SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) is the etiological agent responsible for the global COVID-19 (coronavirus disease 2019) outbreak. The main protease of SARS-CoV-2, M
, is ...a key enzyme that plays a pivotal role in mediating viral replication and transcription. We designed and synthesized two lead compounds (
and
) targeting M
Both exhibited excellent inhibitory activity and potent anti-SARS-CoV-2 infection activity. The x-ray crystal structures of SARS-CoV-2 M
in complex with
or
, both determined at a resolution of 1.5 angstroms, showed that the aldehyde groups of
and
are covalently bound to cysteine 145 of M
Both compounds showed good pharmacokinetic properties in vivo, and
also exhibited low toxicity, which suggests that these compounds are promising drug candidates.
Summary Background Human babesiosis is an emerging zoonosis. “ Babesia venatorum ” has been identified in only four asplenic men and a child so far. We aimed to describe the epidemiological, ...clinical, and laboratory characteristics of a series of cases with “ B venatorum ” infection identified in a sentinel hospital in China. Methods We recruited participants with a recent tick bite at Mudanjiang Forestry Central Hospital, Heilongjiang province, China. Cases were diagnosed through PCR followed by sequencing, microscopic identification, or isolation by animal inoculation, or both. Findings 48 individuals (30 women or girls; median age 45 years, range 7 months to 75 years) with “ B venatorum ” infection were identified. 32 of these individuals were confirmed cases and 16 were probable cases. None of the 48 cases had received a blood transfusion or had a splenectomy. Geographically, cases were distributed diffusely throughout the hospital catchment area. Of the 32 confirmed cases, 21 (66%) presented with a fever, 13 (41%) with a headache, 12 (38%) with myalgia or arthralgia, and three (9%) with chills. 14 (44%) patients had fatigue, eight (25%) had dizziness, and eight (25%) had hypersomnia. Six (19%) patients had an erythematous non-pruritic rash around the tick-bite site and two (6%) had lymphadenopathy. Seven (22%) and four (13%) patients had anaemia and thrombocytopenia, respectively, and seven (50%) of 14 patients with confirmed infection had increased hepatic transaminase concentrations. In the confirmed cases, concentrations of intercellular adhesion molecule 3 (p<0·001), P-selectin (p<0·05), and platelet endothelial cell adhesion molecule 1 (p<0·001) were significantly reduced, whereas tumour necrosis factor α (p<0·01) and vascular cell adhesion molecule 1 (p<0·001) were significantly increased. Interpretation “ B venatorum ” infection should be included in the differential diagnosis of patients with a tick-exposure history in areas where this pathogen has previously been identified in ticks or people. Funding Natural Science Foundation of China and Mega-Project for Infectious Diseases.
The pandemic of coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become a global crisis. Replication of SARS-CoV-2 requires the viral ...RNA-dependent RNA polymerase (RdRp) enzyme, a target of the antiviral drug remdesivir. Here we report the cryo-electron microscopy structure of the SARS-CoV-2 RdRp, both in the apo form at 2.8-angstrom resolution and in complex with a 50-base template-primer RNA and remdesivir at 2.5-angstrom resolution. The complex structure reveals that the partial double-stranded RNA template is inserted into the central channel of the RdRp, where remdesivir is covalently incorporated into the primer strand at the first replicated base pair, and terminates chain elongation. Our structures provide insights into the mechanism of viral RNA replication and a rational template for drug design to combat the viral infection.
Piwi‐interacting RNAs (piRNAs), a novel class of small non‐coding RNAs, were first discovered in germline cells and are thought to silence transposons in spermatogenesis. Recently, piRNAs have also ...been identified in somatic tissues, and aberrant expression of piRNAs in tumor tissues may be implicated in carcinogenesis. However, the function of piR‐823 in colorectal cancer (CRC) remains unclear. Here, we first found that piR‐823 was significantly upregulated in CRC tissues compared with its expression in the adjacent tissues. Inhibition of piR‐823 suppressed cell proliferation, arrested the cell cycle in the G1 phase and induced cell apoptosis in CRC cell lines HCT116 and DLD‐1, whereas overexpression of piR‐823 promoted cell proliferation in normal colonic epithelial cell line FHC. Interestingly, Inhibition of piR‐823 repressed the expression of heat shock protein (HSP) 27, 60, 70. Furthermore, elevated HSPs expression partially abolished the effect of piR‐823 on cell proliferation and apoptosis. In addition, we further demonstrated that piR‐823 increased the transcriptional activity of HSF1, the common transcription factor of HSPs, by binding to HSF1 and promoting its phosphorylation at Ser326. Our study reveals that piR‐823 plays a tumor‐promoting role by upregulating phosphorylation and transcriptional activity of HSF1 and suggests piR‐823 as a potential therapeutic target for CRC.
piR‐823 is up‐regulated in colorectal cancer tissues .piR‐823 promotes proliferation and inhibits apoptosis in colorectal cancer carcinogenesis.piR‐823 elevates the expression of HSP27, 60 and 70 by binding to HSF1 and enhancing its activity.
Combretastatin-4 (CA-4) as a tubulin polymerization inhibitor draws extensive attentions. However, due to its weak stability of
-olefin and poor metabolic stability, structure modifications on
...-configuration are being performed. In this work, we constructed a series of novel CA-4 analogues with linkers on olefin containing diphenylethanone,
-locked dihydrofuran, α-substituted diphenylethanone, cyclobutane and cyclohexane on its
-olefin. Cytotoxic activity of all analogues was measured by an SRB assay. Among them, compound
, a by-product in the preparation of diphenylethanone analogues, was found to be the most potent cytotoxic agents against HepG2 cells with IC
values of less than 0.5 μM. The two isomers of
induced cellular apoptosis tested by Annexin V-FITC and propidium iodide (PI) double staining, arrested cells in the G2/M phase by PI staining analysis, and disrupted microtubule network by immunohistochemistry study in HepG2 cells. Moreover,
displayed a dose-dependent inhibition effect for tubulin assembly in in vitro tubulin polymerization assay. In addition, molecular docking studies showed that two isomers of
could bind efficiently at colchicine binding site of tubulin similar to CA-4.
Progress in chemistry over the past four decades has generated a variety of porous materials for removing iodine—a radioactive emission accompanying nuclear fission. However, most studies are still ...based on the notion that entangled pores together with specific binding sites are essential for iodine capture. Here, an unraveled physical picture of iodine capture that overturns the preconception by exploring 1D channeled porous materials is disclosed. 2D covalent organic frameworks are constructed in a way so that they are free of interpenetration and binding sites but consist of 1D open channels. As verified with different channels shaping from hexagonal to tetragonal and trigonal and ranging from micropores to mesopores, all the 1D channels enable a full access to iodine, generalizing a new paradigm that the pore volume determines the uptake capacity. These results are of fundamental importance to understanding iodine uptake and designing materials to treat coagulative toxic vapors.
Two‐dimensional covalent organic frameworks enable the full occupation of their one‐dimensional channel space for capturing iodine, leading to an exceptional capacity.
A survey was carried out on the microbial community of 20 groundwater samples (4 low and 16 high arsenic groundwater) and 19 sediments from three boreholes (two high arsenic and one low arsenic ...boreholes) in a high arsenic groundwater system located in Hetao Basin, Inner Mongolia, using the 454 pyrosequencing approach. A total of 233,704 sequence reads were obtained and classified into 12-267 operational taxonomic units (OTUs). Groundwater and sediment samples were divided into low and high arsenic groups based on measured geochemical parameters and microbial communities, by hierarchical clustering and principal coordinates analysis. Richness and diversity of the microbial communities in high arsenic sediments are higher than those in high arsenic groundwater. Microbial community structure was significantly different either between low and high arsenic samples or between groundwater and sediments. Acinetobacter, Pseudomonas, Psychrobacter and Alishewanella were the top four genera in high arsenic groundwater, while Thiobacillus, Pseudomonas, Hydrogenophaga, Enterobacteriaceae, Sulfuricurvum and Arthrobacter dominated high arsenic sediments. Archaeal sequences in high arsenic groundwater were mostly related to methanogens. Biota-environment matching and co-inertia analyses showed that arsenic, total organic carbon, SO4(2-), SO4(2-)/total sulfur ratio, and Fe(2+) were important environmental factors shaping the observed microbial communities. The results of this study expand our current understanding of microbial ecology in high arsenic groundwater aquifers and emphasize the potential importance of microbes in arsenic transformation in the Hetao Basin, Inner Mongolia.
Hyperactivated Ras regulates many oncogenic pathways in several malignant human cancers including glioblastoma and it is an attractive target for cancer therapies. Ras activation in cancer cells ...drives protein internalization via macropinocytosis as a key nutrient-gaining process. By utilizing this unique endocytosis pathway, here we create a biologically inspired nanostructure that can induce cancer cells to 'drink drugs' for targeting activating transcription factor-5 (ATF5), an overexpressed anti-apoptotic transcription factor in glioblastoma. Apolipoprotein E3-reconstituted high-density lipoprotein is used to encapsulate the siRNA-loaded calcium phosphate core and facilitate it to penetrate the blood-brain barrier, thus targeting the glioblastoma cells in a macropinocytosis-dependent manner. The nanostructure carrying ATF5 siRNA exerts remarkable RNA-interfering efficiency, increases glioblastoma cell apoptosis and inhibits tumour cell growth both in vitro and in xenograft tumour models. This strategy of targeting the macropinocytosis caused by Ras activation provides a nanoparticle-based approach for precision therapy in glioblastoma and other Ras-activated cancers.
Abstract
Background
In gut microbiome studies, the cultured gut microbial resource plays essential roles, such as helping to unravel gut microbial functions and host-microbe interactions. Although ...several major studies have been performed to elucidate the cultured human gut microbiota, up to 70% of the Unified Human Gastrointestinal Genome species have not been cultured to date. Large-scale gut microbial isolation and identification as well as availability to the public are imperative for gut microbial studies and further characterizing human gut microbial functions.
Results
In this study, we constructed a human Gut Microbial Biobank (hGMB; homepage:
hgmb.nmdc.cn
) through the cultivation of 10,558 isolates from 31 sample mixtures of 239 fresh fecal samples from healthy Chinese volunteers, and deposited 1170 strains representing 400 different species in culture collections of the International Depository Authority for long-term preservation and public access worldwide. Following the rules of the International Code of Nomenclature of Prokaryotes, 102 new species were characterized and denominated, while 28 new genera and 3 new families were proposed. hGMB represented over 80% of the common and dominant human gut microbial genera and species characterized from global human gut 16S rRNA gene amplicon data (
n
= 11,647) and cultured 24 “most-wanted” and “medium priority” taxa proposed by the Human Microbiome Project. We in total sequenced 115 genomes representing 102 novel taxa and 13 previously known species. Further in silico analysis revealed that the newly sequenced hGMB genomes represented 22 previously uncultured species in the Unified Human Gastrointestinal Genome (UHGG) and contributed 24 representatives of potentially “dark taxa” that had not been discovered by UHGG. The nonredundant gene catalogs generated from the hGMB genomes covered over 50% of the functionally known genes (KEGG orthologs) in the largest global human gut gene catalogs and approximately 10% of the “most wanted” functionally unknown proteins in the FUnkFams database.
Conclusions
A publicly accessible human Gut Microbial Biobank (hGMB) was established that contained 1170 strains and represents 400 human gut microbial species. hGMB expands the gut microbial resources and genomic repository by adding 102 novel species, 28 new genera, 3 new families, and 115 new genomes of human gut microbes.
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