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Traumatic injuries to the central nervous system (CNS) afflict millions of individuals worldwide1, yet an effective treatment remains elusive. Following such injuries, the site is populated by a multitude of peripheral immune cells, including T cells, but a comprehensive understanding of the roles and antigen specificity of these endogenous T cells at the injury site has been lacking. This gap has impeded the development of immune-mediated cellular therapies for CNS injuries. Here, using single-cell RNA sequencing, we demonstrated the clonal expansion of mouse and human spinal cord injury-associated T cells and identified that CD4+ T cell clones in mice exhibit antigen specificity towards self-peptides of myelin and neuronal proteins. Leveraging mRNA-based T cell receptor (TCR) reconstitution, a strategy aimed to minimize potential adverse effects from prolonged activation of self-reactive T cells, we generated engineered transiently autoimmune T cells. These cells demonstrated notable neuroprotective efficacy in CNS injury models, in part by modulating myeloid cells via IFNγ. Our findings elucidate mechanistic insight underlying the neuroprotective function of injury-responsive T cells and pave the way for the future development of T cell therapies for CNS injuries.This study presents a new T cell therapy targeting spinal cord injury, providing a potential new approach for injured CNS. [ABSTRACT FROM AUTHOR]

Chest pain, a common initial symptom in hypertrophic cardiomyopathy (HCM) patients, is closely linked to myocardial ischemia, despite the absence of significant coronary artery stenosis. This study explored microvascular dysfunction in HCM patients by employing angiography-derived microcirculatory resistance (AMR) as a novel tool for comprehensive assessment. This retrospective analysis included HCM patients with chest pain as the primary symptom and control patients without cardiac hypertrophy during the same period. The AMR was computed through angiography, providing a wire-free and adenosine-free index for evaluating microcirculatory function. Propensity score matching ensured balanced demographics between groups. This study also investigated the correlation between the AMR and clinical outcomes by utilizing echocardiography and follow-up data. After matching, 76 HCM patients and 152 controls were analyzed. While there was no significant difference in the incidence of epicardial coronary stenosis, the AMR of three epicardial coronary arteries was markedly greater in HCM patients. The criterion of an AMR ≥ 250 mmHg*s/m was that 65.7% of HCM patients experienced coronary microvascular dysfunction (CMD). Independent risk factors for CMD included increased left ventricular (LV) wall thickness (OR = 1.209, 95% CI 1.013–1.443, p = 0.036). Furthermore, an AMR_LAD ≥ 250 mmHg*s/m had an increased cumulative risk of the endpoint (log-rank p = 0.023) and was an independent risk factor for the endpoint (HR = 11.64, 95% CI 1.13–120.03, p = 0.039), providing valuable prognostic insights. [ABSTRACT FROM AUTHOR]

Objective and design: This study aimed to investigate Axin2 effects on myocardial infarction (MI) using a macrophage Axin2 conditional knockout (cKO) mouse model, RAW264.7 cell line, and human subepicardial tissues from patients with coronary artery bypass graft (CABG). Material or subjects: Axin2 cKO mice showed decreased cardiac function, reduced edema, increased lymphangiogenesis, and improved repair in MI Few studies border zones. Hypoxic macrophages with Axin2 depletion exhibited decreased senescence, elevated IL6 expression, and increased LYVE1 transcription. Senescent macrophages decreased in patients with CABG and low Axin2 expression. Treatment: Treatment options included in this study were MI induction in Axin2 cKO mice, in vitro experiments with RAW264.7 cells, and analysis of human subepicardial tissues. Methods: Assays included MI induction, in vitro experiments, and tissue analysis with statistical tests applied. Results: Axin2 cKO improved cardiac function, reduced edema, enhanced lymphangiogenesis, and decreased senescence. Hypoxic macrophages with Axin2 depletion showed reduced senescence, increased IL6 expression, and elevated LYVE1 transcription. Senescent macrophages decreased in patients with CABG and low Axin2 expression. Conclusion: Targeting Axin2 emerges as a novel therapeutic strategy for regulating cardiac lymphatics and mitigating cell senescence post-MI, evidenced by improved outcomes in Axin2-deficient conditions. [ABSTRACT FROM AUTHOR]

The role of ATP6AP1 in colorectal cancer (CRC) remains elusive despite its observed upregulation in pan-cancer. Therefore, the current study aimed to assess the clinical significance of ATP6AP1 and its relationship with the immune infiltration in CRC. Transcriptome data of CRC were obtained from The Cancer Genome Atlas (TCGA) database and analyzed using the combination of R packages and tumor-related databases, including TIMER2, TISIDB, cBioPortal, and MethSurv. The tissue arrays and immunohistochemical staining were performed to verify the expression and clinical characteristics of ATP6AP1. The results revealed that ATP6AP1 expression was significantly elevated in CRC and associated with poor clinicopathological characteristics and prognosis. Furthermore, the analysis demonstrated ATP6AP1 expression was correlated with the infiltration of immune cells and cancer-associated fibroblasts in the microenvironment of CRC. Moreover, ATP6AP1 was found to be linked to various immune checkpoints and chemokines, with enrichment of cytoplasmic vesicle lumen, endopeptidase regulator activity, and endopeptidase inhibitor activity observed in the high ATP6AP1 expressional group. In conclusion, the findings of this study suggest that ATP6AP1 upregulation may serve as a biomarker for poor diagnosis in CRC and offer a potential target for immunotherapy in CRC. [ABSTRACT FROM AUTHOR]

Tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb) is the second-deadliest infectious disease worldwide. Emerging evidence shows that the elongation factor EF-Tu could be an excellent target for treating Mtb infection. Here, we report the crystal structures of Mtb EF-Tu•EF-Ts and EF-Tu•GDP complexes, showing the molecular basis of EF-Tu's representative recycling and inactive forms in protein translation. Mtb EF-Tu binds with EF-Ts at a 1:1 ratio in solution and crystal packing. Mutation and SAXS analysis show that EF-Ts residues Arg13, Asn82, and His149 are indispensable for the EF-Tu/EF-Ts complex formation. The GDP binding pocket of EF-Tu dramatically changes conformations upon binding with EF-Ts, sharing a similar GDP-exchange mechanism in E. coli and T. ther. Also, the FDA-approved drug Osimertinib inhibits the growth of M. smegmatis, H37Ra, and M. bovis BCG strains by directly binding with EF-Tu. Thus, our work reveals the structural basis of Mtb EF-Tu in polypeptide synthesis and may provide a promising candidate for TB treatment. Crystal structures of M. tuberculosis elongation factors EF-Tu and EF-Ts in complex and GDP-bound Ef-Tu reveal the molecular basis of EF-Tu's representative recycling and inactive forms in protein translation. [ABSTRACT FROM AUTHOR]

A novel hydrophilic porous biocomposite was fabricated by incorporating graphene oxide (GO) @chitosan (CS) foam substrate (GO@CS@ZIF-8 foam) with ZIF-8 crystals in situ via a facile stirring method for simultaneous enrichment of glycopeptides and phosphopeptides from complex biological samples. The experimental results demonstrated that GO@CS@ZIF-8 foam exhibited favorable specificity for simultaneous enrichment of N-glycopeptides and phosphopeptides under the same condition for HRP and β-casein tryptic digest mixtures. The novel material was further applied to enriching both glycopeptides and phosphopeptides simultaneously from 4 μL complex human serum, and 423 N-glycopeptides and 40 phosphopeptides corresponding to 133 glycoproteins and 29 phosphoproteins were identified, respectively. [ABSTRACT FROM AUTHOR]

Bioorthogonal chemistry capable of operating in live animals is needed to investigate biological processes such as cell death and immunity. Recent studies have identified a gasdermin family of pore-forming proteins that executes inflammasome-dependent and -independent pyroptosis1–5. Pyroptosis is proinflammatory, but its effect on antitumour immunity is unknown. Here we establish a bioorthogonal chemical system, in which a cancer-imaging probe phenylalanine trifluoroborate (Phe-BF3) that can enter cells desilylates and 'cleaves' a designed linker that contains a silyl ether. This system enabled the controlled release of a drug from an antibody–drug conjugate in mice. When combined with nanoparticle-mediated delivery, desilylation catalysed by Phe-BF3 could release a client protein—including an active gasdermin—from a nanoparticle conjugate, selectively into tumour cells in mice. We applied this bioorthogonal system to gasdermin, which revealed that pyroptosis of less than 15% of tumour cells was sufficient to clear the entire 4T1 mammary tumour graft. The tumour regression was absent in immune-deficient mice or upon T cell depletion, and was correlated with augmented antitumour immune responses. The injection of a reduced, ineffective dose of nanoparticle-conjugated gasdermin along with Phe-BF3 sensitized 4T1 tumours to anti-PD1 therapy. Our bioorthogonal system based on Phe-BF3 desilylation is therefore a powerful tool for chemical biology; our application of this system suggests that pyroptosis-induced inflammation triggers robust antitumour immunity and can synergize with checkpoint blockade. In mouse models of cancer, a biorthogonal chemical system based on desilylation catalysed by phenylalanine trifluoroborate enables the controlled release of gasdermin to induce pyroptosis selectively in tumour cells [ABSTRACT FROM AUTHOR]

Immune recognition of pathogen-associated molecular patterns (PAMPs) by pattern recognition receptors often activates proinflammatory NF-κB signalling1. Recent studies indicate that the bacterial metabolite D-glycero-β-D-manno-heptose 1,7-bisphosphate (HBP) can activate NF-κB signalling in host cytosol2-4, but it is unclear whether HBP is a genuine PAMP and the cognate pattern recognition receptor has not been identified. Here we combined a transposon screen in Yersinia pseudotuberculosis with biochemical analyses and identified ADP-β-D-manno-heptose (ADP-Hep), which mediates type III secretion system-dependent NF-κB activation and cytokine expression. ADP-Hep, but not other heptose metabolites, could enter host cytosol to activate NF-κB. A CRISPR-Cas9 screen showed that activation of NF-κB by ADP-Hep involves an ALPK1 (alpha-kinase 1)-TIFA (TRAF-interacting protein with forkhead-associated domain) axis. ADP-Hep directly binds the N-terminal domain of ALPK1, stimulating its kinase domain to phosphorylate and activate TIFA. The crystal structure of the N-terminal domain of ALPK1 and ADP-Hep in complex revealed the atomic mechanism of this ligand-receptor recognition process. HBP was transformed by host adenylyltransferases into ADP-heptose 7-P, which could activate ALPK1 to a lesser extent than ADP-Hep. ADP-Hep (but not HBP) alone or during bacterial infection induced Alpk1-dependent inflammation in mice. Our findings identify ALPK1 and ADP-Hep as a pattern recognition receptor and an effective immunomodulator, respectively. The bacterial metabolite ADP-heptose activates NF-κB in host cells via alpha-kinase 1 and the TIFA-TRAF signalling pathway. [ABSTRACT FROM AUTHOR]

Pyroptosis is a form of cell death that is critical for immunity. It can be induced by the canonical caspase-1 inflammasomes or by activation of caspase-4, -5 and -11 by cytosolic lipopolysaccharide. The caspases cleave gasdermin D (GSDMD) in its middle linker to release autoinhibition on its gasdermin-N domain, which executes pyroptosis via its pore-forming activity. GSDMD belongs to a gasdermin family that shares the pore-forming domain. The functions and mechanisms of activation of other gasdermins are unknown. Here we show that GSDME, which was originally identified as DFNA5 (deafness, autosomal dominant 5), can switch caspase-3-mediated apoptosis induced by TNF or chemotherapy drugs to pyroptosis. GSDME was specifically cleaved by caspase-3 in its linker, generating a GSDME-N fragment that perforates membranes and thereby induces pyroptosis. After chemotherapy, cleavage of GSDME by caspase-3 induced pyroptosis in certain GSDME-expressing cancer cells. GSDME was silenced in most cancer cells but expressed in many normal tissues. Human primary cells exhibited GSDME-dependent pyroptosis upon activation of caspase-3 by chemotherapy drugs. Gsdme−/− (also known as Dfna5−/−) mice were protected from chemotherapy-induced tissue damage and weight loss. These findings suggest that caspase-3 activation can trigger necrosis by cleaving GSDME and offer new insights into cancer chemotherapy. [ABSTRACT FROM AUTHOR]

The murine caspase-11 non-canonical inflammasome responds to various bacterial infections. Caspase-11 activation-induced pyroptosis, in response to cytoplasmic lipopolysaccharide (LPS), is critical for endotoxic shock in mice. The mechanism underlying cytosolic LPS sensing and the responsible pattern recognition receptor are unknown. Here we show that human monocytes, epithelial cells and keratinocytes undergo necrosis upon cytoplasmic delivery of LPS. LPS-induced cytotoxicity was mediated by human caspase-4 that could functionally complement murine caspase-11. Human caspase-4 and the mouse homologue caspase-11 (hereafter referred to as caspase-4/11) and also human caspase-5, directly bound to LPS and lipid A with high specificity and affinity. LPS associated with endogenous caspase-11 in pyroptotic cells. Insect-cell purified caspase-4/11 underwent oligomerization upon LPS binding, resulting in activation of the caspases. Underacylated lipid IVa and lipopolysaccharide from Rhodobacter sphaeroides (LPS-RS) could bind to caspase-4/11 but failed to induce their oligomerization and activation. LPS binding was mediated by the CARD domain of the caspase. Binding-deficient CARD-domain point mutants did not respond to LPS with oligomerization or activation and failed to induce pyroptosis upon LPS electroporation or bacterial infections. The function of caspase-4/5/11 represents a new mode of pattern recognition in immunity and also an unprecedented means of caspase activation. [ABSTRACT FROM AUTHOR]

Cytosolic inflammasome complexes mediated by a pattern recognition receptor (PRR) defend against pathogen infection by activating caspase 1. Pyrin, a candidate PRR, can bind to the inflammasome adaptor ASC to form a caspase 1-activating complex. Mutations in the Pyrin-encoding gene, MEFV, cause a human autoinflammatory disease known as familial Mediterranean fever. Despite important roles in immunity and disease, the physiological function of Pyrin remains unknown. Here we show that Pyrin mediates caspase 1 inflammasome activation in response to Rho-glucosylation activity of cytotoxin TcdB, a major virulence factor of Clostridium difficile, which causes most cases of nosocomial diarrhoea. The glucosyltransferase-inactive TcdB mutant loses the inflammasome-stimulating activity. Other Rho-inactivating toxins, including FIC-domain adenylyltransferases (Vibrio parahaemolyticus VopS and Histophilus somni IbpA) and Clostridium botulinum ADP-ribosylating C3 toxin, can also biochemically activate the Pyrin inflammasome in their enzymatic activity-dependent manner. These toxins all target the Rho subfamily and modify a switch-I residue. We further demonstrate that Burkholderia cenocepacia inactivates RHOA by deamidating Asn 41, also in the switch-I region, and thereby triggers Pyrin inflammasome activation, both of which require the bacterial type VI secretion system (T6SS). Loss of the Pyrin inflammasome causes elevated intra-macrophage growth of B. cenocepacia and diminished lung inflammation in mice. Thus, Pyrin functions to sense pathogen modification and inactivation of Rho GTPases, representing a new paradigm in mammalian innate immunity. [ABSTRACT FROM AUTHOR]

The tumour necrosis factor (TNF) family is crucial for immune homeostasis, cell death and inflammation. These cytokines are recognized by members of the TNF receptor (TNFR) family of death receptors, including TNFR1 and TNFR2, and FAS and TNF-related apoptosis-inducing ligand (TRAIL) receptors. Death receptor signalling requires death-domain-mediated homotypic/heterotypic interactions between the receptor and its downstream adaptors, including TNFR1-associated death domain protein (TRADD) and FAS-associated death domain protein (FADD). Here we discover that death domains in several proteins, including TRADD, FADD, RIPK1 and TNFR1, were directly inactivated by NleB, an enteropathogenic Escherichia coli (EPEC) type III secretion system effector known to inhibit host nuclear factor-κB (NF-κB) signalling. NleB contained an unprecedented N-acetylglucosamine (GlcNAc) transferase activity that specifically modified a conserved arginine in these death domains (Arg 235 in the TRADD death domain). NleB GlcNAcylation (the addition of GlcNAc onto a protein side chain) of death domains blocked homotypic/heterotypic death domain interactions and assembly of the oligomeric TNFR1 complex, thereby disrupting TNF signalling in EPEC-infected cells, including NF-κB signalling, apoptosis and necroptosis. Type-III-delivered NleB also blocked FAS ligand and TRAIL-induced cell death by preventing formation of a FADD-mediated death-inducing signalling complex (DISC). The arginine GlcNAc transferase activity of NleB was required for bacterial colonization in the mouse model of EPEC infection. The mechanism of action of NleB represents a new model by which bacteria counteract host defences, and also a previously unappreciated post-translational modification. [ABSTRACT FROM AUTHOR]

A correction is presented to the article "Associations between nutrition risk scores and sarcopenia in gastrointestinal cancer patients: a cross‑sectional study."

As the time of ovulation draws near, mouse spermatozoa move out of the isthmic reservoir, which is a prerequisite for fertilization. However, the molecular mechanism remains unclear. The present study revealed that mouse cumulus cells of oocytes–cumulus complexes (OCCs) expressed transforming growth factor-β ligand 1 (TGFB1), whereas ampullary epithelial cells expressed the TGF-β receptors, TGFBR1 and TGFBR2, and all were upregulated by luteinizing hormone (LH)/human chorionic gonadotropin (hCG). OCCs and TGFB1 increased natriuretic peptide type C (NPPC) expression in cultured ampullae via TGF-β signaling, and NPPC treatment promoted spermatozoa moving out of the isthmic reservoir of the preovulatory oviducts. Deletion of Tgfb1 in cumulus cells and Tgfbr2 in ampullary epithelial cells blocked OCC-induced NPPC expression and spermatozoa moving out of the isthmic reservoir, resulting in compromised fertilization and fertility. Oocyte-derived paracrine factors were required for promoting cumulus cell expression of TGFB1. Therefore, oocyte-dependent and cumulus cell-derived TGFB1 promotes the expression of NPPC in oviductal ampulla, which is critical for sperm migration in the oviduct and subsequent fertilization. Oocyte-dependent and cumulus cell-derived transforming growth factor-β promotes natriuretic peptide type C expression in mouse ampullary epithelial cells, which promotes sperm migration into the ampulla for fertilization. [ABSTRACT FROM AUTHOR]

Purpose: Sarcopenia is an independent risk factor for poor prognosis of cancers. The nutritional risk screening 2002 (NRS2002) and patient-generated subjective global assessment (PG-SGA) tools are widely used tools for nutrition risk screening and assessing. The purpose of this study was to investigate whether NRS2002 and PG-SGA scores are associated with sarcopenia in gastrointestinal cancers. Methods: A consecutive cohort comprised of 432 gastrointestinal cancer patients was conducted. We used NRS2002 and PG-SGA to assess their nutrition status. Sarcopenia was diagnosed with CT scan at the third lumber vertebra level. The correlations of nutritional scores with SMI, nutritional categories with sarcopenia were assessed by Spearman's correlation test and point biserial correlation. The cut-off value of nutritional scores for identifying sarcopenia was obtained by maximum Youden index. Logistic regression was used to confirm the associations. Results: Sarcopenia patients had higher NRS2002 (2.63 ± 1.16 vs. 2.15 ± 1.20, p < 0.001) and PG-SGA (8.69 ± 1.16 vs. 5.56 ± 3.28, p < 0.001) scores. The NRS2002 (r = −0.198, p < 0.001) and PG-SGA (r = −0.409, p < 0.001) scores were significantly and negatively correlated with skeletal muscle mass index. The cut-off value of PG-SGA score for predicting sarcopenia was 7. In multivariate logistic regression, the PG-SGA exceeded 7 score (OR = 7.489, 95% CI: 4.122–13.608, p < 0.001) was significantly associated with increased risk of sarcopenia, while NRS2002 score showed no significant association with sarcopenia. Conclusions: PG-SGA ≥ 7 was associated with increased risk of sarcopenia and could serve as a useful criterion for capturing sarcopenia in gastrointestinal cancers. Routine PG-SGA evaluation for patient with gastrointestinal cancers is important. [ABSTRACT FROM AUTHOR]

Thrips hawaiiensis is a common thrips pest that damages the flowers of various plants. The differing population sizes of T. hawaiiensis among host plants suggest its preference and performance vary among host plants. In this study, the host fitness of T. hawaiiensis for different flowers was assessed through field investigation. The behavioral responses of T. hawaiiensis to the color and volatiles of flowers eliciting different apparent fitness levels and their development and survival on the plants were also studied. Adults and larvae of T. hawaiiensis were found in the flowers of 21 species, which were classified into four fitness levels for this thrips species. T. hawaiiensis showed significantly different visual responses to the color and olfactory responses to the volatiles of four tested flowers (each representing one of the four fitness levels), with the rankings of visual preferences for Dianthus caryophyllus > Tulipa gesneriana > Hydrangea macrophylla > Rosa rugosa, and olfactory preferences for H. macrophylla ≥ T. gesneriana > D. caryophyllus > R. rugosa. Plant species had significant influences on the development and survival of T. hawaiiensis, with developmental times from egg to adult of 9.58 d, 9.92 d, 10.35 d and 10.75 d on H. macrophylla, T. gesneriana, D. caryophyllus and R. rugosa, respectively, and corresponding survival rates of 76.33%, 71.33%, 64.00% and 59.00%. In summary, this study shows that olfactory preferences were consistent with the field performance of T. hawaiiensis on the four flower plants tested. Further, fitness levels of host plant flowers are correlated with development rate and survivorship of T. hawaiiensis. Our study adds to the understanding of the mechanism of host selection by thrips and provides basic information to underpin the management of T. hawaiiensis on horticultural plants. [ABSTRACT FROM AUTHOR]

NOD-like receptors (NLRs) localize in the cytosol to recognize intracellular pathogen products and initialize the innate immune response. However, the ligands and ligand specificity of many NLRs remain unclear. One such NLR, NLRP6, plays an important role in maintaining intestinal homeostasis and protecting against various intestinal diseases such as colitis and intestinal tumorigenesis. Here, we show that the major component of the outer membrane of gram-negative bacteria, lipopolysaccharide (LPS), binds NLRP6 directly and induces global conformational change and dimerization. Following stimulation by ATP, the NLRP6 homodimer can further assemble into a linear molecular platform, and ASC is recruited to form higher molecular structures, indicative of a step-by-step activation mechanism. Our study sheds light on the mystery of LPS-induced inflammasome initiation, reveals the architecture and structural basis of potential pre-inflammasome, and suggests a novel molecular assembly pattern for immune receptors. [ABSTRACT FROM AUTHOR]

By using the independence structure of points following a determinantal point process, we study the radii of the spherical ensemble, the truncation of the circular unitary ensemble and the product ensemble with parameters n and k. The limiting distributions of the three radii are obtained. They are not the Tracy-Widom distribution. In particular, for the product ensemble, we show that the limiting distribution has a transition phenomenon: When $$k/n\rightarrow 0$$ , $$k/n\rightarrow \alpha \in (0,\infty )$$ and $$k/n\rightarrow \infty $$ , the liming distribution is the Gumbel distribution, a new distribution $$\mu $$ and the logarithmic normal distribution, respectively. The cumulative distribution function (cdf) of $$\mu $$ is the infinite product of some normal distribution functions. Another new distribution $$\nu $$ is also obtained for the spherical ensemble such that the cdf of $$\nu $$ is the infinite product of the cdfs of some Poisson-distributed random variables. [ABSTRACT FROM AUTHOR]