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Rice is one of the most important food crops in the world. Weeds seriously affect the rice yield and grain quality. In recent years, there are tremendous progresses in the research and application of herbicide-resistant genes in rice worldwide. This article reviews the working mechanisms of six herbicides (glyphosate, glufosinate, acetolactate synthase inhibitor herbicides, acetyl-CoA carboxylase inhibitor herbicides, hydroxyhenylpyruvate dioxygenase (HPPD) inhibitor herbicides and dinitroaniline herbicides), the resistance mutations of the corresponding herbicide-target genes, and the herbicide detoxification mechanisms by non-target genes. Examples are provided on herbicide-resistant rice materials obtained by transformation of exogenous resistance genes, by artificial mutagenesis and mutant screening, and by modifying the target genes through gene editing. This paper also introduces the current application of herbicide-resistant rice, points out problems that may be caused by utilization of herbicide resistant rice and solutions to the problems, and discusses the future prospects for the development of herbicide-resistant rice.

N 6‐methyladenosine (m6A) is the most prevalent modification in mRNA and engages in multiple biological processes. Previous studies indicated that m6A methyltransferase METTL3 (‘writer’) and demethylase FTO (‘eraser’) play critical roles in heart‐related disease. However, in the heart, the function of m6A ‘reader’, such as YTH (YT521‐B homology) domain‐containing proteins remains unclear. Here, we report that the defect in YTHDC1 but not other YTH family members contributes to dilated cardiomyopathy (DCM) in mice. Cardiac‐specific conditional Ythdc1 knockout led to obvious left ventricular chamber enlargement and severe systolic dysfunction. YTHDC1 deficiency also resulted in the decrease of cardiomyocyte contractility and disordered sarcomere arrangement. By means of integrating multiple high‐throughput sequence technologies, including m6A‐MeRIP, RIP‐seq and mRNA‐seq, we identified 42 transcripts as potential downstream targets of YTHDC1. Amongst them, we found that Titin mRNA was decorated with m6A modification and depletion of YTHDC1 resulted in aberrant splicing of Titin. Our study suggests that Ythdc1 plays crucial role in regulating the normal contractile function and the development of DCM. These findings clarify the essential role of m6A reader in cardiac biofunction and provide a novel potential target for the treatment of DCM.

SARS-CoV-2 outbreak has been declared by World Health Organization as a worldwide pandemic. However, there are many unknowns about the antigen-specific T-cell-mediated immune responses to SARS-CoV-2 infection. Here, we present both single-cell TCR-seq and RNA-seq to analyze the dynamics of TCR repertoire and immune metabolic functions of blood T cells collected from recently discharged COVID-19 patients. We found that while the diversity of TCR repertoire was increased in discharged patients, it returned to basal level ~1 week after becoming virus-free. The dynamics of T cell repertoire correlated with a profound shift of gene signatures from antiviral response to metabolism adaptation. We also demonstrated that the top expanded T cell clones (~10% of total T cells) display the key anti-viral features in CD8+ T cells, confirming a critical role of antigen-specific T cells in fighting against SARS-CoV-2. Our work provides a basis for further analysis of adaptive immunity in COVID-19 patients, and also has implications in developing a T-cell-based vaccine for SARS-CoV-2.

African classical swine fever virus (ASFV) has spread seriously around the world and has dealt with a heavy blow to the pig breeding industry due to the lack of vaccines. In this study, we produced recombinant Lactobacillus plantarum (L. plantarum) expressing an ASFV p54 and porcine IL-21 (pIL-21) fusion protein and evaluated the immune effect of NC8-pSIP409-pgsA'-p54-pIL-21 in a mouse model. First, we verified that the ASFV p54 protein and p54-pIL-21 fusion protein were anchored on the surface of L. plantarum NC8 by flow cytometry, immunofluorescence and Western blotting. Then, the results were verified by flow cytometry, ELISA and MTT assays. Mouse-specific humoral immunity and mucosal and T cell-mediated immune responses were induced by recombinant L. plantarum. The results of feeding mice recombinant L. plantarum showed that the levels of serum IgG and mucosal secreted IgA (SIgA), the number of CD4 and CD8 T cells, and the expression of IFN-γ in CD4 and CD8 T cells increased significantly, and lymphocyte proliferation occurred under stimulation with the ASFV p54 protein. Our data lay a foundation for the development of oral vaccines against ASFV in the future.

Coronavirus disease 2019 (COVID-19), a pandemic disease caused by the newly emerging severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has caused more than 3.8 million deaths to date. Neutralizing antibodies are effective therapeutic measures. However, many naturally occurring mutations at the receptor-binding domain (RBD) have emerged, and some of them can evade existing neutralizing antibodies. Here, we utilized RenMab, a novel mouse carrying the entire human antibody variable region, for neutralizing antibody discovery. We obtained several potent RBD-blocking antibodies and categorized them into four distinct groups by epitope mapping. We determined the involved residues of the epitope of three representative antibodies by cryo-electron microscopy (Cryo-EM) studies. Moreover, we performed neutralizing experiments with 50 variant strains with single or combined mutations and found that the mixing of three epitope-distinct antibodies almost eliminated the mutant escape. Our study provides a sound basis for the rational design of fully human antibody cocktails against SARS-CoV-2 and pre-emergent coronaviral threats.

Youcui Wang,1– 3 Xiaoqin Zhang,1– 3 Fenghua Chen,1– 3 Leilei Chen,1– 3 Jun Wang,1– 3 Junxia Xie1– 3 1Institute of Brain Science and Disease, Qingdao University, Qingdao, People’s Republic of China; 2Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders, Qingdao University, Qingdao, People’s Republic of China; 3Shandong Provincial Collaborative Innovation Center for Neurodegenerative Disorders, Qingdao University, Qingdao, People’s Republic of ChinaCorrespondence: Junxia XieInstitute of Brain Science and Disease, Qingdao University, No. 308, Ningxia Road, Qingdao, 266071, People’s Republic of ChinaEmail jxiaxie@public.qd.sd.cnAbstract: Neuroinflammation plays an important role in the pathogenesis of Parkinson’s disease (PD). However, the molecular mechanisms involved in extracellular α‑synuclein-induced proinflammatory microglial responses through Toll-like receptor 2 (TLR2) are unclear. Leucine-rich repeat kinase 2 (LRRK2) is a serine/threonine kinase, and its mutations are closely related to autosomal dominant PD. Recently, Masliah et al characterized a novel-specific neuroinflammation cascade dependent on LRRK2-NFATc2 in microglia activated by neuron-released α-synuclein. LRRK2 selectively phosphorylated and induced nuclear translocation of NFATc2 to activate a neuroinflammation cascade. In this cascade, LRRK2 kinase was activated by neuron-released α-synuclein in microglia via TLR2. Further, NFATc2, as a kinase substrate for LRRK2, was directly phosphorylated, which accelerated nuclear translocation of NFATc2, where cytokine/chemokine gene expression including TNF-α and IL-6 is regulated by NFATc2 transcriptional activity, resulting in a neurotoxic inflammatory environment. Moreover, an abnormal increase of NFATc2 in nuclear was observed in the brains of patients and a mouse model of PD. Additionally, the administration of an LRRK2 inhibitor could ameliorate neuroinflammation, prevent neuronal loss, and improve motor function. Therefore, modulation of LRKK2-NFATc2 signaling cascade might be a potential therapeutic target for the treatment of PD.Keywords: Parkinson’s disease, neuroinflammation, LRKK2, NFATc2, α-synuclein

Therapeutic antibody discovery using synthetic diversity has been proved productive, especially for target proteins not suitable for traditional animal immunization-based antibody discovery approaches. Recently, many lines of evidences suggest that the quality of synthetic diversity design limits the development success of synthetic antibody hits. The aim of our study is to understand the quality limitation and to properly address the challenges with a better design. Using VH3–23 as a model framework, we observed and quantitatively mapped CDR-H3 loop length-dependent usage of human IGHJ4 and IGHJ6 germline genes in the natural human immune repertoire. Skewed usage of DH2-JH6 and DH3-JH6 rearrangements was quantitatively determined in a CDR-H3 length-dependent manner in natural human antibodies with long CDR-H3 loops. Structural modeling suggests choices of JH help to stabilize antibody CDR-H3 loop and JH only partially contributes to the paratope. Our observations shed light on the design of next-generation synthetic diversity with improved probability of success.

Hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) remains a global health concern, and HBV proteins may be ideal targets for T cell-based immunotherapy for HCC. There is a need for fast and efficient identification of HBV-specific T cell receptors (TCRs) for the development of TCR-transduced T (TCR-T) cell-based immunotherapy. Two widely employed TCR identification approaches, T cell clonal expansion and single-cell sequencing, involve a TCR singularization process for the direct identification of Vα and Vβ pairs of TCR chains. Clonal expansion of T cells is well known to have tedious time and effort requirements due to the use of T cell cultures, whereas single-cell sequencing is limited by the requirements of cell sorting and the preparation of a single-cell immune-transcriptome library as well as the massive cost of the whole procedure. Here, we present a next-generation sequencing (NGS)-based HBV-specific TCR identification that does not require the TCR singularization process. Conclusion: Two pairing strategies, ranking-based strategy and α-β chain mixture-based strategy, have proved to be useful for NGS-based TCR identification, particularly for polyclonal T cells purified by a peptide-major histocompatibility complex (pMHC) multimer-based approach. Functional evaluation confirmed the specificity and avidity of two identified HBV-specific TCRs, which may potentially be used to produce TCR-T cells to treat patients with HBV-related HCC.

Objectives: Sorafenib is the only FDA-approved first-line target drug for HCC patients. However, sorafenib merely confers 3-5 months of survival benefit with less than 30% of HCC patients sensitive to sorafenib therapy. Thus, it's necessary to develop a sensitizer for hepatocellular carcinoma (HCC) to sorafenib. Methods: The principal component analysis, gene ontology, and KEGG analysis are utilized following RNA-sequencing. The mass spectrometry analysis following immunoprecipitation is performed to discover the phosphatase targets. Most importantly, both the cell line-derived xenograft (CDX) and the patient-derived xenograft (PDX) mouse model are used to determine the effect of 3-HAA on sorafenib-resistant HCC in vivo. Results: In nude mice carrying HCC xenograft, tumor growth is inhibited by sorafenib or 3-HAA alone. When used in combination, the treatment particularly prevents the xenograft from growing. Combined treatment also suppresses the growth of sorafenib-resistant (≥30mg/kg) PDXs. In a set of mechanistic experiments, we find enhanced AKT activation and decreased apoptotic cells in de novo and acquired sorafenib-resistant HCC cells and tissues. 3-HAA decreases AKT phosphorylation and increases the apoptosis of HCC in both cultured cells and mouse xenografts by upregulation of phosphatases PPP1R15A/DUSP6. PPP1R15A/PPP1α directly reduces Akt phosphorylation while DUSP6 decreases Akt activity through inhibiting PDK1. The AKT activator abolishes 3-HAA inhibition of HCC growth in vitro and in mice. Conclusion: This study demonstrates that 3-HAA sensitizes HCC cells to sorafenib by upregulation of phosphatases, suggesting it as a promising molecule for HCC therapy.

To evaluate the validity of CHAC1 for predicting the prognosis of kidney renal clear cell carcinoma (KIRC) and to explore its therapeutic potential for KIRC, we conducted several bioinformatic analyses using the sequencing data and clinical information derived from online databases. We found CHAC1 is down‐regulated in KIRC samples when compared with normal samples but up‐regulated in KIRC samples with relatively higher malignancy and later stages. Univariate cox analysis and multivariate cox regression analysis were conducted and the results revealed up‐regulated CHAC1 is an independent risk factor for poor prognosis of KIRC. Further, the nomogram model based on the result of multivariate cox regression analysis was constructed and effectively predicted patients' 1‐year, 3‐year and 5‐year survival respectively. The correlation analyses showed CHAC1 is associated with the immune pathway markers of memory B cell, natural killer cell and type1 T helper cell as well as the checkpoint genes like ADORA2A, CD200, CD44, CD70, HHLA2, NRP1, PDCD1LG2 and TNFRSF18. Furthermore, experiments in vitro indicated CHAC1 could induce cell death in KIRC cell lines but had limited influence on cell migration and cell invasion. In conclusion, CHAC1 is found a valid indicator for poor prognosis of kidney renal clear cell carcinoma.

Background Insect body coloration often functions as camouflage to survive from predators or mate selection. Transportation of pigment precursors or related metabolites from cytoplasm to subcellular pigment granules is one of the key steps in insect pigmentation and usually executed via such transporter proteins as the ATP-binding cassette (ABC) transmembrane transporters and small G-proteins (e.g. Rab protein). However, little is known about the copy numbers of pigment transporter genes in the butterfly genomes and about the roles of pigment transporters in the development of swallowtail butterflies. Results Here, we have identified 56 ABC transporters and 58 Rab members in the genome of swallowtail butterfly Papilio xuthus. This is the first case of genome-wide gene copy number identification of ABC transporters in swallowtail butterflies and Rab family in lepidopteran insects. Aiming to investigate the contribution of the five genes which are orthologous to well-studied pigment transporters (ABCG: white, scarlet, brown and ok; Rab: lightoid) of fruit fly or silkworm during the development of swallowtail butterflies, we performed CRISPR/Cas9 gene-editing of these genes using P. xuthus as a model and sequenced the transcriptomes of their morphological mutants. Our results indicate that the disruption of each gene produced mutated phenotypes in the colors of larvae (cuticle, testis) and/or adult eyes in G0 individuals but have no effect on wing color. The transcriptomic data demonstrated that mutations induced by CRISPR/Cas9 can lead to the accumulation of abnormal transcripts and the decrease or dosage compensation of normal transcripts at gene expression level. Comparative transcriptomes revealed 606 ~ 772 differentially expressed genes (DEGs) in the mutants of four ABCG transporters and 1443 DEGs in the mutants of lightoid. GO and KEGG enrichment analysis showed that DEGs in ABCG transporter mutants enriched to the oxidoreductase activity, heme binding, iron ion binding process possibly related to the color display, and DEGs in lightoid mutants are enriched in glycoprotein binding and protein kinases. Conclusions Our data indicated these transporter proteins play an important role in body color of P. xuthus. Our study provides new insights into the function of ABC transporters and small G-proteins in the morphological development of butterflies.

Cytosolic inflammasomes are supramolecular complexes that are formed in response to intracellular pathogens and danger signals. However, as to date, the detailed description of a homotypic caspase recruitment domain (CARD) interaction between NLRP1 and ASC has not been presented. We found the CARD–CARD interaction between purified NLRP1CARD and ASCCARD experimentally and the filamentous supramolecular complex formation in an in vitro proteins solution. Moreover, we determined a high-resolution crystal structure of the death domain fold of the human ASCCARD. Mutational and structural analysis revealed three conserved interfaces of the death domain superfamily (Type I, II, and III), which mediate the assembly of the NLRP1CARD/ASCCARD complex. In addition, we validated the role of the three major interfaces of CARDs in assembly and activation of NLRP1 inflammasome in vitro. Our findings suggest a Mosaic model of homotypic CARD interactions for the activation of NLRP1 inflammasome. The Mosaic model provides insights into the mechanisms of inflammasome assembly and signal transduction amplification.

Dual oxidases (DUOXs) produce hydrogen peroxide by transferring electrons from intracellular NADPH to extracellular oxygen. They are involved in many crucial biological processes and human diseases, especially in thyroid diseases. DUOXs are protein complexes co-assembled from the catalytic DUOX subunits and the auxiliary DUOXA subunits and their activities are regulated by intracellular calcium concentrations. Here, we report the cryo-EM structures of human DUOX1-DUOXA1 complex in both high-calcium and low-calcium states. These structures reveal the DUOX1 complex is a symmetric 2:2 hetero-tetramer stabilized by extensive inter-subunit interactions. Substrate NADPH and cofactor FAD are sandwiched between transmembrane domain and the cytosolic dehydrogenase domain of DUOX. In the presence of calcium ions, intracellular EF-hand modules might enhance the catalytic activity of DUOX by stabilizing the dehydrogenase domain in a conformation that allows electron transfer., Dual oxidases (DUOXs), assembled from the catalytic DUOX and the auxiliary DUOXA subunits, produce hydrogen peroxide by transferring electrons from intracellular NADPH to extracellular oxygen in a calcium-activated manner. Here authors report the cryo-EM structures of human DUOX1-DUOXA1 complex in both high-calcium and low-calcium states.

The objective of this study was to investigate the effects of agar oligosaccharide-iron (AOS-iron) on intestinal tissue pathology and microbiota in IDA rats induced by a low-iron diet, further to find the relationship between intestinal microbiota and iron metabolic disorders. After 4 weeks of AOS-iron supplementation, the fecal iron content of IDA rats markedly increased in a dose-dependent manner, only the damaged cecum and colon tissues in medium-dose (MD) and high-dose (HD) groups were repaired to the baseline, while the diversity of gut microbiota was improved even at low dose (LD). Furthermore, the supplementation of AOS-iron altered the composition of gut microbiota. At the genus level, the beneficial microbiota was enriched in AOS-iron groups, but the relative abundance of potential opportunistic pathogens obviously reduced compared to that in the anemia model (AM) group. Spearman’s correlation analysis revealed that biochemical parameters, including blood metabolic parameters, iron contents, body weight, GSH-PX and T-AOC activity, were positively correlated with SMB53, Anaerotruncus, Anaerostipes and Coprobacillus but negatively correlated with Morganella, Fusobacterium and Serratia. These findings indicated that AOS-iron effectively repaired the damaged intestinal tissue and ameliorated iron metabolic disorders by regulating gut microbiota desirably, which could provide references for the treatment of IDA.

Aims The study aimed to determine whether the microRNA miR21-5p (MiR21) mediates temporomandibular joint osteoarthritis (TMJ-OA) by targeting growth differentiation factor 5 (Gdf5). Methods TMJ-OA was induced in MiR21 knockout (KO) mice and wild-type (WT) mice by a unilateral anterior crossbite (UAC) procedure. Mouse tissues exhibited histopathological changes, as assessed by: Safranin O, toluidine blue, and immunohistochemistry staining; western blotting (WB); and quantitative real-time polymerase chain reaction (RT-qPCR). Mouse condylar chondrocytes were transfected with a series of MiR21 mimic, MiR21 inhibitor, Gdf5 siRNA (si-GDF5), and flag-GDF5 constructs. The effects of MiR-21 and Gdf5 on the expression of OA related molecules were evaluated by immunofluorescence, alcian blue staining, WB, and RT-qPCR. Results UAC altered the histological structure and extracellular matrix content of cartilage in the temporomandibular joint (TMJ), and KO of MiR21 alleviated this effect (p < 0.05). Upregulation of MiR21 influenced the expression of TMJ-OA related molecules in mandibular condylar chondrocytes via targeting Gdf5 (p < 0.05). Gdf5 overexpression significantly decreased matrix metalloproteinase 13 (MMP13) expression (p < 0.05) and reversed the effects of MiR21 (p < 0.05). Conclusion MiR21, which acts as a critical regulator of Gdf5 in chondrocytes, regulates TMJ-OA related molecules and is involved in cartilage matrix degradation, contributing to the progression of TMJ-OA. Cite this article: Bone Joint Res 2020;9(10):689–700.

Epithelial‑mesenchymal transition (EMT), during which cancer cells lose the epithelial phenotype and gain the mesenchymal phenotype, has been verified to result in tumor migration and invasion. Numerous studies have shown that dysregulation of the Wnt/β‑catenin signaling pathway gives rise to EMT, which is characterized by nuclear translocation of β‑catenin and E‑cadherin suppression. Wnt/β‑catenin signaling was confirmed to be affected by microRNAs (miRNAs), several of which are down‑ or upregulated in metastatic cancer cells, indicating their complex roles in Wnt/β‑catenin signaling. In this review, we demonstrated the targets of various miRNAs in altering Wnt/β‑catenin signaling to promote or inhibit EMT, which may elucidate the underlying mechanism of EMT regulation by miRNAs and provide evidence for potential therapeutic targets in the treatment of invasive tumors.

Wet age-related macular degeneration (AMD), which can cause progressive blindness, is characterised by choroid neovascularization (CNV) in the macular area. Although close attention has been paid to AMD, and anti-vascular endothelial growth factor (VEGF) drugs are available, its complex pathogenesis is still elusive. Tie2-expressing macrophages (TEMs) have been found to promote angiogenesis in remodel tissues and tumours. This study aimed to elucidate the role of macrophage Tie2 signalling in laser-induced CNV (LCNV). We observed that TEMs were responsible for the severity of CNV. Mechanistically, TEM deletion resulted in impaired LCNV due to the suppression of inflammatory angiogenesis and the promotion of apoptosis. We also observed that TEMs prevented apoptosis of b.End3 cells, but promoted their migration, proliferation and tube formation via VEGF, extracellular signal-regulated kinase (ERK) and v-akt murine thymoma viral oncogene (AKT)-dependent signalling pathways. The flow cytometry results comparing dry AMD patients and healthy controls with wet AMD patients showed that the percentage of Tie2+CD14+ cells was higher in the wet AMD patients’ peripheral blood. This study demonstrates that Tie2 expression by macrophages intensifies CNV in LCNV murine models, thereby proposing an additional intervention option to inhibit CNV.

Increased expression of the kinesin family member 23 (KIF23) has been verified in gastric cancer (GC) and its upregulation contributes to cell proliferation. Even though, the role of KIF23 has not been fully elucidated in GC, and the mechanisms of KIF23 as an oncogene remain unknown. To further identify its potential role in GC, we analyzed gene expression data from GC patients in GEO and TCGA datasets. KIF23 was upregulated in GC, and increased expression of KIF23 correlated with poor prognosis. Importantly, KIF23 inhibition not only suppressed GC cell proliferation, tumorigenesis, but also migration and invasion, and arrested the cell cycle in the G2/M phase. Mechanistic investigations confirmed that KIF23 activated the Wnt/β-catenin signaling pathway by directly interacting with APC membrane recruitment 1 (Amer1). Furthermore, KIF23 exhibited competitive binding with Amer1 to block the association of Amer1 with adenomatous polyposis coli (APC), thus relocating Amer1 from the membrane and cytoplasm to the nucleus and attenuating the ability of Amer1 to negatively regulate Wnt/β-catenin signaling, resulting in activation of this signaling pathway. Collectively, our findings demonstrated that KIF23 promoted GC cell proliferation by directly interacting with Amer1 and activating the Wnt/β-catenin signaling pathway.

BackgroundCyanobacterial carbohydrates, such as sucrose, have been considered as potential renewable feedstock to support the production of fuels and chemicals. However, the separation and purification processes of these carbohydrates will increase the production cost of chemicals. Co-culture fermentation has been proposed as an efficient and economical way to utilize these cyanobacterial carbohydrates. However, studies on the application of co-culture systems to achieve green biosynthesis of platform chemicals are still rare.ResultsIn this study, we successfully achieved one-step conversion of sucrose derived from cyanobacteria to fine chemicals by constructing a microbial consortium consisting of the fast-growing cyanobacteriumSynechococcus elongatusUTEX 2973 andEscherichia colito sequentially produce sucrose and then the platform chemical 3-hydroxypropionic acid (3-HP) from CO2under photoautotrophic growth conditions. First, efforts were made to overexpress the sucrose permease-coding genecscBunder the strong promoterPcpc560inS. elongatusUTEX 2973 for efficient sucrose secretion. Second, the sucrose catabolic pathway and malonyl-CoA-dependent 3-HP biosynthetic pathway were introduced intoE. coliBL21 (DE3) for heterologous biosynthesis of 3-HP from sucrose. By optimizing the cultivation temperature from 37 to 30 °C, a stable artificial consortium system was constructed with the capability of producing 3-HP at up to 68.29 mg/L directly from CO2. In addition, cell growth ofS. elongatusUTEX 2973 in the consortium was enhanced, probably due to the quick quenching of reactive oxygen species (ROS) in the system byE. coli, which in turn improved the photosynthesis of cyanobacteria.ConclusionThe study demonstrated the feasibility of the one-step conversion of sucrose to fine chemicals using an artificial consortium system. The study also confirmed that heterotrophic bacteria could promote the cell growth of cyanobacteria by relieving oxidative stress in this microbial consortium, which further suggests the potential value of this system for future industrial applications.

BackgroundRecent studies suggest that there is a link between the gut microbiota and glucose metabolism. This study aimed to compare the gut microbiota during early pregnancy of women with hyperglycymia to those with normal blood glucose.MethodsGut microbial composition was analysed in 22 women with hyperglycaemia and 28 age-matched healthy controls during their first prenatal visits (ResultsWomen with hyperglycemia in pregnancy (HIP) had significantly lower microbial richness and diversity compared with healthy pregnant women. The proportions of theFirmicutesandBacteroidetesphyla and the ratio ofFirmicutes:Bacteroideteswere not different between the two groups. We observed that individuals with HIP had an increased abundance ofNocardiaceae,Fusobacteriaceae, etc., whereas healthy controls had significantly higher levels ofChristensenellaceae,Clostridiales_vadinBB60_group,Coriobacteriaceae, etc. Similarly, levels of the members of theRuminococcaceaefamily,includingRuminococcaceae_UCG-014,Ruminococcaceae_UCG-003, andRuminococcaceae_UCG-002,were significantly reduced in the HIP group and were negatively correlated with HbA1c. HbA1c levels were positively correlated withBacteroidaceaeandEnterobacteriaceaeand negatively correlated withChristensenellaceae, etc. CRP was positively correlated with theBacteroidaceaeandFusobacteriaceaefamilies and theFusobacteriumgenus.ConclusionsOur study revealed that individuals with HIP have gut microbial dysbiosis and that certain bacterial groups are associated with glucose metabolism during pregnancy. Further study is needed to provide new ideas to control glucose by modifying the gut microbiota.

Background Shanzhuyu (the dried mature sarcocarp of Cornus officinalis Sieb. et Zucc., DMSCO) is a Chinese herb that can be used for the treatment of Alzheimer’s disease (AD), but its mechanism remains unknown. The present study aimed to investigate the active ingredients and effective mechanisms of DMSCO for the treatment of AD based on a network pharmacology approach. Methods The active components of DMSCO were collected from the TCMSP and ETCM databases and the target proteins of these compounds were predicted using TCMSP, SwissTargetPrediction and the STITCH database. The AD-related target proteins were identified from the OMIM, DisGeNet, GEO and GeneCards databases. The network interaction model of the compound-target-disease was established and was used to obtain the key targets of DMSCO on AD through network topology analysis. Subsequently, gene enrichment in Gene Ontology (GO) and KEGG pathways were conducted using the David 6.8 online tool. Results A total of 30 DMSCO effective compounds and 209 effective drug targets were obtained. A total of 172 AD-related genes and 37 shared targets of DMSCO and AD were identified. A total of 43 key targets for the treatment of AD were obtained from the topological analysis of the DMSCO-AD target network. These key targets were involved in a variety of biological processes, including amyloid deposition, apoptosis, autophagy, inflammatory response and oxidative stress and pathways, such as the PI3K-AKT, MAPK and TNF pathways. Three key compounds, namely ursolic acid, anethole and β-sitosterol were obtained from the analysis of the key targets. Conclusions Ursolic acid, anethole and β-sitosterol may be the main active components of DMSCO in the treatment of AD. DMSCO can treat AD by regulating amyloid deposition, apoptosis, autophagy, inflammatory response and oxidative stress via the PI3K-AKT, MAPK and other signaling pathways.

Antioxidant metabolites contribute to alleviating oxidative stress caused by reactive oxygen species (ROS) in microorganisms. We utilized oxidative stressors such as hydrogen peroxide supplementation to increase the yield of the bioactive secondary metabolite antioxidant antrodin C in submerged fermentations of the medicinal mushroom Antrodia cinnamomea. Changes in the superoxide dismutase and catalase activities of the cells indicate that ROS are critical to promote antrodin C biosynthesis, while the ROS production inhibitor diphenyleneiodonium cancels the productivity-enhancing effects of H2O2. Transcriptomic analysis suggests that key enzymes in the mitochondrial electron transport chain are repressed during oxidative stress, leading to ROS accumulation and triggering the biosynthesis of antioxidants such as antrodin C. Accordingly, rotenone, an inhibitor of the electron transport chain complex I, mimics the antrodin C productivity-enhancing effects of H2O2. Delineating the steps connecting oxidative stress with increased antrodin C biosynthesis will facilitate the fine-tuning of strategies for rational fermentation process improvement.

Background Docosahexaenoic acid (DHA) is essential for human diet. However, high production cost of DHA using C. cohnii makes it currently less competitive commercially, which is mainly caused by low DHA productivity. In recent years, repeated fed-batch strategies have been evaluated for increasing the production of many fermentation products. The reduction in terms of stability of culture system was one of the major challenges for repeated fed-batch fermentation. However, the possible mechanisms responsible for the decreased stability of the culture system in the repeated fed-batch fermentation are so far less investigated, restricting the efforts to further improve the productivity. In this study, a repeated fed-batch strategy for DHA production using C. cohnii M-1-2 was evaluated to improve DHA productivity and reduce production cost, and then the underlying mechanisms related to the gradually decreased stability of the culture system in repeated fed-batch culture were explored through LC– and GC–MS metabolomic analyses. Results It was discovered that glucose concentration at 15–27 g/L and 80% medium replacement ratio were suitable for the growth of C. cohnii M-1-2 during the repeated fed-batch culture. A four-cycle repeated fed-batch culture was successfully developed and assessed at the optimum cultivation parameters, resulting in increasing the total DHA productivity by 26.28% compared with the highest DHA productivity of 57.08 mg/L/h reported using C. cohnii, including the time required for preparing seed culture and fermentor. In addition, LC– and GC–MS metabolomics analyses showed that the gradually decreased nitrogen utilization capacity, and down-regulated glycolysis and TCA cycle were correlated with the decreased stability of the culture system during the long-time repeated fed-batch culture. At last, some biomarkers, such as Pyr, Cit, OXA, FUM, l-tryptophan, l-threonine, l-leucine, serotonin, and 4-guanidinobutyric acid, correlated with the stability of culture system of C. cohnii M-1-2 were identified. Conclusions The study proved that repeated fed-batch cultivation was an efficient and energy-saving strategy for industrial production of DHA using C. cohnii, which could also be useful for cultivation of other microbes to improve productivity and reduce production cost. In addition, the mechanisms study at metabolite level can also be useful to further optimize production processes for C. cohnii and other microbes.

Prostate cancer is the fifth leading cause of cancer‐related deaths in males globally. Tripartite Motif Containing 66 (TRIM66) functions as transcriptional repressor and exerts its effect at least partially through promotion of deacetylase. TRIM66 has been previously reported to play an oncogenic role in a number of human cancers. Here, we investigated the potential oncogenic properties of TRIM66 in prostate cancer. We report that shRNA‐mediated knockdown of TRIM66 significantly suppressed viability and proliferation of both PC‐3 and DU145 prostate cancer cell lines. Furthermore, TRIM66 deficiency inhibited migration and invasion of prostate cancer cells. Mechanistically, TRIM66 positively regulated signal transducer and activator of transcription 2 (STAT2) and interleukin‐2 (IL‐2) expression. The predominance of STAT2–IL‐2 in mediating the oncogenic properties of TRIM66 was determined using a rescue assay, wherein overexpression of either STAT2 or IL‐2 almost completely abolished the inhibitory effects on cell proliferation, migration and invasion elicited by TRIM66 deficiency in prostate cancer cells. Our study highlights the importance of the TRIM66–STAT2–IL‐2 signaling axis in the tumor biology of prostate cancer., Tripartite Motif Containing 66 (TRIM66) knockdown suppressed viability and proliferation of prostate cancer cell lines. TRIM66 deficiency inhibited migration and invasion of prostate cancer cells. TRIM66 positively regulated signal transducer and activator of transcription 2 and interleukin‐2 expression. Our study highlights the importance of the TRIM66–signal transducer and activator of transcription 2–interleukin‐2 signaling axis in the tumor biology of prostate cancer.

Natural products were extracted from traditional Chinese herbal emerging as potential therapeutic drugs for treating cardiovascular diseases. This study examines the role and underlying mechanism of dihydromyricetin (DMY), a natural compound extracted from Ampelopsis grossedentata, in atherosclerosis. DMY treatment significantly inhibits atherosclerotic lesion formation, proinflammatory gene expression and the influx of lesional macrophages and CD4‐positive T cells in the vessel wall and hepatic inflammation, whereas increases nitric oxide (NO) production and improves lipid metabolism in apolipoprotein E‐deficient (Apoe− / −) mice. Yet, those protective effects are abrogated by using NOS inhibitor L‐NAME in Apoe− / − mice received DMY. Mechanistically, DMY decreases microRNA‐21 (miR‐21) and increases its target gene dimethylarginine dimethylaminohydrolase‐1 (DDAH1) expression, an effect that reduces asymmetric aimethlarginine (ADMA) levels, and increases endothelial NO synthase (eNOS) phosphorylation and NO production in cultured HUVECs, vascular endothelium of atherosclerotic lesions and liver. In contrast, systemic delivery of miR‐21 in Apoe− / − mice or miR‐21 overexpression in cultured HUVECs abrogates those DMY‐mediated protective effects. These data demonstrate that endothelial miR‐21‐inhibited DDAH1‐ADMA‐eNOS‐NO pathway promotes the pathogenesis of atherosclerosis which can be rescued by DMY. Thus, DMY may represent a potential therapeutic adjuvant in atherosclerosis management.

Matrix Gla protein (MGP) has been widely reported as an extracellular matrix protein with abnormal expression in various types of cancer. However, the function of intracellular MGP in gastric cancer (GC) cells remains largely unknown. Here, we demonstrated aberrantly high expression of intracellular MGP in GC as compared to adjacent normal tissues by immunohistochemistry. Moreover, The Cancer Genome Atlas (TCGA) dataset analysis suggested a positive correlation between MGP overexpression and unfavorable prognosis. MGP silencing reduced cell proliferation, migration, invasion, and survival in GC cell lines. Gene set enrichment analysis of TCGA dataset indicated significant enrichment of the IL2–STAT5 signaling in MGP‐high GC patients. Immunofluorescence staining and immunoprecipitation showed that MGP binds to p‐STAT5 in the nuclei of GC cells. Furthermore, ChIP‐qPCR and luciferase reporter assays indicated that MGP acts as a transcriptional co‐activator through the enhancement of STAT5 binding to target gene promoters. Use of STAT5 inhibitor revealed that the oncogenic functions of intracellular MGP mainly depend on the JAK2/STAT5 signaling pathway. Taken together, our results indicate that intracellular MGP promotes proliferation and survival of GC cells by acting as a transcriptional co‐activator of STAT5. The detected aberrant, high MGP expression in GC tissues highlights MGP as a potential new prognostic biomarker in patients with GC., Matrix Gla protein is a novel transcriptional co‐activator of STAT5 by interacting with phospho‐STAT5 in the nuclei, which facilitates STAT5 binding to target gene promoters and subsequently promotes gastric cancer cell proliferation, migration, invasion and survival.

Background Obesity is a severe public health threat worldwide. Emerging evidence suggests that gut microbiota dysbiosis is closely associated with obesity and its related metabolic complications. The aim of the present study is to investigate the effects of polysaccharide extracted from WuGuChong (PEW) on high-fat diet (HFD)-induced obesity, and the potential mechanisms involving modulation of the gut microbiota composition. Methods Mice were fed a normal chow diet and a high-fat diet with or without PEW (300 mg/kg/day) by oral gavage for 8 weeks. Body weight, obesity-related metabolic disorders, and gut microbiota were examined at the end of the experiment. Results PEW supplementation reduces body weight, adipose hypertrophy, liver steatosis, insulin resistance and systemic inflammation in HFD-fed mice, as well as maintains intestinal epithelium integrity. High-throughput 16S rRNA analysis demonstrates that PEW supplementation alters the composition of gut microbiota. The Firmicutes to Bacteroidetes ratio and the relative abundance of Proteobacteria are increased in HFD-fed mice, which are reversed by PEW supplementation to approximately the control levels. Conclusions Our results suggest that PEW may be used as a bioactive ingredient to prevent obesity and its related metabolic disorders by modulating the composition of gut microbiota.

Long non-coding RNA gastric cancer associated transcript 3 (GACAT3), is a newly identified non-coding RNA, which has been found to be involved in the tumorigenesis of gastric cancer. However, the biological function of GACAT3 in liver cancer remains unclear. The present study aimed to determine the expression level and function of GACAT3 in liver cancer. The authors cultured liver cancer cells in vitro and GACAT3 was silenced in the cells. Cell proliferation, apoptosis and migration were determined by MTT assay, flow cytometric analysis and transwell assay, respectively. It was demonstrated that GACAT3 was upregulated in liver cancer tissues. The inhibition of GACAT3 decreased the ability of hepatoma cells to proliferate and migrate, and increased apoptosis of the cells. These findings provide the first evidence, to the best of our knowledge, of the exact role of GACAT3 in liver cancer, suggesting GACAT3 as a potential target for liver cancer therapy in the future.

Agaricus blazei Murrill (ABM) is an edible fungus. This study investigated the protective role of ABM fruiting body against streptozotocin (STZ)‐induced diabetic rats. After 4 weeks of ABM supplement, glucose homeostasis was improved in diabetic rats. Quantitative real‐time and Western blot analyses suggested that ABM could promote the gene and protein expression level of insulin receptor, pyruvate dehydrogenase kinase, phospho‐kinase B, kinase B, phosphatidylinositol 3‐kinase, insulin receptor substrate 1, glucose transporter‐4, and glutamine synthetase, while inhibiting the expression of glycogen synthase kinase 3β and c‐jun N‐terminal kinase 1 and 2. According to multivariate and univariate statistical analysis, liver metabolite profiles of the normal and diabetic rats fed basal and experimental diet were clearly separated. The differential liver metabolites from diabetic rats fed basal and ABM diet‐related pathways including the glycolysis pathway, pentose phosphate pathway, tricarboxylic acid cycle, and oxidative phosphorylation were analyzed. A total of 18 potential biomarker metabolites were identified as differential biomarkers associated with ABM supplement diet., Intake of Agaricus blazei Murrill (ABM) modulated characteristics of diabetic rats. ABM reduced elevated blood glucose and improved hepatic function. ABM plays an important role in ameliorating glucose homeostasis.

Graphical abstract, Single-cell genomics has advanced rapidly as trace-DNA amplification technologies evolved. However, current technologies are subject to a variety of pitfalls such as contamination, uneven genomic coverage, and amplification errors. Even for the “golden” strategy of single stem cell-derived clonal formation, high-fidelity amplification is applicable merely to single stem cells. It’s still challenging to accurately define somatic mutations of a single cell in various cell types. Herein, we provided evidence, for the first time, to prove that induced pluripotent stem cells (iPS cells or iPSC), being a single somatic cell-derived clone, are recording almost identical (>90%) mutational profile of the initial cell progenitor. This finding demonstrates iPS technique, applicable to any cell type, can be utilized as a cell cloning strategy favorable for single-cell genomic amplification. This novel strategy is not limited by cell-type constraints or amplification artifacts, and thus enables our detailed investigation on the characteristics of somatic mutations in heterogeneous normal cells.

Postoperative delirium (POD) is a common complication following surgery and anesthesia (Surgery/Anesthesia). Mitochondrial dysfunction, which is demonstrated by energy deficits and excessively activated oxidative stress, has been reported to contribute to POD. The dynamic balance between mitochondrial fusion and fission processes is critical in regulating mitochondrial function. However, the impact of Surgery/Anesthesia on mitochondrial fusion/fission dynamics remains unclear. Here, we evaluate the effects of laparotomy under 1.4% isoflurane anesthesia for 2 hours on mitochondrial fission/fusion dynamics in the brain of aged mice. Mice in Surgery/Anesthesia group showed unbalanced fission/fusion dynamics, with decreased DISC1 expression and increased expression of Drp1 and Mfn2 in the mitochondrial fraction, leading to excessive mitochondrial fission and disturbed mitochondrial morphogenesis in the hippocampus and prefrontal cortex. In addition, surgical mice presented mitochondrial dysfunction, demonstrated by abnormally activated oxidative stress (increased ROS level, decreased SOD level) and energy deficits (decreased levels of ATP and MMP). Surgery/Anesthesia also decreased the expression of neuronal/synaptic plasticity-related proteins such as PSD-95 and BDNF. Furthermore, Surgery/Anesthesia induced delirium-like behavior in aged mice. In conclusion, Surgery/Anesthesia disturbed mitochondrial fission/fusion dynamics and then impaired mitochondrial function in the brain of aged mice; these effects may be involved in the underlying mechanism of POD.

Ruminants (Ruminantia) are among the most successful herbivorous mammals, exhibiting wide-ranging morphological and ecological characteristics (such as headgear and multichambered stomach) and including various key livestock species (e.g., cattle, buffalo, yak, sheep, and goat). Understanding their evolution is of great significance not only in scientific research but also in applications potential for human society. The rapid growth of genomic resources provides unprecedented opportunities to dissect the evolutionary histories and molecular mechanisms underlying the distinct characteristics of ruminants. Here we summarize our current understanding of the genetic, morphological, and ecological diversity of ruminants and provide prospects for future studies.

Autism spectrum disorder (ASD) is a heterogeneous group of complex neurodevelopmental disorders without a unique or definite underlying pathogenesis. Although savant syndrome is common in ASD, few models are available for studying the molecular and cellular mechanisms of this syndrome. In this study, we generated urinary induced pluripotent stem cells (UiPSCs) from a 13-year-old male autistic savant with exceptional memory. The UiPSC-derived neurons of the autistic savant exhibited upregulated expression levels of ASD genes/learning difficulty-related genes, namely PAX6, TBR1 and FOXP2, accompanied by hypertrophic neural somas, enlarged spines, reduced spine density, and an increased frequency of spontaneous excitatory postsynaptic currents. Although this study involved only a single patient and a single control because of the rarity of such cases, it provides the first autistic savant UiPSC model that elucidates the potential cellular mechanisms underlying the condition.

Objective: The QingYu pig is well known for its excellent meat quality attributes in Sichuan province, China. In order to improve its production efficiency, the determination of genetic factors contributing to quantifiable economic traits of livestock is important. Moreover, the cross-breeding of QingYu pigs with western breeds possessing strong growth attributes is an efficient way to improve the performance of this breed.Methods: Here, the genetic parameters of several important reproductive traits of QingYu pigs were estimated, include total number born (TNB), number born alive, litter birth weight, individual birth weight, number of piglets weaned, litter weaning weight, and individual weaning weight. The data was analyzed using the ASReml 3.0 software (NSW Inc., Sydney, Australia). Furthermore, the effects of crossing Berkshire with QingYu (BQ) pigs on carcass and meat quality traits, as well as the effects of slaughter weight on carcass and meat quality of BQ were characterized.Results: QingYu pigs exhibited superior reproductive traits. The TNB available to QingYu pigs was more than 8 per parity. The observed repeatability of the reproductive traits of the QingYu pigs was between 0.10 and 0.23. The significantly correlated genetic and phenotypic of reproduction traits were consistent. Interestingly, the BQ pigs exhibited improved carcass quality, with a significant increase in loin muscle area, lean percentage and reduction in sebum percentage. As a result, BQ had higher L45min, lower cooking scores, and lower drip loss. In addition, the loin muscle area, body length, and sebum percentage were significantly higher in 90 and 100 kg animals. Cooking loss showed a significant increase at 80 kg, and marbling increased significantly from 90 kg.Conclusion: The results of this study suggest that QingYu pigs exhibit excellent reproductive properties and heritability of these traits. Crossing with Berkshire is an efficient strategy to improve the carcass and meat quality of QingYu pigs for commercial operations. Furthermore, it appears as though the optimal slaughter weight of BQ pigs is at approximately 90 kg.

Waxy rice is one of the most popular traditional crops served as a staple food in China. In this study, the effect of different factors including α-amylase activity, protein, and amylopectin structure on the pasting properties of four waxy rice varieties were investigated. Rice flours treated with AgNO3 solution, DL-dithiothreitol (DTT) or protease, suggested that both α-amylase activity and protein significantly decrease the pasting viscosity of waxy rice flours. Chain length distribution of amylopectin as measured by high performance ion exchange chromatography (HPAEC-PAD) showed that starch with higher ratio of short chain leading to a higher pasting viscosity. X-Ray diffractograms showed that the crystal type of all the four varieties of rice starches were characteristic A-type. Relative crystallinity of each rice starch was further calculated, and a higher crystallization resulted in a higher viscosity. Our study would provide a fundamental knowledge of the relationship between different factors and waxy starch pasting properties, as well as be a reference for controlling the quality of waxy rice starch-based food.

Rice (Oryza sativa L.) is an important staple food crop for more than half of the world’s population. Enhancing the grain quality and yield of rice to meet growing demand remains a major challenge. Here, we show that OsMKK3 encode a MAP kinase kinase that controls grain size and chalkiness by affecting cell proliferation in spikelet hulls. We showed that OsSPL16, GS5, and GIF1 have a substantial effect on the OsMKK3-regulated grain size pathway. OsMKK3 has experienced strong directional selection in indica and japonica. Wild rice accessions contained four OsMKK3 haplotypes, suggesting that the OsMKK3 haplotypes present in cultivated rice likely originated from different wild rice accessions during rice domestication. OsMKK3-Hap1, gs3, and gw8 were polymerized to enhance the grain length. Polymerization of beneficial alleles, such as OsMKK3-Hap1, gs3, gw8, fgr, alk, chalk5, and wx, also improved the quality of hybrid rice. Overall, the results indicated that beneficial OsMKK3 alleles could be used for genomic-assisted breeding for rice cultivar improvement and be polymerized with other beneficial alleles.

Ulcerative colitis (UC) is considered an immune disease, which is related to the dysbiosis of intestinal microbiota and disorders of the host immune system and metabolism. Sophora flavescens Aiton has been used for the clinical treatment of UC in China and East Asia for thousands of years. It has many traditional prescriptions and modern preparations, and its curative effects are definite. We are the first to report that the flavonoids in Sophora flavescens (S. flavescens) Aiton EtOAc extract (SFE) could potentially attenuate the dextran sodium sulfate–induced UC in mice, which changed the current understanding of considering alkaloids as the only anti-UC pharmacological substances of S. flavescens Aiton. Based on the 16S rRNA gene sequencing and metabolomic analysis, it was found that the anti-UC effects of SFE were due to the regulation of gut microbiota, reversing the abnormal metabolisms, and regulation of the short-chain fatty acids synthesis. Notably, according to the interaction networks of specific bacteria and “bacteria and metabolites” co-expression network, the SFE could enrich the abundance of the commensal bacterium Lactobacillus, Roseburia, norank_f__Muribaculaceae, Anaerotruncus, Candidatus_Saccharimona, and Parasutterella, which are proposed as potentially beneficial bacteria, thereby playing vital roles in the treatment of UC.

Pseudorabies virus is a typical swine alphaherpesvirus, which can cause obvious neurological disorders and reproductive failure in pigs. It is capable of evading host antiviral immune response. However, the mechanism by which many PRV proteins assist the virus to evade innate immunity is not fully understood. This study identified PRV US3 protein as a crucial antagonistic viral factor that represses interferon beta (IFN-β) expression. A in-depth study showed that US3 protein restricted type I IFN production by targeting interferon regulatory factor 3 (IRF3), a key molecule required for type I IFN induction. Additionally, US3 protein interacted with IRF3, degraded its protein expression to block the phosphorylation of IRF3. These findings suggested a novel strategy utilized by PRV to inhibit IFN-β production and escape the host innate immunity.

BACKGROUND: Several SARS-CoV-2 lineages with spike receptor binding domain (RBD) N501Y mutation have spread globally. We evaluated the impact of N501Y on neutralizing activity of COVID-19 convalescent sera and on anti-RBD IgG assays. METHODS: The susceptibility to neutralization by COVID-19 patients' convalescent sera from Hong Kong were compared between two SARS-CoV-2 isolates (B117-1/B117-2) from the α variant with N501Y and 4 non-N501Y isolates. The effect of N501Y on antibody binding was assessed. The performance of commercially-available IgG assays was determined for patients infected with N501Y variants. FINDINGS: The microneutralization antibody (MN) titers of convalescent sera from 9 recovered COVID-19 patients against B117-1 (geometric mean titer[GMT],80; 95% CI, 47-136) were similar to those against the non-N501Y viruses. However, MN titer of these serum against B117-2 (GMT, 20; 95% CI, 11-36) was statistically significantly reduced when compared with non-N501Y viruses (P

Exportins as the key mediators of nucleocytoplasmic transport have been identified as the controllers of the passage of numerous types of crucial cancer-related proteins. Targeting exportins in cancer cells might represent an emerging strategy in cancer intervention with the potential to affect clinical outcomes. Here, we focused on the prognostic and therapeutic values of Exportin-T (XPOT) in neuroblastoma. The correlation between the expression and prognostic values of XPOT in patients with neuroblastoma was investigated based on both published transcriptome data and our clinical data. Then, decision curve analysis (DCA) was implemented to identify a XPOT risk prediction model. In addition, RNA inference was performed to silence the expression of XPOT to further investigate the specific roles of XPOT in the progression of neuroblastoma in vitro. Overexpression of XPOT mRNA was associated with poor clinical characteristics, such as age at diagnosis more than 18 months, amplification of MYCN, and advanced International Neuroblastoma Staging System (INSS) stage, and XPOT expression was identified as an independent poor prognosis factor for neuroblastoma using Cox proportional hazards model ( P

Postoperative neurocognitive disorders (po-NCD), including postoperative delirium (POD) and delayed neurocognitive recovery (dNCR), are common in geriatric surgical patients. However, the ideal diagnostic biomarkers to predict individual risks of po-NCDs have not been identified. In this study, proteomic analysis was used to detect dysregulated proteins in three cognitive-related brain regions, the hippocampus, prefrontal cortex, and temporal lobe, of aged dNCR rats. The common affected proteins in these three brain regions were further verified by real-time polymerase chain reaction and western blotting. Furthermore, serum samples from aged rats with dNCR and elderly hip fracture patients with POD were also assessed with enzyme linked immunosorbent assays to investigate the biomarker potential of these dysregulated proteins. The increased expression levels of haptoglobin, caseinolytic protease (ClpP), and alpha-2 macroglobulin (A2M) as well as decreased expression levels of 14-3-3β/α and biliverdin reductase-A (BVR-A) were validated by proteomic analysis in the hippocampus, prefrontal cortex, and temporal lobe of aged dNCR rats. The increased expression of haptoglobin and decreased expression of 14-3-3β/α were further demonstrated in the three brain regions by western blotting. Moreover, increased levels of S100A6 and BVR-A in the hippocampus, S100A6 in the prefrontal cortex, and A2M in the temporal lobe were also observed. More intriguingly, both decreased serum 14-3-3β/α and increased A2M in geriatric POD patients as well as decreased serum ClpP in aged dNCR rats were verified. These results not only indicate potential diagnostic biomarkers for po-NCD but also provide directions for further pathological investigations.Clinical Trial Registration:www.ClinicalTrials.gov, identifier [ChiCTR1900027393].

As a pathological biomarker of Parkinson’s disease, α-synuclein is thought to be a prion-like protein, but evidence for the transmission of α-synuclein from blood to the brain is unclear. The goals of this study were to determine whether blood-derived α-synuclein could enter the brains of mice and whether α-synuclein in the brain could be cleared by parabiosis. Heterochronic parabiosis was performed on SNCAA53T transgenic mice (A53T mice) and wildtype mice. The levels of human α-synuclein in the blood and substantia nigra of wildtype mice were significantly increased after 4-month parabiosis with A53T mice. Moreover, the expression of α-synuclein filament, but not of total α-synuclein, was significantly increased in the substantia nigra of wildtype mice that were paired with A53T mice. However, the levels of human α-synuclein displayed no significant change in the serum, blood, or substantia nigra of A53T mice. These results provide direct evidence that pathological α-synuclein can be transmitted from blood to the brain in the heterochronic parabiosis system, however, it appears to be difficult to clear it from the brain in a short period of time.

Primary intracerebral hemorrhage (ICH) is a significant cause of morbidity and mortality throughout the world. ICH is a multifactorial disease that emerges from interactions among multiple genetic and environmental factors. DNA methylation plays an important role in the etiology of complex traits and diseases. We used the Illumina Infinium Human Methylation 850k BeadChip to detect changes in DNA methylation in peripheral blood samples from patients with ICH and healthy controls to explore DNA methylation patterns in ICH. Here, we compared genomic DNA methylation patterns in whole blood from ICH patients (n = 30) and controls (n = 34). The ICH and control groups showed significantly different DNA methylation patterns at 1530 sites (p-value < 5.92E-08), with 1377 hypermethylated sites and 153 hypomethylated sites in ICH patients compared to the methylation status in healthy controls. A total of 371 hypermethylated sites and 35 hypomethylated sites were in promoters, while 738 hypermethylated sites and 67 hypomethylated sites were in coding regions. Furthermore, the differentially methylated genes between ICH patients and controls were largely related to inflammatory pathways. Abnormalities in the DNA methylation pattern identified in the peripheral blood of ICH patients may play an important role in the development of ICH and warranted further investigation.

Objectives: To evaluate the impact of angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) on the inflammatory response and viral clearance in coronavirus disease 2019 (COVID-19) patients.Methods: We included 229 patients with confirmed COVID-19 in a multicenter, retrospective cohort study. Propensity score matching at a ratio of 1:3 was introduced to eliminate potential confounders. Patients were assigned to the ACEI/ARB group (n = 38) or control group (n = 114) according to whether they were current users of medication.Results: Compared to the control group, patients in the ACEI/ARB group had lower levels of plasma IL-1β [(6.20 ± 0.38) vs. (9.30 ± 0.31) pg/ml, P = 0.020], IL-6 [(31.86 ± 4.07) vs. (48.47 ± 3.11) pg/ml, P = 0.041], IL-8 [(34.66 ± 1.90) vs. (47.93 ± 1.21) pg/ml, P = 0.027], and TNF-α [(6.11 ± 0.88) vs. (12.73 ± 0.26) pg/ml, P < 0.01]. Current users of ACEIs/ARBs seemed to have a higher rate of vasoconstrictive agents (20 vs. 6%, P < 0.01) than the control group. Decreased lymphocyte counts [(0.76 ± 0.31) vs. (1.01 ± 0.45)*109/L, P = 0.027] and elevated plasma levels of IL-10 [(9.91 ± 0.42) vs. (5.26 ± 0.21) pg/ml, P = 0.012] were also important discoveries in the ACEI/ARB group. Patients in the ACEI/ARB group had a prolonged duration of viral shedding [(24 ± 5) vs. (18 ± 5) days, P = 0.034] and increased length of hospitalization [(24 ± 11) vs. (15 ± 7) days, P < 0.01]. These trends were similar in patients with hypertension.Conclusions: Our findings did not provide evidence for a significant association between ACEI/ARB treatment and COVID-19 mortality. ACEIs/ARBs might decrease proinflammatory cytokines, but antiviral treatment should be enforced, and hemodynamics should be monitored closely. Since the limited influence on the ACEI/ARB treatment, they should not be withdrawn if there was no formal contraindication.

Tumor progression includes the obtainment of progenitor and stem cell-like features and the gradual loss of a differentiated phenotype. Stemness was defined as the potential for differentiation and self-renewal from the cell of origin. Previous studies have confirmed the effective application of stemness in a number of malignancies. However, the mechanisms underlying the growth and maintenance of multiple myeloma (MM) stem cells remain unclear. We calculated the stemness index for samples of MM by utilizing a novel one-class logistic regression (OCLR) machine learning algorithm and found that mRNA expression-based stemness index (mRNAsi) was an independent prognostic factor of MM. Based on the same cutoff value, mRNAsi could stratify MM patients into low and high groups with different outcomes. We identified 127 stemness-related signatures using weighted gene co-expression network analysis (WGCNA) and differential expression analysis. Functional annotation and pathway enrichment analysis indicated that these genes were mainly involved in the cell cycle, cell differentiation, and DNA replication and repair. Using the molecular complex detection (MCODE) algorithm, we identified 34 pivotal signatures. Meanwhile, we conducted unsupervised clustering and classified the MM cohorts into three MM stemness (MMS) clusters with distinct prognoses. Samples in MMS-cluster3 possessed the highest stemness fractions and the worst prognosis. Additionally, we applied the ESTIMATE algorithm to infer differential immune infiltration among the three MMS clusters. The immune core and stromal score were significantly lower in MMS-cluster3 than in the other clusters, supporting the negative relation between stemness and anticancer immunity. Finally, we proposed a prognostic nomogram that allows for individualized assessment of the 3- and 5-year overall survival (OS) probabilities among patients with MM. Our study comprehensively assessed the MM stemness index based on large cohorts and built a 34-gene based classifier for predicting prognosis and potential strategies for stemness treatment.

Sea cucumbers are a class of marine invertebrates and a source of food and drug. Numerous microorganisms are associated with sea cucumbers. Seventy-eight genera of bacteria belonging to 47 families in four phyla, and 29 genera of fungi belonging to 24 families in the phylum Ascomycota have been cultured from sea cucumbers. Sea-cucumber-associated microorganisms produce diverse secondary metabolites with various biological activities, including cytotoxic, antimicrobial, enzyme-inhibiting, and antiangiogenic activities. In this review, we present the current list of the 145 natural products from microorganisms associated with sea cucumbers, which include primarily polyketides, as well as alkaloids and terpenoids. These results indicate the potential of the microorganisms associated with sea cucumbers as sources of bioactive natural products.

This is the first study to discuss the effects of dark septate endophytes (DSE) on the growth promotion and berberine concentration in Mahonia oiwakensis, whose extract (MOE) has been suggested to have potential therapeutic effects against human lung cancer. First, as per phylogenetic analysis, the strains were divided into four groups: CkDB2, CkDB5, MoAL2 and MoAL5. All of these were DSEs, which could form microsclerotia in M. oiwakensis. The growth response experiment revealed that inoculation of the plant with MoAL5 and CkDB5 promoted an increase in the total fresh weight of the seedlings. Chemical composition analysis showed that seedlings inoculated with CkDB5 had the highest berberine concentration. These results showed that some DSEs have the ability to promote growth and induce phytochemical responses in the host plant.

Summary Innate lymphoid cells (ILCs) are tissue-resident lymphocytes differing from conventional T lymphocytes in having no antigen-specific receptors. ILCs include natural killer (NK) cells, helper-like ILC1s, ILC2s, and ILC3s, and lymphoid tissue-inducer (LTi) cells. Tumor ILCs are frequently found in various cancers, but their roles in cancer immunity and immunotherapy remain largely unclear. We report here the single-cell characterization of blood and gut helper-like ILC subsets in healthy conditions and in colorectal cancer (CRC). The healthy gut contains ILC1s, ILC3s, and ILC3/NKs, but no ILC2s. Additional tumor-specific ILC1-like and ILC2 subsets were identified in CRC patients. Signaling lymphocytic activation molecule family member 1 (SLAMF1) was found to be selectively expressed on tumor-specific ILCs, and higher levels of SLAMF1+ ILCs were observed in the blood of CRC patients. The SLAMF1-high group of CRC patients had a significantly higher survival rate than the SLAMF1-low group, suggesting that SLAMF1 is an anti-tumor biomarker in CRC., Graphical abstract, Highlights Healthy gut contains ILC1s, ILC3s, and ILC3/NKs, but no ILC2s Blood and tumor ILCs from CRC patients have unique transcriptomic features Tumor tissue from CRC patients contains a tumor specific ILC1-like subset and ILC2s SLAMF1 is identified as an anti-tumor biomarker in CRC, The roles and contribution of ILCs to cancer remain poorly defined. Through scRNA-seq profiling the landscape of ILCs from blood, normal mucosa, and tumor tissues from CRC patients, Qi et al. reveal the presence of tumor specific ILC subsets and an anti-tumor biomarker, SLAMF1, in CRC patients.

BACKGROUND AND AIMS: HCC is a leading cause of cancer-related deaths globally with poor outcome and limited therapeutic options. Although the myelocytomatosis (MYC) oncogene is frequently dysregulated in HCC, it is thought to be undruggable. Thus, the current study aimed to identify the critical downstream metabolic network of MYC and develop therapies for MYC-driven HCC. APPROACH AND RESULTS: Liver cancer was induced in mice with hepatocyte-specific disruption of Myc and control mice by administration of diethylnitrosamine. Liquid chromatography coupled with mass spectrometry-based metabolomic analyses revealed that urinary dimethylarginine, especially symmetric dimethylarginine (SDMA), was increased in the HCC mouse model in an MYC-dependent manner. Analyses of human samples demonstrated a similar induction of SDMA in the urines from patients with HCC. Mechanistically, Prmt5, encoding protein arginine N-methyltransferase 5, which catalyzes SDMA formation from arginine, was highly induced in HCC and identified as a direct MYC target gene. Moreover, GSK3326595, a PRMT5 inhibitor, suppressed the growth of liver tumors in human MYC-overexpressing transgenic mice that spontaneously develop HCC. Inhibition of PRMT5 exhibited antiproliferative activity through up-regulation of the tumor suppressor gene Cdkn1b/p27, encoding cyclin-dependent kinase inhibitor 1B. In addition, GSK3326595 induced lymphocyte infiltration and major histocompatibility complex class II expression, which might contribute to the enhanced antitumor immune response. Combination of GSK3326595 with anti–programed cell death protein 1 (PD-1) immune checkpoint therapy (ICT) improved therapeutic efficacy in HCC. CONCLUSIONS: This study reveals that PRMT5 is an epigenetic executer of MYC, leading to repression of the transcriptional regulation of downstream genes that promote hepatocellular carcinogenesis, highlights a mechanism-based therapeutic strategy for MYC-driven HCC by PRMT5 inhibition through synergistically suppressed proliferation and enhanced antitumor immunity, and finally provides an opportunity to mitigate the resistance of “immune-cold” tumor to ICT. (Hepatology 2021;74:1932–1951).

Type 2 diabetes (T2D) is a systematic chronic metabolic condition with abnormal sugar metabolism dysfunction, and its complications are the most harmful to human beings and may be life-threatening after long-term durations. Considering the high incidence and severity at late stage, researchers have been focusing on the identification of specific biomarkers and potential drug targets for T2D at the genomic, epigenomic, and transcriptomic levels. Microbes participate in the pathogenesis of multiple metabolic diseases including diabetes. However, the related studies are still non-systematic and lack the functional exploration on identified microbes. To fill this gap between gut microbiome and diabetes study, we first introduced eggNOG database and KEGG ORTHOLOGY (KO) database for orthologous (protein/gene) annotation of microbiota. Two datasets with these annotations were employed, which were analyzed by multiple machine-learning models for identifying significant microbiota biomarkers of T2D. The powerful feature selection method, Max-Relevance and Min-Redundancy (mRMR), was first applied to the datasets, resulting in a feature list for each dataset. Then, the list was fed into the incremental feature selection (IFS), incorporating support vector machine (SVM) as the classification algorithm, to extract essential annotations and build efficient classifiers. This study not only revealed potential pathological factors for diabetes at the microbiome level but also provided us new candidates for drug development against diabetes.