of this motif.

Fast, accurate, and versatile data analysis platform for the quantification of molecular spatiotemporal signals.

Optical recording of intricate molecular dynamics is becoming an indispensable technique for biological studies, accelerated by the development of new or improved biosensors and microscopy technology. This creates major computational challenges to extract and quantify biologically meaningful spatiotemporal patterns embedded within complex and rich data sources, many of which cannot be captured with existing methods. Here, we introduce activity quantification and analysis (AQuA2), a fast, accurate, and versatile data analysis platform built upon advanced machine-learning techniques.

Impact of peptidylarginine deiminase 4 (PAD4) deficiency in a fecal-induced peritonitis model of sepsis.

Background: Peptidylarginine deiminase 4 (PAD4) citrullinates histones, enabling the release of neutrophil extracellular traps. While neutrophil extracellular traps capture and kill pathogens, they also drive immunothrombosis, potentially worsening sepsis outcomes. However, it remains unclear whether PAD4 deficiency is beneficial or harmful in sepsis.

Development and validation of pan-cancer lesion segmentation AI-model for whole-body 18F-FDG PET/CT in diverse clinical cohorts.

Background: This study develops a deep learning-based automated lesion segmentation model for whole-body 3DF-fluorodeoxyglucose (FDG)-Position emission tomography (PET) with computed tomography (CT) images agnostic to disease location and site.

Method: A publicly available lesion-annotated dataset of 1014 whole-body FDG-PET/CT images was used to train, validate, and test (70:10:20) eight configurations with 3D U-Net as the backbone architecture. The best-performing model on the test set was further evaluated on 3 different unseen cohorts consisting of osteosarcoma or neuroblastoma (OS cohort) (n = 13), pediatric solid tumors (ST cohort) (n = 14), and adult Pheochromocytoma/Paraganglioma (PHEO cohort) (n = 40).

Remote limb ischemic conditioning alleviates steatohepatitis via extracellular vesicle-mediated muscle-liver crosstalk.

Metabolic dysfunction-associated steatohepatitis (MASH) is an advanced form of liver disease with adverse outcomes. Manipulating interorgan communication is considered a promising strategy for managing metabolic disease, including steatohepatitis. Here, we report that remote limb ischemic conditioning (RIC), a clinically validated therapy for distant organ protection by transient muscle ischemia, significantly alleviated steatohepatitis in different mouse models.

Correlating Solvation Free Energy to Electrolyte Properties for Lithium Metal Batteries.

The electrolyte plays a critical role in lithium metal batteries. In particular, ion solvation profoundly impacts key electrolyte properties and battery performance. In this study, we systematically investigate solvation-property relationships in a series of electrolytes with different solvent-diluent ratios.

NR4A1 Acts as a Novel Regulator of Platelet Activation and Thrombus Formation.

Background: Mounting evidence indicates that nuclear receptors play a critical regulatory role in platelet pathophysiology and thrombotic disorders. Although NR4A (the nuclear receptor subfamily 4 group A) plays an important role in cardiovascular pathophysiology, the expression profile and biological function of NR4A member 1 (NR4A1) in platelets have never been reported.

Methods: We evaluated the functions and the underlying mechanisms of NR4A1 in platelet activation and thrombus formation using platelet-specific NR4A1-deficient mice and NR4A1-specific agonists.

Dexamethasone-loaded platelet-inspired nanoparticles improve intracortical microelectrode recording performance.

Long-term robust intracortical microelectrode (IME) neural recording quality is negatively affected by the neuroinflammatory response following microelectrode insertion. This adversely impacts brain-machine interface (BMI) performance for patients with neurological disorders or amputations. Recent studies suggest that the leakage of blood-brain barrier (BBB) and microhemorrhage caused by the IME insertions lead to the increased neuroinflammation and reduced neural recording performance.

Integrating single-cell RNA and T cell/B cell receptor sequencing with mass cytometry reveals dynamic trajectories of human peripheral immune cells from birth to old age.

A comprehensive understanding of the evolution of the immune landscape in humans across the entire lifespan at single-cell transcriptional and protein levels, during development, maturation and senescence is currently lacking. We recruited a total of 220 healthy volunteers from the Shanghai Pudong Cohort (NCT05206643), spanning 13 age groups from 0 to over 90 years, and profiled their peripheral immune cells through single-cell RNA-sequencing coupled with single T cell and B cell receptor sequencing, high-throughput mass cytometry, bulk RNA-sequencing and flow cytometry validation experiments. We revealed that T cells were the most strongly affected by age and experienced the most intensive rewiring in cell-cell interactions during specific age.

Loss of Type 2 Bone Morphogenetic Protein Receptor Activates NOD-Like Receptor Family Protein 3/Gasdermin E-Mediated Pyroptosis in Pulmonary Arterial Hypertension.

Background: Pulmonary arterial hypertension (PAH) is an incurable disease initiated by endothelial dysfunction, secondary to vascular inflammation and occlusive pulmonary arterial vascular remodeling, resulting in elevated pulmonary arterial pressure and right heart failure. Previous research has reported that dysfunction of type 2 bone morphogenetic protein receptor (BMPR2) signaling pathway in endothelium is inclined to prompt inflammation in PAH models, but the underlying mechanism of BMPR2 deficiency-mediated inflammation needs further investigation. This study was designed to investigate whether BMPR2 deficiency contributes to pulmonary arterial hypertension via the NLRP3 (NOD-like receptor family protein 3)/GSDME (gasdermin E)-mediated pyroptosis pathway.

Geometric Study and Clinical Case Series for Mandible Reconstruction With a Single-Piece Scapular Free Flap.

Background: Virtual surgical planning (VSP) with simple cutting templates could help surgeons preoperatively plan scapula reconstructions in the vertical and horizontal orientations.

Methods: Virtually, eight defects were created in ten healthy mandibles and reconstructed with the subject-specific scapula vertically and horizontally. In the clinical series, 15 single-piece scapula mandible reconstructions planned with in-house VSP and guided with simple templates were compared with 15 freehand reconstructions.

S1PR3 in hippocampal neurons improves synaptic plasticity and decreases depressive behavior via downregulation of RhoA/ROCK1.

The study investigates how Sphingosine-1-phosphate receptor 3 (S1PR3) and the Chronic Unpredictable Mild Stress (CUMS) affects depression-like behaviors. The S1P/S1PR3 signaling pathway is known to play a role in mood regulation, but it is not yet fully understood how it is connected to depression. This study looks to further explore this topic.

IP6K1 Rewires LKB1 Signaling to Mediate Hyperglycemic Endothelial Senescence.

Diabetes is a major risk factor for cardiovascular diseases. The mechanisms of hyperglycemia-induced endothelial dysfunction have been elusive. We found that inositol hexakisphosphate kinase 1 (IP6K1) mediates hyperglycemia-induced endothelial senescence by switching liver kinase B1 (LKB1) activation of the AMPK pathway to activation of the p53 pathway.