A Semisynthetic Oligomannuronic Acid-Based Glycoconjugate Vaccine against Pseudomonas aeruginosa.

Pseudomonas aeruginosa is one of the leading causes of nosocomial infections and has become increasingly resistant to multiple antibiotics. However, development of novel classes of antibacterial agents against multidrug-resistant P. aeruginosa is extremely difficult. Herein we develop a semisynthetic oligomannuronic acid-based glycoconjugate vaccine that confers broad protection against infections of both mucoid and nonmucoid strains of P. aeruginosa. The well-defined glycoconjugate vaccine formulated with Freund's adjuvant (FA) employing a highly conserved antigen elicited a strong and specific immune response and protected mice against both mucoid and nonmucoid strains of P. aeruginosa. The resulting antibodies recognized different strains of P. aeruginosa and mediated the opsonic killing of the bacteria at varied levels depending on the amount of alginate expressed on the surface of the strains. Vaccination with the glycoconjugate vaccine plus FA significantly promoted the pulmonary and blood clearance of the mucoid PAC1 strain of P. aeruginosa and considerably improved the survival rates of mice against the nonmucoid PAO1 strain of P. aeruginosa. Thus, the semisynthetic glycoconjugate is a promising vaccine that may provide broad protection against both types of P. aeruginosa.

Terrestrial invertebrate hosts of human pathogens in urban ecosystems.

Terrestrial invertebrates in urban ecosystems are extremely species-rich, have many important roles in material flow and energy circulation, and are host to many human pathogens that pose threats to human health. These invertebrates are widely distributed in urban areas, including both out- and in-door environments. Consequently, humans are frequently in contact with them, which provides many opportunities for them to pose human health risks. However, comprehensive knowledge on human pathogen transfer via invertebrates is lacking, with research to date primarily focused on dipterans (e.g., mosquitoes, flies). Here, we take a broad taxonomic approach and review terrestrial invertebrate hosts (incl. mosquitoes, flies, termites, cockroaches, mites, ticks, earthworms, collembola, fleas, snails, and beetles) of human pathogens, with a focus on transmission pathways. We also discuss how urbanization and global warming are likely to influence the communities of invertebrate hosts and have flow-on risks to human health. Finally, we identify current research gaps and provide perspectives on future directions.

Sonic hedgehog signaling facilitates pyroptosis in mouse heart following ischemia/reperfusion via enhancing the formation of CARD10-BCL10-MALT1 complex.

Pyroptosis has been found to contribute to myocardial ischemia/reperfusion (I/R) injury, but the exact mechanisms that initiate myocardial pyroptosis are not fully elucidated. Sonic hedgehog (SHH) signaling is activated in heart suffered I/R, and intervention of SHH signaling has been demonstrated to protect heart from I/R injury. Caspase recruitment domain-containing protein 10 (CARD10)-B cell lymphoma 10 (BCL10)-mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) (CBM) complex could transduce signals from the membrane and induce inflammatory pathways in non-hematopoietic cells, which could be a downstream effector of SHH signaling pathway. This study aims to explore the role of SHH signaling in I/R-induced myocardial pyroptosis and its relationship with the CBM complex. C57BL/6J mice were subjected to 45 min-ischemia followed by 24 h-reperfusion to establish a myocardial I/R model, and H9c2 cells underwent hypoxia/reoxygenation (H/R) to mimic myocardial I/R model in vitro. Firstly, SHH signaling was significantly activated in heart suffered I/R in an autocrine- or paracrine-dependent manner via its receptor PTCH1, and inhibition of SHH signaling decreased myocardial injury via reducing caspase-11-dependent pyroptosis, concomitant with attenuating CBM complex formation. Secondly, suppression of SHH signaling decreased protein kinase C α (PKCα) level, but inhibition of PKCα attenuated CBM complex formation without impacting the protein levels of SHH and PTCH1. Finally, disruption of the CBM complex prevented MALT1 from recruiting of TRAF6, which was believed to trigger the caspase-11-dependent pyroptosis. Based on these results, we conclude that inhibition of SHH signaling suppresses pyroptosis via attenuating PKCα-mediated CARD10-BCL10-MALT1 complex formation in mouse heart suffered I/R.

Paclitaxel improves thrombopoiesis in the absence of thrombopoietin receptor (Mpl).

BACKGROUND: Platelets are critical for thrombosis and hemostasis. The TPO-MPL pathway is the primary pathway for generating thrombocytes. Dysregulation of thrombopoiesis results in platelet formation and/or function-related disorders, such as thrombocytopenia. Paclitaxel is an extensively utilized chemotherapeutic agent may be related to platelets, but the effect of paclitaxel on thrombocytopoiesis warrants comprehensive exploration. OBJECTIVES: We focused on identifying factors that regulate thrombocyte production and elucidating paclitaxel's regulatory mechanisms on thrombocytopoiesis, with a particular emphasis on discovering bypassed TPO-MPL pathways. METHODS: We performed drug screenings using the Tg(mpl:eGFP) zebrafish model in vivo to identify FDA-approved compounds capable of boosting thrombocyte production. An injury experiment was used to evaluate thrombocyte function. The BrdU, TUNEL, and RNA-Seq analyses were performed to explore cytological and molecular mechanisms. Routine blood testing and flow cytometry were used to analyze mouse phenotypes. RESULTS: We found that paclitaxel is able to expand thrombocytes by accelerating the proliferation of thrombocytic lineage cells in zebrafish, and elevates platelet levels in mice. This effect occurs bypassing the thrombopoietin receptor (Mpl). We found that paclitaxel promotes thrombopoiesis potentially involving the JAK2-ERK1/2 MAPK signaling cascade, a pathway integral to MPL and other regulators. Our results further demonstrate that ERK1/2 is at least partially downstream of JAK2 in paclitaxel-induced thrombopoiesis. CONCLUSION: Paclitaxel could promote thrombopoiesis by bypassing Mpl but presumably via the Jak2-Erk1/2 MAPK pathways. It will aid in understanding the relationship between paclitaxel and platelets clinically, and paclitaxel may have potential value for safeguarding platelets and improving thrombocytosis in related diseases.

Single-cell exploration of active phosphate-solubilizing bacteria across diverse soil matrices for sustainable phosphorus management.

Phosphate-solubilizing bacteria (PSB) are crucial for enhancing phosphorus bioavailability and regulating phosphorus transformation processes. However, the in situ phosphorus-solubilizing activity and the link between phenotypes and genotypes for PSB remain unidentified. Here we employed single-cell Raman spectroscopy combined with heavy water to discern and quantify soil active PSB. Our results reveal that PSB abundance and in situ activity differed significantly between soil types and fertilization treatments. Inorganic fertilizer input was the key driver for active PSB distribution. Targeted single-cell sorting and metagenomic sequencing of active PSB uncovered several low-abundance genera that are easily overlooked within bulk soil microbiota. We elucidate the underlying functional genes and metabolic pathway, and the interplay between phosphorus and carbon cycling involved in high phosphorus solubilization activity. Our study provides a single-cell approach to exploring PSB from native environments, enabling the development of a microbial solution for the efficient agronomic use of phosphorus and mitigating the phosphorus crisis.

Regional Active Transcription Associates with Homoeologous Exchange Breakpoints in Synthetic Brassica Tetraploids.

Polyploidization plays a crucial role in plant evolution and is becoming increasingly important in breeding. Structural variations and epigenomic repatterning have been observed in synthetic polyploidizations. However, the mechanisms underlying the occurrence and their effects on gene expression and phenotype remain unknown. Here, we investigated genome-wide large deletion/duplication regions (DelDups) and genomic methylation dynamics in leaf organs of progeny from the first eight generations of synthetic tetraploids derived from Chinese cabbage (Brassica rapa L. ssp. pekinensis) and cabbage (Brassica oleracea L. var. capitata). One- or two-copy DelDups, with a mean size of 5.70 Mb (400 kb - 65.85 Mb), occurred from the first generation of selfing and thereafter. The duplication of a fragment in one subgenome consistently coincided with the deletion of its syntenic fragment in the other subgenome, and vice versa, indicating that these DelDups were generated by homoeologous exchanges (HEs). Interestingly, the larger the genomic syntenic region, the higher the frequency of DelDups, further suggesting that the pairing of large homoeologous fragments is crucial for HEs. Moreover, we found that the active transcription of continuously distributed genes in local regions is positively associated with the occurrence of HE breakpoints. In addition, the expression of genes within DelDups exhibited a dosage effect, and plants with extra parental genomic fragments generally displayed phenotypes biased towards the corresponding parent. Genome-wide methylation fluctuated remarkably, which did not clearly affect gene expression on a large scale. Our findings provide insights into the early evolution of polyploid genomes, offering valuable knowledge for polyploidization-based breeding.

Nitrifying niche in estuaries is expanded by the plastisphere.

The estuarine plastisphere, a novel ecological habitat in the Anthropocene, has garnered global concerns. Recent geochemical evidence has pointed out its potential role in influencing nitrogen biogeochemistry. However, the biogeochemical significance of the plastisphere and its mechanisms regulating nitrogen cycling remain elusive. Using 15N- and 13C-labelling coupled with metagenomics and metatranscriptomics, here we unveil that the plastisphere likely acts as an underappreciated nitrifying niche in estuarine ecosystems, exhibiting a 0.9 ~ 12-fold higher activity of bacteria-mediated nitrification compared to surrounding seawater and other biofilms (stone, wood and glass biofilms). The shift of active nitrifiers from O2-sensitive nitrifiers in the seawater to nitrifiers with versatile metabolisms in the plastisphere, combined with the potential interspecific cooperation of nitrifying substrate exchange observed among the plastisphere nitrifiers, collectively results in the unique nitrifying niche. Our findings highlight the plastisphere as an emerging nitrifying niche in estuarine environment, and deepen the mechanistic understanding of its contribution to marine biogeochemistry.

Rashba-Type Band Splitting Effect in 2D (PEA)2PbI4 Perovskites and Its Impact on Exciton-Phonon Coupling.

Despite a few recent reports on Rashba effects in two-dimensional (2D) Ruddlesden-Popper (RP) hybrid perovskites, the precise role of organic spacer cations in influencing Rashba band splitting remains unclear. Here, using a combination of temperature-dependent two-photon photoluminescence (2PPL) and time-resolved photoluminescence spectroscopy, alongside density functional theory (DFT) calculations, we contribute to significant insights into the Rashba band splitting found for 2D RP hybrid perovskites. The results demonstrate that the polarity of the organic spacer cation is crucial in inducing structural distortions that lead to Rashba-type band splitting. Our investigations show that the intricate details of the Rashba band splitting occur for organic cations with low polarity but not for more polar ones. Furthermore, we have observed stronger exciton-phonon interactions due to the Rashba-type band splitting effect. These findings clarify the importance of selecting appropriate organic spacer cations to manipulate the electronic properties of 2D perovskites.

2023 White Paper on Recent Issues in Bioanalysis: Deuterated Drugs; LNP; Tumor/FFPE Biopsy; Targeted Proteomics; Small Molecule Covalent Inhibitors; Chiral Bioanalysis; Remote Regulatory Assessments; Sample Reconciliation/Chain of Custody (PART 1A - Recommendations on Mass Spectrometry, Chromatography, Sample Preparation Latest Developments, Challenges, and Solutions and BMV/Regulated Bioanalysis PART 1B - Regulatory Agencies' Inputs on Regulated Bioanalysis/BMV, Biomarkers/IVD/CDx/BAV, Immunogenicity, Gene & Cell Therapy and Vaccine).

The 17th Workshop on Recent Issues in Bioanalysis (17th WRIB) took place in Orlando, FL, USA on June 19-23, 2023. Over 1000 professionals representing pharma/biotech companies, CROs, and multiple regulatory agencies convened to actively discuss the most current topics of interest in bioanalysis. The 17th WRIB included 3 Main Workshops and 7 Specialized Workshops that together spanned 1 week to allow an exhaustive and thorough coverage of all major issues in bioanalysis of biomarkers, immunogenicity, gene therapy, cell therapy and vaccines.Moreover, in-depth workshops on "EU IVDR 2017/746 Implementation and impact for the Global Biomarker Community: How to Comply with this NEW Regulation" and on "US FDA/OSIS Remote Regulatory Assessments (RRAs)" were the special features of the 17th edition.As in previous years, WRIB continued to gather a wide diversity of international, industry opinion leaders and regulatory authority experts working on both small and large molecules as well as gene, cell therapies and vaccines to facilitate sharing and discussions focused on improving quality, increasing regulatory compliance, and achieving scientific excellence on bioanalytical issues.This 2023 White Paper encompasses recommendations emerging from the extensive discussions held during the workshop and is aimed to provide the bioanalytical community with key information and practical solutions on topics and issues addressed, in an effort to enable advances in scientific excellence, improved quality and better regulatory compliance. Due to its length, the 2023 edition of this comprehensive White Paper has been divided into three parts for editorial reasons.This publication covers the recommendations on Mass Spectrometry Assays, Regulated Bioanalysis/BMV (Part 1A) and Regulatory Inputs (Part 1B). Part 2 (Biomarkers, IVD/CDx, LBA and Cell-Based Assays) and Part 3 (Gene Therapy, Cell therapy, Vaccines and Biotherapeutics Immunogenicity) are published in volume 16 of Bioanalysis, issues 7 and 8 (2024), respectively.

The independent storage mechanisms of visual and vibrotactile working memory.

Whether information in working memory (WM) is stored in a domain-independent or domain-specific system is still the subject of intense debate. This study used the delayed match-to-sample paradigm, the dual-task paradigm, and the selective interference paradigm to investigate the mechanism of cross-modal storage in visual and vibrotactile WM. We postulated that WM may store cross-modal data from haptics and vision independently, and we proposed domain-specific WM storage. According to the findings, the WM can store cross-modal information from vision and haptics independently, and the storage of visual and tactile WM may be domain-specific. This study provides early support for the hypothesis that haptic and visuospatial sketchpads are dissociated. In addition, the current study provides evidence to elucidate the mechanisms by which WM stores and processes data from different modalities and content. The results also indicate that a cross-modal approach can broaden the cognitive processing bandwidth of WM.

The Systemic Immune-Inflammation Index (SII) and coronary artery lesions in Kawasaki disease.

Coronary artery lesions (CALs) are the most common complications of Kawasaki disease (KD) and play a crucial role in determining the prognosis of the disease. Consequently, the early identification of children with KD who are at risk of developing coronary artery damage is vitally important. We sought to investigate the relationship between the Systemic Immune-Inflammation Index (SII) and CALs in patients with KD and to assess its predictive value. We carried out a retrospective review and analysis of medical records for KD patients treated at the First Affiliated Hospital of Anhui Medical University between January 2017 and January 2023. We utilized single-variable tests, binary logistic regression analysis, ROC curve analysis, restricted cubic spline tests, and curve fitting to evaluate the association between SII and CALs. In our study, 364 patients were included, with 63 (17.3%) presenting with CALs at the time of admission. The binary logistic regression analysis indicated that SII was a significant risk factor for CALs at admission, evident in both unadjusted and models adjusted for confounders. The ROC curve analysis revealed an AUC (Area Under the Curve) value of 0.789 (95%CI 0.723-0.855, P < 0.001) for SII's predictive ability regarding CALs at admission. A consistent positive linear relationship between SII and the risk of CALs at admission was observed in both the raw and adjusted models. Our research findings suggest that SII serves as a risk factor for CALs and can be used as an auxiliary laboratory biomarker for predicting CALs.

Cebp1 and Cebpß transcriptional axis controls eosinophilopoiesis in zebrafish.

Eosinophils are a group of granulocytes well known for their capacity to protect the host from parasites and regulate immune function. Diverse biological roles for eosinophils have been increasingly identified, but the developmental pattern and regulation of the eosinophil lineage remain largely unknown. Herein, we utilize the zebrafish model to analyze eosinophilic cell differentiation, distribution, and regulation. By identifying eslec as an eosinophil lineage-specific marker, we establish a Tg(eslec:eGFP) reporter line, which specifically labeled cells of the eosinophil lineage from early life through adulthood. Spatial-temporal analysis of eslec+ cells demonstrates their organ distribution from larval stage to adulthood. By single-cell RNA-Seq analysis, we decipher the eosinophil lineage cells from lineage-committed progenitors to mature eosinophils. Through further genetic analysis, we demonstrate the role of Cebp1 in balancing neutrophil and eosinophil lineages, and a Cebp1-Cebpß transcriptional axis that regulates the commitment and differentiation of the eosinophil lineage. Cross-species functional comparisons reveals that zebrafish Cebp1 is the functional orthologue of human C/EBPεP27 in suppressing eosinophilopoiesis. Our study characterizes eosinophil development in multiple dimensions including spatial-temporal patterns, expression profiles, and genetic regulators, providing for a better understanding of eosinophilopoiesis.

Identification and characterization of human hematopoietic mesoderm.

The embryonic mesoderm comprises heterogeneous cell subpopulations with distinct lineage biases. It is unclear whether a bias for the human hematopoietic lineage emerges at this early developmental stage. In this study, we integrated single-cell transcriptomic analyses of human mesoderm cells from embryonic stem cells and embryos, enabling us to identify and define the molecular features of human hematopoietic mesoderm (HM) cells biased towards hematopoietic lineages. We discovered that BMP4 plays an essential role in HM specification and can serve as a marker for HM cells. Mechanistically, BMP4 acts as a downstream target of HDAC1, which modulates the expression of BMP4 by deacetylating its enhancer. Inhibition of HDAC significantly enhances HM specification and promotes subsequent hematopoietic cell differentiation. In conclusion, our study identifies human HM cells and describes new mechanisms for human hematopoietic development.

Supramolecular pyrrole radical cations for bacterial theranostics.

Bacterial infections with emerging resistance to antibiotics require urgent development of antibacterial agents with new core skeletons. Recently, a series of antibacterial agents have been reported based on positively charged organic groups, such as ammonium, guanidine, and phosphonium groups, which can selectively bind and destroy negatively charged bacterial membranes. To achieve imaging-guided precise antibacterial therapy, these positively charged organic groups usually require further decoration with imaging modalities, such as fluorescence. However, most fluorophores with electron-closed shell structures usually suffer from tedious synthetic procedures for preparation. We herein prepare a series of positively charged and deep-red fluorescent supramolecular pyrrole radical cations (P˙+-CB[7]) based on the simple mixing of pyrroles and CB[7] in water under air. The readily available deep-red fluorescent P˙+-CB[7] can not only be used for selective imaging and killing of live Gram-positive bacteria with excellent biocompatibility, but also for imaging of dead Gram-negative bacteria killed by drugs and in vivo monitoring of phagocytosis of bacteria by innate immune cells in zebrafish. It is believed that the deep-red fluorescent pyrrole radical cations as a new core skeleton are promising in bacterial theranostics.

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To investigate the diversity and community structure of gut microbiome of the invasive species, Achatina fulica, along an urbanization gradient, we collected 30 A. fulica samples from five parks in the urban, suburban, and rural areas of Xiamen City. Using full-length 16S rRNA gene sequencing performed by the third generation PacBio sequencing platform, we analyzed the community characteristics of gut microbiome and soil microbiome in different habitats. We found a significant disparity between the composition of gut microbiome of A. fulica and that of the soil microbiome in their habitats. Furthermore, the gut microbiome of A. fulica were more sensitive to urbanization. The microbial α-diversity indices (Sobs, Chao, Shannon indices) in the soil of A. fulica habitats were consistently higher than those within their guts. Despite the similar ß-diversity indices of microbial communities in urban, suburban, and rural soils, we found a significant discrepancy in gut microbiome composition. Urbanization significantly influenced A. fulica gut microbiome composition. Gut microbiome of A. fulica in urban and suburban regions primarily consisted of Enterobacteriaceae, Xanthomonadaceae, and Mycoplasmataceae, while that in rural areas chiefly composed of Streptococcaceae and Paenibacillaceae. The diversity and abundance of potential human pathogenic bacteria within the gut microbiome of A. fulica significantly increased in urban environments, suggesting that urbanization escalated the risk of A. fulica transmitting potential pathogens.

The pooled prevalence and influential factors of non-suicidal self-injury in non-clinical samples during the COVID-19 outbreak: A meta-analysis.

BACKGROUND: COVID-19 has had an enormous impact on the mental health of people around the world, particularly adolescents. Non-suicidal self-injury (NSSI) is one of the most prominent and dangerous behaviors associated with suicide. However, few meta-analyses of the NSSI prevalence have ever been conducted since the COVID-19 outbreak. Here, we conducted a meta-analysis to estimate the pooled prevalence and elucidate the influencing factors for NSSI. METHODS: We searched PubMed, Web of Science, Embase, APA PsycINFO, CNKI and Wanfang Database for relevant literature published before April 2022. Pooled prevalence and 95 % confidence interval (CI) were used to assess NSSI prevalence. Subgroup and meta-regression analyses were performed to clarify the potential influencing factors. RESULTS: A total of 15 studies with 24,055 participants were eventually included. The results showed that the pooled overall prevalence of NSSI among overall samples during the COVID-19 pandemic was 22.5 % (95 % CI: 17.2 % to 28.9 %). Subgroup and meta-regression analyses revealed that the crucial influencing factors for NSSI included gender, age, regional distribution, and suicidal ideation. Specifically, the NSSI prevalence among adolescents and adults during the pandemic was 32.40 % and 15.70 %, respectively. Most importantly, gender is a significant influencing factor for NSSI among adolescents. CONCLUSIONS: The pooled prevalence of NSSI during the COVID-19 outbreak has surged to alarming heights, especially among adolescents. The prevalence of NSSI may be influenced by complex factors such as gender and age. Therefore, it is critical to pay attention to NSSI behaviors in the adolescent population, particularly male adolescents who appear to be susceptible.

The lack of negative association between TE load and subgenome dominance in synthesized Brassica allotetraploids.

Polyploidization is important to the evolution of plants. Subgenome dominance is a distinct phenomenon associated with most allopolyploids. A gene on the dominant subgenome tends to express to higher RNA levels in all organs as compared to the expression of its syntenic paralogue (homoeolog). The mechanism that underlies the formation of subgenome dominance remains unknown, but there is evidence for the involvement of transposon/DNA methylation density differences nearby the genes of parents as being causal. The subgenome with lower density of transposon and methylation near genes is positively associated with subgenome dominance. Here, we generated eight generations of allotetraploid progenies from the merging of parental genomes Brassica rapa and Brassica oleracea. We found that transposon/methylation density differ near genes between the parental (rapa:oleracea) existed in the wide hybrid, persisted in the neotetraploids (the synthetic Brassica napus), but these neotetraploids expressed no expected subgenome dominance. This absence of B. rapa vs. B. oleracea subgenome dominance is particularly significant because, while there is no negative relationship between transposon/methylation level and subgenome dominance in the neotetraploids, the more ancient parental subgenomes for all Brassica did show differences in transposon/methylation densities near genes and did express, in the same samples of cells, biased gene expression diagnostic of subgenome dominance. We conclude that subgenome differences in methylated transposon near genes are not sufficient to initiate the biased gene expressions defining subgenome dominance. Our result was unexpected, and we suggest a "nuclear chimera" model to explain our data.

Sulindac selectively induces autophagic apoptosis of GABAergic neurons and alters motor behaviour in zebrafish.

Nonsteroidal anti-inflammatory drugs compose one of the most widely used classes of medications, but the risks for early development remain controversial, especially in the nervous system. Here, we utilized zebrafish larvae to assess the potentially toxic effects of nonsteroidal anti-inflammatory drugs and found that sulindac can selectively induce apoptosis of GABAergic neurons in the brains of zebrafish larvae brains. Zebrafish larvae exhibit hyperactive behaviour after sulindac exposure. We also found that akt1 is selectively expressed in GABAergic neurons and that SC97 (an Akt1 activator) and exogenous akt1 mRNA can reverse the apoptosis caused by sulindac. Further studies showed that sulindac binds to retinoid X receptor alpha (RXRα) and induces autophagy in GABAergic neurons, leading to activation of the mitochondrial apoptotic pathway. Finally, we verified that sulindac can lead to hyperactivity and selectively induce GABAergic neuron apoptosis in mice. These findings suggest that excessive use of sulindac may lead to early neurodevelopmental toxicity and increase the risk of hyperactivity, which could be associated with damage to GABAergic neurons.

Telaprevir Improves Memory and Cognition in Mice Suffering Ischemic Stroke via Targeting MALT1-Mediated Calcium Overload and Necroptosis.

Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) has been confirmed to contribute to brain injury in ischemic stroke via promoting excitotoxicity and necroptosis. Telaprevir, a hepatitis C virus protease inhibitor, is predicted to be a potential MALT1 inhibitor. Here, we showed that telaprevir protected against cerebral ischemic injury via inhibiting MALT1, thereby preventing glutamate receptor ionotropic NMDA 2B (GluN2B) activation, limiting calcium overload, and suppressing necroptosis. In ischemic stroke mice, telaprevir reduced infarct volume, improved the long-term survival rate, and enhanced sensorimotor, memory, and cognitive functions. In hypoxia-treated nerve cells, telaprevir decreased the intracellular calcium concentrations and reduced LDH release. Mechanistically, telaprevir inhibited MALT1 protease activity, thus decreasing the membrane protein level of GluN2B and its phosphorylation through reducing the level of STEP61. Moreover, telaprevir was able to inhibit the levels of necroptosis-associated proteins. According to these results, it can be concluded that telaprevir alleviates neuronal brain injury in stroke mice via restraining GluN2B activation and suppresses the receptor-interacting protein kinase 1 (RIPK1)/receptor-interacting protein kinase 3 (RIPK3)/mixed lineage kinase domain-like pseudokinase (MLKL) pathway through inhibiting MALT1. Thus, telaprevir might have a novel indication for treating patients with ischemic stroke.