Identification of immune signatures associated with both SARS-CoV-2 infection and lung transplantation.

Lung transplantation (lung-tx) offers the last life-saving option for patients with COVID-19-associated lung injury (CALI). We show that the RBD-specific antibodies are dramatically reduced in these CALI lung-tx patients despite a comparable frequency of CD19 B cells in circulating blood between CALI lung-tx patients and sero-negative controls. In contrast, non-transplant COVID-19 groups maintain a high level of RBD-specific antibodies.

Succinate drives gut inflammation by promoting FOXP3 degradation through a molecular switch.

Succinate levels are increased in inflammatory bowel disease (IBD), but its role in disease pathogenicity remains unknown. Here we showed that succinate promoted colitis in mice by reducing the expression of FOXP3 and increasing the expression of interleukin-17 in regulatory T (T) cells. Succinate selectively reduced the expression of 2-oxoglutarate dehydrogenase complex (OGDHc), the enzyme for succinyl-CoA synthesis, which in turn reduced FOXP3 succinylation and made FOXP3 lysine residues available for ubiquitination and FOXP3 protein degradation.

Careful design of Large Language Model pipelines enables expert-level retrieval of evidence-based information from syntheses and databases.

Wise use of evidence to support efficient conservation action is key to tackling biodiversity loss with limited time and resources. Evidence syntheses provide key recommendations for conservation decision-makers by assessing and summarising evidence, but are not always easy to access, digest, and use. Recent advances in Large Language Models (LLMs) present both opportunities and risks in enabling faster and more intuitive systems to access evidence syntheses and databases.

Ubiquitin-specific peptidase 22 controls integrin-dependent cancer cell stemness and metastasis.

Integrins play critical roles in connecting the extracellular matrix and actin. While the upregulation of integrins is thought to promote cancer stemness and metastasis, the mechanisms underlying their upregulation in cancer stem cells (CSCs) remain poorly understood. Herein, we show that USP22 is essential in maintaining breast cancer cell stemness by promoting the transcription of integrin β1 ().

Acidity induces durable enhancement of T cell suppressive functions for tumor immune evasion.

The microenvironment within solid tumors often becomes acidic due to various factors associated with abnormal metabolism and cellular activities, including increased lactate production as a result of dysregulated tumor glycolysis. Recently, we have identified multiple tumor microenvironment (TME) factors that potentiate regulatory T (T) cell function in evading anti-tumor immunosurveillance. Despite the strong correlation between lactate and acidity, the potential roles of acidity in intratumoral T cell adaptation and underlying molecular mechanisms have gone largely unstudied.

Novel antibody language model accelerates IgG screening and design for broad-spectrum antiviral therapy.

Therapeutic antibodies have become one of the most influential therapeutics in modern medicine to fight against infectious pathogens, cancer, and many other diseases. However, experimental screening for highly efficacious targeting antibodies is labor-intensive and of high cost, which is exacerbated by evolving antigen targets under selective pressure such as fast-mutating viral variants. As a proof-of-concept, we developed a machine learning-assisted antibody generation pipeline AbGen that greatly accelerates the screening and re-design of immunoglobulins G (IgGs) against a broad spectrum of SARS-CoV-2 coronavirus variant strains.

Mediator complex subunit 1 architects a tumorigenic Treg cell program independent of inflammation.

While immunotherapy has revolutionized cancer treatment, its safety has been hampered by immunotherapy-related adverse events. Unexpectedly, we show that Mediator complex subunit 1 (MED1) is required for T regulatory (T) cell function specifically in the tumor microenvironment. T cell-specific MED1 deletion does not predispose mice to autoimmunity or excessive inflammation.

CRISPR screening identifies the deubiquitylase ATXN3 as a PD-L1-positive regulator for tumor immune evasion.

Regulation of tumoral PD-L1 expression is critical to advancing our understanding of tumor immune evasion and the improvement of existing antitumor immunotherapies. Herein, we describe a CRISPR-based screening platform and identified ATXN3 as a positive regulator for PD-L1 transcription. TCGA database analysis revealed a positive correlation between ATXN3 and CD274 in more than 80% of human cancers.

Multifaceted immune dysregulation characterizes individuals at-risk for rheumatoid arthritis.

Molecular markers of autoimmunity, such as antibodies to citrullinated protein antigens (ACPA), are detectable prior to inflammatory arthritis (IA) in rheumatoid arthritis (RA) and may define a state that is 'at-risk' for future RA. Here we present a cross-sectional comparative analysis among three groups that include ACPA positive individuals without IA (At-Risk), ACPA negative individuals and individuals with early, ACPA positive clinical RA (Early RA). Differential methylation analysis among the groups identifies non-specific dysregulation in peripheral B, memory and naïve T cells in At-Risk participants, with more specific immunological pathway abnormalities in Early RA.

Ubiquitin-specific peptidase 22 controls integrin-dependent cancer cell stemness and metastasis.

Integrins plays critical roles in connecting the extracellular matrix and actin skeleton for cell adhesion, migration, signal transduction, and gene transcription, which upregulation is involved in cancer stemness and metastasis. However, the molecular mechanisms underlying how integrins are upregulated in cancer stem cells (CSCs) remain as a biomedical mystery. Herein, we show that the death from cancer signature gene USP22 is essential to maintain the stemness of breast cancer cells through promoting the transcription of a group of integrin family members in particular integrin β1 Both genetic and pharmacological USP22 inhibition largely impaired breast cancer stem cell self-renewal and prevented their metastasis.

Oral mucosal breaks trigger anti-citrullinated bacterial and human protein antibody responses in rheumatoid arthritis.

Periodontal disease is more common in individuals with rheumatoid arthritis (RA) who have detectable anti-citrullinated protein antibodies (ACPAs), implicating oral mucosal inflammation in RA pathogenesis. Here, we performed paired analysis of human and bacterial transcriptomics in longitudinal blood samples from RA patients. We found that patients with RA and periodontal disease experienced repeated oral bacteremias associated with transcriptional signatures of ISG15HLADR and CD48S100A2 monocytes, recently identified in inflamed RA synovia and blood of those with RA flares.

The ubiquitin-specific peptidase 22 is a deubiquitinase of CD73 in breast cancer cells.

Cancer cells evade the immune system by expressing inhibitory immune checkpoint receptors such as ecto-5'-nucleotidase (NT5E), also known as CD73, which consequently suppress tumor neoantigen-specific immune response. Blockade of CD73 in mouse models of breast cancer showed a reduction in tumor growth and metastasis. CD73 expression is elevated in a variety of human tumors including breast cancer.

A deubiquitination module essential for T fitness in the tumor microenvironment.

The tumor microenvironment (TME) enhances regulatory T (T) cell stability and immunosuppressive functions through up-regulation of lineage transcription factor Foxp3, a phenomenon known as T fitness or adaptation. Here, we characterize previously unknown TME-specific cellular and molecular mechanisms underlying T fitness. We demonstrate that TME-specific stressors including transforming growth factor-β (TGF-β), hypoxia, and nutrient deprivation selectively induce two Foxp3-specific deubiquitinases, ubiquitin-specific peptidase 22 () and , by regulating TGF-β, HIF, and mTOR signaling, respectively, to maintain T fitness.

The NALCN channel regulates metastasis and nonmalignant cell dissemination.

We identify the sodium leak channel non-selective protein (NALCN) as a key regulator of cancer metastasis and nonmalignant cell dissemination. Among 10,022 human cancers, NALCN loss-of-function mutations were enriched in gastric and colorectal cancers. Deletion of Nalcn from gastric, intestinal or pancreatic adenocarcinomas in mice did not alter tumor incidence, but markedly increased the number of circulating tumor cells (CTCs) and metastases.

Antibody cross-reactivity between casein and myelin-associated glycoprotein results in central nervous system demyelination.

Multiple sclerosis (MS) is a neuroinflammatory demyelinating disease of the central nervous system (CNS) with a high socioeconomic relevance. The pathophysiology of MS, which is both complex and incompletely understood, is believed to be influenced by various environmental determinants, including diet. Since the 1990s, a correlation between the consumption of bovine milk products and MS prevalence has been debated.

COVID-19 Surveillance for Local Decision Making : An Academic, School District, and Public Health Collaboration.

Objective: Data-informed decision making is valued among school districts, but challenges remain for local health departments to provide data, especially during a pandemic. We describe the rapid planning and deployment of a school-based COVID-19 surveillance system in a metropolitan US county.

Methods: In 2020, we used several data sources to construct disease- and school-based indicators for COVID-19 surveillance in Franklin County, an urban county in central Ohio.

Effect of Dispersion Medium Composition and Ionomer Concentration on the Microstructure and Rheology of Fe-N-C Platinum Group Metal-free Catalyst Inks for Polymer Electrolyte Membrane Fuel Cells.

We present an investigation of the microstructure and rheological behavior of catalyst inks consisting of Fe-N-C platinum group metal-free catalysts and a perfluorosulfonic acid ionomer in a dispersion medium (DM) of water and 1-propanol (PA). The effects of the ionomer-to-catalyst (I/C) ratio and weight percentage of water (HO %) in the DM on the ink microstructure were studied. Steady-shear and dynamic-oscillatory-shear rheology, in combination with synchrotron X-ray scattering, was utilized to understand interparticle interactions and the level of agglomeration of the inks.

RET receptor expression and interaction with TRK receptors in neuroblastomas.

Neuroblastomas (NBs) have heterogeneous clinical behavior, from spontaneous regression or differentiation to relentless progression. Evidence from our laboratory and others suggests that neurotrophin receptors contribute to these disparate behaviors. Previously, the role of TRK receptors in NB pathogenesis was investigated.

Mechanisms of Entrectinib Resistance in a Neuroblastoma Xenograft Model.

TrkB with its ligand, brain-derived neurotrophic factor (BDNF), are overexpressed in the majority of high-risk neuroblastomas (NB). Entrectinib is a novel pan-TRK, ALK, and ROS1 inhibitor that has shown excellent preclinical efficacy in NB xenograft models, and recently it has entered phase 1 trials in pediatric relapsed/refractory solid tumors. We examined entrectinib-resistant NB cell lines to identify mechanisms of resistance.

Bandgap Engineering of Indium Phosphide-Based Core/Shell Heterostructures Through Shell Composition and Thickness.

The large bulk bandgap (1.35 eV) and Bohr radius (~10 nm) of InP semiconductor nanocrystals provides bandgap tunability over a wide spectral range, providing superior color tuning compared to that of CdSe quantum dots. In this paper, the dependence of the bandgap, photoluminescence emission, and exciton radiative lifetime of core/shell quantum dot heterostructures has been investigated using colloidal InP core nanocrystals with multiple diameters (1.

Adrb2 controls glucose homeostasis by developmental regulation of pancreatic islet vasculature.

A better understanding of processes controlling the development and function of pancreatic islets is critical for diabetes prevention and treatment. Here, we reveal a previously unappreciated function for pancreatic β2-adrenergic receptors (Adrb2) in controlling glucose homeostasis by restricting islet vascular growth during development. Pancreas-specific deletion of results in glucose intolerance and impaired insulin secretion in mice, and unexpectedly, specifically in females.

Role of microRNAs in epigenetic silencing of the CHD5 tumor suppressor gene in neuroblastomas.

Neuroblastoma (NB), a tumor of the sympathetic nervous system, is the most common extracranial solid tumor of childhood. We and others have identified distinct patterns of genomic change that underlie diverse clinical behaviors, from spontaneous regression to relentless progression. We first identified CHD5 as a tumor suppressor gene that is frequently deleted in NBs.

Entrectinib is a potent inhibitor of Trk-driven neuroblastomas in a xenograft mouse model.

Neuroblastoma (NB) is one of the most common and deadly childhood solid tumors. These tumors are characterized by clinical heterogeneity, from spontaneous regression to relentless progression, and the Trk family of neurotrophin receptors plays an important role in this heterogeneous behavior. We wanted to determine if entrectinib (RXDX-101, Ignyta, Inc.