Trichinella spiralis -induced immunomodulation signatures on gut microbiota and metabolic pathways in mice.

The hygiene hypothesis proposes that decreased exposure to infectious agents in developed countries may contribute to the development of allergic and autoimmune diseases. Trichinella spiralis, a parasitic roundworm, causes trichinellosis, also known as trichinosis, in humans. T. spiralis had many hosts, and almost any mammal could become infected. Adult worms lived in the small intestine, while the larvae lived in muscle cells of the same mammal. T. spiralis was a significant public health threat because it could cause severe illness and even death in humans who eat undercooked or raw meat containing the parasite. The complex interactions between gastrointestinal helminths, gut microbiota, and the host immune system present a challenge for researchers. Two groups of mice were infected with T. spiralis vs uninfected control, and the experiment was conducted over 60 days. The 16S rRNA gene sequences and untargeted LC/MS-based metabolomics of fecal and serum samples, respectively, from different stages of development of the Trichinella spiralis-mouse model, were examined in this study. Gut microbiota alterations and metabolic activity accompanied by parasite-induced immunomodulation were detected. The inflammation parameters of the duodenum (villus/crypt ratio, goblet cell number and size, and histological score) were involved in active inflammation and oxidative metabolite profiles. These profiles included increased biosynthesis of phenylalanine, tyrosine, and tryptophan while decreasing cholesterol metabolism and primary and secondary bile acid biosynthesis. These disrupted metabolisms adapted to infection stress during the enteral and parenteral phases and then return to homeostasis during the encapsulated phase. There was a shift from an abundance of Bacteroides in the parenteral phase to an abundance of probiotic Lactobacillus and Treg-associated-Clostridia in the encapsulated phase. Th2 immune response (IL-4/IL-5/IL-13), lamina propria Treg, and immune hyporesponsiveness metabolic pathways (decreased tropane, piperidine and pyridine alkaloid biosynthesis and biosynthesis of alkaloids derived from ornithine, lysine, and nicotinic acid) were all altered. These findings enhanced our understanding of gut microbiota and metabolic profiles of Trichinella -infected mice, which could be a driving force in parasite-shaping immune system maintenance.

MicroRNAs balance growth and salt stress responses in sweet sorghum.

Salt stress is one of the major causes of reduced crop production, limiting agricultural development globally. Plants have evolved with complex systems to maintain the balance between growth and stress responses, where signaling pathways such as hormone signaling play key roles. Recent studies revealed that hormones are modulated by microRNAs (miRNAs). Previously, two sweet sorghum (Sorghum bicolor) inbred lines with different salt tolerance were identified: the salt-tolerant M-81E and the salt-sensitive Roma. The levels of endogenous hormones in M-81E and Roma varied differently under salt stress, showing a different balance between growth and stress responses. miRNA and degradome sequencing showed that the expression of many upstream transcription factors regulating signal transduction and hormone-responsive genes was directly induced by differentially expressed miRNAs, whose levels were very different between the two sweet sorghum lines. Furthermore, the effects of representative miRNAs on salt tolerance in sorghum were verified through a transformation system mediated by Agrobacterium rhizogenes. Also, miR-6225-5p reduced the level of Ca2+ in the miR-6225-5p-overexpressing line by inhibiting the expression of the Ca2+ uptake gene SbGLR3.1 in the root epidermis and affected salt tolerance in sorghum. This study provides evidence for miRNA-mediated growth and stress responses in sweet sorghum.

FASN-mediated fatty acid biosynthesis remodels immune environment in Clonorchis sinensis infection-related intrahepatic cholangiocarcinoma.

BACKGROUND & AIMS: Intrahepatic cholangiocarcinoma (iCCA) is the second most common primary liver cancer and is highly lethal. Clonorchis sinensis (C. sinensis) infection is an important risk factor for iCCA. Here we investigated the clinical impact and underlying molecular characteristics of C. sinensis infection-related iCCA. METHODS: We performed single-cell RNA sequencing, whole-exome sequencing, RNA sequencing, metabolomics and spatial transcriptomics in 251 patients with iCCA from three medical centers. Alterations in metabolism and the immune microenvironment of C. sinensis-related iCCAs were validated through an in vitro co-culture system and in a mouse model of iCCA. RESULTS: We revealed that C. sinensis infection was significantly associated with iCCA patients' overall survival and response to immunotherapy. Fatty acid biosynthesis and the expression of fatty acid synthase (FASN), a key enzyme catalyzing long-chain fatty acid synthesis, were significantly enriched in C. sinensis-related iCCAs. iCCA cell lines treated with excretory/secretory products of C. sinensis displayed elevated FASN and free fatty acids. The metabolic alteration of tumor cells was closely correlated with the enrichment of tumor-associated macrophage (TAM)-like macrophages and the impaired function of T cells, which led to formation of an immunosuppressive microenvironment and tumor progression. Spatial transcriptomics analysis revealed that malignant cells were in closer juxtaposition with TAM-like macrophages in C. sinensis-related iCCAs than non-C. sinensis-related iCCAs. Importantly, treatment with a FASN inhibitor significantly reversed the immunosuppressive microenvironment and enhanced anti-PD-1 efficacy in iCCA mouse models treated with excretory/secretory products from C. sinensis. CONCLUSIONS: We provide novel insights into metabolic alterations and the immune microenvironment in C. sinensis infection-related iCCAs. We also demonstrate that the combination of a FASN inhibitor with immunotherapy could be a promising strategy for the treatment of C. sinensis-related iCCAs. IMPACT AND IMPLICATIONS: Clonorchis sinensis (C. sinensis)-infected patients with intrahepatic cholangiocarcinoma (iCCA) have a worse prognosis and response to immunotherapy than non-C. sinensis-infected patients with iCCA. The underlying molecular characteristics of C. sinensis infection-related iCCAs remain unclear. Herein, we demonstrate that upregulation of FASN (fatty acid synthase) and free fatty acids in C. sinensis-related iCCAs leads to formation of an immunosuppressive microenvironment and tumor progression. Thus, administration of FASN inhibitors could significantly reverse the immunosuppressive microenvironment and further enhance the efficacy of anti-PD-1 against C. sinensis-related iCCAs.

Blended BA.5 infection within 8 days after a boosted bivalent mRNA vaccination strengthens and lengthens the host immunity.

The impact of SARS-CoV-2 infection shortly after vaccination on vaccine-induced immunity is unknown, which is also one of the concerns for some vaccinees during the pandemic. Here, based on a cohort of individuals who encountered BA.5 infection within 8 days after receiving the fourth dose of a bivalent mRNA vaccine, preceded by three doses of inactivated vaccines, we show that booster mRNA vaccination provided 48% protection efficacy against symptomatic infections. At Day 7 postvaccination, the level of neutralizing antibodies (Nabs) against WT and BA.5 strains in the uninfected group trended higher than those in the symptomatic infection group. Moreover, there were greater variations in Nabs levels and a significant decrease in virus-specific CD4+ T cell response observed in the symptomatic infection group. However, symptomatic BA.5 infection significantly increased Nab levels against XBB.1.9.1 and BA.5 (symptomatic > asymptomatic > uninfected group) at Day 10 and resulted in a more gradual decrease in Nabs against BA.5 compared to the uninfected group at Day 90. Our data suggest that BA.5 infection might hinder the early generation of Nabs and the recall of the CD4+ T cell response but strengthens the Nab and virus-specific T cell response in the later phase. Our data confirmed that infection can enhance host immunity regardless of the short interval between vaccination and infection and alleviate concerns about infections shortly after vaccination, which provides valuable guidance for developing future vaccine administration strategies.

Structural elucidation a complex galactosyl and glucosyl-rich pectin from the pericarp of immature fruits of Juglans mandshurica Maxim.

A glucosyl-rich pectin, JMMP-3 (Mw, 2.572 × 104 g/mol, O-methyl % = 3.62%), was isolated and purified from the pericarp of the immature fruit of Juglans mandshurica Maxim. (QingLongYi). The structure of JMMP-3 was studied systematically by infrared spectroscopy, monosaccharide compositions, methylation analysis, partial acid hydrolysis, and 1/2D-NMR. The backbone of JMMP-3 possessed a smooth region (→ 4GalA1 →) and a hairy region (→ 4GalA1 → 2Rha1 →) with a molar ratio of 2: 5. The substitution of four characteristic side chains (R1-R4) occurs at C-4 of → 2,4)-α-Rhap-(1→, where R1 is composed of → 5)-α-Araf-(1→, R2 is composed of → 4)-ß-Galp-(1 → and ß-Galp-(1→, R3 is composed of α-Glcp-(1→, →4)-α-Glcp-(1 → and → 4,6)-α-Glcp-(1→, and R4 is composed of → 5)-α-Araf-(1→, ß-Galp-(1→, → 4)-ß-Galp-(1→, → 3,4)-ß-Galp-(1→, → 4,6)-ß-Galp-(1 → and → 2,4)-ß-Galp-(1 → . In addition, the antitumor activity of JMMP-3 on HepG2 cells was preliminarily investigated.

Theoretical Validation of Non-Noble Cu Sites Integrated on SnO2 Nanoflowers for Enhanced Gas Sensing of Ethanethiol at Room Temperature.

Ethanethiol (EtSH), being highly toxic, flammable, and explosive, poses significant risks to human health and safety and is capable of causing fires and explosions. Room-temperature detection using chemiresistive gas sensors is essential for managing these risks. However, the gas-sensing performance of conventional metal-oxide sensing materials may be limited by their weak interaction with EtSH at room temperature. Herein, SnO2 nanoflowers assembled with non-noble Cu-site-enriched porous nanosheets were designed and prepared by an in situ self-template pyrolysis synthesis strategy to enable highly sensitive and selective room-temperature detection of EtSH. By regulating the number of non-noble Cu sites, these nanoflowers achieved efficient EtSH sensing with a Ra/Rg value of 11.0 at 50 ppb, ensuring high selectivity, reproducibility, and stability at room temperature. Moreover, a comparative analysis of the room-temperature gas-sensing performance of SnO2 nanoflowers with non-noble Fe- or Ni-site-enriched nanosheets highlights the benefits of non-noble Cu sites for EtSH detection. Density functional theory (DFT) analysis reveals that non-noble Cu sites have a unique affinity for EtSH, offering preferential binding over other gases and explaining the outstanding sensing performance of non-noble Cu-site-enriched nanosheet-assembled SnO2 nanoflowers. The structural and interface engineering of the sensing materials presented in this work provides a promising approach for offering efficient and durable gas sensors operable at room temperature.

O-GlcNAcylation of TLR4 inhibits osteogenic differentiation of periodontal ligament stem cells.

BACKGROUND: Toll-like receptor 4 (TLR4)-mediated inflammatory responses are associated with diabetes and periodontitis, which are dysregulated by O-GlcNAcylation. OBJECTIVE: This study aimed to investigate the effects of O-GlcNAc transferase (OGT)-mediated TLR4 O-GlcNAcylation on the osteogenesis of periodontal ligament stem cells (PDLCs). METHODS: PDLCs were treated with high glucose (HG) to establish a cell model. Osteogenic differentiation was evaluated using western blotting, an alkaline phosphatase activity assay, and an alizarin red S staining assay. The regulation of OGT on the O-GlcNAcylation of TLR4 was analyzed using co-immunoprecipitation, immunoprecipitation, western blotting, and immunofluorescence staining. RESULTS: The results showed that HG inhibited osteogenic differentiation and promoted inflammatory response. Knockdown of OGT promoted osteogenic differentiation of HG-treated PDLCs. OGT interacted with TLR4 and increased the O-GlcNAcylation and protein levels of TLR4 in the cytomembrane of PDLCs. Moreover, silenced TLR4 reversed the effects on osteogenic differentiation induced by OGT in HG-treated PDLCs. CONCLUSION: O-GlcNAcylation of TLR4 induced by OGT suppresses osteogenic differentiation of PDLCs after HG stimulation. The findings suggest a promising strategy for treating DP.

Ac2-26 activated the AKT1/GSK3ß pathway to reduce cerebral neurons pyroptosis and improve cerebral function in rats after cardiopulmonary bypass.

BACKGROUND: Cardiopulmonary bypass (CPB) results in brain injury, which is primarily caused by inflammation. Ac2-26 protects against ischemic or hemorrhage brain injury. The present study was to explore the effect and mechanism of Ac2-26 on brain injury in CPB rats. METHODS: Forty-eight rats were randomized into sham, CPB, Ac, Ac/AKT1, Ac/GSK3ßi and Ac/AKT1/GSK3ßa groups. Rats in sham group only received anesthesia and in the other groups received standard CPB surgery. Rats in the sham and CPB groups received saline, and rats in the Ac, Ac/AKT1, Ac/GSK3ßi and Ac/AKT1/GSK3ßa groups received Ac2-26 immediately after CPB. Rats in the Ac/AKT1, Ac/GSK3ßi and Ac/AKT1/GSK3ßa groups were injected with shRNA, inhibitor and agonist of GSK3ß respectively. The neurological function score, brain edema and histological score were evaluated. The neuronal survival and hippocampal pyroptosis were assessed. The cytokines, activity of NF-κB, S100 calcium-binding protein ß(S100ß) and neuron-specific enolase (NSE), and oxidative were tested. The NLRP3, cleaved-caspase-1 and cleaved-gadermin D (GSDMD) in the brain were also detected. RESULTS: Compared to the sham group, all indicators were aggravated in rats that underwent CPB. Compared to the CPB group, Ac2-26 significantly improved neurological scores and brain edema and ameliorated pathological injury. Ac2-26 reduced the local and systemic inflammation, oxidative stress response and promoted neuronal survival. Ac2-26 reduced hippocampal pyroptosis and decreased pyroptotic proteins in brain tissue. The protection of Ac2-26 was notably lessened by shRNA and inhibitor of GSK3ß. The agonist of GSK3ß recovered the protection of Ac2-26 in presence of shRNA. CONCLUSIONS: Ac2-26 significantly improved neurological function, reduced brain injury via regulating inflammation, oxidative stress response and pyroptosis after CPB. The protective effect of Ac2-26 primarily depended on AKT1/ GSK3ß pathway.

PGAM5 exacerbates acute renal injury by initiating mitochondria-dependent apoptosis by facilitating mitochondrial cytochrome c release.

Acute kidney injury (AKI) is a worldwide public health problem characterized by the massive loss of tubular cells. However, the precise mechanism for initiating tubular cell death has not been fully elucidated. Here, we reported that phosphoglycerate mutase 5 (PGAM5) was upregulated in renal tubular epithelial cells during ischaemia/reperfusion or cisplatin-induced AKI in mice. PGAM5 knockout significantly alleviated the activation of the mitochondria-dependent apoptosis pathway and tubular apoptosis. Apoptosis inhibitors alleviated the activation of the mitochondria-dependent apoptosis pathway. Mechanistically, as a protein phosphatase, PGAM5 could dephosphorylate Bax and facilitate Bax translocation to the mitochondrial membrane. The translocation of Bax to mitochondria increased membrane permeability, decreased mitochondrial membrane potential and facilitated the release of mitochondrial cytochrome c (Cyt c) into the cytoplasm. Knockdown of Bax attenuated PGAM5 overexpression-induced Cyt c release and tubular cell apoptosis. Our results demonstrated that the increase in PGAM5-mediated Bax dephosphorylation and mitochondrial translocation was implicated in the development of AKI by initiating mitochondrial Cyt c release and activating the mitochondria-dependent apoptosis pathway. Targeting this axis might be beneficial for alleviating AKI.

Atypical characteristic changes of surface morphology and structural covariance network in developmental dyslexia.

BACKGROUND: Developmental dyslexia (DD) is a neurodevelopmental disorder that is characterized by difficulties with all aspects of information acquisition in the written word, including slow and inaccurate word recognition. The neural basis behind DD has not been fully elucidated. METHOD: The study included 22 typically developing (TD) children, 16 children with isolated spelling disorder (SpD), and 20 children with DD. The cortical thickness, folding index, and mean curvature of Broca's area, including the triangular part of the left inferior frontal gyrus (IFGtriang) and the opercular part of the left inferior frontal gyrus, were assessed to explore the differences of surface morphology among the TD, SpD, and DD groups. Furthermore, the structural covariance network (SCN) of the triangular part of the left inferior frontal gyrus was analyzed to explore the changes of structural connectivity in the SpD and DD groups. RESULTS: The DD group showed higher curvature and cortical folding of the left IFGtriang than the TD group and SpD group. In addition, compared with the TD group and the SpD group, the structural connectivity between the left IFGtriang and the left middle-frontal gyrus and the right mid-orbital frontal gyrus was increased in the DD group, and the structural connectivity between the left IFGtriang and the right precuneus and anterior cingulate was decreased in the DD group. CONCLUSION: DD had atypical structural connectivity in brain regions related to visual attention, memory and which might impact the information input and integration needed for reading and spelling.

R-loops and regulatory changes in chronologically ageing fission yeast cells drive non-random patterns of genome rearrangements.

Aberrant repair of DNA double-strand breaks can recombine distant chromosomal breakpoints. Chromosomal rearrangements compromise genome function and are a hallmark of ageing. Rearrangements are challenging to detect in non-dividing cell populations, because they reflect individually rare, heterogeneous events. The genomic distribution of de novo rearrangements in non-dividing cells, and their dynamics during ageing, remain therefore poorly characterized. Studies of genomic instability during ageing have focussed on mitochondrial DNA, small genetic variants, or proliferating cells. To characterize genome rearrangements during cellular ageing in non-dividing cells, we interrogated a single diagnostic measure, DNA breakpoint junctions, using Schizosaccharomyces pombe as a model system. Aberrant DNA junctions that accumulated with age were associated with microhomology sequences and R-loops. Global hotspots for age-associated breakpoint formation were evident near telomeric genes and linked to remote breakpoints elsewhere in the genome, including the mitochondrial chromosome. Formation of breakpoint junctions at global hotspots was inhibited by the Sir2 histone deacetylase and might be triggered by an age-dependent de-repression of chromatin silencing. An unexpected mechanism of genomic instability may cause more local hotspots: age-associated reduction in an RNA-binding protein triggering R-loops at target loci. This result suggests that biological processes other than transcription or replication can drive genome rearrangements. Notably, we detected similar signatures of genome rearrangements that accumulated in old brain cells of humans. These findings provide insights into the unique patterns and possible mechanisms of genome rearrangements in non-dividing cells, which can be promoted by ageing-related changes in gene-regulatory proteins.

A systematic review of qualitative research on the self-management experience of breast cancer patients.

OBJECTIVE: To integrate the qualitative research on the self-management experience of breast cancer patients and conduct a systematic review of their self-management experience. METHODS: Using a computer to search a series of databases such as CNKI, Wanfang, VIP, and China Biomedical Database, systematically collect and integrate qualitative research on the self-management experience of breast cancer patients, and the search time is limited to January 2010 to December 2022. The qualitative research quality evaluation standard of the Joanna Briggs Institute Centre for Evidence-Based Health Care in Australia was used as the evaluation standard of this project to complete the accurate evaluation of the literature; Meta-analysis was used to complete the effective integration of the results. RESULTS: 17 pieces of literature were included in this project, and 37 research results with strong integrity were extracted accordingly. On this basis, 7 different categories were summarised, and three integrated results were obtained: the experience of maintaining self-management, symptom recognition, and self-management. CONCLUSION: In the different stages of self-management of breast cancer patients, medical staff should give targeted guidance to help patients obtain a good prognosis.

Overexpression of GmPAP4 Enhances Symbiotic Nitrogen Fixation and Seed Yield in Soybean under Phosphorus-Deficient Condition.

Legume crops establish symbiosis with nitrogen-fixing rhizobia for biological nitrogen fixation (BNF), a process that provides a prominent natural nitrogen source in agroecosystems; and efficient nodulation and nitrogen fixation processes require a large amount of phosphorus (P). Here, a role of GmPAP4, a nodule-localized purple acid phosphatase, in BNF and seed yield was functionally characterized in whole transgenic soybean (Glycine max) plants under a P-limited condition. GmPAP4 was specifically expressed in the infection zones of soybean nodules and its expression was greatly induced in low P stress. Altered expression of GmPAP4 significantly affected soybean nodulation, BNF, and yield under the P-deficient condition. Nodule number, nodule fresh weight, nodule nitrogenase, APase activities, and nodule total P content were significantly increased in GmPAP4 overexpression (OE) lines. Structural characteristics revealed by toluidine blue staining showed that overexpression of GmPAP4 resulted in a larger infection area than wild-type (WT) control. Moreover, the plant biomass and N and P content of shoot and root in GmPAP4 OE lines were also greatly improved, resulting in increased soybean yield in the P-deficient condition. Taken together, our results demonstrated that GmPAP4, a purple acid phosphatase, increased P utilization efficiency in nodules under a P-deficient condition and, subsequently, enhanced symbiotic BNF and seed yield of soybean.

Special issue "The advance of solid tumor research in China": Participants with a family history of cancer have a higher participation rate in low-dose computed tomography for lung cancer screening.

We aimed to determine participation in low-dose computed tomography (LDCT) of individuals with a family history of common cancers in a population-based screening program to provide timely evidence in high-risk populations in China. The analysis was conducted using data from the Cancer Screening Program in Urban China (CanSPUC), which recruited 282 377 participants aged 40 to 74 years from eight cities in the Henan province. Using the CanSPUC risk score system, 55 428 participants were evaluated to have high risk for lung cancer and were recommended for LDCT. We calculated the overall and group-specific participation rates using family history of common cancers and compared differences in participation rates between different groups. Odds ratios (ORs) and 95% confidence intervals were derived by multivariable logistic regression. Of the 55 428 participants, 22 260 underwent LDCT (participation rate, 40.16%). Family history of lung, esophageal, stomach, liver and colorectal cancer was associated with increased participation in LDCT screening. The odds of participants with a family history of one, two, three and four or more cancer cases undergoing LDCT screening were 1.9, 2.7, 2.8 and 3.5 times, respectively, than those without a family history of cancer. Compared to those without a history of cancer, participation in LDCT gradually increased as the number of cancer cases in the family increased (P < .001). Our findings suggest that there is room for improvement in lung cancer screening given the relatively low participation rate. Lung cancer screening in populations with a family history of cancer may improve efficiency and cost-effectiveness; however, this requires further verification.

Phosphoglycerate mutase 5 initiates inflammation in acute kidney injury by triggering mitochondrial DNA release by dephosphorylating the pro-apoptotic protein Bax.

Acute kidney injury (AKI) is a worldwide public health problem characterized by excessive inflammation with no specific therapy in clinic. Inflammation is not only a feature of AKI but also an essential promoter for kidney deterioration. Phosphoglycerate mutase 5 (PGAM5) was up-regulated and positively correlated with kidney dysfunction in human biopsy samples and mouse kidneys with AKI. PGAM5 knockout in mice significantly alleviated ischemia/reperfusion-induced kidney injury, mitochondrial abnormality and production of inflammatory cytokines. Elevated PGAM5 was found to be mainly located in kidney tubular epithelial cells and was also related to inflammatory response. Knockdown of PGAM5 inhibited the hypoxia/reoxygenation-induced cytosolic release of mitochondrial DNA (mtDNA) and binding of mtDNA with the cellular DNA receptor cGAS in cultured cells. cGAS deficiency also attenuated the inflammation and kidney injury in AKI. Mechanistically, as a protein phosphatase, PGAM5 was able to dephosphorylate the pro-apoptotic protein Bax and facilitate its translocation to mitochondrial membranes, and then initiate increased mitochondrial membrane permeability and release of mtDNA. Leaked mtDNA recognized by cGAS then initiated its downstream-coupled STING pathway, a component of the innate immune system that functions to detect the presence of cytosolic DNA. Thus, our results demonstrated mtDNA release induced by PGAM5-mediated Bax dephosphorylation and the activation of cGAS-STING pathway as critical determinants of inflammation and kidney injury. Hence, targeting this axis may be useful for treating AKI.

High-Throughput CRISPR/Cas9 Mutagenesis Streamlines Trait Gene Identification in Maize.

Maize (Zea mays) is one of the most important crops in the world. However, few agronomically important maize genes have been cloned and used for trait improvement, due to its complex genome and genetic architecture. Here, we integrated multiplexed CRISPR/Cas9-based high-throughput targeted mutagenesis with genetic mapping and genomic approaches to successfully target 743 candidate genes corresponding to traits relevant for agronomy and nutrition. After low-cost barcode-based deep sequencing, 412 edited sequences covering 118 genes were precisely identified from individuals showing clear phenotypic changes. The profiles of the associated gene-editing events were similar to those identified in human cell lines and consequently are predictable using an existing algorithm originally designed for human studies. We observed unexpected but frequent homology-directed repair through endogenous templates that was likely caused by spatial contact between distinct chromosomes. Based on the characterization and interpretation of gene function from several examples, we demonstrate that the integration of forward and reverse genetics via a targeted mutagenesis library promises rapid validation of important agronomic genes for crops with complex genomes. Beyond specific findings, this study also guides further optimization of high-throughput CRISPR experiments in plants.

Knockout of Sema4D alleviates liver fibrosis by suppressing AOX1 expression.

Liver fibrosis can occur in many chronic liver diseases, and no effective treatments are available due to the poorly characterized molecular pathogenesis. Semaphorin 4D (Sema4D) has immune functions and serves important roles in T cell priming. Here, we found that Sema4D was highly expressed in fibrotic liver, and the expression of Sema4D increased with hepatic stellate cells (HSCs) activation. Knockout of Sema4D alleviated liver fibrosis. Mechanistically, knockout of Sema4D alleviated liver fibrosis by suppressing the expression of AOX1 in retinol metabolism. Further investigation demonstrated that retinoic acid receptor α (RARA), an important nuclear receptor of retinoic acid, was reduced by Sema4D knockout during liver fibrogenesis. Sema4D knockout-mediated suppression of liver fibrosis was partly mediated by regulating the balance of Th1, Th2, Th17, and T-bet+Treg cells via inhibiting AOX1/RARA. Thus, targeting Sema4D may hold promise as a potential therapeutic approach for treating liver fibrosis.

Accelerated screening and assembly of promising MOFs with open Cu sites for isobutene/isobutane separation using a data-driven approach.

As the by-products of catalytic cracking or alkane dehydrogenation, isobutene (2-methyl-propylene) and isobutane (2-methyl-propane) are important chemical feedstocks, but the separation of their mixture is a challenging issue in the petrochemical industry. Herein, we report the first example of large-scale computational screening of metal-organic frameworks (MOFs) with copper open metal sites (Cu-OMS) on the adsorptive separation of isobutene/isobutane using configuration-bias Monte Carlo (CBMC) simulations and machine learning among >330 000 MOFs data. We discovered that the optimal structural features governing the MOFs-based separation of isobutene/isobutane were density (ρ) and porosity (φ), with ranges of 0.2-0.5 g cm-3 and 0.8-0.9, respectively. Furthermore, the key genes (metal nodes or linkers of frameworks) contributing to such adsorptive separation were data-mined by feature engineering of ML. These genes were cross-assembled into novel frameworks using a material-genomics strategy. The screened AVAKEP, XAHPON, HUNCIE, Cu2O8-mof177-TDPAT_No730 and assembled Cu2O8-BTC_B-core-4_No1 possessed high isobutene uptake and isobutene/isobutane selectivity of >19.5 mmol g-1 and 4.7, with high thermal stability (as validated by molecular-dynamics simulations) overcoming the critical "trade-off" problem to some extent. The macroporous structures (pore-limiting diameter >12 Å) of these five promising frameworks with multi-layer adsorption on isobutene resulted in high isobutene loading, as validated by adsorption isotherms and CBMC simulations. The higher adsorption energy and heat of adsorption of isobutene than those of isobutane indicated that the thermodynamic equilibrium drove their selective adsorption. Generalized charge decomposition analysis and localized orbit locator calculations based on density functional theory wavefunctions suggested that high selectivity was due to complexation of feedback π bonds between isobutene and Cu-OMS, but also the strong π-π stacking interaction induced by the CC bond of isobutene with the multiple aromatic rings and unsaturated bonds of frameworks. Our theoretical results and data-driven approach may provide insights into the development of efficient MOF materials for the separation of isobutene/isobutane and other mixtures.

Deubiquitinating enzyme USP11 promotes renal tubular cell senescence and fibrosis via inhibiting the ubiquitin degradation of TGF-ß receptor II.

Transforming growth factor-ß1 (TGF-ß1) is regarded as a key factor in promoting renal fibrosis during chronic kidney disease (CKD). Signaling transduction of TGF-ß1 starts with binding to TGF-ß type II receptor (Tgfbr2), a constitutively activated kinase that phosphorylates TGF-ß type I receptor (Tgfbr1), and then activates downstream Smad2/3 or noncanonical pathways. Previous studies show that cellular senescence is associated with the progression of CKD, and accelerated tubular cell senescence is implicated in promoting renal fibrosis. In the present study we investigated the renal parenchymal cell senescence in fibrosis from the sight of posttranslational regulation and focused on Tgfbr2, the important gatekeeper for TGF-ß1 downstream signaling. In mice with unilateral ureteral obstruction (UUO) and folic acid (FA)-induced fibrotic kidneys, we found that Tgfbr2 was markedly elevated without obvious change in its mRNA levels. As an important member of deubiquitinating enzymes, ubiquitin-specific protease 11 (Usp11) was also significantly increased in fibrotic kidneys, and co-distributed with Tgfbr2 in tubular epithelial cells. Pretreatment with Usp11 inhibitor mitoxantrone (MTX, 30 mg · kg-1 · d-1, i.p.) twice a week, for 2 weeks significantly attenuated the elevation of Tgfbr2, activation in downstream senescence-related signaling pathway, as well as renal senescence and fibrosis. In cultured mouse tubular epithelial cells (MTECs), treatment with angiotensin II (Ang-II, 10-7, 10-6 M) dose-dependently elevated both Tgfbr2 and Usp11 levels. Inhibition or knockdown on Usp11 attenuated Ang-II-induced elevation in Tgfbr2 level, and attenuated the activation of downstream senescent-related signaling pathway and as well as cell senescence. We conducted Co-IP experiments, which revealed that Usp11 was able to interact with Tgfbr2, and inhibition of Usp11 increased the ubiquitination of Tgfbr2. Taken together, these results demonstrate that the elevation of Usp11 under pathological condition is implicated in promoting renal fibrosis. Usp11 promotes the development of renal fibrosis by deubiquitinating Tgfbr2, reducing Tgfbr2 ubiquitination degradation, and then facilitating the activation of downstream senescent signaling pathway.

Host liver-derived extracellular vesicles deliver miR-142a-3p induces neutrophil extracellular traps via targeting WASL to block the development of Schistosoma japonicum.

Schistosomiasis is an important neglected tropical disease. Interactions between the host immune system and schistosomes are complex. Neutrophils contribute to clearance of large pathogens primarily by releasing neutrophil extracellular traps (NETs). However, the functional role of NETs in clearing schistosomes remains unclear. Herein, we report that extracellular vesicles (EVs) derived from the liver of Schistosoma japonicum-infected mice (IL-EVs) induce NET release by delivering miR-142a-3p to target WASL and block the development of S. japonicum. WASL knockout accelerated the formation of NETs that blocked further development of S. japonicum. miR-142a-3p and NETs upregulated the expression of CCL2, which recruits macrophages that block S. japonicum development. However, S. japonicum inhibited NET formation in wild-type mice by upregulating host interleukin-10 (IL-10) expression. In contrast, in WASL knockout mice, IL-10 expression was downregulated, and S. japonicum-mediated inhibition of NET formation was significantly reduced. IL-EV-mediated induction of NET formation is thus an anti-schistosome response that can be counteracted by S. japonicum. These findings suggest that IL-EV-mediated induction of NET formation plays a key role in schistosome infection and that WASL is a potential therapeutic target in schistosomiasis and other infectious diseases.