Venoms are known to modulate immunological processes. In this study, we investigated the immunomodulatory properties of venoms from two stonefish species, Synanceia verrucosa (SvV) and Synanceia horrida (ShV), using immunological assays including reverse-transcription quantitative polymerase chain reaction (RT-qPCR), cytometric bead array (CBA), and enzyme-linked immunosorbent assay (ELISA). Both venoms exhibited significant immunosuppressive activity, particularly in lipopolysaccharide (LPS)-stimulated human peripheral blood mononuclear cells (PBMCs), with less pronounced effects on phorbol 12-myristate 13-acetate with ionomycin (P/I)-stimulated cells. The venoms primarily suppressed Th1-associated cytokines (TNF, IFN-γ, IL-6, and IL-12), as well as IL-10 (Th2) and MCP-1, indicating a stronger inhibition of the Th1 subset. SvV demonstrated greater activity compared to ShV, suppressing cytokines on which ShV had no effect, and having activity at concentrations as low as 1.25 μg/mL. Stability studies showed that both frozen and lyophilized venoms retained immunosuppressive activity comparable to fresh venom, while reversed-phase high-performance liquid chromatography (RP-HPLC) abolished this activity entirely. Size-exclusion chromatography (SEC) revealed the immunosuppressive activity was strongest in the early and late fractions of each venom. Our results highlight the selective immunosuppressive effects of S. verrucosa and S. horrida venoms on human PBMCs, particularly via modulation of Th1 cytokines in response to LPS. The stability and bioactivity of specific venom fractions underscore their potential as sources for novel immunotherapeutic agents.

Mucosal-associated invariant T (MAIT) cells represent a unique unconventional T cell population important in eliciting immunomodulatory responses in a range of diseases, including infectious diseases, autoimmunity and cancer. This innate-like T cell subset predominantly express CD8 in humans. Unlike conventional CD8+ T cells, which recognize peptide antigen presented by polymorphic major histocompatibility complex (MHC) molecules, MAIT cells are restricted by MR1, a non-polymorphic antigen-presenting molecule widely expressed in multiple tissues. Thus, identification of proteomic signature of MAIT cells in relation to conventional T cells is pivotal in understanding it's specific functional characteristics. The high-resolution dataset presents here comprehensively describes and compare the whole cell proteomes of MAIT (TCRVα7.2+CD161+) and conventional/non-MAIT T cells (TCR Vα7.2−CD161−) in humans. The dataset was generated using the proteomic samples prepared from matched T cell subsets sorted from peripheral blood mononuclear cells (PBMC) of three healthy volunteers. Peptides obtained from trypsin-digested cell lysates were analysed using Data-Dependent Mass Spectrometry (DDA-MS). Label-free quantitation of DDA-MS data using MaxQuant and MaxLFQ software identified 4,442 proteins at a 1 % false discovery rate. Of them, 3680 proteins that were detected with single UniProt accession and a minimum of 2 unique or razor peptides were assessed to identify differentially abundant proteins between MAIT cells and conventional T cells, including total T cells and CD8+ T cells. The dataset comprises high-quality label-free quantitative proteomic data that can be used to compare the expression pattern of whole cell proteomes between the above-mentioned T cell populations. Further, this can be used as a reference proteome of human MAIT cells for the in-depth understanding of the MAIT cell behaviour among T cells and to discover potential therapeutic targets to modulate MAIT cell function.

Engagement of the T cell receptor (TCR) triggers molecular reprogramming leading to the acquisition of specialized effector functions by CD4 helper and CD8 cytotoxic T cells. While transcription factors, chemokines, and cytokines are known drivers in this process, the temporal proteomic and transcriptomic changes that regulate different stages of human primary T cell activation remain to be elucidated. Here, we report an integrative temporal proteomic and transcriptomic analysis of primary human CD4 and CD8 T cells following ex vivo stimulation with anti-CD3/CD28 beads, which revealed major transcriptome-proteome uncoupling. The early activation phase in both CD4 and CD8 T cells was associated with transient downregulation of the mRNA transcripts and protein of the central glucose transport GLUT1. In the proliferation phase, CD4 and CD8 T cells became transcriptionally more divergent while their proteome became more similar. In addition to the kinetics of proteome-transcriptome correlation, this study unveils selective transcriptional and translational metabolic reprogramming governing CD4 and CD8 T cell responses to TCR stimulation. This temporal transcriptome/proteome map of human T cell activation provides a reference map exploitable for future discovery of biomarkers and candidates targeting T cell responses.

Background Injury rates and patterns in rugby union (rugby) vary between male and female players at international level but limited data exists in the female community level game. Systematic injury surveillance is a prerequisite to effective injury prevention, but current rugby injury prevention initiatives follow a one size fits all approach based on injury surveillance studies in men. Objective To determine the incidence, severity and nature of match and training injuries in women's rugby across Scotland, England and Wales. Design One-season, prospective observational study, recording time-loss injury following the Community Rugby Consensus for injury surveillance. Setting National level adult women's competitive leagues. Participants Players were aged >18yrs registered and playing for a women's league team. 287 players (153 forwards; 134 backs) from 14 teams participated in the study during the 2022/23 season. Assessment of Risk Factors Match and training exposure Main Outcome Measures Injury incidence, severity, nature and causes. Results Combined tri-nations match injury incidence was 28.5 injuries (95%CI: 23.3–33.7)/1000 player match hours (median severity 15 days) and training injury incidence 0.96 (0.47–1.45)/1000 player training hours (25d). The head (30% of injuries), ankle (16%), shoulder (10%) and knee (7%) were most frequently injured during matches, and head and ankle during training. Common diagnoses were concussion 6.2 injuries (3.8–8.6)/1000 match hours (23%; 23d), followed by ankle (12%; 13d) and knee (7%, 76d) ligament injuries. Two-thirds of match injuries occurred in the tackle (being tackled 42%, 26.5d; tackling 24%, 32.7d), and 76% of match concussions occurred in tackles. Injury patterns were similar for forwards and backs. Conclusion Injury rates were highest during matches. Concussion was the most frequent match injury diagnosis with three-quarters occurring in the tackle. Findings were similar by player position, and across sites. Female-specific injury prevention initiatives should be used to reduce injury and concussion risk in woman's rugby.

Supplementary Figure S5. Anti-CD96 combines with anti-CTLA4 or anti-PD1 to enhance survival following challenge with experimental lung metastases.

T-cells are critical components of the adaptive immune system. Upon activation, they acquire effector functions through a complex interplay between mRNA transcripts and proteins, the landscape of which remains to be fully elucidated. In this resource article, we present an integrative temporal proteomic and transcriptomic analysis of primary human CD4 + and CD8 + T-cells following ex vivo activation with anti-CD3/CD28 Dynabeads. Our data reveal a time-dependent dissociation between the T-cell transcriptome and proteome during activation. A transient downregulation of GLUT1, the central glucose transporter in T-cells, marked the onset of reprogramming in both CD4 + and CD8 + T-cells. At late activation, CD4 + T-cells upregulated enzymes associated with degradation of fatty acids while CD8 + T-cells preferentially upregulated enzymes in the metabolism of cofactors and vitamins. Surprisingly, we found that activated CD4 + and CD8 + T-cells became transcriptionally more divergent at the same time their proteome became more similar. In addition to the metabolic reprogramming highlighted in our analysis, this dataset provides a public resource for understanding temporal molecular changes governing the acquisition of effector functions by T-cells.

Supplementary Figure S6. Anti-CD96 combines with anti-CTLA4, anti-PD1 or doxorubicin to increase survival and reduce metastases in mice bearing 4T1.2 spontaneous metastases.

Supplementary Figure S1. CD96 and CD226 have opposite roles in the control of experimental lung tumor metastases.

Supplementary Figure S4. The effect of anti-CD96 combined with anti-PD1 or anti-CTLA4 in reducing experimental lung metastases is additive.

Supplementary Figure S2. Anti-metastatic activity of anti-CD96 is dependent on NK cells and IL-12p35, but independent of T cells.

Supplementary Methods, Figure Legends

Supplementary Figure S8. Anti-CD96 and anti-PD1 therapy does not induce significant toxicities in B16F10 tumor bearing mice.

Supplementary Methods, Figure Legends

Supplementary Figure S3. Cd96-/- mice are resistant to EO771 spontaneous lung metastases and treatment with anti-CD96 mAb does not increase anti-metastatic effect.

Brief summary: using a murine model of diabetes and ex vivo experiments in human T-cell cultures, this study showed that short-term administration of an antagonist to the receptor for advanced glycation end products (sRAGE) modulates functional T regulatory cells (Treg) expansion and thus prevents diabetes.

Supplementary Figure S7. Reduction in B16F10 lung metastases by anti-CD96/anti-PD1 is dependent on NK cells.

Over past decades, targeted therapies and immunotherapy have improved survival and reduced the morbidity of patients with BRAF‐mutated melanoma. However, drug resistance and relapse hinder overall success. Therefore, there is an urgent need for novel compounds with therapeutic efficacy against BRAF‐melanoma. This prompted us to investigate the antiproliferative profile of a tachykinin‐peptide from the Octopus kaurna, Octpep‐1 in melanoma.

A decline in the prevalence of parasites such as hookworms appears to be correlated with the rise in non-communicable inflammatory conditions in people from high- and middle-income countries. This correlation has led to studies that have identified proteins produced by hookworms that can suppress inflammatory bowel disease (IBD) and asthma in animal models. Hookworms secrete a family of abundant netrin-domain containing proteins referred to as AIPs (Anti-Inflammatory Proteins), but there is no information on the structure-function relationships. Here we have applied a downsizing approach to the hookworm AIPs to derive peptides of 20 residues or less, some of which display anti-inflammatory effects when co-cultured with human peripheral blood mononuclear cells and oral therapeutic activity in a chemically induced mouse model of acute colitis. Our results indicate that a conserved helical region is responsible, at least in part, for the anti-inflammatory effects. This helical region has potential in the design of improved leads for treating IBD and possibly other inflammatory conditions.