Acetaminophen (APAP) overdose is a major cause of the morbidity of acute liver failure. The current clinically approved treatment for APAP poisoning, N-acetylcysteine (NAC), has a limited therapeutic window, and prolonged treatment with NAC delays liver regeneration. Mesenchymal stem cells (MSCs) also have therapeutic effects on APAP-induced mouse liver failure, but whether the effects are comparable to those of NAC has not been determined, and the mechanism still needs further exploration.

Two-dimensional ultrathin Ti3C2 (MXene) nanosheets have been extensively explored for various biomedical applications. However, safety issues and the effects of Ti3C2 on human health remain poorly understood.

The recombinase RAD51 catalyzes the DNA strand exchange reaction in homologous recombination (HR) during both mitosis and meiosis. However, the physiological role of RAD51 during spermatogenesis remains unclear since RAD51 null mutation is embryonic lethal in mice. In this study, we generated a conditional knockout mouse model to study the role of RAD51 in spermatogenesis. Conditional disruption of RAD51 in germ cells by Vasa-Cre led to spermatogonial loss and Sertoli cell-only syndrome. Furthermore, tamoxifen-inducible RAD51 knockout by UBC-CreERT2 confirmed that RAD51 deletion led to early spermatogenic cells loss and apoptosis. Notably, inducible knockout of RAD51 in adult mice caused defects in meiosis, with accumulated meiotic double-strand breaks (DSBs), reduced numbers of pachytene spermatocytes and less crossover formation. Our study revealed an essential role for Rad51 in the maintenance of spermatogonia as well as meiotic progression in mice.

Dopamine receptors are involved in several immunological diseases. We previously found that dopamine D3 receptor (D3R) on mast cells showed a high correlation with disease activity in patients with rheumatoid arthritis, but the mechanism remains largely elusive. In this study, a murine collagen-induced arthritis (CIA) model was employed in both DBA/1 mice and D3R knockout mice. Here, we revealed that D3R-deficient mice developed more severe arthritis than wild-type mice. D3R suppressed mast cell activation in vivo and in vitro via a Toll-like receptor 4 (TLR4)-dependent pathway. Importantly, D3R promoted LC3 conversion to accelerate ubiquitin-labeled TLR4 degradation. Mechanistically, D3R inhibited mTOR and AKT phosphorylation while enhancing AMPK phosphorylation in activated mast cells, which was followed by autophagy-dependent protein degradation of TLR4. In total, we found that D3R on mast cells alleviated inflammation in mouse rheumatoid arthritis through the mTOR/AKT/AMPK-LC3-ubiquitin-TLR4 signaling axis. These findings identify a protective function of D3R against excessive inflammation in mast cells, expanding significant insight into the pathogenesis of rheumatoid arthritis and providing a possible target for future treatment.

Accumulating evidence has revealed that the dysregulation of circular RNAs (circRNAs) plays crucial roles in the occurrence and progression of cancers. However, the aberrant expression profile and dysfunction of circRNAs in non-small cell lung cancer (NSCLC) have not been fully explored. Herein, we discovered that a circRNA, hsa_circ_0001666 (circ0001666), was highly expressed in NSCLC tissues and cell lines, and it was positively correlated with NSCLC tumor pathological grade and lymph node metastasis. Moreover, Kaplan-Meier survival analysis implied that NSCLC patients with high circ0001666 expression were negatively correlated with favorable survival. Functionally, circ0001666 could promote migration and invasion of NSCLC cells in vitro and in vivo. Mechanistically, circ0001666 could act as a sponge to miR-1184/miR-548I and upregulate the expression of AGO1, thereby promoting the activation of the phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR signaling pathway in NSCLC cells. Collectively, these findings demonstrated that circ0001666 could serve as an oncogene to promote the migration and invasion of NSCLC via a novel miR-1184/miR-548I/AGO1 axis, which might be a promising therapeutic target for NSCLC treatment.

The purpose of this study was to design an automated algorithm that can detect fluorescence leakage accurately and quickly without the use of a large amount of labeled data.

Rhabdoid tumors (RT) are rare and deadly pediatric cancers driven by loss of SMARCB1, which encodes the SNF5 component of the SWI/SNF chromatin remodeler. Loss of SMARCB1 is associated with a complex set of phenotypic changes including vulnerability to inhibitors of protein synthesis and of the p53 ubiquitin-ligase HDM2. Recently, we discovered small molecule inhibitors of the 'WIN' site of WDR5, which in MLL-rearranged leukemia cells decrease the expression of a set of genes linked to protein synthesis, inducing a translational choke and causing p53-dependent inhibition of proliferation. Here, we characterize how WIN site inhibitors act in RT cells. As in leukemia cells, WIN site inhibition in RT cells causes the comprehensive displacement of WDR5 from chromatin, resulting in a decrease in protein synthesis gene expression. Unlike leukemia cells, however, the growth response of RT cells to WIN site blockade is independent of p53. Exploiting this observation, we demonstrate that WIN site inhibitor synergizes with an HDM2 antagonist to induce p53 and block RT cell proliferation in vitro. These data reveal a p53-independent action of WIN site inhibitors and forecast that future strategies to treat RT could be based on dual WDR5/HDM2 inhibition.

Quercetin (Que) exhibits excellent biological activity; however, its clinical development is hindered owing to the poor water solubility. In this study, Que. was loaded on polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (PVCL-PVA-PEG, Soluplus) micelles through a thin-film hydration process, and their tumor angiogenesis inhibition ability was investigated. The particle size of Soluplus-Que micelles was 55.3 ± 1.8 nm, and the micelles stayed stability within 9 months. Soluplus-Que micelles can enhance the cell uptake of Que. and transport the micelles to intracellular lysosomes and mitochondria. The MTT assay results revealed that Soluplus-Que micelles enhanced the cytotoxicity of Que. on HUVEC cells. Furthermore, Soluplus-Que micelles inhibited migration and invasion of HUVEC cells, as well as inhibited the neovascularization of chick embryo allantoic membrane (CAM). The in vivo study revealed that Soluplus-Que micelles significantly inhibit the growth of H22 solid tumors, with low toxic side effects. Soluplus-Que inhibited the expression of CD31 (a marker of angiogenesis) and the PI3K/Akt/VEGF pathway in tumor tissues, indicating its potential to hold back tumor growth via the inhibition of angiogenesis. Our findings indicated that as a delivery system, Soluplus micelles demonstrate potential for the delivery of poorly soluble drugs for tumor treatment.

The SARS-CoV-2 B.1.1.529 (Omicron) variant contains 15 mutations of the receptor-binding domain (RBD). How Omicron evades RBD-targeted neutralizing antibodies requires immediate investigation. Here we use high-throughput yeast display screening1,2 to determine the profiles of RBD escaping mutations for 247 human anti-RBD neutralizing antibodies and show that the neutralizing antibodies can be classified by unsupervised clustering into six epitope groups (A-F)-a grouping that is highly concordant with knowledge-based structural classifications3-5. Various single mutations of Omicron can impair neutralizing antibodies of different epitope groups. Specifically, neutralizing antibodies in groups A-D, the epitopes of which overlap with the ACE2-binding motif, are largely escaped by K417N, G446S, E484A and Q493R. Antibodies in group E (for example, S309)6 and group F (for example, CR3022)7, which often exhibit broad sarbecovirus neutralizing activity, are less affected by Omicron, but a subset of neutralizing antibodies are still escaped by G339D, N440K and S371L. Furthermore, Omicron pseudovirus neutralization showed that neutralizing antibodies that sustained single mutations could also be escaped, owing to multiple synergetic mutations on their epitopes. In total, over 85% of the tested neutralizing antibodies were escaped by Omicron. With regard to neutralizing-antibody-based drugs, the neutralization potency of LY-CoV016, LY-CoV555, REGN10933, REGN10987, AZD1061, AZD8895 and BRII-196 was greatly undermined by Omicron, whereas VIR-7831 and DXP-604 still functioned at a reduced efficacy. Together, our data suggest that infection with Omicron would result in considerable humoral immune evasion, and that neutralizing antibodies targeting the sarbecovirus conserved region will remain most effective. Our results inform the development of antibody-based drugs and vaccines against Omicron and future variants.

Parkinson's disease (PD) is a chronic and progressive movement disorder caused by the selective loss of midbrain dopaminergic neurons of unknown etiology. Up to now, although there is a great development on treatments of PD, cures with neuroprotective or nerve regenerative effects are underway for PD patients. Here we reported neuroprotective effects of Ginkgolide K (GK) when mice were upon acute MPTP exposure, in which GK ameliorated the gait dysfunction and dopaminergic neuron loss. GK exhibits its ability in immunomodulation, including switching microglia to M2 phenotype and decreasing the microglia-mediated inflammation, inhibiting peripheral CD4+IFN-γ+ and CD4+IL-17+ T cells and α-synuclein specific autoantibodies. The expression of neurotrophic factors BDNF, GDNF and NT-3 was promoted with a treatment of GK in MPTP mice brains. Notably, GK enhanced the expression of nestin in GFAP+ astrocytes followed by the transdifferentiation of astrocyte-to-neuron independent on the Wnt signaling although GK induced the expression of Wnt signaling on astrocytes. Based on these results, our work implicates a therapeutic potential of GK for protecting TH+ neurons by multiple and intercellular pathways to modify nerve regeneration in MPTP mice. However, its exactly cellular and molecular mechanisms need to be further explored and confirmed.

Genome-wide association studies (GWAS) have identified more than 160 susceptibility loci for colorectal cancer (CRC). The effects of these variants, particularly their mechanisms, however, remain unclear. In this study, a comprehensive functional annotation of CRC-related GWAS signals was firstly conducted to identify the potential causal variants. We found that the SNP rs7229639 in intron 3 of SMAD7 at 18q21.1 might serve as a putative functional variant in CRC. The SNP rs7229639 is located in a region with evidence of regulatory potential. Dual-luciferase reporter assays revealed that three other SNPs (rs77544449, rs60385309 and rs72917785), in strong linkage disequilibrium (LD) with rs7229639, exhibited allele-specific enhancer activity, of which one of the target genes may conceivably be LIPG, as suggested by eQTL association data and Hi-C data. We also verified that LIPG promoted malignancy of CRC cells in vitro, with supporting clinical data indicating that LIPG is upregulated and correlated with a poor prognosis in CRC. Finally, pitavastatin was observed to exhibit an anti-CRC activity and modest inhibition of LIPG mRNA levels. Collectively, our data suggest that these functional variants at 18q21.1 are involved in the pathogenesis of CRC by modulating enhancer activity, and possibly LIPG expression, thus indicating a promising therapeutic target for CRC. The results of functional annotation in our investigation could also serve as an inventory for CRC susceptibility SNPs and offer guides for post-GWAS downstream functional studies.

Given the lack of visual discrepancy between malignant and surrounding normal tissue, current breast conserving surgery (BCS) is associated with a high re-excision rate. Due to the increasing cases of BCS, a novel method of complete tumour removal at the initial surgical resection is critically needed in the operating room to help optimize the surgical procedure and to confirm tumour-free edges.

The study examined the relationship between health insurance coverage and access to needed healthcare including preventive, primary, and tertiary care among Chinese adult population.

Drug addiction can be described as a chronic and relapsing brain disease. Behavioral sensitization is common animal model in the study of addiction and N-Methyl-D-aspartate subtype of glutamate receptor (NMDAR) is believed play key role in this process. LY235959 is a competitive NMDAR antagonist, however, its effect on methamphetamine (METH)-induced behavioral sensitization is not been reported yet. In this study, we choose three doses (0.33 mg/kg, 1.0 mg/kg, and 3.0 mg/kg) of LY235959 to investigate its effect on locomotor activity, METH-induced behavioral sensitization and different phases of it in C57/BL6 mice. We also used western blotting to examine the PP2A/B - AKT cascade which had been proved involved in METH-induced behavioral sensitization in the dorsal striatum (DS). The results showed that only 0.33 mg/kg LY235959 increased locomotor activity dramatically, however, 1.0 mg/kg and 3.0 mg/kg of LY235959 could attenuate METH-induced behavioral sensitization markedly. We also found that LY235959 only disrupted the development phase of METH-induced behavioral sensitization and the following western blotting results further indicated that PP2A/B - AKT cascade might involve in this process. Taken together, these results indicated that LY235959 attenuates development phase of METH-induced behavioral sensitization through the PP2A/B - AKT cascade in the DS.

Myelodysplastic syndromes (MDS) are heterogeneous neoplastic disorders of hematopoietic stem cells (HSCs). The current standard of care for patients with MDS is hypomethylating agent (HMA)-based therapy; however, almost 50% of MDS patients fail HMA therapy and progress to acute myeloid leukemia, facing a dismal prognosis due to lack of approved second-line treatment options. As cancer stem cells are the seeds of disease progression, we investigated the biological properties of the MDS HSCs that drive disease evolution, seeking to uncover vulnerabilities that could be therapeutically exploited. Through integrative molecular profiling of HSCs and progenitor cells in large patient cohorts, we found that MDS HSCs in two distinct differentiation states are maintained throughout the clinical course of the disease, and expand at progression, depending on recurrent activation of the anti-apoptotic regulator BCL-2 or nuclear factor-kappa B-mediated survival pathways. Pharmacologically inhibiting these pathways depleted MDS HSCs and reduced tumor burden in experimental systems. Further, patients with MDS who progressed after failure to frontline HMA therapy and whose HSCs upregulated BCL-2 achieved improved clinical responses to venetoclax-based therapy in the clinical setting. Overall, our study uncovers that HSC architectures in MDS are potential predictive biomarkers to guide second-line treatments after HMA failure. These findings warrant further investigation of HSC-specific survival pathways to identify new therapeutic targets of clinical potential in MDS.

Atherosclerosis (AS) is recognized as the original cause of most cardiovascular and cerebrovascular diseases. The dual-protein (DP) nutrition that consists of soy protein and whey protein is reported to be associated with a reduction in AS; however, the relationship between DP and AS remains ambiguous. Therefore, this study aimed to verify the effect of DP on AS and explore the optimal DP intake to improve AS. ApoE-/- mice were administrated with low- (LDP), middle- (MDP), and high-dose (HDP) DP. The MDP group exhibited significant improvements in AS. In terms of lipid metabolism, the levels of plasma total triglyceride and LDL-C and the mRNA expression levels of Cyp7a1 and PCSK9 were markedly tuned in the MDP group. In addition, the MDP treatment group had a substantially lower inflammatory response and better intestinal barrier function than LDP and HDP groups. The species richness demonstrated by the Chao1 index was distinctly increased in the MDP group, and the relative abundance of intestinal-permeability-protective microbes Blautia and Akkermansia was significantly elevated. In summary, an adequate intake of DP was able to counteract atherosclerosis development in ApoE-/- mice, and this study provides a scientific theoretical basis for the application of DP in the food and pharmaceutical fields.

Sepsis is a highly heterogeneous syndrome with stratified severity levels and immune states. Even in patients with similar clinical appearances, the underlying signal transduction pathways are significantly different. To identify the heterogeneities of sepsis from multiple angles, we aimed to establish a combined risk model including the molecular risk score for rapid mortality prediction, pathway risk score for the identification of biological pathway variations, and immunity risk score for guidance with immune-modulation therapy.

Lakes are important methane (CH4) sources to the atmosphere, especially eutrophic lakes with cyanobacterial blooms accompanied by volatile sulfur compound (VSC) emissions. CH4 oxidation is a key strategy to mitigate CH4 emission from lakes. In this study, we characterized the fate of CH4-derived carbon and active microbial communities in lake sediments with CS2 used as a typical VSC, based on the investigation of CH4 and VSC fluxes from Meiliang Bay in Lake Taihu. Stable isotope probing microcosm incubation showed that the efficiency of CH4-derived carbon incorporated into organic matter was 21.1% in the sediment with CS2 existence, which was lower than that without CS2 (27.3%). SO42--S was the main product of CS2 oxidation under aerobic condition, accounting for 59.3-62.7% of the input CS2-S. CS2 and CH4 coexistence led to a decrease of methanotroph and methylotroph abundances and stimulated the production of extracellular polymeric substances. CS2 and its metabolites including total sulfur, SO42- and acid volatile sulfur acted as the main drivers influencing the active microbial community structure in the sediments. Compared with α-proteobacteria methanotrophs, γ-proteobacteria methanotrophs Methylomicrobium, Methylomonas, Crenothrix and Methylosarcina were more dominant in the sediments. CH4-derived carbon mainly flowed into methylotrophs in the first stage. With CH4 consumption, more CH4-derived carbon flowed into non-methylotrophs. CS2 could prompt more CH4-derived carbon flowing into non-methanotrophs and non-methylotrophs, such as sulfur-metabolizing bacteria. These findings can help elucidate the influence of VSCs on microorganisms and provide insights to carbon fluxes from eutrophic lake systems.

This study aimed to investigate the prevalence of fosfomycin fosA7 in Salmonella enterica isolates from food animals and retail meat products in China and the impact of fosA7 on bacterial fitness. A total of 360 Salmonella isolates collected from 11 provinces and cities in China were detected for fosA7. All fosA7-positive Salmonella isolates were determined minimum inhibitory concentrations (MICs) and sequenced by Illumina Hiseq. The fosA7 gene of S. Derby isolate HA2-WA5 was knocked out. The full length of fosA7 was cloned into vector pBR322 and then transformed into various hosts. MICs of fosfomycin, growth curves, stability, and fitness of fosA7 were evaluated. The fosA7 gene was identified in S. Derby (ST40, n = 30) and S. Reading (ST1628, n = 5). MICs to fosfomycin of 35 fosA7-positive isolates were 1 to 32 mg/L. All fosA7 were located on chromosomes of Salmonella. The deletion of fosA7 in HA2-WA5 decreased fosfomycin MIC by 16-fold and slightly affected its fitness. The acquisition of plasmid-borne fosA7 enhanced MICs of fosfomycin in Salmonella (1,024-fold) and Escherichia coli (16-fold). The recombinant plasmid pBR322-fosA7 was stable in Salmonella Typhimurium, S. Pullorum, S. Derby, and E. coli, except for Salmonella Enteritidis, and barely affected on the growth of them but significantly increased biological fitness in Salmonella. The spread of specific Salmonella serovars such as S. Derby ST40 will facilitate the dissemination of fosA7. fosA7 can confer high-level fosfomycin resistance and enhance bacterial fitness in Salmonella if transferred on plasmids; thus, it has the potential to be a reservoir of the mobilized fosfomycin resistance gene.

Pulmonary fibrosis (PF) is the end stage of various chronic and progressive interstitial lung diseases. TGF-β, a profibrotic cytokine, can promote epithelial-mesenchymal transition (EMT), extracellular matrix (ECM) accumulation, and fibroblast proliferation, which contribute to progressive lung remodeling in PF. The Wenfei Buqi Tongluo (WBT) formula has been certified to be effective in the prevention and treatment of PF in clinical practice and has inhibitory effects on EMT, inflammation, and profibrotic factors. However, the pharmacological mechanisms of WBT against PF need to be further explored. In this study, we first analyzed the chemical components of the WBT formula using the UHPLC/Q-TOF-MS analysis. The potential targets of the identified compounds from WBT were predicted by the network pharmacology, which was confirmed by in vivo and in vitro study. After screening by the PubChem database, we first identified the 36 compounds of WBT and predicted the TGF-β signaling pathway, with ECM degradation as potential mechanism of WBT against PF by the network pharmacology. Furthermore, WBT treatment inhibited the levels of TGF-β and Smad3 phosphorylation and subsequently alleviated EMT and ECM accumulation in the bleomycin-induced mouse model and TGF-β1-induced cell model. These findings indicate that WBT can block the progressive process of PF by inhibiting EMT and promoting ECM degradation via the TGF-β/Smad3 pathway. This study may provide new insights into the molecular mechanism of WBT for the prevention and treatment of PF in the clinical application.