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The excessive lactate in the tumor microenvironment always leads to poor therapeutic outcomes of chemotherapy. In this study, a self-driven bioreactor (defined as SO@MDH, where SO isiShewanella oneidensis/iMR-1 and MDH is MIL-101 metal-organic framework nanoparticles/doxorubicin/hyaluronic acid) is rationally constructedivia/ithe integration of doxorubicin (DOX)-loaded metal-organic framework (MOF) MIL-101 nanoparticles with SO to sensitize chemotherapy. Owing to the intrinsic tumor tropism and electron-driven respiration of SO, the biohybrid SO@MDH could actively target and colonize hypoxic and eutrophic tumor regions and anaerobically metabolize lactate accompanied by the transfer of electrons to Fesup3+/sup, which is the key component of the MIL-101 nanoparticles. As a result, the intratumoral lactate would undergo continuous catabolism coupled with the reduction of Fesup3+/supto Fesup2+/supand the subsequent degradation of MIL-101 frameworks, leading to an expeditious drug release for effective chemotherapy. Meanwhile, the generated Fesup2+/supwill be promptly oxidized by the abundant hydrogen peroxide in the tumor microenvironment to reproduce Fesup3+/sup, which is, in turn, beneficial to circularly catabolize lactate and boost chemotherapy. More importantly, the consumption of intratumoral lactic acid could significantly inhibit the expression of multidrug resistance-related ABCB1 protein (also named P-glycoprotein (P-gp)) for conquering drug-resistant tumors. SO@MDH demonstrated here holds high tumor specificity and promising chemotherapeutic efficacy for suppressing tumor growth and overcoming multidrug resistance, confirming its potential prospects in cancer therapy.

The increasing numbers of infected cases of coronavirus disease 2019 (COVID‐19) caused by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) poses serious threats to public health and the global economy. Most SARS‐CoV‐2 neutralizing antibodies target the receptor binding domain (RBD) and some the N‐terminal domain (NTD) of the spike protein, which is the major antigen of SARS‐CoV‐2. While the antibody response to RBD has been extensively characterized, the antigenicity and immunogenicity of the NTD protein are less well studied. Using 227 plasma samples from COVID‐19 patients, we showed that SARS‐CoV‐2 NTD‐specific antibodies could be induced during infection. As compared to the results of SARS‐CoV‐2 RBD, the serological response of SARS‐CoV‐2 NTD is less cross‐reactive with SARS‐CoV, a pandemic strain that was identified in 2003. Furthermore, neutralizing antibodies are rarely elicited in a mice model when NTD is used as an immunogen. We subsequently demonstrate that NTD has an altered antigenicity when expressed alone. Overall, our results suggest that while NTD offers a supplementary strategy for serology testing, it may not be suitable as an immunogen for vaccine development., Receptor binding domain (RBD) of the SARS‐CoV‐2 spike protein has been extensively studied in functional antibody screening and COVID‐19 vaccine design. To explore the function of N‐terminal domain (NTD) of spike protein, we reveal that NTD is a supplementary antigen for serology testing, but not a suitable immunogen for vaccine design.

Engineered bacteria are promising bioagents to synthesize antitumor drugs at tumor sites with the advantages of avoiding drug leakage and degradation during delivery. Here, we report an optically controlled material-assisted microbial system by biosynthesizing gold nanoparticles (AuNPs) on the surface of Shewanella algae K3259 (S. algae) to obtain Bac@Au. Leveraging the dual directional electron transport mechanism of S. algae, the hybrid biosystem enhances in situ synthesis of antineoplastic tetrodotoxin (TTX) for a promising antitumor effect. Because of tumor hypoxia-targeting feature of facultative anaerobic S. algae, Bac@Au selectively target and colonize at tumor. Upon light irradiation, photoelectrons produced by AuNPs deposited on bacterial surface are transferred into bacterial cytoplasm and participate in accelerated cell metabolism to increase the production of TTX for antitumor therapy. The optically controlled material-assisted microbial system enhances the efficiency of bacterial drug synthesis in situ and provides an antitumor strategy that could broaden conventional therapy boundaries.

The characterization of cancer genomes has provided insight into somatically altered genes across tumors, transformed our understanding of cancer biology, and enabled tailoring of therapeutic strategies. However, the function of most cancer alleles remains mysterious, and many cancer features transcend their genomes. Consequently, tumor genomic characterization does not influence therapy for most patients. Approaches to understand the function and circuitry of cancer genes provide complementary approaches to elucidate both oncogene and non-oncogene dependencies. Emerging work indicates that the diversity of therapeutic targets engendered by non-oncogene dependencies is much larger than the list of recurrently mutated genes. Here we describe a framework for this expanded list of cancer targets, providing novel opportunities for clinical translation.

Cav3.1, a subfamily of T-type calcium channel, is overexpressed in various human cancers and exerts important functions in tumor progression. This study is to identify the expression pattern and clinical significance of Cav3.1 in oral squamous cell carcinoma (OSCC). Firstly, the expression levels of Cav3.1 in oral mucosa (OM), dysplasia and oral squamous cell carcinoma (OSCC) were determined and compared by real-time quantitative PCR and Western blot analysis. After that, human tissue microarrays, containing 29 OM, 23 dysplasia and 122 primary OSCC samples, were applied to investigate the expression levels of Cav3.1, proliferation markers [Ki-67, proliferating cell nuclear antigen (PCNA)] and cellular anti-apoptosis markers [B cell lymphoma 2 (Bcl-2)] by immunohistochemistry and digital pathology analysis. In addition, we determined the function of Cav3.1 using knockdown assays of Cav3.1 in vitro. The results demonstrated that the mRNA and protein expression of Cav3.1 were significantly higher in OSCC specimens, and Cav3.1 expression in primary OSCCs was correlated with tumor size and pathological grade. Statistical analysis of immunohistochemical staining showed that Cav3.1 was closely correlated with Ki-67, PCNA and Bcl-2. Functional studies showed that the knockdown of Cav3.1 in OSCC cell lines using RNA interference influenced cell proliferation and apoptosis in vitro. Taken together, these findings suggested that Cav3.1 is overexpressed in OSCC tissues, also associated with proliferative and anti-apoptotic activity in oral squamous cell carcinoma.

Autophagy is an evolutionarily conserved process, designed to maintain cellular homeostasis during a range of internal and external stimuli. Conventionally, autophagy is known for co-ordinated degradation and recycling of intracellular components and removal of cytosolic pathogens. More recently, several lines of evidence have indicated an unconventional, non-degradative role of autophagy for secretion of cargo that lacks a signal peptide. This process referred to as secretory autophagy has also been implicated in the infection cycle of several virus species. This review focuses on the current evidence available on the non-degradative features of autophagy, emphasizing its potential role and unresolved questions in the release and spread of (-) and (+) RNA viruses.

G protein-coupled receptors (GPCRs) play important roles in human physiology. GPCRs are involved in immunoregulation including regulation of the inflammatory response. Chemotaxis of phagocytes and lymphocytes is mediated to a great extent by the GPCRs for chemoattractants including myriads of chemokines. Accumulation and activation of phagocytes at the site of inflammation contribute to local inflammatory response. A handful of GPCRs have been found to transduce anti-inflammatory signals that promote resolution of inflammation. These GPCRs interact with selected metabolites of arachdonic acid, such as lipoxins, and of omega-3 essential fatty acids, such as resolvins and protectins. Despite mounting evidence for the in vivo functions of these anti-inflammatory and pro-resolving ligands paired with their respective GPCRs, the underlying signaling mechanisms have not been fully delineated. The present review summarizes what we have learned about these GPCRs, their structures and signaling pathways and the prospect of targeting these receptors for novel anti-inflammatory therapies.

Objective Colorectal cancer (CRC) is one of the most common malignant tumors in the digestive tract, which accounts for 10% of all the malignant tumors in the world. The aim of this study was to identify key genes and miRNAs in CRC diagnosis, prognosis, and therapy and to further explore the potential molecular mechanisms of CRC. Methods The infiltration and metastasis of neutrophils in primary colorectal cancer tissue and paracancerous tissue were observed by immunohistochemical staining. After inducing N2 neutrophils with TGF-β1 in vitro, exosomes were extracted and sequenced, and then the expression differences of miRNAs were screened by using Agilent miRNA microarrays. The data were imported to the Web CARMA for differential expression analysis. The GO and KEGG enrichment analysis were performed using DIANA-MirPath v3.0 using TargetScan database. And the corresponding targets were imported into Gephi for network analysis. The expression level of differentially expressed miRNA using quantitative real-time polymerase chain reaction (RT-PCR) was validated. Results A total of 2 miRNAs were found to be associated with N2 neutrophils, in which the expression of hsa-miR-4780 was upregulated and the expression of hsa-miR-3938 was downregulated in N2 neutrophils, compared with the neutrophils. In addition, the results of miRNA-targets networks showed that the hsa-mir-3938 and hsa-mir-4780 could regulate TUSC1 and ZNF197. The expression level of hsa-miR-4780 and hsa-miR-3938 wase validated in accordance with the results of RT-PCR. Conclusion The hsa-mir-3938 and hsa-mir-4780 were differentially expressed between N2 neutrophils and neutrophils. Moreover, the regulation of TUSC1 and ZNF197 by these DEmiRNA established the theoretical basis for the mechanism of N2 type neutrophils regulating the invasion and metastasis of CRC cells and provided the potential biomarker for prognosis for clinical treatment of CRC.

Summary: Deubiquitylases (DUBs) regulate critical signaling pathways at the intersection of host immunity and viral pathogenesis. Although RIG-I activation is heavily dependent on ubiquitylation, systematic analyses of DUBs that regulate this pathway have not been performed. Using a ubiquitin C-terminal electrophile, we profile DUBs that function during influenza A virus (IAV) infection and isolate OTUB1 as a key regulator of RIG-I-dependent antiviral responses. Upon infection, OTUB1 relocalizes from the nucleus to mitochondrial membranes together with RIG-I, viral PB2, and NS1. Its expression depends on competing effects of interferon stimulation and IAV-triggered degradation. OTUB1 activates RIG-I via a dual mechanism of K48 polyubiquitin hydrolysis and formation of an E2-repressive complex with UBCH5c. We reconstitute this mechanism in a cell-free system comprising [35S]IRF3, purified RIG-I, mitochondrial membranes, and cytosol expressing OTUB1 variants. A range of IAV NS1 proteins trigger proteasomal degradation of OTUB1, antagonizing the RIG-I signaling cascade and antiviral responses. : Jahan et al. describe the role of Otub1, a deubiquitylase that is induced during virus infection in an interferon-dependent manner to regulate optimal signaling via the RIG-I pathway. Influenza A virus NS1 is able to bind and degrade newly synthesized Otub1 as a means to evade the innate immune response. Keywords: deubiquitylases, RIG-I signaling, ubiquitylation, innate immune response, RNA virus, influenza A, viral subversion strategies

Reperfusion of the ischemic intestine often leads to drive distant organ injury, especially injuries associated with hepatocellular dysfunction. The precise molecular mechanisms and effective multiple organ protection strategies remain to be developed. In the current study, significant remote liver dysfunction was found after 6 hours of reperfusion according to increased histopathological scores, serum lactate dehydrogenase (LDH), alanine aminotransferase (ALT)/aspartate aminotransferase (AST) levels, as well as enhanced bacterial translocation in a rat intestinal ischemia/reperfusion (I/R) injury model. Moreover, receptor-interacting protein kinase 1/3 (RIP1/3) and phosphorylated-MLKL expressions in tissue were greatly elevated, indicating that necroptosis occurred and resulted in acute remote liver function impairment. Inhibiting the necroptotic pathway attenuated HMGB1 cytoplasm translocation and tissue damage. Meanwhile, macrophage-depletion study demonstrated that Kupffer cells (KCs) are responsible for liver damage. Blocking HMGB1 partially restored the liver function via suppressed hepatocyte necroptosis, tissue inflammation, hepatic KCs, and circulating macrophages M1 polarization. What's more, HMGB1 neutralization further protects against intestinal I/R-associated liver damage in microbiota-depleted rats. Therefore, intestinal I/R is likely associated with acute liver damage due to hepatocyte necroptosis, and which could be ameliorated by Nec-1 administration and HMGB1 inhibition with the neutralizing antibody and inhibitor. Necroptosis inhibition and HMGB1 neutralization/inhibition, may emerge as effective pharmacological therapies to minimize intestinal I/R-induced acute remote organ dysfunction.

In order to fully understand and effectively utilize the genetic diversity of Jerusalem artichoke accessions in China. 257 Jerusalem artichoke accessions were analyzed. Among them, 12 quantitative traits had 6%–50% of the coefficient of variation, with a mean of 24.75%, which was the highest in tuber weight per plant (50%) and the smallest in growth period (6%). The diversity index ( H′ ) of these 12 traits was 1.24–1.53, with a mean of 1.44, which was the highest in tuber number per plant (1.53) and the lowest in leaf width (1.24). The diversity index of the eight quality traits was 0.85–1.08, with a mean of 0.98, which was the highest in tuber habit and the lowest in tuber uniformity, showing rich genetic diversity in most traits. The subordinate function of 257 Jerusalem artichoke accessions was 0.12–0.58, in which the highest was in JA1095 (0.58) with the obvious advantages of flower number and tuber weight per plant. The correlation analysis of 12 quantitative traits indicated that stem diameter, leaf length, flower and disk size could be used as the main target traits for high yield Jerusalem artichoke varieties breeding in the future. The results of principal component analysis showed that the cumulative contribution rate of the seven principal component factors was 66.794%. Among them, the number of flowers, the tuber number per plant, the number of tuber hairs and the smoothness of tuber epidermis were the main factors contributing to the phenotypic difference of Jerusalem artichoke. By cluster analysis, 257 accessions materials were divided into five categories based on 20 traits,among them class I and class II accounted for 85% of the total germplasm resources. This results can provide an important reference for the utilization of Jerusalem artichoke accessions and variety breeding.

Background Patients undergoing major non-cardiac surgery are at risk of cardiovascular complications. Raised levels of high-sensitivity troponin are frequently detected before operation among these patients. However, the prognostic value of high-sensitivity troponin in predicting postoperative outcomes remains unclear. Methods A systematic search of PubMed, Embase and Science Citation Index Expanded was undertaken for observational studies published before March 2018 that reported associations between raised preoperative levels of high-sensitivity troponin and postoperative major adverse cardiac events and/or mortality after non-cardiac surgery. Meta-analyses were performed, where possible, using random-effects models. Results Seven cohort studies with a total of 4836 patients were included. A raised preoperative high-sensitivity troponin level was associated with a higher risk of short-term major adverse cardiac events (risk ratio (RR) 2·92, 95 per cent c.i. 1·96 to 4·37; I2 = 82·6 per cent), short-term mortality (RR 5·39, 3·21 to 9·06; I2 = 0 per cent) and long-term mortality (RR 2·90, 1·83 to 4·59, I2 = 74·2 per cent). The addition of preoperative high-sensitivity troponin measurement provided improvements in cardiovascular risk discrimination (increase in C-index ranged from 0·058 to 0·109) and classification (quantified by continuous net reclassification improvement) compared with Lee's Revised Cardiac Risk Index alone. There was substantial heterogeneity and inadequate risk stratification analysis in the included studies. Conclusion Raised preoperative levels of high-sensitivity troponin appear to represent a risk for postoperative major adverse cardiac events and mortality. Further study is required before high-sensitivity troponin can be used to predict risk stratification in routine clinical practice.

Inflammation plays a major role in etiology of multiple diseases and it has become an imperative therapeutic target in pharmacological interventions. Over the years, natural products originating fr...

Background The comparisons of molecular characterization and antibiotic resistance of Klebsiella pneumoniae (KP) isolates from humans and other animal hosts are not well studied. Our goal was to compare the molecular epidemiology of KP strains that were isolated from urban rodents, shrews, and healthy people. Results K. pneumoniae (KP) isolates were isolated from fecal samples of rodents, shrews and healthy adults in 2015 in southern China. In total, 465 fecal samples were collected, of which 85 from rodents, 105 from shrews, and 275 from healthy adults. Antimicrobial susceptibility and production of extended-spectrum β-lactamases (ESBL) of the isolates were tested. PCR-based methods were used to detect specific genes, including ESBL genes (blaTEM, blaSHV, and blaCTX-M) in ESBL-producing isolates, capsular serotypes (K1, K2, K5, K20, K54, and K57) in hypervirulent KPs (hvKPs), and virulence genes (magA, wcaG, rmpA, uge, kfu, and aerobactin) in hvKP isolates. Multilocus sequence type (MLST) and pulsed-field gel electrophoresis (PFGE) were performed to exclude the homology of these isolates. The carriage rate of KP in urban rodents and shrews (78.42%) was higher than that in healthy adults (66.18%) (χ2 = 8.206, P = 0.004). The prevalence rates of ESBL-producing isolates among rodents, shrews, and humans were 7.94, 12.79, and 17.03%, respectively. The positive rates of CTX-M, TEM and SHV types in ESBL-producing isolates were 29.79, 27.66, and 17.02%, respectively. Serotype K1, K5, K20, and K57 were detected in both small mammals and humans. PFGE typing revealed thirty-six clusters. PFGE cluster A was clustered by samples of shrews and healthy adult, with a similarity of 88.4%. MLST typing revealed thirty-eight types. ST23 and ST35 were detected in samples of shrews and healthy adults. ST37 was detected in samples of 2 rodents and a healthy adult. Conclusions Overlapping serotypes of hvKP were observed in both the animals and humans. The same PFGE or MLST types were also found in isolates derived humans, rodents and shrews. Therefore, urban rodents and shrews might play a certain role in the transmission of drug-resistant and hypervirulent KP.

Ubiquitin-like protein ISG15 (interferon-stimulated gene 15) (ISG15) is a ubiquitin-like modifier induced during infections and involved in host defense mechanisms. Not surprisingly, many viruses encode deISGylating activities to antagonize its effect. Here we show that infection by Zika, SARS-CoV-2 and influenza viruses induce ISG15-modifying enzymes. While influenza and Zika viruses induce ISGylation, SARS-CoV-2 triggers deISGylation instead to generate free ISG15. The ratio of free versus conjugated ISG15 driven by the papain-like protease (PLpro) enzyme of SARS-CoV-2 correlates with macrophage polarization toward a pro-inflammatory phenotype and attenuated antigen presentation. In vitro characterization of purified wild-type and mutant PLpro revealed its strong deISGylating over deubiquitylating activity. Quantitative proteomic analyses of PLpro substrates and secretome from SARS-CoV-2-infected macrophages revealed several glycolytic enzymes previously implicated in the expression of inflammatory genes and pro-inflammatory cytokines, respectively. Collectively, our results indicate that altered free versus conjugated ISG15 dysregulates macrophage responses and probably contributes to the cytokine storms triggered by SARS-CoV-2.

Klebsiella pneumoniae carbapenemase (KPC)-producing Pseudomonas aeruginosa (KPC-PA) has been reported sporadically. However, epidemiological and antimicrobial susceptibility data specific for KPC-PA are lacking. We collected 374 carbapenem-resistant P. aeruginosa (CRPA) isolates from seven hospitals in China from June 2016 to February 2019 and identified the blaKPC-2 gene in 40.4% (n = 151/374) of the isolates. Approximately one-half of all KPC-PA isolates (n = 76/151; 50.3%) were resistant to ceftazidime-avibactam (CAZ-AVI). Combining Kraken2 taxonomy identification and Nanopore sequencing, we identified eight plasmid types, five of which carried blaKPC-2, and 13 combination patterns of these plasmid types. In addition, we identified IS26-ΔTn6296 and Tn1403-like–ΔTn6296 as the two mobile genetic elements that mediated blaKPC-2 transmission. blaKPC-2 plasmid curing in 28 strains restored CAZ-AVI susceptibility, suggesting that blaKPC-2 was the mediator of CAZ-AVI resistance. Furthermore, the blaKPC-2 copy number was found to correlate with KPC expression and, therefore, CAZ-AVI resistance. Taken together, our results suggest that KPC-PA is becoming a clinical threat and that using CAZ-AVI to treat this specific pathogen should be done with caution. IMPORTANCE Previous research has reported several cases of KPC-PA strains and three KPC-encoding P. aeruginosa plasmid types in China. However, the prevalence and clinical significance of KPC-PA are not available. In addition, the susceptibility of the strains to CAZ-AVI remains unknown. Samples in this study were collected from seven tertiary hospitals prior to CAZ-AVI clinical approval in China. Therefore, our results represent a retrospective study establishing the baseline efficacy of the novel β-lactam/β-lactamase combination agent for treating KPC-PA infections. The observed correlation between the blaKPC copy number and CAZ-AVI resistance suggests that close monitoring of the susceptibility of the strain during treatment is required. It would also be beneficial to screen for the blaKPC gene in CRPA strains for antimicrobial surveillance purposes.

Dysfunctional megakaryopoiesis hampers platelet production, which is closely associated with thrombocytopenia (PT). Macrophages (MФs) are crucial cellular components in the bone marrow (BM) microenvironment. However, the specific effects of M1 MФs or M2 MФs on regulating megakaryocytes (MKs) are largely unknown. In the current study, aberrant BM-M1/M2 MФ polarization, characterized by increased M1 MФs and decreased M2 MФs and accompanied by impaired megakaryopoiesis-supporting abilities, was found in patients with PT post-allotransplant. RNA-seq and western blot analysis showed that the PI3K-AKT pathway was downregulated in the BM MФs of PT patients. Moreover, in vitro treatment with PI3K-AKT activators restored the impaired megakaryopoiesis-supporting ability of MФs from PT patients. Furthermore, we found M1 MФs suppress, whereas M2 MФs support MK maturation and platelet formation in humans. Chemical inhibition of PI3K-AKT pathway reduced megakaryopoiesis-supporting ability of M2 MФs, as indicated by decreased MK count, colony-forming unit number, high-ploidy distribution, and platelet count. Importantly, genetic knockdown of the PI3K-AKT pathway impaired the megakaryopoiesis-supporting ability of MФs both in vitro and in a MФ-specific PI3K-knockdown murine model, indicating a critical role of PI3K-AKT pathway in regulating the megakaryopoiesis-supporting ability of M2 MФs. Furthermore, our preliminary data indicated that TGF-β released by M2 MФs may facilitate megakaryopoiesis through upregulation of the JAK2/STAT5 and MAPK/ERK pathways in MKs. Taken together, our data reveal that M1 and M2 MФs have opposing effects on MKs in a PI3K-AKT pathway-dependent manner, which may lead to new insights into the pathogenesis of thrombocytopenia and provide a potential therapeutic strategy to promote megakaryopoiesis.

Hepatitis is a major global health concern. However, the etiology of 10–20% hepatitis cases remains unclear. Some hepatitis-associated viruses, like the hepatitis E virus, are zoonotic pathogens. Rats, shrews, and bats are reservoirs for many zoonotic pathogens. Therefore, understanding the virome in the liver of these animals is important for the investigation of the etiologies of hepatitis and monitoring the emerging zoonotic viruses. In this study, viral metagenomics and PCR methods were used to investigate viral communities in rats, mice, house shrews, and bats livers. Viral metagenomic analysis showed a diverse set of sequences in liver samples, comprising: sequences related to herpesviruses, orthomyxoviruses, anelloviruses, hepeviruses, hepadnaviruses, flaviviruses, parvoviruses, and picornaviruses. Using PCR methods, we first detected hepatovirus sequences in Hipposideros larvatus (3.85%). We also reported the first detection of Zika virus-related sequences in rats and house shrews. Sequences related to influenza A virus and herpesviruses were detected in liver. Higher detection rates of pegivirus sequences were found in liver tissue and serum samples from rats (7.85% and 15.79%, respectively) than from house shrews. Torque teno virus sequences had higher detection rates in the serum samples of rats and house shrews (52.72% and 5.26%, respectively) than in the liver. Near-full length genomes of pegivirus and torque teno virus were amplified. This study is the first to compare the viral communities in the liver of bats, rats, mice, and house shrews. Its findings expand our understanding of the virome in the liver of these animals and provide an insight into hepatitis-related viruses.

Elderly individuals exhibit unbalanced bone marrow (BM) effector T cell subset differentiation, such as increased T helper type 1 (Th1) and T cytotoxic type 1 (Tc1) cell frequencies, but the underlying mechanism is still unclear. Endothelial cells (ECs), which are instructive components of the BM microenvironment, exhibit the phenotype of semi-professional antigen-presenting cells and regulate T cell recruitment and activation. Thus, we compared the frequency and function of BM ECs, especially their capacity to regulate effector T cell subsets, between young and elderly healthy individuals, and explored the underlying mechanism of this immunomodulatory discrepancy. Although the young and elderly EC percentages were comparable, young ECs showed fewer reactive oxygen species and better migratory and tube-forming abilities than elderly ECs. Notably, increased T cell activation molecules and inflammatory cytokines were found in elderly ECs which regulated T cells to differentiate into more proinflammatory T cells, including Th1 and Tc1 cells, than young ECs.

Nemaline myopathy, a rare congenital myopathy, is characterized by generalized muscle weakness, hypotonia, respiratory insufficiency, and the presence of rod structures on muscle biopsy, which is caused by mutations in at least 13 known genes. A patient showing gradually deteriorated proximal muscle weakness and rod-shaped structures found in muscle fibers was suspected of having nemaline myopathy, following by the next-generation sequencing. We report two novel compound heterozygous variants in nebulin gene in a family residing in China. One is an intron event caused by an underlying variant at the + 3 position of the donor site. Another is a novel nonsense variant, which may lead to the end of protein translation and have a significant impact on protein function. The pathogenicity of this novel compound heterozygous variant remains to be verified. Variants reported here could help to diagnose NM for clinicians.

Exponential fertilization (EF) can cause seedlings to load more nutrients than they need to grow to establish reserves. Lighting spectrum adjustment may strengthen the growth and nutrient u...

Tyrosine hydroxylase (TH) is the initial enzyme responsible for cuticle sclerotization and pigmentation in many insect species, but to date, no direct functional studies have focused on TH in Zeugodacus tau. Here, the 3336-bp full-length cDNA of TH was isolated from Z. tau, a notorious horticultural pest infesting fruits and vegetables. qRT-polymerase chain reaction revealed that ZtTH transcripts were highly abundant at the time of pupal tanning and during adult emergence and were expressed in the midgut, integument and head of molting larvae. The pupation and eclosion rates gradually decreased when the 1st-instar larvae were fed diets containing higher concentrations of the TH inhibitor 3-iodo-tyrosine (3-IT). Moreover, pupal weights were significantly decreased, and abnormal uncolored phenotypes were observed after 20 mg/g 3-IT was incorporated into the diet. In addition, the suppression of TH function (mediated by RNA interference) led to a decrease in TH mRNAs and eclosion rates, accompanied by less-pigmented phenotypes. There was a severe impairment of larval-pupal cuticle tanning, leading to pupae with less yellowish pigment or that were completely white and transparent, when we injected 2 μL of 24.4 mM or 73.27 mM 3-IT into 3rd-instar larvae or prepupae. These results suggest that TH is an important enzyme for the normal growth and pupal pigmentation of Z. tau and that TH is a potential gene target for use in the control of Z. tau.

This study investigated the effects of dietary supplementation with alternative sources of α-linolenic acid on growth, the composition of rumen microbiota, and the interactions between rumen microbiota and long-chain fatty acid (FA) concentrations, in goat kids. Sixty 4-month-old castrated male Albas white cashmere kids (average BW 18.6 ± 0.1 kg) were randomly allocated among three dietary treatments: (i) basal diet without supplementation (Control), (ii) basal diet supplemented with linseed oil (LSO), (iii) basal diet supplemented with heated linseed grain (HLS). The concentrate:forage ratio was 5:5 and the LSO and HLS treatments provided the kids with similar dietary FA profiles. The diets were fed for 104 d, consisting of 14 d for adaptation followed by 90 d of experimental observation. Treatment did not significantly influence BW, DMI, or bacterial richness or diversity. On the other hand, the relative abundance of bacteria participating in hydrogenation differed significantly among the three groups: the Veillonellaceae and Christensenellaceae were more abundant in LSO kids, Prevotellaceae were more abundant in HLS kids, and the Fibrobacteriaceae were more abundant in Control kids (P < 0.05). Spearman correlation analysis indicated that Ruminobacter, Selenomonas_1, Fretibacterium, Prevotellaceae_UCG-001, Succinimonas, and Ruminococcaceae_NK4A214_group were the genera that participated in hydrogenation of long-chain FAs. HLS-fed kids had a lower relative abundance of Ruminobacter, but a higher abundance of Prevotellaceae_UCG-001 and Fretibacterium than LSO-fed kids. These changes were associated with greater rumen concentrations of C18:3n3 and n-3 PUFA, but lower concentrations of n-6 PUFA and lower n-6/n-3 ratios, in HLS than in LSO-fed kids. In conclusion, feeding kids with HLS increased rumen concentrations of C18:3n3 and n-3 PUFA, but decreased the n-6/n-3 ratio by decreasing the abundance of bacteria that hydrogenate C18:3n3 and increasing the abundance of bacteria that hydrogenate C18:2n6.

To date, an innovative strategy to control dengue is to release Wolbachia-infected male mosquitoes into wild areas to sterilize wild female mosquito vectors by cytoplasmic incompatibility (CI). To investigate the efficacy of Wolbachia in blocking dengue virus transmission, we develop a deterministic mathematical model of human and mosquito populations in which one dengue serotype circulates. The delay differential equation model captures the respective extrinsic and intrinsic incubation periods (EIP and IIP) in the mosquito and human, as well as the maturation delay between mating and emergence of adult mosquitoes, which have received relatively little attention. We analyze the existence and stability of disease-free equilibria, and obtain a sufficient and necessary condition on the existence of the disease-endemic equilibrium. We also determine two threshold values of the release ratio $\theta$, denoted by $\theta_1^*$ and $\theta_2^*$ with $\theta_1^*>\theta_2^*$. When $\theta>\theta_1^*$, the mosquito population will be eradicated eventually. When $\theta_2^* < \theta < \theta_1^*$, a complete mosquito eradication becomes impossible, but virus eradication is ensured at the meantime. When $\theta < \theta_2^*$, the disease-endemic equilibrium emerges that allows dengue virus to circulate between humans and mosquitoes. We carry out sensitivity analysis of the threshold values in terms of the model parameters, and simulate several possible control strategies with different release ratios, which confirm the public awareness that reducing mosquito bites and killing adult mosquitoes are the most effective strategy to control the epidemic. Our model provides new insights on the effectiveness of Wolbachia in reducing dengue at a population level.

Rationale: Tumor metastasis is the main cause for cancer-related death. However, the driving molecules of metastasis remain largely unknown. Here, we aim to identify long non-coding RNAs (lncRNAs) critical for human hepatocellular carcinoma (HCC) metastasis. Methods: Microarrays were used to screen a comprehensive set of lncRNAs with differential expression profiles in sulfatide-treated cells. Mass spectrometry, protein arrays, and RNA pull-down experiments were used to identify proteins that interacted with lncRNA. Epigenetic analysis was used to study lncRNA-mediated regulation mechanisms. Results: We identified lncRNA AY927503 (AY) as a metastasis-associated molecule that was highly expressed in human hepatocellular carcinoma (HCC) and correlated with metastatic events and poor prognosis in patients with HCC. AY promoted HCC cell migration, stemness, 5-fluorouracil resistance, and metastasis in mice. However, knockdown of integrin αV (ITGAV) abolished AY-stimulated migration, cell viability in HCC cells or tube formation. AY strongly promoted ITGAV transcription and αVβ3 expression by interacting with the ITGAV promoter specifically and stimulating its activity. AY was identified to interact with histone 1FX (H1FX), but deletion of the central domain of AY (AY∆371-522) abolished H1FX binding and ITGAV promoter stimulation. AY significantly enriched H3K4Me3 and acH3K9/14 but reduced H3K27Me3 and H1FX occupancy on the ITGAV promoter, which remodeled chromatin structures for RNA polymerase II recruitment. Knockdown of H1FX abrogated ITGAV transcription stimulated by AY. Conclusions: Our findings suggested that lncRNA AY promoted HCC metastasis via induction of chromatin modification for ITGAV transcription as a pioneer factor and was a potential molecular signature for metastasis or poor prognosis in patients with HCC.

Traditionally, cell culture medium in iPSC-derived cell work is not the main focus of the research and often is considered as just "food for cells". We demonstrate that by manipulation of the media and optimized methodology, it is possible to use this solution to study the proteins that the cell secretes (the "secretome"). This is particularly useful in the study of iPSC-derived neurons, which require long culture time. We demonstrate that media can be used to model diseases with optimized incubation and sampling times. The ability not to sacrifice cells allows significant cost and research benefits. In this manuscript we describe an optimized method for the analysis of the cell media from iPSC-derived neuronal lines from control and Parkinson's disease patients. We have evaluated the use of standard and supplement B27-free cell media as well as five different sample preparation techniques for proteomic analysis of the cell secretome. Mass spectral analysis of culture media allowed for the identification of >500 proteins, in 500 μL of media, which is less volume than reported previously (20-40 mL). Using shorter incubation times and our optimized methodology, we describe the use of this technique to study and describe potential disease mechanisms in Parkinson's disease.

The subterranean insect Bradysia odoriphaga (Diptera: Sciaridae) is an important pest in China and is especially damaging to Chinese chive. This study determined the exposure temperatures and times required to kill various stages of B. odoriphaga in vitro, the optimal plastic film for soil solarization, and the effects of soil solarization on control of B. odoriphaga. In vitro mortality was 100% when adults, eggs, larvae, or pupae were exposed to a constant temperature of 40 °C for 1.3, 1.8, 2.8, or 3.7 h. Among four kinds of plastic film (white common plastic film, light blue anti-dropping film [LBADF], white anti-dropping film, and black-white film), soil temperature increased fastest and remained over 40 °C for the longest time with 0.12-mm-thick LBADF located 30 cm above the soil surface. Favorable soil solarization with 0.12-mm-thick LBADF located at 30 cm above the soil surface or on the soil surface just 1 d after treatment provided 100% control of B. odoriphaga. The growth of Chinese chive was slower in solarized plots than in control plots for about 10 days but subsequently was faster in the solarized plots. At 20 days after treatment, the differences in yields between solarized plots and control plots were not statistically significant. This is the first report that soil solarization can be used to control B. odoriphaga in Chinese chive fields. This approach needs to be investigated for management of other plant diseases and insect pests.

The ability of cells to sense and respond to the mechanical stiffness of the surrounding matrix is important to support normal cell function, wound healing, and development. Central to the process of durosensing is the cytoskeleton composed of three classes of filaments: F-actin, microtubules, and intermediate filaments (IFs). Vimentin is an IF protein that contributes significantly to cell mechanics and cell traction force, which is required to probe extracellular matrix. The role of vimentin in how cells sense and respond to the mechanical rigidity of extracellular matrix is largely unclear. To investigate the role of vimentin in durosensing, we knocked down the vimentin expression level in 3T3 fibroblasts using shRNA transfection and measured cellular responses as functions of substrate stiffness. We quantified durosensitivity by the rates at which cell area and traction force change with substrate stiffness. Our results show that that vimentin plays a role in durosensing by modulating traction force and knocking out vimentin did not significantly affect durosensitivity. These results indicate that vimentin may be a redundant component of the machinery that cells use to sense substrate stiffness. This article is protected by copyright. All rights reserved.

Autophagy is a lysosome-dependent degradation process. During autophagy, cytoplasmic components are sequestered and catabolized to supply nutrition and energy under starvation conditions. Recent work has demonstrated that many cargos can be specifically recognized and then eliminated via the core mechanism of autophagy which is termed as selective autophagy. The cargo recognition program provides the basis for the specific degradation of selective autophagy; thus, the exploration of the interaction between the cargo and the receptor is the key for revealing the underlying mechanism. Also, receptor protein complexes are required in various selective autophagy subtypes which process and guide the cargo to the core mechanism. Ubiquitination and phosphorylation are the main methods to modulate the affinity of the receptor toward cargo. Although many key processes of selective autophagy subtypes have been discovered and intensively studied, the precise ways in which the mechanisms of cargo recognition function remain mostly elusive. A fuller mechanistic understanding of selective autophagy will be important for efforts to promote disease treatment and drug development.

BackgroundThe clinical significance of cardiac troponin measurement in patients hospitalised for coronavirus disease 2019 (covid-19) is uncertain. We investigated the prevalence of elevated troponins in these patients and its prognostic value for predicting mortality.MethodsStudies were identified by searching electronic databases and preprint servers. We included studies of hospitalised covid-19 patients that reported the frequency of troponin elevations above the upper reference limit and/or the association between troponins and mortality. Meta-analyses were performed using random-effects models.ResultsFifty-one studies were included. Elevated troponins were found in 20.8% (95% confidence interval [CI] 16.8–25.0 %) of patients who received troponin test on hospital admission. Elevated troponins on admission were associated with a higher risk of subsequent death (risk ratio 2.68, 95% CI 2.08–3.46) after adjusting for confounders in multivariable analysis. The pooled sensitivity of elevated admission troponins for predicting death was 0.60 (95% CI 0.54–0.65), and the specificity was 0.83 (0.77–0.88). The post-test probability of death was about 42% for patients with elevated admission troponins and was about 9% for those with non-elevated troponins on admission. There was significant heterogeneity in the analyses, and many included studies were at risk of bias due to the lack of systematic troponin measurement and inadequate follow-up.ConclusionElevated troponins were relatively common in patients hospitalised for covid-19. Troponin measurement on admission might help in risk stratification, especially in identifying patients at high risk of death when troponin levels are elevated. High-quality prospective studies are needed to validate these findings.Systematic review registrationPROSPEROCRD42020176747

Background Rattus norvegicus and Suncus murinus are important reservoirs of zoonotic bacterial diseases. An understanding of the composition of gut and oropharynx bacteria in these animals is important for monitoring and preventing such diseases. We therefore examined gut and oropharynx bacterial composition in these animals in China. Results Proteobacteria, Firmicutes and Bacteroidetes were the most abundant phyla in faecal and throat swab samples of both animals. However, the composition of the bacterial community differed significantly between sample types and animal species. Firmicutes exhibited the highest relative abundance in throat swab samples of R. norvegicus, followed by Proteobacteria and Bacteroidetes. In throat swab specimens of S. murinus, Proteobacteria was the predominant phylum, followed by Firmicutes and Bacteroidetes. Firmicutes showed the highest relative abundance in faecal specimens of R. norvegicus, followed by Bacteroidetes and Proteobacteria. Firmicutes and Proteobacteria had almost equal abundance in faecal specimens of S. murinus, with Bacteroidetes accounting for only 3.07%. The family Streptococcaceae was most common in throat swab samples of R. norvegicus, while Prevotellaceae was most common in its faecal samples. Pseudomonadaceae was the predominant family in throat swab samples of S. murinus, while Enterobacteriaceae was most common in faecal samples. We annotated 33.28% sequences from faecal samples of S. murinus as potential human pathogenic bacteria, approximately 3.06-fold those in R. norvegicus. Potential pathogenic bacteria annotated in throat swab samples of S. murinus were 1.35-fold those in R. norvegicus. Conclusions Bacterial composition of throat swabs and faecal samples from R. norvegicus differed from those of S. murinus. Both species carried various pathogenic bacteria, therefore both should be closely monitored in the future, especially for S. murinus.

Background: Castor is a dicotyledon, ricinus communis, Euphorbiaceae, and is oneof world ten oil crops. Lm female line castor has three inflorescence types(female with marker, haplometrotic and monoecious). Female with marker castor was realized as a restorer line and as a maintainer line,which was applied to castor hybrid breeding. The developmental mechanism of the three inflorescences is not clear.Results: Therefor, in this study , proteomic and metabolomic analyses of different inflorescences axis were performed. Seventy-three diferentially abundant protein species (DAPS) were detected in the proteomics analysis and 86 differentially abundant metabolites (DAMs) were identified from the proteomic and metabolomic analyses of the inflorescences axis, respectively. These DAPS and DAMs are primarily mainly involved in carbon metabolism, comprising carbon fixation in the photosynthetic organism pathway, the glycolysis pathway, carbon metabolic pathways, and the biosynthesis of amino acids. Quantitative real-time PCR (qRT-PCR) results demonstrated that the proteomics and metabolomic data collected in this study were reliable.Conclusions: The results of this study provides some valuable insights into the inflorescence development of castor: Specifically, the results showed that DAPS and DAMs are involved in photosynthesis and respiration to control the distribution of imported carbohydrates and exported photoassimilates and thus affect inflorescence development of castor. Furthermore, the dynamic balance of amino acids in different types of inflorescences was also shown to be essential in affecting inflorescence structure.

Summary Young donors are reported to be associated with better transplant outcomes than older donors in allogeneic hematopoietic stem cell transplantation (allo-HSCT), but the mechanism is still unclear. The current study compared the different subsets of haematopoietic stem cells (HSCs) and their progenitors as well as immune cells in bone marrow (BM) between young and older donors. The frequencies of HSCs, multipotent progenitors (MPPs) and myeloid progenitors, including common myeloid progenitors (CMPs) and megakaryocyte–erythroid progenitors (MEPs), were decreased, whereas those of lymphoid progenitors, including multi-potent lymphoid progenitors (MLPs) and common lymphoid progenitors (CLPs), were increased in the BM of young donors compared with in that of older donors. Lower reactive oxygen species (ROS) levels were observed in BM HSCs and six progenitor lines in young donors. Furthermore, young donors demonstrated higher frequencies of naive T cells and immune suppressor cells, such as alternative macrophages (M2) and lower frequencies of memory T cells and immune effectors, including T helper-1 and T cytotoxic-1 cells, in BM than older donors. Multivariate analysis demonstrated that donor age was independently correlated with BM HSC frequency. Although further validation is required, our results suggest that the differences in the frequency and immune differentiation potential of HSCs in BM between young donors and older donors may partly explain the different outcomes of allo-HSCT.

Chronic HIV-1 infection is generally characterized by progressive CD4(+) T cell depletion due to direct and bystander death that is closely associated with persistent HIV-1 replication and an inflammatory environment in vivo. The mechanisms underlying the loss of CD4(+) T cells in patients with chronic HIV-1 infection are incompletely understood. In this study, we simultaneously monitored caspase-1 and caspase-3 activation in circulating CD4(+) T cells, which revealed that pyroptotic and apoptotic CD4(+) T cells are distinct cell populations with different phenotypic characteristics. Levels of pyroptosis and apoptosis in CD4(+) T cells were significantly elevated during chronic HIV-1 infection, and decreased following effective antiretroviral therapy. Notably, the occurrence of pyroptosis was further confirmed by elevated gasdermin D activation in lymph nodes of HIV-1–infected individuals. Mechanistically, caspase-1 activation closely correlated with the inflammatory marker expression and was shown to occur through NLRP3 inflammasome activation driven by virus-dependent and/or -independent ROS production, while caspase-3 activation in CD4(+) T cells was more closely related to T cell activation status. Hence, our findings show that NLRP3-dependent pyroptosis plays an essential role in CD4(+) T cell loss in HIV-1–infected patients and implicate pyroptosis signaling as a target for anti–HIV-1 treatment.

Background The emergence of coronavirus disease 2019 (COVID-19) is a major healthcare threat. The current method of detection involves a quantitative polymerase chain reaction (qPCR)–based technique, which identifies the viral nucleic acids when present in sufficient quantity. False-negative results can be achieved and failure to quarantine the infected patient would be a major setback in containing the viral transmission. We aim to describe the time kinetics of various antibodies produced against the 2019 novel coronavirus (SARS-CoV-2) and evaluate the potential of antibody testing to diagnose COVID-19. Methods The host humoral response against SARS-CoV-2, including IgA, IgM, and IgG response, was examined by using an ELISA-based assay on the recombinant viral nucleocapsid protein. 208 plasma samples were collected from 82 confirmed and 58 probable cases (qPCR negative but with typical manifestation). The diagnostic value of IgM was evaluated in this cohort. Results The median duration of IgM and IgA antibody detection was 5 (IQR, 3–6) days, while IgG was detected 14 (IQR, 10–18) days after symptom onset, with a positive rate of 85.4%, 92.7%, and 77.9%, respectively. In confirmed and probable cases, the positive rates of IgM antibodies were 75.6% and 93.1%, respectively. The detection efficiency by IgM ELISA is higher than that of qPCR after 5.5 days of symptom onset. The positive detection rate is significantly increased (98.6%) when combining IgM ELISA assay with PCR for each patient compared with a single qPCR test (51.9%). Conclusions The humoral response to SARS-CoV-2 can aid in the diagnosis of COVID-19, including subclinical cases., The time kinetics of humoral responses against the novel coronavirus (SARS-CoV-2) are characterized in patients with COVID-19 by nucleocapsid-based ELISA. The antibody testing can aid in the diagnosis of COVID-19 when combined with qPCR, including in subclinical cases.

Multidrug-resistant hypervirulent Klebsiella pneumoniae (MDR-hvKP) has been increasingly reported and is now recognized as a significant threat to public health; however, characterization of MDR-hvKP has not been systematically investigated. In the present study, 124 of 428 (28.92%) K. pneumoniae clinical isolates collected from January 2010 to December 2016 were identified with aerobactin and defined as hvKP; these included 79 (48.77%) non-MDR-KP, 35 (15.63%) extended spectrum β-lactamase-producing K. pneumoniae (ESBL-KP), and 10 (23.81%) carbapenem-resistant K. pneumoniae (CR-KP) isolates. The remaining 304 isolates that were not hypervirulent phenotypes were defined as classic K. pneumoniae (cKP). The antimicrobial resistance rate of cKP was significantly higher than that of the hvKP isolates in the non-MDR-KP group, but showed no significant differences in the ESBL-KP and CR-KP groups. The detection frequencies of K1 serotype, hypermucoviscosity, sequence type 23 (ST23), and two virulence genes—mucoviscosity-associated gene A (magA) and regulator of mucoid phenotype A (rmpA)—were significantly high in the hvKP than cKP isolates in all three groups (P < 0.05). Most of the hypervirulent ESBL-KP and CR-KP isolates were K non-typeable (28/45) and harbored at least one gene for virulence (36/45). The hypervirulent ESBL-KP isolates primarily carried blaSHV (25/35, 71.42%) genes, and the hypervirulent CR-KP isolates mainly carried blaNDM-1 (8/10, 80%) genes. Moreover, four hypervirulent ESBL-KP and two hypervirulent CR-KP isolates showed resistance to tigecycline. The transcriptional levels of rmpA in cKP were much lower than that in hvKP isolates in all three groups. Furthermore, overexpression of rmpA could partly restore the hypervirulent phenotype of the rmpA-low-expression cKP isolates. In conclusion, our data suggest that the K1 serotype, rmpA, magA, hypermucoviscosity, and ST23 were strongly associated with hvKP in non-MDR-KP, ESBL-KP, and CR-KP groups, and low rmpA expression levels contributed to the absence of hypervirulent phenotype.

By leveraging the ability of Shewanella oneidensis MR-1 (S. oneidensis MR-1) to anaerobically catabolize lactate through the transfer of electrons to metal minerals for respiration, a lactate-fueled biohybrid (Bac@MnO2 ) was constructed by modifying manganese dioxide (MnO2 ) nanoflowers on the S. oneidensis MR-1 surface. The biohybrid Bac@MnO2 uses decorated MnO2 nanoflowers as electron receptor and the tumor metabolite lactate as electron donor to make a complete bacterial respiration pathway at the tumor sites, which results in the continuous catabolism of intercellular lactate. Additionally, decorated MnO2 nanoflowers can also catalyze the conversion of endogenous hydrogen peroxide (H2 O2 ) into generate oxygen (O2 ), which could prevent lactate production by downregulating hypoxia-inducible factor-1α (HIF-1α) expression. As lactate plays a critical role in tumor development, the biohybrid Bac@MnO2 could significantly inhibit tumor progression by coupling bacteria respiration with tumor metabolism.

Clostridium difficile infection (CDI) is the leading cause of antibiotic-associated diarrhoea worldwide. In order to gain a better understanding about the molecular epidemiology of C. difficile in Beijing, China, molecular typing, antimicrobial susceptibility testing and drug resistance gene sequencing were performed on 174 strains of C. difficile collected from four large tertiary hospitals in Beijing. In total, 31 sequence types (STs) were identified among the 174 strains. ST81 was found to be the most prevalent (26.4%, 46/174), followed by ST2 (16.7%, 29/174) and ST54 (9.8%, 17/174). All isolates were susceptible to metronidazole and vancomycin. The test strains displayed resistance rates of 97.1%, 44.3% and 44.3% for ciprofloxacin, levofloxacin and moxifloxacin, respectively. ST81 isolates displayed a drug resistance rate of 97.8% for levofloxacin and moxifloxacin, which was significantly higher than ST2 (0%), ST54 (17.6%) and ST42 (0%) isolates (P

Bocaparvovirus infections of humans and both wild and domestic animals have been widely reported around the world. In this study, we detected and genetically characterized porcine bocavirus (PBoV) carried by murine rodents (Rattus norvegicus, Rattus tanezumi, and Rattus losea) and house shrews (Suncus murinus) in China. Between May 2015 and May 2017, 496 murine rodents and 23 house shrews were captured in four Chinese provinces. Nested polymerase chain reaction was used to investigate the prevalence of PBoV in throat swab, faecal and serum samples. A total of 7.5% (39/519) throat swab samples, 60.5% (309/511) faecal samples, and 22.9% (52/227) serum samples were PBoV-positive. The prevalence among R. norvegicus and R. tanezumi was higher than that among R. losea and house shrews. PBoV-positive samples were found in all four provinces. Phylogenetic analysis based on partial viral capsid protein 1/2 (VP1/VP2) showed that sequences obtained in this study formed a novel group (PBoV G4). In addition, five near full-length PBoV genomes (4,715-4,798 nt) were acquired. These genomes encoded two non-structural proteins, NS1 (1,908 nt in four genomes and 1,923 nt in the remaining genome) and NP1 (600 nt), and the structural proteins, VP1/VP2 (1,851 nt). Phylogenetic analysis showed that PBoV G4 is distinct from rodent, human, and other bocaviruses. In conclusion, PBoV G4 prevalence was high among two common murine rodents in China, and the pathogenecity of PBoV G4 need to be further clarified.

Background There are about 2.4 hundred thousand new cases and 1.5 hundred thousand deaths of ovarian cancer (OC) annually in the world. Chronic inflammation is a risk factor for OC. C-X-C motif chemokine ligand 1 (CXCL1) defects may facilitate inflammation and transactivate EGFR in ovarian cancer, but the precise haplotypes associated with the potential diseases remained largely unknown. In this work, we characterized CXCL1 gene variations to elucidate their possible associations with OC. Methods We analyzed the CXCL1 gene for 300 OC patients with 400 healthy participants as controls. The statistical analyses and Hardy-Weinberg equilibrium tests of the patients and control populations were conducted using the SPSS software (version 19.0) and Plink (version 1.9). Results The variants rs11547681, rs201090116, rs199791199, rs181868085, rs4074 and rs1814092 within or near the CXCL1 gene were characterized. The genetic heterozygosity of rs11547681 and rs4074 was very high. Statistical analysis showed that the variant rs11547681 in the gene was closely associated with the risk of OC in the Chinese Han population, although this variant was not associated with FIGO stages or pathological grades of the patients. Conclusions Rs11547681 in CXCL1 gene was associated with the risk of OC in the Chinese Han population.

Background A fraction of patients with penetrating artery infarction (PAI) experience progressive motor deficit deterioration (PMD). We sought to investigate the role of high-sensitivity C-reactive protein (hs-CRP) at admission in predicting PMD. Methods From January 2015 to September 2018, consecutive patients with PAI from three centers were prospectively enrolled in this study. PMD was defined as worsening of motor function score by ≥1 point on the National Institutes of Health Stroke Scale during the first 5 days after admission. Multivariable logistic regression analyses were performed to explore the relationship between hs-CRP and PMD in patients with PAI. We also performed receiver operating characteristic curve analysis and constructed a nomogram to assess the overall discriminative ability of hs-CRP in predicting PMD. Results We ultimately included 544 patients (mean age, 65.4 ± 11.8 years). A total of 85 (15.6%) patients were identified to have PMD. Multivariate logistic regression analysis showed that hs-CRP was independently associated with PMD (P = 0.001). The optimal cutoff value for hs-CRP as a predictor for PMD was 3.48 mg/L, with a sensitivity of 73.64% and a specificity of 82.35% (area under curve, 0.792). Moreover, the nomogram we constructed indicated that higher level of hs-CRP was an indicator of PMD (c-index = 0.780, P Conclusions Our study suggested that hs-CRP might be a useful biomarker for predicting the risk of PMD in patients with PAI.

Glioblastoma is the most common and aggressive adult brain cancer. Tumors show frequent dysregulation of the PI3K–mTOR pathway. Although a number of small molecules target the PI3K–AKT–mTOR axis, their preclinical and clinical efficacy has been limited. Reasons for treatment failure include poor penetration of agents into the brain and observations that blockade of PI3K or AKT minimally affects downstream mTOR activity in glioma. Clinical trials using allosteric mTOR inhibitors (rapamycin and rapalogs) to treat patients with glioblastoma have also been unsuccessful or uncertain, in part, because rapamycin inefficiently blocks the mTORC1 target 4EBP1 and feeds back to activate PI3K–AKT signaling. Inhibitors of the mTOR kinase (TORKi) such as TAK-228/MLN0128 interact orthosterically with the ATP- and substrate-binding pocket of mTOR kinase, efficiently block 4EBP1 in vitro, and are currently being investigated in the clinical trials. Preclinical studies suggest that TORKi have poor residence times of mTOR kinase, and our data suggest that this poor pharmacology translates into disappointing efficacy in glioblastoma xenografts. RapaLink-1, a TORKi linked to rapamycin, represents a drug with improved pharmacology against 4EBP1. In this review, we clarify the importance of 4EBP1 as a biomarker for the efficacy of PI3K–AKT–mTOR inhibitors in glioblastoma. We also review mechanistic data by which RapaLink-1 blocks p-4EBP1 and discuss future clinical strategies for 4EBP1 inhibition in glioblastoma. Clin Cancer Res; 24(1); 14–21. ©2017 AACR.

Objective: To investigate the prevalence of the adeno-associated virus (AAV) in murine rodents and house shrews in 4 provinces of China. Methods: A total of 469 murine rodents and 19 house shrews were captured between May 2015 and May 2017. Cap gene of AAV sequences was obtained to evaluate the genetic characteristics of rat AAV. Results: Rat AAVs were found in 54.7% (267/488) of throat swabs, 14.3% (70/488) of fecal samples, and 18.4% (41/223) of serum samples. Rat AAVs were detected in 3 species of murine rodents including Rattus norvegicus (34.8%), R. tanezumi (43.0%), and R. losea (2.3%), and house shrews (Suncus murinus) (26.1%) from the selected sampling sites. Fourteen near-full-length Cap gene sequences, ranging in length from 2,156 to 2,169 nt, were isolated from the fecal samples of R. norvegicus and R. tanezumi. These 14 sequences shared a high identity of 97.4% at the nucleotide level and 99.1% at the amino acid level. Phylogenetic analysis showed that the rat AAV formed a distinct clade, distinguishable from the AAV discovered in humans and in other animals. Conclusions: A high prevalence of rat AAV that was highly conserved within the Cap gene was found in 3 common murine rodents and house shrews in China.

We investigated the effect on rheumatoid arthritis (RA) of an anti-gp130 monoclonal antibody (mAb) and its mechanism using RA fibroblast-like synoviocytes (FLS) and a collagen antibody-induced arthritis (CAIA) mouse model. We determined the interleukin 6 (IL-6), IL-6 receptor α (IL-6Rα), gp130, receptor activator of nuclear factor κB ligand (RANKL), matrix metalloproteinase 3 (MMP3), TIMP metallopeptidase inhibitor 1 (TIMP1), and Bcl-2 levels in RA and osteoarthritis (OA) serum and synovial fluid. RA FLS were cultured with or without IL-6/IL-6Rα; WNT5A and RANKL levels were detected. We generated an anti-gp130 mAb (M10) with higher affinity and specificity, blocked IL-6 signaling with it, and assessed its effects on the CAIA model, WNT5A and RANKL expression, and signal transducer and activator of transcription 3 (STAT3) phosphorylation. The IL-6 signaling system in patients with RA was increased; RANKL, MMP3, TIMP1, and Bcl-2 in RA bone were elevated. IL-6/IL-6Rα increased RA FLS WNT5A and RANKL expression. M10 ameliorated arthritis in the CAIA model, and inhibited RANKL, WNT5A, and Bcl-2 expression in RA FLS by blocking IL-6 signaling, likely via Janus kinase-STAT3 pathway downregulation. The IL-6-soluble IL-6Rα-gp130 complex is hyperactive in RA and OA. M10 may be the basis for a novel RA treatment drug.

In recent years, hepatitis B virus (HBV) has been detected in some species of animals. In this study, we found HBV-like nucleotide sequences in murine rodents and Asian house shrews (Suncu...

The 3′ untranslated regions (3′ UTRs) of mRNAs play important roles in the regulation of mRNA localization, translation, and stability. Alternative cleavage and polyadenylation (APA) generates mRNAs with different 3′ UTRs, but the involvement of this process in stress response has not yet been clarified. Here, we report that a subset of stress-related genes exhibits 3′ UTR extensions of their mRNAs during dehydration stress. These extended 3′ UTRs have characteristics of long noncoding RNAs and likely do not interact with miRNAs. Functional studies using T-DNA insertion mutants reveal that they can act as antisense transcripts to repress expression levels of sense genes from the opposite strand or can activate the transcription or lead to read-through transcription of their downstream genes. Further analysis suggests that transcripts with 3′ UTR extensions have weaker poly(A) signals than those without 3′ UTR extensions. Finally, we show that their biogenesis is partially dependent on a trans-acting factor FPA. Taken together, we report that dehydration stress could induce transcript 3′ UTR extensions and elucidate a novel function for these stress-induced 3′ UTR extensions as long noncoding RNAs in the regulation of their neighboring genes.

Cardiovascular disease still remains the primary cause of death worldwide and obesity is becoming recognized as one of the most critical contributing risk factors. The increased prevalence of obesity casts a cloud over the global health and the whole societies and will still be burdened in the future. Therefore, prevention and therapy of obesity is a beneficial strategy for the prevention of chronic cardiovascular disease. Numerous studies have demonstrated that gut microbiota takes part in human health and disease including obesity. Traditional herbs hold great potential to improve people's health and wellness, particularly in the area of chronic inflammatory diseases although the mechanisms of action remain poorly understood. Emerging explorations of gut microbiotaherb interactions provide a potential to revolutionize the way we view herbal therapeutics. This review summarizes the experimental studies performed on animals and humans regarding the gut microbiota-herb interactions targeting obesity. This review also discusses the opportunity of herbs with potent activities but low oral bioavailability conundrum for prevention and therapy for obesity and related cardiovascular disease.