Background Atrial fibrillation (AF) is the most common form of clinical cardiac dysrhythmia responsible for thromboembolic cerebral stroke, congestive heart failure, and death. Aggregating evidence highlights the strong genetic basis of AF. Nevertheless, AF is of pronounced genetic heterogeneity, and in an overwhelming majority of patients, the genetic determinants underpinning AF remain elusive. Methods and Results By genome-wide screening with polymorphic microsatellite markers and linkage analysis in a 4-generation Chinese family affected with autosomal-dominant AF, a novel locus for AF was mapped to chromosome 1q24.2-q25.1, a 3.20-cM (≈4.19 Mbp) interval between markers D1S2851 and D1S218, with the greatest 2-point logarithm of odds score of 4.8165 for the marker D1S452 at recombination fraction=0.00. Whole-exome sequencing and bioinformatics analyses showed that within the mapping region, only the mutation in the paired related homeobox 1 (PRRX1) gene, NM_022716.4:c.319C>T;(p.Gln107*), cosegregated with AF in the family. In addition, sequencing analyses of PRRX1 in another cohort of 225 unrelated patients with AF revealed a new mutation, NM_022716.4:c.437G>T; (p.Arg146Ile), in a patient. The 2 mutations were absent in 908 control subjects. Biological analyses in HeLa cells demonstrated that the 2 mutants had significantly diminished transactivation on the target genes ISL1 and SHOX2 and markedly decreased ability to bind the promoters of ISL1 and SHOX2 (2 genes causally linked to AF), although with normal intracellular distribution. Conclusions This study first indicates that PRRX1 loss-of-function mutations predispose to AF, which provides novel insight into the molecular pathogenesis underpinning AF, implying potential implications for precisive prophylaxis and management of AF.

To longitudinally analyze and compare the accommodative micro-fluctuation (MFs) and accommodative function between myopic patients after implantable collamer lens (ICL) implantation and laser in situ keratomileusis (LASIK).

The goal of this study was to identify and compare the main biomarkers of Taxillus chinensis from different hosts. A metabolomics approach utilizing ultra-pressure liquid chromatography coupled with tandem mass spectrometry (UPLC-MS), including cluster analysis, sample correlation analysis and orthogonal partial least squares discriminant analysis, was used to explore the flavonoid metabolites of Taxillus chinensis growing on different hosts. Results: The total flavonoids content (up to 30.08 mg/g) in Taxillus chinensis from Morus alba (CSG) was significantly higher than that from growth on Liquidambar formosana (CFG) or Clausena lansium (CHG) (p < 0.01). There were 23 different metabolites between CSG and CHG, 23 different metabolites between CSG and CFG, and 19 different metabolites between CHG and CFG. The results demonstrated that different hosts exerted a large influence on the metabolites of Taxillus chinensis; it was found that CSG differed from CFG and CHG in eleven metabolic compounds, ten of which were upregulated and one of which was downregulated. Most of these metabolites derive from compounds contained in the host plant, white mulberry (Morus alba); many feature potent anti-cancer effects. Differences in host can influence the type and abundance of flavonoids in parasitic plants such as Taxillus chinensis, which is of great significance to researchers seeking to understand the formation mechanism of Taxillus chinensis metabolites. Therefore, attention should be paid to the species of host plant when studying the Taxillus chinensis metabolome. Plants grown on Morus alba offer the greatest potential for the development of new anti-cancer drugs.

Monascus pigments (MPs) have been used as food colorants for several centuries in Asian countries and are currently used around the world via Asian catering. The MPs biosynthetic pathway has been well-illustrated; however, the functions of a few genes including mrpigH in the MPs gene cluster of M. ruber M7 are still unclear. In the current study, mrpigH was disrupted in Δmrlig4ΔmrpyrG, a highly efficient gene modification system, using mrpyrG as a selection marker, and ΔmrpigHΔmrlig4ΔmrpyrG::mrpyrG and ΔmrpigHΔmrlig4ΔmrpyrG have been obtained. Subsequently, their morphologies, biomasses, MPs and citrinin (CIT) production were analyzed, respectively. These results have revealed that the deletion of mrpigH has significant effects on the morphology and growth of M. ruber M7. Moreover, compared with M. ruber M7, the yields of MPs and CIT were drastically increased and decreased in mrpigH mutants, respectively.

Radiation-induced lung injury (RILI) is a common complication of radiotherapy for which no effective interventions are available. NVP-AUY922, a resorcinylic isoxazole amide drug, exhibits anti-inflammatory, immunomodulatory, and therapeutic effects against various types of cancers. In this study, we explore the role and underlying mechanisms of NVP-AUY922 in the treatment of RILI. We established a model of BEAS-2B cell injury and a mouse model of RILI. Cell proliferation, death, gross weight, and survival rates of mice, and histological parameters were assessed. Additionally, inflammation-related indices and indicators related to ferroptosis were evaluated. Furthermore, immunofluorescence and co-immunoprecipitation were used to determine the interaction between GPX4, LAMP-2A, and HSC70. NVP-AUY922 significantly ameliorated radiation-induced lung tissue damage, inflammatory cell infiltration, proinflammatory cytokine release, and lung epithelial BEAS-2B cell damage. NVP-AUY922 markedly limited the activation of ferroptosis, which is involved in RILI. Mechanistically, NVP-AUY922 prevented chaperone-mediated autophagy of the GPX4 pathway in vitro and in vivo, and the autophagy inhibitor Baf-A1 significantly increased the level of GPX4 and alleviated lung inflammation. NVP-AUY922 can alleviate RILI by inhibiting chaperone-mediated lysosomal degradation of GPX4, demonstrating its potential as a novel protective agent against RILI.

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.

The Cyclophyllidea comprises the most species-rich order of tapeworms (Platyhelminthes, Cestoda) and includes species with some of the most severe health impact on wildlife, livestock, and humans. We collected seven Cyclophyllidea specimens from rodents in Qinghai-Tibet Plateau (QTP) and its surrounding mountain systems, of which four specimens in QTP were unsequenced, representing "putative new species." Their complete mitochondrial (mt) genomes were sequenced and annotated. Phylogenetic reconstruction of partial 28S rDNA, cox1 and nad1 datasets provided high bootstrap frequency support for the categorization of three "putative new species," assigning each, respectively, to the genera Mesocestoides, Paranoplocephala, and Mosgovoyia, and revealing that some species and families in these three datasets, which contain 291 species from nine families, may require taxonomic revision. The partial 18S rDNA phylogeny of 29 species from Taeniidae provided high bootstrap frequency support for the categorization of the "putative new species" in the genus Hydatigera. Combined with the current investigation, the other three known Taeniidae species found in this study were Taenia caixuepengi, T. crassiceps, and Versteria mustelae and may be widely distributed in western China. Estimates of divergence time based on cox1 + nad1 fragment and mt protein-coding genes (PCGs) showed that the differentiation rate of Cyclophyllidea species was strongly associated with the rate of change in the biogeographic scenarios, likely caused by the uplift of the QTP; i.e., species differentiation of Cyclophyllidea might be driven by host-parasite co-evolution caused by the uplift of QTP. We propose an "out of QTP" hypothesis for the radiation of these cyclophyllidean tapeworms.

Hereditary spastic paraplegia (HSP) is a rare group of genetically heterogeneous, neurodegenerative disorders. The aim of this study was to identify pathological candidate genes and variants in a large pedigree cohort of 11 purely HSP patients in Yunnan Province.

Loss of Klotho, an anti-aging protein, plays a critical role in the pathogenesis of chronic kidney diseases. As Klotho is a large transmembrane protein, it is challenging to harness it as a therapeutic remedy. Here we report the discovery of a Klotho-derived peptide 1 (KP1) protecting kidneys by targeting TGF-β signaling. By screening a series of peptides derived from human Klotho protein, we identified KP1 that repressed fibroblast activation by binding to TGF-β receptor 2 (TβR2) and disrupting the TGF-β/TβR2 engagement. As such, KP1 blocked TGF-β-induced activation of Smad2/3 and mitogen-activated protein kinases. In mouse models of renal fibrosis, intravenous injection of KP1 resulted in its preferential accumulation in injured kidneys. KP1 preserved kidney function, repressed TGF-β signaling, ameliorated renal fibrosis and restored endogenous Klotho expression. Together, our findings suggest that KP1 recapitulates the anti-fibrotic action of Klotho and offers a potential remedy in the fight against fibrotic kidney diseases.

The prevalence and development of New Delhi metallo-β-lactamase-1 (NDM-1) have led to increases in bacterial resistance to the majority of clinically used antibiotics, including carbapenems. This study attempts to identify a novel inhibitor of NDM-1 for resistant bacteria infection. Herein, we found that fisetin, as an agent, distinctly inhibits the activity of NDM-1 (IC50 = 9.68 μg/mL) through on enzyme activity inhibition screening. Notably, fisetin is a metallo-β-lactamases inhibitor without the ability to chelate zinc ions, as well as with a significantly inhibitory effect on NDM-9, VIM-1, IMP-1 and KPC-2. The combination of fisetin with meropenem could attenuate meropenem resistance in NDM-1-positive Escherichia coli. The MIC values of combined treatment were lower than those found for meropenem or fisetin alone (FICI from 0.25 ± 0.00 to 0.38 ± 0.00) although fisetin lacks antibacterial activities (MIC＞1024 μg/mL). Furthermore, fisetin combined with meropenem could kill all tested bacteria no more than 3 h in vitro and this synergistic effect could also be observed in vivo. Molecular dynamics simulations revealed that fisetin successfully inhibit the hydrolytic activity of NDM-1. Additionally, the mutation of NDM-1 resulted in a decreased inhibition of NDM-1 activity by fisetin compared with the WT protein. Finally, our results indicate that fisetin is an effective NDM-1 inhibitor, which suggests the combination of this compound with meropenem is a promising strategy for carbapenem-resistant bacterial infection.

Background: HAUS6 participates in microtubule-dependent microtubule amplification, but its role in malignancies including colorectal cancer (CRC) has not been explored. We therefore assessed the potential oncogenic activities of HAUS6 in CRC. Results: HAUS6 mRNA and protein expression is higher in CRC tissues, and high HAUS6 expression is correlated with shorter overall survival in CRC patients. HAUS6 knockdown in CRC cell lines suppressed cell growth in vitro and in vivo by inhibiting cell viability, survival and arresting cell cycle progression at G0/G1, while HAUS6 over-expression increased cell viability. We showed that these effects are dependent on activation of the p53/p21 signalling pathway by reducing p53 and p21 degradation. Moreover, combination of HAUS6 knockdown and 5-FU treatment further enhanced the suppression of cell proliferation of CRC cells by increasing activation of the p53/p21 pathway. Conclusion: Our study highlights a potential oncogenic role for HAUS6 in CRC. Targeting HAUS6 may be a promising novel prognostic marker and chemotherapeutic target for treating CRC patients.

Chinese herbal medicine is made up of hundreds of natural drug molecules and has played a major role in traditional Chinese medicine (TCM) for several thousand years. Therefore, it is of great significance to study the target of natural drug molecules for exploring the mechanism of treating diseases with TCM. However, it is very difficult to determine the targets of a fresh natural drug molecule due to the complexity of the interaction between drug molecules and targets. Compared with traditional biological experiments, the computational method has the advantages of less time and low cost for targets screening, but it remains many great challenges, especially for the molecules without social ties.

The SQUAMOSA-PROMOTER BINDING PROTEIN-LIKE (SPL) gene family affects plant architecture, panicle structure, and grain development, representing key genes for crop improvements. The objective of the present study is to utilize the well characterized SPLs' functions in rice to facilitate the functional genomics of TaSPL genes. To achieve these goals, we combined several approaches, including genome-wide analysis of TaSPLs, comparative genomic analysis, expression profiling, and functional study of TaSPL3 in rice. We established the orthologous relationships of 56 TaSPL genes with the corresponding OsSPLs, laying a foundation for the comparison of known SPL functions between wheat and rice. Some TaSPLs exhibited different spatial-temporal expression patterns when compared to their rice orthologs, thus implicating functional divergence. TaSPL2/6/8/10 were identified to respond to different abiotic stresses through the combination of RNA-seq and qPCR expression analysis. Additionally, ectopic expression of TaSPL3 in rice promotes heading dates, affects leaf and stem development, and leads to smaller panicles and decreased yields per panicle. In conclusion, our work provides useful information toward cataloging of the functions of TaSPLs, emphasized the conservation and divergence between TaSPLs and OsSPLs, and identified the important SPL genes for wheat improvement.

Taurine-upregulated gene 1 (TUG1) is a long noncoding RNA (lncRNA) that has previously been linked to the development and progression of several cancer types. Its expression and mechanistic role in retinoblastoma (RB), however, remains to be established. Herein, we found that RB tissue samples exhibited TUG1 upregulation. RB cell lines similarly exhibited marked TUG1 upregulation. Real-time cellular analysis (RTCA) and colony formation assays were then used to gauge RB cell proliferation, while transwell assays were conducted to assess the metastatic and invasive potential of these cells. In these assays, TUG1 upregulation was found to promote RB cell proliferative, migratory, and invasive activity while inducing the epithelial-mesenchymal transition (EMT). Subsequent quantitative real-time polymerase chain reaction (qPCR) and Western blotting indicated that this lncRNA functions at least in part by influencing the expression of Notch signaling pathway genes, which were downregulated following TUG1 knockdown in RB cells. Together, these data suggested that TUG1 can promote RB cell malignancy via the Notch signaling and EMT pathways, contributing to negative patient outcomes.

Researchers commonly anneal metals, alloys, and semiconductors to repair defects and improve microstructures via recrystallization. Theoretical studies indicate that simulated annealing on biological macromolecules helps predict the final structures with minimum free energy. Experimental validation of this homogenizing effect and further exploration of its applications are fascinating scientific questions that remain elusive. Here, we chose the apo-state 70S ribosome from Escherichia coli as a model, wherein the 30S subunit undergoes a thermally driven intersubunit rotation and exhibits substantial structural flexibility as well as distinct free energy. We experimentally demonstrate that annealing at a fast cooling rate enhances the 70S ribosome homogeneity and improves local resolution on the 30S subunit. After annealing, the 70S ribosome is in a nonrotated state with respect to corresponding intermediate structures in unannealed or heated ribosomes. Manifold-based analysis further indicates that the annealed 70S ribosome takes a narrow conformational distribution and exhibits a minimum-energy state in the free-energy landscape. Our experimental results offer a facile yet robust approach to enhance protein stability, which is ideal for high-resolution cryogenic electron microscopy. Beyond structure determination, annealing shows great potential for synchronizing proteins on a single-molecule level and can be extended to study protein folding and explore conformational and energy landscapes.

Quorum sensing (QS) can regulate the pathogenicity of bacteria and the production of some virulence factors. It is a promising target for screening to find anti-virulence agents in the coming post-antibiotics era. Cyclo (L-Trp-L-Ser), one variety of cyclic dipeptides (CDPs), isolated from a marine bacterium Rheinheimera aquimaris, exhibited anti-QS activity against Chromobacterium violaceum CV026 and Pseudomonas aeruginosa PAO1. Unlike the CDPs composed of phenylalanine or tyrosine, the anti-QS activity has been widely studied; however, cyclo (L-Trp-L-Ser) and derivatives, containing one tryptophan unit and one non-aromatic amino acid, have not been systematically explored. Herein, the cyclo (L-Trp-L-Ser) and seven derivatives were synthesized and evaluated. All tryptophane-contained CDPs were able to decrease the production of violacein in C.violaceum CV026 and predicted as binding within the same pocket of receptor protein CviR, but in lower binding energy compared with the natural ligand C6HSL. As for P. aeruginosa PAO1, owning more complicated QS systems, these CDPs also exhibited inhibitory effects on pyocyanin production, swimming motility, biofilm formation, and adhesion. These investigations suggested a promising way to keep the tryptophan untouched and make modifications on the non-aromatic unit to increase the anti-QS activity and decrease the cytotoxicity, thus developing a novel CDP-based anti-virulence agent.

Sunitinib is one of the first-line multi-tyrosine kinase inhibitors for metastatic renal cell carcinoma, and resistance to sunitinib continues to be a limiting factor for the successful treatment. As interleukin-6 (IL-6) is overexpressed in sunitinib-resistant cells, the purpose of this study was to explore the potential of IL-6 inhibition with tocilizumab, an IL-6 receptor inhibitor, to overcome resistance. In vitro, two sunitinib-resistant renal cell carcinoma cell lines (Caki-1 and SN12K1) were treated with tocilizumab. A mouse subcutaneous xenograft model was also used. Cell viability was studied by MTT assay, and apoptosis by morphology and ApopTag. Expression of IL-6, vascular endothelial growth factor (VEGF), and Bcl-2 was analyzed by qPCR. In vitro, tocilizumab induced significant cell death, and reduced the expression of IL-6, VEGF, and Bcl-2 in sunitinib-resistant cells. However, the in vitro findings could not be successfully translated in vivo, as tocilizumab did not decrease the growth of the tumors.

Combined biomarkers can improve the sensitivity and specificity of ovarian cancer (OC) diagnosis and effectively predict patient prognosis. This study explored the diagnostic and prognostic values of serum CCL18 and CXCL1 antigens combined with C1D, FXR1, ZNF573, and TM4SF1 autoantibodies in OC.

Freezing injury is a devastating yet common damage that occurs to winter rapeseed during the overwintering period which directly reduces the yield and causes heavy economic loss. Thus, it is an important and urgent task for crop breeders to find the freezing-tolerant rapeseed materials in the process of breeding. Existing large-scale freezing-tolerant rapeseed material recognition methods mainly rely on the field investigation conducted by the agricultural experts using some professional equipments. These methods are time-consuming, inefficient and laborious. In addition, the accuracy of these traditional methods depends heavily on the knowledge and experience of the experts.

Obstructive sleep apnea syndrome (OSAS) is the most common type of sleep apnea disorder. The disease seriously affects the patient's respiratory system. At present, the prognosis of the disease is poor and there is a lack of effective treatments. Therefore, it is urgent to explore its pathogenesis and treatment methods.