Some pathogens and pests deliver small RNAs (sRNAs) into host cells to suppress host immunity. Conversely, hosts also transfer sRNAs into pathogens and pests to inhibit their virulence. Although sRNA ...trafficking has been observed in a wide variety of interactions, how sRNAs are transferred, especially from hosts to pathogens and pests, is still unknown. Here, we show that host
cells secrete exosome-like extracellular vesicles to deliver sRNAs into fungal pathogen
These sRNA-containing vesicles accumulate at the infection sites and are taken up by the fungal cells. Transferred host sRNAs induce silencing of fungal genes critical for pathogenicity. Thus,
has adapted exosome-mediated cross-kingdom RNA interference as part of its immune responses during the evolutionary arms race with the pathogen.
The outbreak of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in China has been declared a public health emergency of international ...concern. The cardiac injury is a common condition among the hospitalized patients with COVID-19. However, whether N terminal pro B type natriuretic peptide (NT-proBNP) predicted outcome of severe COVID-19 patients was unknown.
The study initially enrolled 102 patients with severe COVID-19 from a continuous sample. After screening out the ineligible cases, 54 patients were analyzed in this study. The primary outcome was in-hospital death defined as the case fatality rate. Research information and following-up data were obtained from their medical records.
The best cut-off value of NT-proBNP for predicting in-hospital death was 88.64 pg/mL with the sensitivity for 100% and the specificity for 66.67%. Patients with high NT-proBNP values (> 88.64 pg/mL) had a significantly increased risk of death during the days of following-up compared with those with low values (≤88.64 pg/mL). After adjustment for potential risk factors, NT-proBNP was independently correlated with in-hospital death.
NT-proBNP might be an independent risk factor for in-hospital death in patients with severe COVID-19.
ClinicalTrials, NCT04292964. Registered 03 March 2020.
ObjectiveThere is little evidence that adjuvant therapy after radical surgical resection of hepatocellular carcinoma (HCC) improves recurrence-free survival (RFS) or overall survival (OS). We ...conducted a multicentre, randomised, controlled, phase IV trial evaluating the benefit of an aqueous extract of Trametes robinophila Murr (Huaier granule) to address this unmet need.Design and resultsA total of 1044 patients were randomised in 2:1 ratio to receive either Huaier or no further treatment (controls) for a maximum of 96 weeks. The primary endpoint was RFS. Secondary endpoints included OS and tumour extrahepatic recurrence rate (ERR). The Huaier (n=686) and control groups (n=316) had a mean RFS of 75.5 weeks and 68.5 weeks, respectively (HR 0.67; 95% CI 0.55 to 0.81). The difference in the RFS rate between Huaier and control groups was 62.39% and 49.05% (95% CI 6.74 to 19.94; p=0.0001); this led to an OS rate in the Huaier and control groups of 95.19% and 91.46%, respectively (95% CI 0.26 to 7.21; p=0.0207). The tumour ERR between Huaier and control groups was 8.60% and 13.61% (95% CI −12.59 to −2.50; p=0.0018), respectively.ConclusionsThis is the first nationwide multicentre study, involving 39 centres and 1044 patients, to prove the effectiveness of Huaier granule as adjuvant therapy for HCC after curative liver resection. It demonstrated a significant prolongation of RFS and reduced extrahepatic recurrence in Huaier group.Trial registration NCT01770431; Post-results.
The low resection and high recurrence rates in hepatocellular carcinoma (HCC) are the major challenges to improving prognosis. Neoadjuvant and conversion therapies are underlying strategies to ...overcome these challenges. To date, no guideline or consensus has been published on the neoadjuvant and conversion therapies in HCC. Recent studies showed that neoadjuvant therapy for resectable HCC and conversion therapy for unresectable HCC are safe, feasible, and effective. Neoadjuvant and conversion therapies have the following advantages in treating HCC: R0 resection with sufficient volume of future liver remnant, relatively simple operation, and wide applicability. Therefore, it was necessary to conduct a widely accepted consensus among the experts in China who have extensive expertise and experience in treating HCC using neoadjuvant and conversion therapies, which is important to standardize the application of neoadjuvant and conversion therapies for the management of HCC. The strategies of neoadjuvant therapy include the selection of the eligible patients, therapy regimen, cycles, effect evaluations, and multidisciplinary treatment. The management of patients with insufficient volume of future liver remnant and patients who cannot achieve R0 resection is the key to the strategies of conversion therapy. Here, we present the resultant evidence- and experience-based consensus to guide the application of neoadjuvant and conversion therapies in clinical practice.
Background
The gut is implicated in the pathogenesis of acute pancreatitis (AP) and the infectious complications of AP are commonly associated with enteric bacteria, yet whether gut microbiota ...dysbiosis participants in AP severity remains largely unknown.
Methods
We collected clinical information and fecal samples from 165 adult participants, including 41 with mild AP (MAP), 59 with moderately severe AP (MSAP), 30 with severe AP (SAP) and 35 healthy controls (HC). The serum inflammatory cytokines and gut barrier indexes were detected. Male C57BL/6 mice with AP were established and injuries of pancreas were evaluated in antibiotic-treated mice, germ-free mice as well as those transplanted with fecal microbiota. The gut microbiota was analyzed by 16S rRNA gene sequencing.
Results
The structure of gut microbiota was significantly different between AP and HC, and the disturbed microbiota was closely correlated with systematic inflammation and gut barrier dysfunction. Notably, the microbial composition changed further with the worsening of AP and the abundance of beneficial bacteria such as
Blautia
was decreased in SAP compared with MAP and MSAP. The increased capacity for the inferred pathway, bacterial invasion of epithelial cells in AP, highly correlated with the abundance of
Escherichia
–
Shigella
. Furthermore, the antibiotic-treated mice and germ-free mice exhibited alleviated pancreatic injury after AP induction and subsequent fecal microbiota transplantation in turn exacerbated the disease.
Conclusions
This study identifies the gut microbiota as an important mediator during AP and its dysbiosis is associated with AP severity, which suggests its role as potential therapeutic target.
State Key Laboratory of Hybrid Rice, College of Life Sciences, Wuhan University, Wuhan, China Affiliation: Department of Microbiology and Plant Pathology, Center for Plant Cell Biology, Institute for ...Integrative Genome Biology, University of California, Riverside, California, United States of America Baoye He Affiliation: Department of Microbiology and Plant Pathology, Center for Plant Cell Biology, Institute for Integrative Genome Biology, University of California, Riverside, California, United States of America ORCID logo http://orcid.org/0000-0003-0401-4955 Arne Weiberg Affiliation: Department of Biology, Ludwig-Maximilians University of Munich (LMU), Munich, Germany ORCID logo http://orcid.org/0000-0003-4300-4864 Amy H. Buck Affiliations Institute of Immunology and Infection Research, School of Biological Sciences, University of Edinburgh, Edinburgh, United Kingdom, Centre for Immunity, Infection and Evolution, School of Biological Sciences, University of Edinburgh, Edinburgh, United Kingdom ORCID logo http://orcid.org/0000-0003-2645-7191 Hailing Jin * E-mail: hailingj@ucr.edu Affiliation: Department of Microbiology and Plant Pathology, Center for Plant Cell Biology, Institute for Integrative Genome Biology, University of California, Riverside, California, United States of America ORCID logo http://orcid.org/0000-0001-5778-5193 Citation: Cai Q, He B, Weiberg A, Buck AH, Jin H (2019) Small RNAs and extracellular vesicles: In detail, Botrytis cinerea, the grey mold fungal pathogen that infects over 1,000 plant species, delivers sRNAs into plant cells and hijacks host RNAi machinery by loading its sRNAs into the Arabidopsis AGO1 protein to trigger silencing of host immunity genes, including mitogen-activated protein kinases (MAPKs), cell-wall–associated kinases, and other defense and signaling proteins 2. AGO, Argonaute; EE, early endosome; ER, endoplasmic reticulum; EV, extracellular vesicle; MV, microvesicle; MVB, multivesicular body; RNAi, RNA interference; sRNA, small RNA; TGN, trans-Golgi network. https://doi.org/10.1371/journal.ppat.1008090.g001 Cross-kingdom sRNA trafficking from a fungal pathogen to an animal host was also observed recently. Patients who suffer from sickle cell anemia show abnormal erythrocyte development but exhibit resistance to the malaria parasite Plasmodium falciparum.
Plant extracellular vesicles (EVs) play critical roles in the cross‐kingdom trafficking of molecules from hosts to interacting microbes, most notably in plant defense responses. However, the ...isolation of pure, intact EVs from plants remains challenging. A variety of methods have been utilized to isolate plant EVs from apoplastic washing fluid (AWF). Here, we compare published plant EV isolation methods, and provide our recommended method for the isolation and purification of plant EVs. This method includes a detailed protocol for clean AWF collection from Arabidopsis thaliana leaves, followed by EV isolation via differential centrifugation. To further separate and purify specific subclasses of EVs from heterogeneous vesicle populations, density gradient ultracentrifugation and immunoaffinity capture are then utilized. We found that immunoaffinity capture is the most precise method for specific EV subclass isolation when suitable specific EV biomarkers and their corresponding antibodies are available. Overall, this study provides a guide for the selection and optimization of EV isolation methods for desired downstream applications.
Plants secrete membrane‐bound extracellular vesicles that mediate cell‐to‐cell communication via the transfer of molecules between plant cells and pathogen cells. In this study, we provide detailed methods for isolating and purifying plant extracellular vesicles from the model flowering plant Arabidopsis thaliana.
A nickel-catalyzed benzylic substitution of secondary phosphine oxide was described, affording the dialkylated P-stereogenic tertiary phosphine oxides with high to excellent enantioselectivities. The ...reaction was performed under mild conditions with commercially available benzyl chlorides and bench stable secondary phosphine oxides, exhibiting broad functional group tolerance. It represented a practical example for the preparation of P-stereogenic phosphine compounds.
The phase-to-ground admittance in distribution networks is asymmetric. This asymmetry is aggravated by the arc suppression coil, resulting in zero-sequence overvoltage. The magnitude of zero-sequence ...overvoltage can exceed the line-to-ground voltage, endangering the operation of electrical equipment. Moreover, after the occurrence of a single-line-to-ground fault, the change law of the three-phase voltage is affected by the zero-sequence overvoltage, leading to misjudgment of the fault phase. Accordingly, this paper proposes a fault phase selection method based on active current injection that can adapt to asymmetric distribution networks. The fault phase is selected by injecting current and calculating the equivalent power supply voltage of the faulty line without increasing the ground-fault current. The high sensitivity of the proposed fault phase selection method was verified for high impedance faults through software simulations and prototype experiments. Moreover, the zero-sequence overvoltage can be suppressed by a single-phase flexible arc suppression device during the normal operation of distribution networks. The ground-fault current can be quickly suppressed at different ground-fault locations and resistance values, ensuring the extinguishment of the ground-fault arc.
Gallbladder cancer is the most common biliary tract malignancy and not sensitive to chemotherapy. Autophagy is an important factor prolonging the survival of cancer cells under chemotherapeutic ...stress. We aimed to investigate the role of long non-coding RNAs (lncRNAs) in autophagy and chemoresistance of gallbladder cancer cells.
We established doxorubicin (Dox)-resistant gallbladder cancer cells and used microarray analysis to compare the expression profiles of lncRNAs in Dox-resistant gallbladder cancer cells and their parental cells. Knockdown or exogenous expression of lncRNA combined with in vitro and in vivo assays were performed to prove the functional significance of lncRNA. The effects of lncRNA on autophagy were assessed by stubRFP-sensGFP-LC3 and western blot. We used RNA pull-down and mass spectrometry analysis to identify the target proteins of lncRNA.
The drug-resistant property of gallbladder cancer cells is related to their enhanced autophagic activity. And we found a lncRNA ENST00000425894 termed gallbladder cancer drug resistance-associated lncRNA1 (GBCDRlnc1) that serves as a critical regulator in gallbladder cancer chemoresistance. Furthermore, we discovered that GBCDRlnc1 is upregulated in gallbladder cancer tissues. Knockdown of GBCDRlnc1, via inhibiting autophagy at initial stage, enhanced the sensitivity of Dox-resistant gallbladder cancer cells to Dox in vitro and in vivo. Mechanically, we identified that GBCDRlnc1 interacts with phosphoglycerate kinase 1 and inhibits its ubiquitination in Dox-resistant gallbladder cancer cells, which leads to the down-regulation of autophagy initiator ATG5-ATG12 conjugate.
Our findings established that the chemoresistant driver GBCDRlnc1 might be a candidate therapeutic target for the treatment of advanced gallbladder cancer.
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