Nexinhib20 inhibits JFC1-mediated mobilization of a subset of CD11b/CD18+ vesicles decreasing integrin avidity, but does not inhibit Rac1.

Regulated sequential exocytosis of neutrophil granules is essential in orchestrating the innate immune response, while uncontrolled secretion causes inflammation. We developed and characterized Nexinhib20, a small-molecule inhibitor that targets azurophilic granule exocytosis in neutrophils by blocking the interaction between the small GTPase Rab27a and its effector JFC1. Its therapeutic potential has been demonstrated in several pre-clinical models of inflammatory disease.

CBX2 suppresses interferon signaling to diminish tumor immunogenicity via a noncanonical corepressor complex.

Chromobox 2 (CBX2), a crucial component of the polycomb repressive complex (PRC), has been implicated in the development of various human cancers. However, its role in the regulation of tumor immunogenicity and immune evasion remains inadequately understood. In this study, we found that ablation of CBX2 led to tumor growth inhibition, activation of the tumor immune microenvironment, and enhanced therapeutic efficacy of anti-PD1 or adoptive T cell therapies by using murine syngeneic tumor models.

Activation of the conserved Hippo kinases by inflammasome-triggered proteolytic cleavage controls programmed cell death in macrophages.

The mammalian Hippo kinases, MST1 and MST2, regulate organ development and suppress tumor formation by balancing cell proliferation and death. In macrophages, inflammasomes detect molecular patterns from invading pathogens or damaged host cells and trigger programmed cell death. In addition to lytic pyroptosis, the signatures associated with apoptosis are induced by inflammasome activation, but how the inflammasomes coordinate different cell death processes remains unclear.

Bone Marrow Niche in Cardiometabolic Disease: Mechanisms and Therapeutic Potential.

Cardiovascular and cardiometabolic diseases are leading causes of morbidity and mortality worldwide, driven in part by chronic inflammation. Emerging research suggests that the bone marrow microenvironment, or marrow niche, plays a critical role in both immune system regulation and disease progression. The bone marrow niche is essential for maintaining hematopoietic stem cells (HSCs) and orchestrating hematopoiesis.

Scratching more than an itch.

Enhanced antibacterial skin inflammation is an adaptation of the itch-scratch cycle.

Pre-exposure antibody prophylaxis protects macaques from severe influenza.

Influenza virus pandemics and seasonal epidemics have claimed countless lives. Recurrent zoonotic spillovers of influenza viruses with pandemic potential underscore the need for effective countermeasures. In this study, we show that pre-exposure prophylaxis with broadly neutralizing antibody (bnAb) MEDI8852 is highly effective in protecting cynomolgus macaques from severe disease caused by aerosolized highly pathogenic avian influenza H5N1 virus infection.

TIR signaling activates caspase-like immunity in bacteria.

Caspase family proteases and Toll/interleukin-1 receptor (TIR)-domain proteins have central roles in innate immunity and regulated cell death in humans. We describe a bacterial immune system comprising both a caspase-like protease and a TIR-domain protein. We found that the TIR protein, once it recognizes phage invasion, produces the previously unknown immune signaling molecule adenosine 5'-diphosphate-cyclo[N7:1'']-ribose (N7-cADPR).

Scratching promotes allergic inflammation and host defense via neurogenic mast cell activation.

Itch is a dominant symptom in dermatitis, and scratching promotes cutaneous inflammation, thereby worsening disease. However, the mechanisms through which scratching exacerbates inflammation and whether scratching provides benefit to the host are largely unknown. We found that scratching was required for skin inflammation in mouse models dependent on FcεRI-mediated mast cell activation.

Tolerance mechanisms in polysaccharide biosynthesis: Implications for undecaprenol phosphate recycling in Escherichia coli and Shigella flexneri.

Bacterial polysaccharide synthesis is catalysed on the universal lipid carrier, undecaprenol phosphate (UndP). The cellular UndP pool is shared by different polysaccharide synthesis pathways including peptidoglycan biogenesis. Disruptions in cytosolic polysaccharide synthesis steps are detrimental to bacterial survival due to effects on UndP recycling.

Possible influence of sex on the relationship between dual-task gait costs and cognitive decline in older adults.

The impact of cognitive decline in older adults can be evaluated with dual-task gait (DTG) testing in which a cognitive task is performed during walking, leading to increased costs of gait. Previous research demonstrated that higher DTG costs correlate with increasing cognitive deficits and with age. The present study was conducted to explore whether the relationship between the DTG costs and cognitive abilities in older individuals is influenced by sex differences.

Pilin antigenic variants impact gonococcal lifestyle and antibiotic tolerance by modulating interbacterial forces.

Type 4 pili (T4P) are multifunctional filaments involved in adhesion, surface motility, biofilm formation, and horizontal gene transfer. These extracellular polymers are surface-exposed and, therefore, act as antigens. The human pathogen Neisseria gonorrhoeae uses pilin antigenic variation to escape immune surveillance, yet it is unclear how antigenic variation impacts most other functions of T4P.

The impact of intermittent preventive treatment in school aged children with dihydroartemisinin piperaquine and artesunate amodiaquine on IgG response against six blood stage Plasmodium falciparum antigens.

Several interventional strategies have been implemented in malaria endemic areas where the burden is high, that include among others, intermittent preventive treatment (IPT), a tactic that blocks transmission and can reduce disease morbidity. However, the implementation IPT strategies raises a genuine concern, intervening the development of naturally acquired immunity to malaria which requires continuous contact with parasite antigens. This study investigated whether dihydroartemisinin-piperaquine (DP) or artesunate-amodiaquine (ASAQ) IPT in schoolchildren (IPTsc) impairs IgG reactivity to six malaria antigens.

Prognostic value of immune biomarkers in melanoma loco-regional metastases.

The prognosis for patients with melanoma loco-regional metastases is very heterogenous. Adjuvant PD-L1-inhibitors have improved clinical outcome for this patient group, but the prognostic impact of tumour PD-L1 expression and number of tumour infiltrating lymphocytes (TILs) is still largely unknown. Here, we investigated the impact on survival for CD3, CD8, FOXP3 and PD-L1 TIL counts and tumour PD-L1 expression in melanoma loco-regional metastases.

In vitro cytotoxicity (irritant potency) of toothpaste ingredients.

Purpose: This study aimed to determine the cytotoxicity (irritant potency) of toothpaste ingredients, of which some had known to have sensitizing properties.

Materials: From the wide variety of toothpaste ingredients, Xylitol, Propylene glycol (PEG), Sodium metaphosphate (SMP), Lemon, Peppermint, Fluoride, Cinnamon, and Triclosan and Sodium dodecyl sulphate (SDS) have been selected for evaluation of their cytotoxic properties.

Methods: Reconstructed human gingiva (RHG) were topically exposed to toothpaste ingredients at different concentrations.

Effect of cytotoxic CD8+ T-cells secretory proteins on hypoxic pancreatic cancer cells.

Background: Hypoxia in tumor cells is linked to increased drug resistance and more aggressive behavior. In pancreatic cancer, the tumor microenvironment is notably hypoxic and exhibits strong immunosuppressive properties. Given that immunotherapy is now approved for pancreatic cancer treatment, further understanding of how pancreatic tumor cell hypoxia influences T-cell cytotoxicityis essential.

Guards and decoys: RIPoptosome and inflammasome pathway regulators of bacterial effector-triggered immunity.

Virulent microbes produce proteins that interact with host cell targets to promote pathogenesis. For example, virulent bacterial pathogens have proteins called effectors that are typically enzymes and are secreted into host cells. To detect and respond to the activities of effectors, diverse phyla of host organisms evolved effector-triggered immunity (ETI).

Immune-related adverse events in older adults receiving immune checkpoint inhibitors: a comprehensive analysis of the Food and Drug Administration Adverse Event Reporting System.

Background: Immune checkpoint inhibitors (ICIs) have revolutionised cancer therapy, yet they carry a unique spectrum of immune-related adverse events (irAEs). Given the ageing global population and the underrepresentation of older adults in clinical trials for ICIs, we investigated the occurrence and characteristics of irAEs in older versus younger adults as well as among different age subsets within the older adult population.

Methods: We analysed the U.

Incidence of ANCA associated vasculitis and polyarteritis nodosa in Norfolk, UK, from 2011-2020.

Objective: To report the annual and age-specific incidence of ANCA associated vasculitis and polyarteritis nodosa in the adult population of Norfolk County, UK.

Methods: Individuals newly diagnosed with ANCA associated vasculitis or polyarteritis nodosa between 1st Jan 2011 and 31st December 2020, residing in the postal areas of NR1-NR30 were included. Patients were classified according to the European Medicines Agency algorithm.

Bone Health and Linear Growth in Children with Familial Hypoparathyroidism Treated with Human Parathyroid Hormone 1-34.

Context: Our study explores the impact of human PTH 1-34 injections (PTH therapy) on growth, areal bone mineral density (BMD), and bone quality (measured by trabecular bone score, TBS) in hypoparathyroidism due to autoimmune polyendocrine syndrome type 1 (APS-1) or an activating variant of the calcium sensing receptor (CaR).

Objective: To assess associations of 1) age and PTH therapy duration with age-standardized Z-scores for height (HAZ), BMD (BMD-Z), and TBS (TBS-Z) in CaR or APS-1, and 2) APS-1 disease severity with BMD-Z and TBS-Z.

Methods: This secondary analysis pooled linear growth and lumbar spine (LS) DXA data from studies of hypoparathyroidism with mean baseline age of 13.

Long-term Thyroid Outcomes After COVID-19 Vaccination: A Cohort Study of 2,333,496 Patients from the TriNetX Network.

Context: Reports on long-term thyroid dysfunction following COVID-19 vaccination are limited. Understanding the risk of subacute thyroiditis, hyperthyroidism, and hypothyroidism in vaccinated individuals is crucial for post-vaccination monitoring.

Objective: This study evaluated the risk of thyroid dysfunction in COVID-19 vaccinated individuals compared to unvaccinated individuals using a large cohort.

Multimodal integration of blood RNA and ctDNA reflects response to immunotherapy in metastatic urothelial cancer.

Background: Previously, we demonstrated that changes in circulating tumor DNA (ctDNA) are promising biomarkers for early response prediction (ERP) to immune checkpoint inhibitors (ICI) in metastatic urothelial cancer (mUC). In this study, we investigated the value of whole blood immunotranscriptomics for ERP-ICI and integrated both biomarkers into a multimodal model to boost accuracy.

Methods: Blood samples of 93 patients were collected at baseline and after 2-6 weeks of ICI for ctDNA (N=88) and immunotranscriptome (N=79) analyses.

Systematic bias in malaria parasite relatedness estimation.

Genetic studies of Plasmodium parasites increasingly feature relatedness estimates. However, various aspects of malaria parasite relatedness estimation are not fully understood. For example, relatedness estimates based on whole-genome-sequence (WGS) data often exceed those based on sparser data types.

Elevated protein lactylation promotes immunosuppressive microenvironment and therapeutic resistance in pancreatic ductal adenocarcinoma.

Metabolic reprogramming shapes tumor microenvironment (TME) and may lead to immunotherapy resistance in pancreatic ductal adenocarcinoma (PDAC). Elucidating the impact of pancreatic cancer cell metabolism in the TME is essential to therapeutic interventions. "Immune cold" PDAC is characterized by elevated lactate levels resulting from tumor cell metabolism, abundance of pro-tumor macrophages, and reduced cytotoxic T cell in the TME.

A comprehensive benchmarking for evaluating TCR embeddings in modeling TCR-epitope interactions.

The complexity of T cell receptor (TCR) sequences, particularly within the complementarity-determining region 3 (CDR3), requires efficient embedding methods for applying machine learning to immunology. While various TCR CDR3 embedding strategies have been proposed, the absence of their systematic evaluations created perplexity in the community. Here, we extracted CDR3 embedding models from 19 existing methods and benchmarked these models with four curated datasets by accessing their impact on the performance of TCR downstream tasks, including TCR-epitope binding affinity prediction, epitope-specific TCR identification, TCR clustering, and visualization analysis.

A model of care redesign within rheumatology: A mixed methods approach integrating nurse practitioners and physician assistants.

Background: Increasing patient demand and clinician burnout in rheumatology practices have highlighted the need for more efficient models of care (MOC). Interprofessional collaboration is essential for improving patient outcomes and clinician satisfaction.

Local Problem: Our current MOC lacks standardization and formal integration of Nurse Practitioners (NPs) and Physician Assistants (PAs), resulting in reduced clinician satisfaction and limited patient access.