deficiency disrupts V(D)J recombination to cause SCID and Omenn syndrome.

Inborn errors of T cell development present a pediatric emergency in which timely curative therapy is informed by molecular diagnosis. In 11 affected patients across four consanguineous kindreds, we detected homozygosity for a single deleterious missense variant in the gene NudC domain-containing 3 () Two infants had severe combined immunodeficiency with the complete absence of T and B cells (TB SCID), whereas nine showed classical features of Omenn syndrome (OS). Restricted antigen receptor gene usage by residual T lymphocytes suggested impaired V(D)J recombination.

Towards a Holistic Model of Care for Moral Injury: An Australian and New Zealand Investigation into the Role of Police Chaplains in Supporting Police Members following exposure to Moral Transgression.

Police members can be exposed to morally transgressive events with potential for lasting psychosocial and spiritual harm. Through interviews with police members and police chaplains across Australia and New Zealand, this qualitative study explores the current role that police chaplains play in supporting members exposed to morally transgressive events. The availability of chaplains across police services and the close alignment between the support they offer, and the support sought by police, indicates they have an important role.

Meningeal dendritic cells drive neuropathic pain through elevation of the kynurenine metabolic pathway in mice.

Neuropathic pain is one of the most important clinical consequences of injury to the somatosensory system. Nevertheless, the critical pathophysiological mechanisms involved in neuropathic pain development are poorly understood. In this study, we found that neuropathic pain is abrogated when the kynurenine metabolic pathway (KYNPATH) initiated by the enzyme indoleamine 2,3-dioxygenase 1 (IDO1) is ablated pharmacologically or genetically.

Size and Shape Dependence of the Electronic Structure of Gold Nanoclusters on TiO.

Understanding the mechanism behind the superior catalytic power of single- or few-atom heterogeneous catalysts has become an important topic in surface chemistry. This is particularly the case for gold, with TiO being an efficient support. Here we use scanning tunneling microscopy/spectroscopy with theoretical calculations to investigate the adsorption geometry and local electronic structure of several-atom Au clusters on rutile TiO(110), with the clusters fabricated by controlled manipulation of single atoms.

The immunotherapeutic role of indoleamine 2,3-dioxygenase in head and neck squamous cell carcinoma: A systematic review.

Background: Novel cancer immunotherapy seeks to harness the body's own immune system and tip the balance in favour of antitumour activity. The intracellular enzyme indoleamine 2,3-dioxygenase (IDO) is a critical regulator of the tumour microenvironment (TME) via tryptophan metabolism. The potential immunotherapeutic role of IDO in head and neck squamous cell carcinoma (HNSCC) requires further exploration.

Indoleamine 2,3 dioxygenase, age, and immune activation in people living with HIV.

Immune activation complicates HIV despite antiretroviral therapy (ART). Indoleamine 2,3 dioxygenase (IDO) catabolizes tryptophan (T) to kynurenine (K), regulating immune activity, and IDO activity increases with age. This study examines the relationship of IDO activity, bacterial translocation, and aging in people living with HIV (PLWH) on ART.

STING negatively regulates allogeneic T-cell responses by constraining antigen-presenting cell function.

Stimulator of interferon genes (STING)-mediated innate immune activation plays a key role in tumor- and self-DNA-elicited antitumor immunity and autoimmunity. However, STING can also suppress tumor immunity and autoimmunity. STING signaling in host nonhematopoietic cells was reported to either protect against or promote graft-versus-host disease (GVHD), a major complication of allogeneic hematopoietic cell transplantation (allo-HCT).

Exosome-derived miR-142-5p remodels lymphatic vessels and induces IDO to promote immune privilege in the tumour microenvironment.

Clinical response to immunotherapy is closely associated with the immunosuppressive tumour microenvironment (TME), and influenced by the dynamic interaction between tumour cells and lymphatic endothelial cells (LECs). Here, we show that high levels of miR-142-5p positively correlate with indoleamine 2,3-dioxygenase (IDO) expression in tumour-associated lymphatic vessels in advanced cervical squamous cell carcinoma (CSCC). The miR-142-5p is transferred by CSCC-secreted exosomes into LECs to exhaust CD8 T cells via the up-regulation of lymphatic IDO expression, which was abrogated by an IDO inhibitor.

Overcoming resistance to STING agonist therapy to incite durable protective antitumor immunity.

Background: Activating the Stimulator of Interferon Genes (STING) adaptor incites antitumor immunity against immunogenic tumors in mice, prompting clinical trials to test STING activators. However, STING signaling in the tumor microenvironment (TME) during development of Lewis lung carcinoma (LLC) suppresses antitumor immunity to promote tumor growth. We hypothesized that local immune balance favoring suppression of antitumor immunity also attenuates antitumor responses following STING activation.

Co-treatments to Boost IDO Activity and Inhibit Production of Downstream Catabolites Induce Durable Suppression of Experimental Autoimmune Encephalomyelitis.

Reinforcing defective tolerogenic processes slows progression of autoimmune (AI) diseases and has potential to promote drug-free disease remission. Previously, we reported that DNA nanoparticles (DNPs) and cyclic dinucleotides (CDNs) slow progression of experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis, by activating the Stimulator of Interferon Genes (STING) signaling adaptor to stimulate interferon type 1 (IFN-I) production, which induced dendritic cells to express indoleamine 2,3 dioxygenase (IDO) and acquire immune regulatory phenotypes. Here, we show that therapeutic responses to DNPs depend on DNA sensing via cyclic GAMP synthase (cGAS) and interactions between Programmed Death-1 (PD-1) and PD-1 ligands.

CD40 Accelerates the Antigen-Specific Stem-Like Memory CD8 T Cells Formation and Human Papilloma Virus (HPV)-Positive Tumor Eradication.

Antigen-specific stem-like memory CD8 T cells (Tscm) have a series of stem cell characteristics, including long-term survival, self-renewal, anti-apoptosis and persistent differentiation into cytotoxic T cells. The effective induction of tumor-specific CD8 Tscm could persistently eradicate tumor in pro-tumor hostile microenvironment. This study was to investigate the role of CD40 in HPV16-specific CD8 Tscm induction and its anti-tumor function.

Novel delivery of cellular therapy to reduce ischemia reperfusion injury in kidney transplantation.

Ex vivo normothermic machine perfusion (NMP) of donor kidneys prior to transplantation provides a platform for direct delivery of cellular therapeutics to optimize organ quality prior to transplantation. Multipotent Adult Progenitor Cells (MAPC ) possess potent immunomodulatory properties that could minimize ischemia reperfusion injury. We investigated the potential capability of MAPC cells in kidney NMP.

Multibody interactions and nonlinear consensus dynamics on networked systems.

Multibody interactions can reveal higher-order dynamical effects that are not captured by traditional two-body network models. In this work, we derive and analyze models for consensus dynamics on hypergraphs, where nodes interact in groups rather than in pairs. Our work reveals that multibody dynamical effects that go beyond rescaled pairwise interactions can appear only if the interaction function is nonlinear, regardless of the underlying multibody structure.

CD73 on cancer-associated fibroblasts enhanced by the A-mediated feedforward circuit enforces an immune checkpoint.

CD73, an ecto-5'-nucleotidase (NT5E), serves as an immune checkpoint by generating adenosine (ADO), which suppresses immune activation through the A receptor. Elevated CD73 levels in tumor tissues correlate with poor clinical outcomes. However, the crucial source of CD73 activity within the tumor microenvironment remains unspecified.

Stimulator of interferon genes agonists attenuate type I diabetes progression in NOD mice.

Reagents that activate the signaling adaptor stimulator of interferon genes (STING) suppress experimentally induced autoimmunity in murine models of multiple sclerosis and arthritis. In this study, we evaluated STING agonists as potential reagents to inhibit spontaneous autoimmune type I diabetes (T1D) onset in non-obese diabetic (NOD) female mice. Treatments with DNA nanoparticles (DNPs), which activate STING when cargo DNA is sensed, delayed T1D onset and reduced T1D incidence when administered before T1D onset.

Limited Effect of Indolamine 2,3-Dioxygenase Expression and Enzymatic Activity on Lupus-Like Disease in B6.Nba2 Mice.

B6.Nba2 mice spontaneously develop a lupus-like disease characterized by elevated levels of serum anti-nuclear autoantibody (ANA) immune complexes and constitutive type I interferon (IFNα) production. During disease progression, both plasmacytoid dendritic cells (pDCs) and antibody secreting plasma cells accumulate in spleens of B6.

A Validation Study on IDO Immune Biomarkers for Survival Prediction in Non-Small Cell Lung Cancer: Radiation Dose Fractionation Effect in Early-Stage Disease.

Purpose: We recently reported that indoleamine 2, 3-dioxygenase (IDO) activity is significantly correlated with more distant metastasis and worse survival. The present study examined whether radiotherapy (RT) dose fractionation correlates with IDO-mediated immune activity in patients with early-stage NSCLC. Patients with newly diagnosed stage I-II NSCLC treated with either conventionally fractionated 3-dimensional conformal radiotherapy (3DCRT) or stereotactic body radiotherapy (SBRT) were analyzed.

Adoptive CD8 T cell therapy against cancer:Challenges and opportunities.

Cancer immunotherapy is a new and promising option for cancer treatment. Unlike traditional chemo- and radiotherapy, immunotherapy actives host immune system to attack malignancies, and this potentially offers long-term protection from recurrence with less toxicity in comparison to conventional chemo- and radiation therapy. In adoptive CD8 T cell therapy (ACT), large numbers of tumor-specific T cells are sourced from patients and expanded in vitro and infused back to patients.

Graph comparison via the nonbacktracking spectrum.

The comparison of graphs is a vitally important, yet difficult task which arises across a number of diverse research areas including biological and social networks. There have been a number of approaches to define graph distance, however, often these are not metrics (rendering standard data-mining techniques infeasible) or are computationally infeasible for large graphs. In this work we define a new pseudometric based on the spectrum of the nonbacktracking graph operator and show that it cannot only be used to compare graphs generated through different mechanisms but can reliably compare graphs of varying size.

Immune control by amino acid catabolism during tumorigenesis and therapy.

Immune checkpoints arise from physiological changes during tumorigenesis that reprogramme inflammatory, immunological and metabolic processes in malignant lesions and local lymphoid tissues, which constitute the immunological tumour microenvironment (TME). Improving clinical responses to immune checkpoint blockade will require deeper understanding of factors that impact local immune balance in the TME. Elevated catabolism of the amino acids tryptophan (Trp) and arginine (Arg) is a common TME hallmark at clinical presentation of cancer.