The pan-ErbB negative regulator Lrig1 is an intestinal stem cell marker that functions as a tumor suppressor.

Lineage mapping has identified both proliferative and quiescent intestinal stem cells, but the molecular circuitry controlling stem cell quiescence is incompletely understood. By lineage mapping, we show Lrig1, a pan-ErbB inhibitor, marks predominately noncycling, long-lived stem cells that are located at the crypt base and that, upon injury, proliferate and divide to replenish damaged crypts. Transcriptome profiling of Lrig1(+) colonic stem cells differs markedly from the profiling of highly proliferative, Lgr5(+) colonic stem cells; genes upregulated in the Lrig1(+) population include those involved in cell cycle repression and response to oxidative damage. Loss of Apc in Lrig1(+) cells leads to intestinal adenomas, and genetic ablation of Lrig1 results in heightened ErbB1-3 expression and duodenal adenomas. These results shed light on the relationship between proliferative and quiescent intestinal stem cells and support a model in which intestinal stem cell quiescence is maintained by calibrated ErbB signaling with loss of a negative regulator predisposing to neoplasia.

BMSCs promote alveolar epithelial cell autophagy to reduce pulmonary fibrosis by inhibiting core fucosylation modifications.

BACKGROUND: Idiopathic pulmonary fibrosis (PF) is a chronic progressive interstitial lung disease characterized by alveolar epithelial cell (AEC) injury and fibroblast activation. Inadequate autophagy in AECs may result from the activation of several signaling pathways following AEC injury, with glycoproteins serving as key receptor proteins. The core fucosylation (CF) modification in glycoproteins is crucial. Mesenchymal stem cells derived from bone marrow (BMSCs) have the ability to regenerate damaged tissue and treat PF. This study aimed to elucidate the relationship and mechanism of interaction between BMSCs, CF modification, and autophagy in PF. METHODS: C57BL/6 male mice, AEC-specific FUT8 conditional knockout (CKO) mice, and MLE12 cells were administered bleomycin (BLM), FUT8 siRNA, and mouse BMSCs, respectively. Experimental techniques including tissue staining, Western blotting, immunofluorescence, autophagic flux detection, and flow cytometry were used in this study. RESULTS: First, we found that autophagy was inhibited while FUT8 expression was elevated in PF mice and BLM-induced AEC injury models. Subsequently, CKO mice and MLE12 cells transfected with FUT8 siRNA were used to demonstrate that inhibition of CF modification induces autophagy in AECs and mitigates PF. Finally, mouse BMSCs were used to demonstrate that they alleviate the detrimental autophagy of AECs by inhibiting CF modification and decreasing PF. CONCLUSIONS: Suppression of CF modification enhanced the suppression of AEC autophagy and reduced PF in mice. Additionally, through the prevention of CF modification, BMSCs can assist AECs deficient in autophagy and partially alleviate PF.

Combined analysis of the effects of hypoxia and oxidative stress on DNA methylation and the transcriptome in HTR-8/SVneo trophoblast cells.

The alterations in DNA methylation and transcriptome in trophoblast cells under conditions of low oxygen and oxidative stress have major implications for pregnancy-related disorders. However, the exact mechanism is still not fully understood. In this study, we established models of hypoxia (H group) and oxidative stress (HR group) using HTR-8/SVneo trophoblast cells and performed combined analysis of genome-wide DNA methylation changes using reduced representation bisulphite sequencing and transcriptome expression changes using RNA sequencing. Our findings revealed that the H group exhibited a higher number of differentially methylated genes and differentially expressed genes than the HR group. In the H group, only 0.90% of all differentially expressed genes displayed simultaneous changes in DNA methylation and transcriptome expression. After the threshold was expanded, this number increased to 6.29% in the HR group. Notably, both the H group and HR group exhibited concurrent alterations in DNA methylation and transcriptome expression within Axon guidance and MAPK signalling pathway. Among the top 25 differentially methylated KEGG pathways in the promoter region, 11 pathways were commonly enriched in H group and HR group, accounting for 44.00%. Among the top 25 KEGG pathways in transcriptome with significant differences between the H group and HR group, 10 pathways were consistent, accounting for 40.00%. By integrating our previous data on DNA methylation from preeclamptic placental tissues, we identified that the ANKRD37 and PFKFB3 genes may contribute to the pathogenesis of preeclampsia through DNA methylation-mediated transcriptome expression under hypoxic conditions.

Coronary Artery Calcium Score-Weighted Clinical Likelihood Model Performance in Patients with Stable Chest Pain and Coronary Artery Calcium Scores of Zero.

Background: For individuals with persistent stable chest pain (SCP) and a coronary artery calcium score (CACS) of 0, it might be challenging to establish the best risk assessment method for determining the individuals who will not benefit from further cardiovascular imaging testing (CIT). Thus, we investigated the CACS-weighted clinical likelihood (CACS-CL) model in SCP patients with a CACS of 0. Methods: Thus, to assess SCP, we originally enrolled 14,232 individuals for CACS and coronary computed tomography angiography (CCTA) scans between January 2016 and January 2018. Finally, patients with a CACS of 0 were included and followed up ​until January 2022. According to the established CACS-CL cutoffs of 15% and 5%, the associations between coronary artery disease (CAD) and major adverse cardiovascular events (MACEs) in risk groups were evaluated, alongside the net reclassification improvement (NRI). Results: Of the 6689 patients with a CACS of 0, the prevalence of CAD increased significantly (p < 0.0001) in patients with higher CACS-CL. However, there was no significant difference in the CAD distribution (p = 0.0637) between patients with CACS-CL < 5% and 5-15%. The association between the CACS-CL = 15%-determined risk groups and the occurrence of MACEs was stronger than for a CACS-CL = 5% (adjusted hazard ratio (HR): 7.24 (95% CI: 1.93-16.42) versus 3.68 (95% CI: 1.50-8.26)). Compared with the cutoff for CACS-CL = 5%, the NRI was 10.61% when using a cutoff for CACS-CL = 15%. Conclusions: Among patients with an SCP and CACS of 0, the CACS-CL model provided accurate predictions of CAD and MACEs. Compared to the cutoff for CACS-CL = 5%, the cutoff for CACS-CL = 15% seemed to be more effective and safer for deferring further CIT. Clinical Trial registration: NCT04691037.

System-wide identification of novel de-ubiquitination targets for USP10 in gastric cancer metastasis through multi-omics screening.

OBJECTIVE: Ubiquitin-specific peptidase 10 (USP10), a typical de-ubiquitinase, has been found to play a double-edged role in human cancers. Previously, we reported that the expression of USP10 was negatively correlated with the depth of gastric wall invasion, lymph node metastasis, and prognosis in gastric cancer (GC) patients. However, it remains unclear whether USP10 can regulate the metastasis of GC cells through its de-ubiquitination function. METHODS: In this study, proteome, ubiquitinome, and transcriptome analyses were conducted to comprehensively identify novel de-ubiquitination targets for USP10 in GC cells. Subsequently, a series of validation experiments, including in vitro cell culture studies, in vivo metastatic tumor models, and clinical sample analyses, were performed to elucidate the regulatory mechanism of USP10 and its de-ubiquitination targets in GC metastasis. RESULTS: After overexpression of USP10 in GC cells, 146 proteins, 489 ubiquitin sites, and 61 mRNAs exhibited differential expression. By integrating the results of multi-omics, we ultimately screened 9 potential substrates of USP10, including TNFRSF10B, SLC2A3, CD44, CSTF2, RPS27, TPD52, GPS1, RNF185, and MED16. Among them, TNFRSF10B was further verified as a direct de-ubiquitination target for USP10 by Co-IP and protein stabilization assays. The dysregulation of USP10 or TNFRSF10B affected the migration and invasion of GC cells in vitro and in vivo models. Molecular mechanism studies showed that USP10 inhibited the epithelial-mesenchymal transition (EMT) process by increasing the stability of TNFRSF10B protein, thereby regulating the migration and invasion of GC cells. Finally, the retrospective clinical sample studies demonstrated that the downregulation of TNFRSF10B expression was associated with poor survival among 4 of 7 GC cohorts, and the expression of TNFRSF10B protein was significantly negatively correlated with the incidence of distant metastasis, diffuse type, and poorly cohesive carcinoma. CONCLUSIONS: Our study established a high-throughput strategy for screening de-ubiquitination targets for USP10 and further confirmed that inhibiting the ubiquitination of TNFRSF10B might be a promising therapeutic strategy for GC metastasis.

Time in hand: Temporal focus in risk discourse and audience emotions on knowledge-sharing platforms.

Online knowledge-sharing platforms construct risk knowledge and provide the audience with risk-related scientific facts. We study how speakers organize narratives in past, present, and future foci to influence the audience's emotions through the audience's appraisal of motive congruency and coping potential. Empirical evidence from 210 Technology, Entertainment, Design talks about disasters from 2002 to 2018 demonstrates that emphasizing the past, present, and future in risk narrative leads to the audience's comments with more negative, less positive, and more positive emotions, respectively. Concrete (vs. abstract) portrayal of the risk narrative improves the audience's situational awareness, enhances their risk appraisal, and intensifies the impact of temporal focus on emotions, providing evidence of how temporal focus impacts. These findings demonstrate that temporal focus can effectively reduce risk overreaction or ignorance and facilitate emotion regulation in risk communication.

The synergy effect of multi-country policy actions announced in reaction to global risk: A network structure perspective.

The policy actions of countries reflect adaptive responses of local components within the system to the dynamic global risk landscape. These responses can generate interactions and synergy effects on alleviating the evolution of global risks. Adopting a network perspective, the study proposes a theoretical framework that connects three structural characteristics of policy synergy, namely, synergy scale, alignment intensity, and timing synchronization. Focusing on the Covid-19 pandemic as a typical global risk context, the study finds that policy synergy with a larger scale, stronger alignment intensity, and more synchronized timing has a positive impact on mitigating global risks. The effect of alignment intensity is particularly pronounced when polycentric governance involves 20 countries facing severe risks, whereas the effect of timing synchronization is more significant when the multicenter group comprises more countries. Building upon the concept of an efficient scale of polycentric governance in various dimensions, this study develops a policy synergy index model. Through multiple empirical analyses, this study validates the causal relationship between policy synergy and the future evolution of global pandemic risk. Policymakers can leverage the dynamic changes in the policy synergy to predict future risk situations and implement well-rounded and appropriate policy actions, thereby enhancing the efficacy of the synergy effect of multi-country policy actions for risk governance.

Sarcopenia predicts postoperative complications in head and neck cancer: a systematic review and meta-analysis.

PURPOSE: We performed this systematic review and meta-analysis to explore the impact of preoperative sarcopenia on postoperative complication risks after head and neck cancer (HNC) surgery. METHODS: We identified eligible studies by searching Ovid-MEDLINE, Ovid-Embase, EBM Reviews-Cochrane Central Register of Controlled Trials, Web of Science Core Collection, and Scopus. This systematic review was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidance. RESULTS: Twenty-one studies with a total of 3480 patients met our inclusion criteria. The presence of sarcopenia significantly increased the incidence of overall postoperative complications (OR = 1.72, 95% CI 1.23, 2.41; P = 0.002; I2 = 59%). Subgroup analyses showed a higher risk of postoperative complications in the populations in which sarcopenia was diagnosed with low L3-skeletal muscle index (L3-SMI) or low cross-sectional area of the rectus femoris, but not in the group that sarcopenia was diagnosed with low C3-SMI. Preoperative sarcopenia also substantially increased the risk of severe postoperative complications (OR = 2.26), pharyngocutaneous fistulas (OR = 2.15), free flap-related complications (OR = 1.63), and surgical site infections (OR = 1.84). We also found a tendency toward a higher incidence of wound complications and 30-day mortality in patients with sarcopenia. CONCLUSION: Preoperative sarcopenia is a negative prognostic indicator for postoperative complications in patients with HNC after surgery. To reduce the incidence of postoperative complications and improve poor prognosis, further attention needs to be paid to the evaluation and management of preoperative sarcopenia.

Heme Oxygenase-1 Regulates Zearalenone-Induced Oxidative Stress and Apoptosis in Sheep Follicular Granulosa Cells.

Zearalenone (ZEA) is a common non-steroidal estrogenic mycotoxin found in a range of animal feeds and poses a serious threat to the reproductive health of farm animals and humans. However, the mechanism underlying ZEA-induced reproductive toxicity in sheep remains unknown. Granulosa cells are crucial for egg maturation and the fertility of female sheep. In this study, we aimed to examine the impact of different ZEA concentrations on sheep follicular granulosa cells and to elucidate the potential molecular mechanism underlying ZEA-induced toxicity using transcriptome sequencing and molecular biological approaches. Treating primary sheep follicular granulosa cells with different concentrations of ZEA promoted the overproduction of reactive oxygen species (ROS), increased lipid peroxidation products, led to cellular oxidative stress, decreased antioxidant enzyme activities, and induced cell apoptosis. Using transcriptome approaches, 1395 differentially expressed genes were obtained from sheep follicular granulosa cells cultured in vitro after ZEA treatment. Among them, heme oxygenase-1 (HMOX1) was involved in 11 biological processes. The protein interaction network indicated interactions between HMOX1 and oxidative and apoptotic proteins. In addition, N-acetylcysteine pretreatment effectively reduced the ZEA-induced increase in the expression of HMOX1 and Caspase3 by eliminating ROS. Hence, we suggest that HMOX1 is a key differential gene involved in the regulation of ZEA-induced oxidative stress and apoptosis in follicular granulosa cells. These findings provide novel insights into the prevention and control of mycotoxins in livestock.

The effect of land use and land cover on soil carbon storage in the Yellow River Delta, China: Implications for wetland restoration and adaptive management.

Gaining a comprehensive understanding of the effect of land use/land cover (LULC) and soil depth on soil carbon storage, through the manipulation of external carbon input and turnover processes, is crucial for accurate predictions of regional soil carbon storage. Numerous research investigations have been conducted to examine the impact of LULC on the storage and cycling of carbon in the surface soils of coastal wetlands. Nevertheless, there remains a dearth of understanding concerning the implications of this phenomenon on subterranean soils, a crucial factor in discerning the capacity for carbon sequestration in coastal wetlands and implementing measures for their preservation. The study focused on the Yellow River Delta (YRD) in China, which serves as a representative model system. It aimed to assess the impact of LULC as well as soil depth on carbon storage. This was achieved by a combination of remote sensing interpretation and field samplings. The findings of the study indicate that there was an increase in soil organic carbon storage with both the area covered and the depth of the soil across the four different land use types, namely forest, grass, tidal flat, and cultivated land. Cultivated land was identified as the predominant LULC type, encompassing 41.73% of the entire YRD. Furthermore, it accounted for a substantial carbon storage of 76.08%. In comparison to soil layers at depths of 0-20 cm and 20-40 cm, 40-60 cm was discovered to have the maximum carbon storage, accounting for 42.29% of total carbon storage. Furthermore, one of the main factors influencing carbon storage is salinity, which shows a negative association with carbon storage. Moreover, the aforementioned findings underscore the significance of the conjoined physical and chemical properties induced by LULC in influencing the dynamics of soil carbon. This suggests that the inclusion of deep soil carbon in the estimation and restoration of soil carbon storage is necessary. This inclusion will support the realization of the United Nations' "Toward Zero Carbon" effort and facilitate the implementation of China's national carbon neutrality objectives.

IL-1ß promotes IL-17A production of ILC3s to aggravate neutrophilic airway inflammation in mice.

IL-17A-producing group 3 innate lymphoid cells (ILC3s) have been found to participate in the development of various phenotypes of asthma, however, little is known about how ILC3s mediate neutrophilic airway inflammation. Elevated IL-1ß has been reported in neutrophilic asthma (NA) and IL-1ß receptor is highly expressed on lung ILC3s. Therefore, we hypothesize that IL-1ß aggravates neutrophilic airway inflammation via provoking IL-17A-producing ILC3s. We sought to determine the pathological roles of the IL-1ß-ILC3-IL-17A axis in neutrophilic airway inflammation. Lung ILC subsets were measured in eosinophilic asthma (ovalbumin [OVA]/Alum) and NA (OVA/lipopolysaccharides [LPS]) murine models. Rag2-/- (lacking adaptive immunity), RORc-/- (lacking transcription factor RORγt), Rag2-/- RORc-/- (lacking adaptive immunity and ILC3s), and ILCs depletion mice were used to verify the roles of ILC3s in neutrophilic airway inflammation by measurement of CXCL-1, IL-17A, IL-22 and neutrophil counts in bronchoalveolar lavage fluid (BALF), detection of Muc5ac in lung tissues, and quantification of IL-17A-producing ILC3s after treatment of anti-IL-17A or recombinant IL-1ß (rIL-1ß) and its monoclonal antibody. NLRP3, Caspase 1 and their induction of IL-1ß were detected in lung tissues of OVA/LPS-induced mice. The OVA/LPS model was characterized by an enrichment of airway neutrophilia, lung RORγt+ ILC3s and Th17 cytokines (IL-17A and IL-22) and neutrophilic chemokine C-X-C motif (chemokine) ligand 1 (CXCL-1), compared to the phenotypic features of airway eosinophilia, GATA3+ ILC2s and type-2 cytokines in OVA/Alum model. The concentration of CXCL-1 and neutrophil counts in BALF were decreased by anti-IL-17A. RORγt deficiency led to a decrease in IL-17A and CXCL-1 levels and neutrophil counts in BALF. ILC depletion in Rag2-/- mice ameliorated OVA/LPS-induced IL-17A, IL-22, CXCL-1 and airway neutrophil counts. IL-17A-producing ILCs and BALF neutrophil counts were significantly lower in Rag2-/- RORc-/- mice than those in Rag2-/- mice. IL-1ß was highly expressed in BALF and bronchial epithelial cells (BECs) in OVA/LPS model, and administration of rIL-1ß substantially aggravated airway inflammation and promoted upregulation of RORγt+ and IL-17A-producing lung ILC3s, which were reversed by anti-IL-1ß. NLRP3 and Caspase 1 expressions were enhanced by OVA/LPS, and their inhibitors abolished the OVA/LPS-induced IL-1ß in BECs. ILC3s play a pathogenic role in the pathogenesis of NA, which is triggered by IL-1ß via promoting IL-17A production of lung ILC3s.

Establishment of Bactrian Camel Induced Pluripotent Stem Cells and Prediction of Their Unique Pluripotency Genes.

Induced pluripotent stem cells (iPSCs) can differentiate into all types of cells and can be used in livestock for research on biological development, genetic breeding, and in vitro genetic resource conservation. The Bactrian camel is a large domestic animal that inhabits extreme environments and holds value in the treatment of various diseases and the development of the local economy. Therefore, we transferred four mouse genes (Oct4, Sox2, Klf4, and c-Myc) into Bactrian camel fetal fibroblasts (BCFFs) using retroviruses with a large host range to obtain Bactrian camel induced pluripotent stem cells (bciPSCs). They were comprehensively identified based on cell morphology, pluripotency gene and marker expression, chromosome number, transcriptome sequencing, and differentiation potential. The results showed the pluripotency of bciPSCs. However, unlike stem cells of other species, late formation of stem cell clones was observed; moreover, the immunofluorescence of SSEA1, SSEA3, and SSEA4 were positive, and teratoma formation took four months. These findings may be related to the extremely long gestation period and species specificity of Bactrian camels. By mining RNA sequence data, 85 potential unique pluripotent genes of Bactrian camels were predicted, which could be used as candidate genes for the production of bciPSC in the future. Among them, ASF1B, DTL, CDCA5, PROM1, CYTL1, NUP210, Epha3, and SYT13 are more attractive. In conclusion, we generated bciPSCs for the first time and obtained their transcriptome information, expanding the iPSC genetic information database and exploring the applicability of iPSCs in livestock. Our results can provide an experimental basis for Bactrian camel ESC establishment, developmental research, and genetic resource conservation.

Evaluation of risk factors for surgical site infections in osteoarthritis patients undergoing total knee arthroplasty.

This research sought to delineate risk factors associated with surgical site infections (SSIs) post-total knee arthroplasty (post-TKA) in elderly osteoarthritis patients, aiming to enhance post-surgical outcomes. A retrospective examination was conducted on a cohort of 650 elderly patients who underwent unilateral TKA between January 2018 and August 2022. Data procurement was from the hospital's Electronic Health Record, and a comprehensive statistical evaluation was performed using IBM SPSS Statistics version 24.0. Both univariate and multivariate techniques assessed a spectrum of risk determinants such as age, body mass index (BMI), coexisting medical conditions and surgical variables. The univariate examination spotlighted age, BMI, diabetes prevalence, chronic corticosteroid consumption and American Society of Anesthesiologists (ASA) physical status classification as notable predictors of SSIs. The multivariate logistic regression pinpointed age, BMI, history of smoking and diabetes diagnosis as salient risk attributors for post-TKA infections. Concurrently, parameters like ASA classification, surgical duration and intraoperative haemorrhage further enriched the risk landscape. Geriatric patients undergoing TKA for knee osteoarthritis manifest a tangible infection susceptibility post-surgery. Precision interventions concentrating on amendable risk components, including meticulous preoperative evaluations and strategic postoperative care, are imperative to attenuate SSI incidence, thereby amplifying surgical efficacy and optimizing patient recuperation trajectories.

Tandem reduction and trifluoroethylation of quinolines and quinoxalines with trifluoroacetic acid and trimethylamine borane.

A metal-free tandem reduction and N-trifluoroethylation of quinolines and quinoxalines has been developed. It provided a convenient route to access trifluoroethylated tetrahydroquinolines and tetrahydroquinoxalines. This one-pot method avoids the purification process of the intermediate. Mechanistically, the in situ-generated boryl acetal species reacted with tetrahydroquinolines to generate iminiums followed by reduction to give the target compounds.

RBP4 regulates androgen receptor expression and steroid synthesis in Sertoli cells from Bactrian camels.

Retinol-binding protein (RBP4) plays an important role in the transport and metabolism of retinol. In addition, RBP4 contributes to testicular homeostasis, including maintenance of spermatogenesis and synthesis of androgens that mediate their physiological functions through the androgen receptor. RBP4 in Sertoli cells regulates testosterone and dihydrotestosterone synthesis and secretion, although the mechanisms have yet to be revealed. In this study, we examined the expression and function of RBP4 in Sertoli cells isolated from Bactrian camels. qRT-PCR analysis of various Bactrian camel tissues revealed high expression of RBP4 in the testis and epididymis. To examine RBP4 function, Sertoli cells isolated from testes were transfected with an RBP4 overexpression plasmid or RBP4-targeting siRNA. RBP4 overexpression resulted in significant inhibition of transcription and translation of the steroidogenic enzymes 3ßHSD and SRD5A1 concomitant with a significant decrease in androgen receptor expression and dihydrotestosterone secretion. Conversely, RBP4 knockdown significantly increased the expression of 3ßHSD, SRD5A1 and androgen receptor and enhanced the secretion of dihydrotestosterone and testosterone. These data reveal a novel role for RBP4 in regulating steroid synthesis in Sertoli cells from Bactrian camels.

Orthodontic loading activates cell-specific autophagy in a force-dependent manner.

INTRODUCTION: Orthodontic tooth movement (OTM) relies on bone remodeling and controlled aseptic inflammation. Autophagy, a conserved homeostatic pathway, has been shown to play a role in bone turnover. We hypothesize that autophagy participates in regulating bone remodeling during OTM in a force-dependent and cell type-specific manner. METHODS: A split-mouth design was used to load molars with 1 of 3 force levels (15, 30, or 45 g of force) in mice carrying a green fluorescent protein-LC3 transgene to detect cellular autophagy. Fluorescent microscopy and quantitative polymerase chain reaction analyses were used to evaluate autophagy activation and its correlation with force level. Cell type-specific antibodies were used to identify cells with green fluorescent protein-positive puncta (autophagosomes) in periodontal tissues. RESULTS: Autophagic activity increased shortly after loading with moderate force and was associated with the expression of bone turnover, inflammatory, and autophagy markers. Different load levels resulted in altered degrees of autophagic activation, gene expression, and osteoclast recruitment. Autophagy was specifically induced by loading in macrophages and osteoclasts found in the periodontal ligament and alveolar bone. Data suggest autophagy participates in regulating bone turnover during OTM. CONCLUSIONS: Autophagy is induced in macrophage lineage cells by orthodontic loading in a force-dependent manner and plays a role during OTM, possibly through modulation of osteoclast bone resorption. Exploring the roles of autophagy in OTM is medically relevant, given that autophagy is associated with oral and systemic inflammatory conditions.

Relevant mediators involved in and therapies targeting the inflammatory response induced by activation of the NLRP3 inflammasome in ischemic stroke.

The nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) family pyrin domain-containing 3 (NLRP3) inflammasome is a member of the NLR family of inherent immune cell sensors. The NLRP3 inflammasome can detect tissue damage and pathogen invasion through innate immune cell sensor components commonly known as pattern recognition receptors (PRRs). PRRs promote activation of nuclear factor kappa B (NF-κB) pathways and the mitogen-activated protein kinase (MAPK) pathway, thus increasing the transcription of genes encoding proteins related to the NLRP3 inflammasome. The NLRP3 inflammasome is a complex with multiple components, including an NAIP, CIITA, HET-E, and TP1 (NACHT) domain; apoptosis-associated speck-like protein containing a CARD (ASC); and a leucine-rich repeat (LRR) domain. After ischemic stroke, the NLRP3 inflammasome can produce numerous proinflammatory cytokines, mediating nerve cell dysfunction and brain edema and ultimately leading to nerve cell death once activated. Ischemic stroke is a disease with high rates of mortality and disability worldwide and is being observed in increasingly younger populations. To date, there are no clearly effective therapeutic strategies for the clinical treatment of ischemic stroke. Understanding the NLRP3 inflammasome may provide novel ideas and approaches because targeting of upstream and downstream molecules in the NLRP3 pathway shows promise for ischemic stroke therapy. In this manuscript, we summarize the existing evidence regarding the composition and activation of the NLRP3 inflammasome, the molecules involved in inflammatory pathways, and corresponding drugs or molecules that exert effects after cerebral ischemia. This evidence may provide possible targets or new strategies for ischemic stroke therapy.

Efficacy and Safety of Prostaglandin D2 Receptor 2 Antagonism with Fevipiprant for Patients with Asthma: a Systematic Review and Meta-analysis of Randomized Controlled Trials.

PURPOSE OF REVIEW: Accumulating evidence has shown that prostaglandin D2 (PGD2)-chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2) pathway plays an important role in promoting eosinophilic airway inflammation in asthma. We aimed to assess the efficacy and safety of CRTH2 antagonist fevipiprant in patients with persistent asthma compared with placebo. RECENT FINDINGS: We identified eligible studies by searching PubMed, EMBASE, the Cochrane Central Register of Controlled Trials and ClinicalTrials.gov. The study was registered as CRD 42020221714 ( http://www.crd.york.ac.uk/PROSPERO ). Ten randomized controlled trials with 7902 patients met our inclusion criteria. A statistically significant benefit of fevipiprant compared with placebo was shown in improving forced expiratory volume in 1 s (MD 0.05 L, 95% CI: 0.02 to 0.07; p < 0.0001), Asthma Control Questionnaire score (MD -0.10, 95% CI: -0.16 to -0.04; p = 0.001), and Asthma Quality of Life Questionnaire score (MD 0.08, 95% CI: 0.03 to 0.13; p = 0.003). Fevipiprant decreased number of patients with at least one asthma exacerbation requiring administration of systemic corticosteroids for 3 days or more (RR 0.86, 95% CI: 0.77 to 0.97; p = 0.01). Some benefits were a little more pronounced in the high eosinophil population (with an elevated blood eosinophil count or sputum eosinophil percentage) and in the 450 mg dose group. Fevipiprant was well tolerated with no safety issues compared with placebo. Fevipiprant could safely improve asthma outcomes compared to placebo. However, most of the differences didn't reach the minimal clinically important difference (MCID), thus the clinical benefits remained to be confirmed.

Metal-free regioselective nitration of quinoxalin-2(1H)-ones with tert-butyl nitrite.

A metal-free coupling of quinoxalin-2(1H)-ones with tert-butyl nitrite has been developed. Distinctly from the previous functionalization of quinoxalin-2(1H)-ones, this nitration reaction took place selectively at the C7 or C5 position of the phenyl ring, affording a series of 7-nitro and 5-nitro quinoxalin-2(1H)-ones in moderate to good yields. Preliminary mechanistic studies revealed that the reaction may involve a radical process.

Novel Pathway for Vanadium(V) Bio-Detoxification by Gram-Positive Lactococcus raffinolactis.

Whereas prospects of bioremediation for a vanadium(V) [V(V)]-contaminated environment are widely recognized, reported functional species are extremely limited, with the vast majority of Gram-negative bacteria in Proteobacteria. Herein, the effectiveness of V(V) reduction is proved for the first time by Lactococcus raffinolactis, a Gram-positive bacterium in Firmicutes. The V(V) removal efficiency was 86.5 ± 2.17% during 10-d operation, with an average removal rate of 4.32 ± 0.28 mg/L·d in a citrate-fed system correspondingly. V(V) was bio-reduced to insoluble vanadium(IV) and distributed both inside and outside the cells. Nitrite reductase encoded by gene nirS mainly catalyzed intracellular V(V) reduction, revealing a previously unrecognized pathway. Oxidative stress induced by reactive oxygen species from dissimilatory V(V) reduction was alleviated through strengthened superoxide dismutase and catalase activities. Extracellular polymeric substances with chemically reactive hydroxyl (-OH) and carboxyl (-COO-) groups also contributed to V(V) binding and reduction as well as ROS scavenging. This study can improve the understanding of Gram-positive bacteria for V(V) bio-detoxification and offer microbial resources for bioremediation of a V(V)-polluted environment.