Untargeted metabolomics analysis as a potential screening tool for 3-methylglutaconic aciduria syndromes.

The 3-methylglutaconic aciduria (3-MGA-uria) syndromes comprise a heterogeneous group of inborn errors of metabolism defined biochemically by detectable elevation of 3-methylglutaconic acid (3-MGA) in the urine. In type 1 (or primary) 3-MGA-uria, distal defects in the leucine catabolism pathway directly cause this elevation. Secondary 3-MGA-uria syndromes, however, are unrelated to leucine metabolism-specific defects but share a common biochemical phenotype of elevated 3-MGA.

Uncovering Phenotypic Expansion in AXIN2-Related Disorders through Precision Animal Modeling.

Heterozygous pathogenic variants in are associated with oligodontia-colorectal cancer syndrome (ODCRCS), a disorder characterized by oligodontia, colorectal cancer, and in some cases, sparse hair and eyebrows. We have identified four individuals with one of two , heterozygous variants (NM_004655.4:c.

Dual CD47 and PD-L1 blockade elicits anti-tumor immunity by intratumoral CD8 T cells.

Objectives: Bispecific antibodies targeting CD47 and PD-L1 (CD47 × PD-L1 BisAb) demonstrate efficacy against a range of solid cancers. While dual blockade negates anti-CD47-mediated toxicity, the effect of combined innate and adaptive immune activation on protective tumor-resident CD8 T cells has yet to be fully elucidated.

Methods: CD8 T cell populations were tracked upon CD47 × PD-L1 BisAb treatment in an orthotopic model of murine breast cancer where anti-tumor immunity is mediated by CD8 T cells.

Selective regulation of IFN-γ and IL-4 co-producing unconventional T cells by purinergic signaling.

Unconventional T cells, including mucosal-associated invariant T (MAIT), natural killer T (NKT), and gamma-delta T (γδT) cells, comprise distinct T-bet+, IFN-γ+ and RORγt+, IL-17+ subsets which play differential roles in health and disease. NKT1 cells are susceptible to ARTC2-mediated P2X7 receptor (P2RX7) activation, but the effects on other unconventional T-cell types are unknown. Here, we show that MAIT, γδT, and NKT cells express P2RX7 and are sensitive to P2RX7-mediated cell death.

Retinoic acid and TGF-β orchestrate organ-specific programs of tissue residency.

Tissue-resident memory T (T) cells are integral to tissue immunity, persisting in diverse anatomical sites where they adhere to a common transcriptional framework. How these cells integrate distinct local cues to adopt the common T cell fate remains poorly understood. Here, we show that whereas skin T cells strictly require transforming growth factor β (TGF-β) for tissue residency, those in other locations utilize the metabolite retinoic acid (RA) to drive an alternative differentiation pathway, directing a TGF-β-independent tissue residency program in the liver and synergizing with TGF-β to drive T cells in the small intestine.

Distinct epigenomic landscapes underlie tissue-specific memory T cell differentiation.

The memory CD8 T cell pool contains phenotypically and transcriptionally heterogeneous subsets with specialized functions and recirculation patterns. Here, we examined the epigenetic landscape of CD8 T cells isolated from seven non-lymphoid organs across four distinct infection models, alongside their circulating T cell counterparts. Using single-cell transposase-accessible chromatin sequencing (scATAC-seq), we found that tissue-resident memory T (T) cells and circulating memory T (T) cells develop along distinct epigenetic trajectories.

Succinic semialdehyde dehydrogenase deficiency: a metabolic and genomic approach to diagnosis.

Genomic sequencing offers an untargeted, data-driven approach to genetic diagnosis; however, variants of uncertain significance often hinder the diagnostic process. The discovery of rare genomic variants without previously known functional evidence of pathogenicity often results in variants being overlooked as potentially causative, particularly in individuals with undifferentiated phenotypes. Consequently, many neurometabolic conditions, including those in the GABA (gamma-aminobutyric acid) catabolism pathway, are underdiagnosed.

Towards targeting the breast cancer immune microenvironment.

The tumour immune microenvironment is shaped by the crosstalk between cancer cells, immune cells, fibroblasts, endothelial cells and other stromal components. Although the immune tumour microenvironment (TME) serves as a source of therapeutic targets, it is also considered a friend or foe to tumour-directed therapies. This is readily illustrated by the importance of T cells in triple-negative breast cancer (TNBC), culminating in the advent of immune checkpoint therapy in combination with cytotoxic chemotherapy as standard of care for both early and advanced-stage TNBC, as well as recent promising signs of efficacy in a subset of hormone receptor-positive disease.

The Multifaceted Role of Tissue-Resident Memory T Cells.

Regionalized immune surveillance relies on the concerted efforts of diverse memory T cell populations. Of these, tissue-resident memory T (T) cells are strategically positioned in barrier tissues, where they enable efficient frontline defense against infections and cancer. However, the long-term persistence of these cells has been implicated in a variety of immune-mediated pathologies.

A Cluster Randomised Controlled Trial of a Targeted Distributed Toothpaste and Toothbrushing Programme.

Introduction: The aim was to assess the effectiveness of a distributed, targeted toothbrush and toothpaste programme on referrals for tooth extraction under Dental General Anaesthetic (DGA), in children of high-risk families compared to usual care.

Methods: A recruiter and assessor-blinded, clustered parallel randomised control trial (RCT). Families with one or more children aged between 3 and 10 years having undergone a DGA operation for extraction of carious teeth, were approached within hospitals in the North West of England.

Prior infection with unrelated neurotropic virus exacerbates influenza disease and impairs lung T cell responses.

Immunity to infectious diseases is predominantly studied by measuring immune responses towards a single pathogen, although co-infections are common. In-depth mechanisms on how co-infections impact anti-viral immunity are lacking, but are highly relevant to treatment and prevention. We established a mouse model of co-infection with unrelated viruses, influenza A (IAV) and Semliki Forest virus (SFV), causing disease in different organ systems.

Childhood outcomes after maternal antenatal sildenafil treatment for severe early-onset fetal growth restriction: a randomized trial (STRIDER NZAus).

In this follow-up at 2.5 years of children from the STRIDER NZAus Trial (N = 112), in which women with singleton pregnancies affected by severe early fetal growth restriction were randomized to sildenafil citrate 75 mg daily or placebo until 32 weeks, there was no difference between groups in survival without neurosensory impairment, defined as any of cerebral palsy, deafness, blindness, cognitive delay (Bayley III cognition or language score >1 SD below mean) or motor delay: 30/56[54%] vs. 34/56[61%]; aOR = 0.

Divergent molecular networks program functionally distinct CD8 skin-resident memory T cells.

Skin-resident CD8 T cells include distinct interferon-γ-producing [tissue-resident memory T type 1 (T1)] and interleukin-17 (IL-17)-producing (T17) subsets that differentially contribute to immune responses. However, whether these populations use common mechanisms to establish tissue residence is unknown. In this work, we show that T1 and T17 cells navigate divergent trajectories to acquire tissue residency in the skin.

T cells: not born this way.

Human tissue-resident memory T (T) cells seeded early in life undergo an age-associated functional maturation and residency acquisition throughout childhood.

A three-stage developmental pathway for human Vγ9Vδ2 T cells within the postnatal thymus.

Vγ9Vδ2 T cells are the largest population of γδ T cells in adults and can play important roles in providing effective immunity against cancer and infection. Many studies have suggested that peripheral Vγ9Vδ2 T cells are derived from the fetal liver and thymus and that the postnatal thymus plays little role in the development of these cells. More recent evidence suggested that these cells may also develop postnatally in the thymus.

Single-cell protein expression profiling resolves circulating and resident memory T cell diversity across tissues and infection contexts.

Memory CD8 T cells can be broadly divided into circulating (T) and tissue-resident memory T (T) populations. Despite well-defined migratory and transcriptional differences, the phenotypic and functional delineation of T and T cells, particularly across tissues, remains elusive. Here, we utilized an antibody screening platform and machine learning prediction pipeline (InfinityFlow) to profile >200 proteins in T and T cells in solid organs and barrier locations.

Human circulating and tissue-resident memory CD8 T cells.

Our current knowledge of human memory CD8 T cells is derived largely from studies of the intravascular space. However, emerging data are starting to challenge some of the dogmas based on this work, suggesting that a conceptual revision may be necessary. In this review, we provide a brief history of the field and summarize the biology of circulating and tissue-resident memory CD8 T cells, which are ultimately responsible for effective immune surveillance.

Expansion of MAIT cells in the combined absence of NKT and γδ-T cells.

Mucosal-associated invariant T (MAIT) cells, natural killer T (NKT) cells, and γδT cells are collectively referred to as 'unconventional T cells' due to their recognition of non-peptide antigens and restriction to MHC-I-like molecules. However, the factors controlling their widely variable frequencies between individuals and organs are poorly understood. We demonstrated that MAIT cells are increased in NKT or γδT cell-deficient mice and highly expand in mice lacking both cell types.

Early immune pressure initiated by tissue-resident memory T cells sculpts tumor evolution in non-small cell lung cancer.

Tissue-resident memory T (T) cells provide immune defense against local infection and can inhibit cancer progression. However, it is unclear to what extent chronic inflammation impacts T activation and whether T cells existing in tissues before tumor onset influence cancer evolution in humans. We performed deep profiling of healthy lungs and lung cancers in never-smokers (NSs) and ever-smokers (ESs), finding evidence of enhanced immunosurveillance by cells with a T-like phenotype in ES lungs.

Intratumoral CD8 T cells with a tissue-resident memory phenotype mediate local immunity and immune checkpoint responses in breast cancer.

CD8 tumor-infiltrating lymphocytes with a tissue-resident memory T (T) cell phenotype are associated with favorable prognosis in patients with triple-negative breast cancer (TNBC). However, the relative contribution of CD8 T cells to anti-tumor immunity and immune checkpoint blockade efficacy in breast cancer remains unknown. Here, we show that intratumoral CD8 T cells in murine mammary tumors transcriptionally resemble those from TNBC patients.

Novel phenotype of aortic root dilatation and late-onset metabolic decompensation in a patient with TMEM70 deficiency.

TMEM70 deficiency causing mitochondrial complex V deficiency, nuclear type 2 (MIM: 614052) is the most common nuclear encoded defect affecting ATP synthase and has been well described in the literature as being characterized by neonatal or infantile onset of poor feeding, hypotonia, lethargy, respiratory compromise, heart failure, lactic acidosis, hyperammonemia, and 3-methylglutaconic aciduria progressing to a phenotype of developmental delay, failure to thrive, short stature, nonprogressive cardiomyopathy, microcephaly, facial dysmorphisms, hypospadias, persistent pulmonary hypertension of the newborn, and Wolff-Parkinson-White syndrome, as well as metabolic crises followed by developmental regression. The patient with TMEM70 deficiency herein reported has the unique presentation of aortic root dilatation, differing facial dysmorphisms, and no history of neonatal metabolic decompensation or developmental delay, as well as a plasma metabolomics signature, including elevated 3-methylglutaconic acid, 3-methylglutarylcarnitine, alanine, and lactate, in addition to the commonly described increased 3-methylglutaconic acid on urine organic acid analysis that helped aid in the diagnostic interpretation of variants of uncertain significance in TMEM70.