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We applied AMS 14C dates, Mg/Ca estimated sea surface temperature (SST), planktonic foraminiferal abundance, coarse component and X-ray diffraction mineral composition analyses for an International Ocean Discovery Program (IODP) sediment Hole U1467C in the Maldives inner sea, to reveal factors that affected the depositional process in the Maldives inner sea over the past 30 kyr. We found that the linear sedimentation rate (LSR) in Holocene (6.8 cm/kyr) was obviously higher than that in glacial period (3.45 cm/kyr); the average SST during the Holocene was 2–3°C higher than that in glacial stage. High abundance of planktonic foraminifera occurred during the glacial period, which was consistent with the variation of pelagic biogenic component. Reef-sourced material showed apparent high percentage during the Holocene (43.5%), in contrast to the low values during the glacial stage (20.7%). Terrigenous matter, only accounting for a small percentage in carbonate platform, was relatively high during the glacial period than that in the Holocene. We therefore conclude that reef-sourced material, dominated in the glacial-interglacial sediment sources, was mainly affected by sea level and climate changes. During glacial stage, sea level low-stand and weakened weathering in Maldives limited the input of the eroded material into the inner sea, resulting in low LSR; while the Holocene high sea level accompanied with rapid growth of the reef atoll and enhanced weathering, brought more reef-sourced material to the inner sea, leading to increased LSR and lowered abundance of planktonic foraminifera. The sea level and climate-controlled reef-sourced material changes are the key to understand the sedimentary process of the Maldives inner sea. Our study will shed some light on the evolution of glacial-interglacial sedimentary process of carbonate platform.

This paper is to illustrate the infestation and related ecological characteristics of chigger mites on the Asian house rat (Rattus tanezumi). A total of 17,221 chigger mites were collected from 2,761 R. tanezumi rats, and then identified as 131 species and 19 genera in 2 families. Leptotrombidium deliense, the most powerful vector of scrub typhus in China, was the first major dominant species on R. tanezumi. All the dominant mite species were of an aggregated distribution among different individuals of R. tanezumi. The species composition and infestations of chiggers on R. tanezumi varied along different geographical regions, habitats and altitudes. The species-abundance distribution of the chigger mite community was successfully fitted and the theoretical curve equation was. Ŝ (R)=37e–(0.28R)2 The total chigger species on R. tanezumi were estimated to be 199 species or 234 species, and this further suggested that R. tanezumi has a great potential to harbor abundant species of chigger mites. The results of the species-plot relationship indicated that the chigger mite community on R. tanezumi in Yunnan was an uneven community with very high heterogeneity. Wide geographical regions with large host samples are recommended in the investigations of chigger mites.

The lack of tumor specific antigens (TSA) and the immune tolerance are two major obstacles for the immunotherapy of cancer. Current immune checkpoint inhibitors (ICIs) show clinical responses in only limited subsets of cancer patients, which, to some extent, depends on the mutation load of tumor cells that may generate neoantigens. Here, we aimed to generate a neoantigen MDP to exhibit stronger anti-tumor efficacy. Methods: In this study, we utilized chemically modified sialic acid precursor tetra acetyl-N-azidoacetyl-mannosamine (AC4ManNAZ) to engineer the glycoproteins on the membranes of tumor cells for the covalent ligation of hapten adjuvant Pam3CSK4 in vivo, which eventually generated a neoantigen, i.e., ManNAZ-DBCO-Pam3CSK4 (MDP), on tumor cells. The high labeling efficiency, relatively specific biodistribution in tumor tissues and the anti-tumor efficacy were confirmed in the syngeneic murine models of the breast cancer and the lung cancer. Results: The generation of MDP neoantigen in tumor-bearing mice significantly evoked both the humoral and the T-cell-dependent antitumor immune responses, resulting in a strong inhibition on the growth of the breast cancer and the lung cancer allografts and significantly prolonged survival of tumor-bearing mice. Interestingly, MDP neoantigen was able to dramatically increase the sensitivity of cancer cells to ICIs and greatly enhance the anti-tumor efficacy in the murine models of both breast cancer and the lung cancer, which showed no or low responses to the immunotherapy with anti-PD1 antibody alone. Conclusions: We developed a simple metabolic glycoengineering method to artificially generate neoantigens on tumor cells to enhance tumor cell immunogenicity, which is able to significantly improve the response and the clinical outcome of ICIs.

When recruited to promoters, histone 3 lysine 4 (H3K4) methyltransferases KMT2 (KMT2A-D) activate transcription by opening chromatin through H3K4 methylation. Here, we report that KMT2 mutations occur frequently in non–small cell lung cancer (NSCLC) and are associated with high mutation loads and poor survival. KMT2C regulated DNA damage responses (DDR) through direct recruitment to DNA damage sites by Ago2 and small noncoding DNA damage response RNA, where it mediates H3K4 methylation, chromatin relaxation, secondary recruitment of DDR factors, and amplification of DDR signals along chromatin. Furthermore, by disrupting homologous recombination (HR)–mediated DNA repair, KMT2C/D mutations sensitized NSCLC to Poly(ADP-ribose) polymerase inhibitors (PARPi), whose efficacy is unclear in NSCLC due to low BRCA1/2 mutation rates. These results demonstrate a novel, transcription-independent role of KMT2C in DDR and identify high-frequency KMT2C/D mutations as much-needed biomarkers for PARPi therapies in NSCLC and other cancers with infrequent BRCA1/2 mutations. Significance: This study uncovers a critical role for KMT2C in DDR via direct recruitment to DNA damage sites, identifying high-frequency KMT2C/D mutations as biomarkers for response to PARP inhibition in cancer.

Leptotrombidium scutellare is one of the 6 main vectors of scrub typhus in China. It has been found in more than 15 provinces of China. Especially in Yunnan, it was found to be mainly distributed in some mountainous areas with high altitude, low temperature and low precipitation. Rodents and some other small mammals were the most common hosts of L. scutellare. To date, more than 40 host species of L. scutellare have been recorded with very low host specificity, and the main hosts varied in different geographical regions. L. scutellare had a strong resistance against the cold environment, and the temperature and humidity were 2 important factors affecting its growth and development. Among different individuals of their rodent hosts, L. scutellare mites often showed an aggregated distribution pattern, which reflected the interspecific cooperation of the mites. The chromosome karyotype of L. scutellare was 2n=16 and all the 8 pairs of chromosomes were short rod-shaped with metacentric or sub-metacentric types. The isozyme spectrum supported that L. scutellare, L. deliense and L. rubellum were in the same species group. Based on the natural infection, experimental transmission and epidemiological evidence, L. scutellare has been eventually confirmed as the second major vector of scrub typhus in China, which is second only to L. deliense.

Olfaction, the sense of smell, is a fundamental trait crucial to many species. The olfactory bulb (OB) plays pivotal roles in processing and transmitting odor information from the environment to the brain. The cellular heterogeneity of the mouse OB has been studied using single-cell RNA sequencing. However, the epigenetic landscape of the mOB remains mostly unexplored. Herein, we apply single-cell assay for transposase-accessible chromatin sequencing to profile the genome-wide chromatin accessibility of 9,549 single cells from the mOB. Based on single-cell epigenetic signatures, mOB cells are classified into 21 clusters corresponding to 11 cell types. We identify distinct sets of putative regulatory elements specific to each cell cluster from which putative target genes and enriched potential functions are inferred. In addition, the transcription factor motifs enriched in each cell cluster are determined to indicate the developmental fate of each cell lineage. Our study provides a valuable epigenetic data set for the mOB at single-cell resolution, and the results can enhance our understanding of regulatory circuits and the therapeutic capacity of the OB at the single-cell level.

Multiple osteochondromas (MO) is an autosomal dominant hereditary disorder, which typically manifests as skeletal dysplasia, mainly involving long bones and knees, ankles, elbows, wrists, shoulders, and pelvis. Previous studies have demonstrated that mutations in exostosin glycosyl transferase-1 (EXT1) and exostosin glycosyl transferase-2 (EXT2) were the main cause of MO. In this study, we enrolled 2 families with MO. Sanger sequencing revealed 2 novel frameshift mutations – c.1432_1433insCCCCCCT; p.Lys479Profs*44 and c.1431_1431delC; p.S478PfsX10 – in the EXT1 gene detected in 2 families, respectively. Both novel mutations, located in the conserved domain of EXT1 and predicted to be disease causing by informatics programs, were absent in our 200 control cohorts and other public databases. Our study expanded the spectrum of EXT1 mutations and contributed to genetic diagnosis and counseling of patients with MO.

New planktonic and benthic foraminiferal stable isotope records from core YDY05 (northeastern Indian Ocean) provide new insights into paleoceanographic changes in the northeastern Indian Ocean since the last glacial period. The distinct δ18O decrease was observed since the beginning of the deglaciation to the mid-Holocene (∼8–6 kyr BP), possibly reflecting a reduction in surface salinity in the central Bay of Bengal (BoB) water, which probably resulted from strengthened precipitation, concurrent enhanced river discharge and rising sea-level, related to the intensification of Indian Summer Monsoon (ISM). Variations in benthic δ13C and δ13CPlanktonic-Benthic in our core site reflect significant variations in source water characteristics over the LGM-Holocene. The large δ13CPlanktonic-Benthic offset during the glacial period suggests a more sluggish deep water circulation, and lower δ13CPlanktonic-Benthic from the deglaciation to the Holocene suggests an enhanced deep water circulation in the central BoB. The drastic depletion in benthic δ13C during the glacial period suggests a significant reduction of North Atlantic Deep Water (NADW) intrusion and a progressive influx of Antarctic Bottom Water (AABW) and 12C-rich Circumpolar Deep Water (CDW) into the central BoB. In contrast, since the deglaciation, the central BoB experienced a drastically increased intrusion of better ventilated and 13C-rich NADW. The differences in benthic δ18O between the LGM section and the Holocene exceeds the ice volume effect by ∼0.5‰, providing further evidence that the deep water mass of the central BoB was influenced by the less dense NADW, instead of the AABW, since the last deglaciation.

Tumor-associated macrophages (TAMs) play a critical role in the tumor inflammatory microenvironment and facilitate tumor growth and metastasis. Most types of tumors aberrantly express microRNAs (miRNAs), which can be transferred between cells by exosomes and can regulate gene expression in recipient cells, but it remains unclear whether tumor-derived miRNAs are transferred by exosomes and regulate the TAM phenotype. We report that mouse 4T1 breast cancer cell–derived exosomes enhanced TAM expression of IL-1β, IL-6, and TNF-α and that inhibition of 4T1-cell exosome secretion through short hairpin RNA–mediated Rab27a/b depletion repressed tumor growth and metastasis and markedly downregulated IL-1β, IL-6, and TNF-α in a 4T1 breast tumor model. Furthermore, miRNA expression profiling revealed that three miRNAs (miR-100-5p, miR-183-5p, and miR-125b-1-3p) were considerably more abundant in 4T1 cell exosomes than in mouse bone marrow–derived macrophages, indicating potential exosome-mediated transfer of the miRNAs, and, notably, miR-183-5p was found to be transferred from 4T1 cells to macrophages through exosomes. Moreover, PPP2CA was verified as an miR-183-5p target gene, and PPP2CA downregulation enhanced NF-κB signaling and promoted macrophage expression of IL-1β, IL-6, and TNF-α. Lastly, when miR-183-5p was downregulated in exosomes through miR-183-5p sponge expression in 4T1 cells, these 4T1-derived exosomes triggered diminished p65 phosphorylation and IL-1β, IL-6, and TNF-α secretion, and the miRNA downregulation also led to repression of tumor growth and metastasis in the 4T1 breast tumor model in vivo. Thus, miR-183-5p expressed in tumor cells was transferred to macrophages by exosomes and promoted the secretion of proinflammatory cytokines by inhibiting PPP2CA expression, which contributed to tumor progression in a breast cancer model.

Lung cancer has the highest mortality of all cancers worldwide. To identify epigenetic markers for early diagnosis of lung adenocarcinoma (LUAD), we integrated genome‐wide DNA methylation and gene expression analyses. We identified methylation signatures in three genes (CMTM2, TBX4, and DPP6) for early diagnosis of LUAD. Our findings may contribute toward an earlier LUAD diagnosis, potentially improving outcomes for patients., Lung cancer has the highest mortality of all cancers worldwide. Epigenetic alterations have emerged as potential biomarkers for early diagnosis of various cancer tissue types. To identify methylation markers for early diagnosis of lung adenocarcinoma, we aimed to integrate genome‐wide DNA methylation and gene expression data from The Cancer Genome Atlas. To this end, we first examined the global DNA methylation pattern of lung adenocarcinoma and investigated the relationship between DNA methylation subtypes and clinical features. We then extracted differentially methylated and expressed genes, and adopted feature selection techniques to determine the final methylation markers. The performance of the markers in predicting lung adenocarcinoma was evaluated on three independent datasets from Gene Expression Omnibus. Protein levels of marker genes were validated by immunohistochemistry, and their biological function was further verified in vivo. We identified three novel methylation markers in lung adenocarcinoma including cg08032924, cg14823851, and cg19161124, mapping to CMTM2, TBX4, and DPP6, respectively. Validating these results on three independent datasets indicated that the three markers can achieve extremely high sensitivity and specificity in distinguishing lung adenocarcinoma from normal samples. Immunohistochemistry quantification results confirmed that markers are weakly expressed in human lung adenocarcinoma, and CMTM2 decreased tumor growth of mouse Lewis lung carcinoma in vivo. Overall, our study identified three novel methylation markers in lung adenocarcinoma which may contribute toward an improved diagnosis potentially leading to a better outcome for patients with lung adenocarcinoma.

Metastases are the main cause of cancer-related mortality in breast cancer. Although significant progress has been made in the field of tumor metastasis, the exact molecular mechanisms involved in tumor metastasis are still unclear. Here, we report that ATOH8-V1, a novel isoform of ATOH8, is highly expressed in breast cancer and is a negative prognostic indicator of survival for patients. Forced expression of ATOH8-V1 dramatically enhances, while silencing of ATOH8-V1 decreases the metastasis of breast cancer cell lines. Moreover, ATOH8-V1 directly binds to the RhoC promoter and stimulates the expression of RhoC, which in turn enhances the metastasis of breast cancer. Altogether, our data demonstrate that ATOH8-V1 is a novel pro-metastatic factor that enhances cancer metastasis, suggesting that ATOH8-V1 is a potential therapeutic target for treatment of metastatic cancers.

Cancer stem cells (CSCs) are a small population of stem cell-like cancer cells that can initiate tumors in vivo, and are the major source of cancer initiation, relapse, and drug resistance. We previously reported that the p38 MAPK, through its downstream effectors MK2 and HSP27, suppressed CSC properties by downregulating the expression of transcription factors that mediate stemness in non-small-cell lung cancer (NSCLC) cells, and that despite unaltered total expression of total p38 proteins, the levels of activated p38 were reduced in NSCLC tissues. However, the mechanism underlying the reduced levels of activated p38 in NSCLC is unknown. In this study, we identified WIP1, a p38 phosphatase frequently overexpressed in cancer, as a suppressor of p38 in a pathway that regulates CSC properties in NSCLC. Increased WIP1 expression correlated with reduced levels of activated p38, and with increased levels of a CSC marker in NSCLC tissues. Further investigation revealed that WIP1 promoted stemness-related protein expression and CSC properties by inhibiting p38 activity in NSCLC cells. WIP1 inhibitors are currently under development as anticancer drugs based on their ability to reactivate p53. We found that a WIP1 inhibitor suppressed stemness-related protein expression and CSC properties by activating p38 in NSCLC cells in vitro and in vivo. These studies have identified the WIP1–p38–MK2–HSP27 cascade as a novel signaling pathway that, when altered, promotes CSC properties in NSCLC development, and have defined novel mechanisms underlying the oncogenic activity of WIP1 and the anticancer efficacy of WIP1 inhibitors.

ObjectivesTo characterize the genetic environment of the carbapenem resistance determinant in Proteus vulgaris of swine origin.MethodsThe carbapenem-resistant P. vulgaris strain BC22 was isolated from a faecal swab from a diseased pig with diarrhoea in Sichuan Province of China in 2018. The presence of carbapenemase genes was screened by PCR. WGS and bioinformatics analysis were performed to analyse the genetic environment of the carbapenem resistance determinant.ResultsP. vulgaris strain BC22 was found to harbour the carbapenemase gene blaNDM-1. WGS data revealed that blaNDM-1 was located in a truncated ISAba125 composite transposon. The carbapenem resistance gene blaNDM-1 and 20 other resistance genes, including the multiresistance gene cfr and the bifunctional aminoglycoside/quinolone resistance gene aac(6′)-lb-cr, were located in a novel SXT/R391 integrative and conjugative element (ICE). This new SXT/R391 ICE of 148.7 kb was chromosomally located, and could be transferred to Escherichia coli.ConclusionsHere, we report a carbapenemase gene, blaNDM-1, integrated into an SXT/R391 ICE. Our study highlights that this SXT/R391 ICE may facilitate the dissemination of clinically important resistance genes such as blaNDM-1, cfr and aac(6′)-lb-cr.

A novel series of cyclin-dependent kinases (CDKs) inhibitors, which play critical roles in the cell cycle control and regulation of cell transcription, were synthesised. A systematic study of enzymatic and cellular assays led to the identification of compound X22 with a nanomolar potency against CDK4 and CDK9 and potent antiproliferative activities against a panel of tumour cell lines. X22 could induce cell cycle arrest and cell apoptosis in cancer cell lines. X22 dose-dependently inhibits signalling pathways downstream of CDKs in cancer cells. In vivo antitumor activity assays, oral administration of X22 led to significant tumour regression in mouse model without obvious toxicity. Superior anti-cancer efficacy in vitro and in vivo of X22 demonstrated combined depletion of cell cycle and transcriptional CDK all contributed to antitumor activity. Taken together, concomitant inhibition of cell cycle and transcriptional CDK activities provided valuable guide for further structural optimisation.

Small extracellular vesicles (sEVs) play a key role in intercellular communication. Cargo molecules carried by sEVs may affect the phenotype and function of recipient cells. Epithelial cancer cell‐derived sEVs, particularly those enriched in CD151 or tetraspanin8 (TSPAN8) and associated integrins, promote tumour progression. The mechanism of binding and modulation of sEVs to recipient cells remains elusive. Here, we used genetically engineered breast cancer cells to derive TSPAN8‐enriched sEVs and evaluated the impact of TSPAN8 on target cell membrane's diffusion and transport properties. The single‐particle tracking technique showed that TSPAN8 significantly promoted sEV binding via confined diffusion. Functional assays indicated that the transgenic TSPAN8‐sEV cargo increased cancer cell motility and epithelial‐mesenchymal transition (EMT). In vivo, transgenic TSPAN8‐sEV promoted uptake of sEVs in the liver, lung, and spleen. We concluded that TSPAN8 encourages the sEV‐target cell interaction via forced confined diffusion and significantly increases cell motility. Therefore, TSPAN8‐sEV may serve as an important direct or indirect therapeutic target.

SUMMARYDrosophila has long been a successful model organism in multiple fields such as genetics and developmental biology. Drosophila genome is relatively smaller and less redundant, yet largely conserved with mammals, making it a productive model in studies of embryogenesis, cell signaling, disease mechanisms, etc. Spatial gene expression pattern is critical for understanding of complex signaling pathways and cell-cell interactions, whereas temporal gene expression changes need to be tracked during highly dynamic activities such as tissue development and disease progression. Systematic studies in Drosophila as a whole are still impeded by lack of these spatiotemporal transcriptomic information. Drosophila embryos and tissues are of relatively small size, limiting the application of current technologies to comprehensively resolve their spatiotemporal gene expression patterns. Here, utilizing SpaTial Enhanced REsolution Omics-sequencing (Stereo-seq), we dissected the spatiotemporal transcriptomic changes of developing Drosophila with high resolution and sensitivity. Our data recapitulated the spatial transcriptomes of embryonic and larval development in Drosophila. With these data, we identified known and previously undetected subregions in several tissues during development, and revealed known and potential gene regulatory networks of transcription factors within their topographic background. We further demonstrated that Stereo-seq data can be used for 3D reconstruction of Drosophila embryo spatial transcriptomes. Our data provides Drosophila research community with useful resources of spatiotemporally resolved transcriptomic information across developmental stages.

BackgroundClear cell renal cell carcinoma (ccRCC) is a common genitourinary cancer type with a high mortality rate. Due to a diverse range of biochemical alterations and a high level of tumor heterogeneity, it is crucial to select highly validated prognostic biomarkers to be able to identify subtypes of ccRCC early and apply precision medicine approaches.MethodsTranscriptome data of ccRCC and clinical traits of patients were obtained from the GSE126964 dataset of Gene Expression Omnibus and The Cancer Genome Atlas Kidney Renal Clear Cell Carcinoma (TCGA-KIRC) database. Weighted gene co-expression network analysis (WGCNA) and differentially expressed gene (DEG) screening were applied to detect common differentially co-expressed genes. Gene Ontology, Kyoto Encyclopedia of Genes and Genomes analysis, survival analysis, prognostic model establishment, and gene set enrichment analysis were also performed. Immunohistochemical analysis results of the expression levels of prognostic genes were obtained from The Human Protein Atlas. Single-gene RNA sequencing data were obtained from the GSE131685 and GSE171306 datasets.ResultsIn the present study, a total of 2,492 DEGs identified between ccRCC and healthy controls were filtered, revealing 1,300 upregulated genes and 1,192 downregulated genes. Using WGCNA, the turquoise module was identified to be closely associated with ccRCC. Hub genes were identified using the maximal clique centrality algorithm. After having intersected the hub genes and the DEGs in GSE126964 and TCGA-KIRC dataset, and after performing univariate, least absolute shrinkage and selection operator, and multivariate Cox regression analyses, ALDOB, EFHD1, and ESRRG were identified as significant prognostic factors in patients diagnosed with ccRCC. Single-gene RNA sequencing analysis revealed the expression profile of ALDOB, EFHD1, and ESRRG in different cell types of ccRCC.ConclusionsThe present results demonstrated that ALDOB, EFHD1, and ESRRG may act as potential targets for medical therapy and could serve as diagnostic biomarkers for ccRCC.

Neoantigen-based immunotherapy has yielded promising results in clinical trials. However, it is limited to tumor-specific mutations, and is often tailored to individual patients. Identifying suitable tumor-specific antigens is still a major challenge. Previous proteogenomics studies have identified peptides encoded by predicted non-coding sequences in human genome. To investigate whether tumors express specific peptides encoded by non-coding genes, we analyzed published proteomics data from five cancer types including 933 tumor samples and 275 matched normal samples and compared these to data from 31 different healthy human tissues. Our results reveal that many predicted non-coding genes such as DGCR9 and RHOXF1P3 encode peptides that are overexpressed in tumors compared to normal controls. Furthermore, from the non-coding genes-encoded peptides specifically detected in cancers, we predict a large number of “dark antigens” (neoantigens from non-coding genomic regions), which may provide an alternative source of neoantigens beyond standard tumor specific mutations., Rong Xiang et al. analyze the expression of non-coding genes encoded peptides in publicly-available proteomics data from five cancer types and matched controls. They identify peptides from non-coding genes including DGCR9 and RHOXF1P3 that are upregulated in tumors compared to controls, suggesting that non-coding gene-encoded peptides may be a source of neoantigens in some cancers.

Isoniazid (INH)-induced liver injury is a great challenge for tuberculosis treatment. Existing biomarkers cannot accurately determine the occurrence of this injury in the early stage. Therefore, developing early specific sensitive biomarkers of INH-induced liver injury is urgent. A rat model of liver injury was established with gastric infusion of INH or INH plus rifampicin (RFP). We examined seven potential novel serum biomarkers, namely, glutamate dehydrogenase (GLDH), liver-fatty acid-binding protein (L-FABP), high-mobility group box-1 (HMGB1), macrophage colony-stimulating factor receptor (MCSF1R), osteopontin (OPN), total cytokeratin 18 (K18), and caspase-cleaved cytokeratin-18 (ccK18), to evaluate their sensitivity and specificity on INH-induced liver injury. With the increase of drug dosage, combining with RFP and prolonging duration of administration, the liver injury was aggravated, showing as decreased weight of the rats, upgraded liver index and oxidative stress level, and histopathological changes of liver becoming marked. But the activity of serum aminotransferases decreased significantly. The area under the curve (AUC) of receiver-operating characteristic (ROC) curve of OPN, L-FABP, HMGB1, MCSF1R, and GLDH was 0.88, 0.87, 0.85, 0.71, and 0.70 (≥0.7), respectively, and 95% confidence interval of them did not include 0.5, with statistical significance, indicating their potential abilities to become biomarkers of INH-induced liver injury. In conclusion, we found traditional biomarkers ALT and AST were insufficient to discover the INH-induced liver injury accurately and OPN, L-FABP, and HMGB1 can be promising novel biomarkers.

MYB proteins play a crucial role in plant growth and development and stress responses. In this study, 160 members of the MYB gene family from the pepper genome database were used to analyze gene structures, chromosome localization, collinearity, genetic affinity and expression in response to heavy metals. The results identified R2R3-MYB members and further phylogenetically classified them into 35 subgroups based on highly conserved gene structures and motifs. Collinearity analysis showed that segmental duplication events played a crucial role in the functional expansion of the CaMYB gene family by intraspecific collinearity, and at least 12 pairs of CaMYB genes existed between species prior to the differentiation between monocots and dicots. Moreover, the upstream CaMYB genes were mainly localized to the phytohormone elements ABRE and transcription factor elements MYB and MYC. Further analysis revealed that MYB transcription factors were closely associated with a variety of abiotic stress-related proteins (e.g., MAC-complex and SKIP). Under the stress of five metal ions, Cd2+, Cu2+, Pb2+, Zn2+, and Fe3+, the expression levels of some CaMYB family genes were upregulated. Of these genes, pairing homologous 1 (PH-1), PH-13, and PH-15 in the roots of Capsicum annuum were upregulated to the greatest extent, indicating that these three MYB family members are particularly sensitive to these five metals. This study provides a theoretical reference for the analysis of the molecular regulatory mechanism of MYB family genes in mediating the response to heavy metals in plants. This study reveals the mode of interaction between MYB and a variety of abiotic stress proteins and clarifies the biological functions of CaMYB family members in the regulation of heavy metal stress.

Waardenburg syndrome (WS) is a group of autosomal-dominant hereditary conditions with a global incidence of 1/42,000. WS can be categorized into at least four types: WS1–4, and these are characterized by heterochromia iridis, white forelock, prominent nasal root, dystopia canthorum, hypertrichosis of the medial part of the eyebrows, and deaf-mutism. WS3 is extremely rare, with a unique phenotype (upper limb abnormality). Heterozygous mutations of PAX3 are commonly associated with WS1, whereas partial or total deletions of PAX3 are often observed in WS3 cases. Deletions, together with insertions, translocations, inversions, mobile elements, tandem duplications, and complexes, constitute structural variants (SVs), which can be fully and accurately detected by third-generation sequencing (TGS), a new generation of high-throughput DNA sequencing technology. In this study, after failing to identify the causative gene by Sanger sequencing, SNP-array, and whole-exome sequencing (WES), we finally detected a heterozygous gross deletion of PAX3 (10.26kb, chr2: 223153899-223164405) in a WS family by TGS. Our description would enrich the genetic map of WS and help us to further understand this disease. Our findings also demonstrated the value of TGS in clinical genetics researches.

The pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has resulted in an unprecedented setback for global economy and health. SARS-CoV-2 has an exceptionally high level of transmissibility and extremely broad tissue tropism. However, the underlying molecular mechanism responsible for sustaining this degree of virulence remains largely unexplored. In this article, we review the current knowledge and crucial information about how SARS-CoV-2 attaches on the surface of host cells through a variety of receptors, such as ACE2, neuropilin-1, AXL, and antibody–FcγR complexes. We further explain how its spike (S) protein undergoes conformational transition from prefusion to postfusion with the help of proteases like furin, TMPRSS2, and cathepsins. We then review the ongoing experimental studies and clinical trials of antibodies, peptides, or small-molecule compounds with anti-SARS-CoV-2 activity, and discuss how these antiviral therapies targeting host–pathogen interaction could potentially suppress viral attachment, reduce the exposure of fusion peptide to curtail membrane fusion and block the formation of six-helix bundle (6-HB) fusion core. Finally, the specter of rapidly emerging SARS-CoV-2 variants deserves a serious review of broad-spectrum drugs or vaccines for long-term prevention and control of COVID-19 in the future.

As microtubule-based structures, primary cilia are typically present on the cells during the G0 or G1-S/G2 phase of the cell cycle and are closely related to the development of the central nervous system. The presence or absence of this special organelle may regulate the central nervous system tumorigenesis (e.g., glioblastoma) and several degenerative diseases. Additionally, the development of primary cilia can be regulated by several pathways. Conversely, primary cilia are able to regulate a few signaling transduction pathways. Therefore, development of the central nervous system tumors in conjunction with abnormal cilia can be regulated by up- or downregulation of the pathways related to cilia and ciliogenesis. Here, we review some pathways related to ciliogenesis and tumorigenesis, aiming to provide a potential target for developing new therapies at genetic and molecular levels.

Deregulated telomere length is a causative factor in many physiological and pathological processes, including aging and cancer. Many studies focusing on telomeres have revealed important roles for cooperation between the Shelterin protein complex and telomerase in maintaining telomere length. However, it remains largely unknown whether and how aging-related stresses, such as deregulated protein homeostasis, impact telomere length. Here, we explored the possible roles of aminoacyl tRNA synthetases (AARSs), key enzymes catalyzing the first reactions in protein synthesis, in regulating telomere length and aging. We selected seryl tRNA synthetase (SerRS) since our previous studies discovered expanded functions of SerRS in the nucleus in addition to its canonical cytoplasmic role in protein synthesis. In this study, we revealed that overexpression of SerRS promoted cellular senescence and inhibited the growth of cervical tumor xenografts in mice by triggering the senescence of tumor cells. In the nucleus, SerRS directly bound to telomeric DNA repeats and tethered more POT1 proteins to telomeres through a direct interaction between the UNE-S domain of SerRS and the OB1 domain of POT1. We further demonstrated that SerRS-induced enrichment of POT1 prevented the recruitment of telomerase to telomeres, resulting in progressive telomere shortening. Our data suggested a possible molecular link between protein synthesis and telomere length control, the deregulation of which may be associated with aging and cancer.

Infectious bronchitis virus (IBV) and Newcastle disease virus (NDV) are both important viruses seriously affecting poultry industry worldwide. In this study, reverse-transcription LAMP (RT-LAMP) was combined with lateral flow dipstick (LFD) forming a novel detection tool which could simultaneously detect IBV and NDV visually. Primers targeted the 5'-untranslated region (5'-UTR) of IBV genome and the conserved region of NDV large polymerase gene (LP). The specificity and sensitivity of this multiple reverse transcription-LAMP-LFD (mRT-LAMP-LFD) assay were compared with those of conventional RT-PCR, nested RT-PCR (nRT-PCR), quantification RT-PCR (qRT-PCR), and RT-LAMP monitored by electrophoresis. No non-specific amplifications were observed when the assays were tested with unrelated viruses. According to the sensitivity study, when detecting IBV or NDV alone, the lowest detection limits of mRT-LAMP-LFD were 100.8 IBV RNA copies/reaction and 100.7 NDV RNA copies/reaction. Furthermore, when detecting IBV and NDV simultaneously, the lowest detection limit was the same as that of the single detection assays. In the clinical sample study, mRT-LAMP-LFD performed the best among these assays. When tested with IBV or NDV single infected samples, the mean detection rates were 98.65% and 97.25%, respectively. In the IBV and NDV co-infected sample study, the mean detection rates of IBV and NDV were both 95%. This study showed that mRT-LAMP-LFD was a promising qualitative detection tool suitable for field single or multiple IBV and NDV detection.

Salmonella strains are major foodborne pathogens for the animals and humans, presenting a significant threat to food safety and public health worldwide. The rapid and accurate diagnosis of Salmonella infection is required for effective control and management of disease epidemics. In this study, we developed a rapid and efficient assay that combines loop-mediated isothermal amplification with lateral flow dipstick (LAMP-LFD) for detection of the Salmonella hilA gene. Compared with PCR and real-time PCR methods, the LAMP-LFD assay has the same specificity and higher sensitivity, and required only 40 min (10 min for LFD detection) at 65 °C. All 52 strains of Salmonella yielded positive results using the LAMP-LFD assay and showed no cross reaction with 37 tested non-Salmonella strains. The detection limit of the LAMP-LFD assay was 13.5 fg/μl (genomic DNA) and 6.7 CFU/mL (cell), which was 1000-fold more sensitive than conventional PCR and 100-fold more sensitive than real-time PCR. Additionally, the LAMP-LFD method could detect Salmonella in artificially contaminated food samples (milk, pork, beef and chicken) when present as low as 144 CFU/mL or CFU/g and without the use of an enrichment step. Nevertheless, the sensitivity was increased to 1.44 CFU/mL or CFU/g after culturing at 37 °C for 6 h. Fifty food samples (chicken meat) were used to test the practicality of the LAMP-LFD assay. After an enrichment step at 37 °C for 6 h, the results showed 100% accuracy compared to the standard culture-based method (ISO 6579:2002) in which 17 out of 50 food samples gave positive results. Overall, the results demonstrated that the developed LAMP-LFD method targeting the hilA gene is rapid, specific, sensitive and allows ease of operation for Salmonella detection, suggesting the potential for this assay to be used as an alternative to traditional testing methods and could applied in low-resource settings.

Zona occludens-1 (ZO-1) is a key component of tight junctions that govern the function of the endothelial barrier against tumor metastasis. Factors secreted by tumor cells contribute to the maintenance of tumor vascular networks. How tumor cell-derived protein signals regulate ZO-1 expression is unclear. Here, we explored the effect of tumor cell-secreted asparaginyl endopeptidase (AEP) on the permeability of endothelial cells in the tumor microenvironment. First, we confirmed the existence of AEP in conditioned medium (CM) from AEP-overexpressing MDA-MB-231 and 4T1 cells. Treatment with CM from AEP-overexpressing tumor cells increased the permeability and tumor cell transversal of an endothelial monolayer. Furthermore, CM from AEP-overexpressing tumor cells suppressed endothelial ZO-1 expression, as well as ZO-1-associated nucleic acid binding protein ZONAB. In addition, the level of phosphorylated STAT3 was increased by treatment with AEP-containing CM. A mutation of RGD or blocking integrin αvβ3 with antibody recovered the ZO-1 downregulation induced by AEP. In vivo, a lung metastatic mouse model showed increased endothelial permeability in the AEP-overexpressing group compared with the control group. An orthotopic tumor transplantation model was established using AEP-overexpression and compared with mice receiving control 4T1 cells. Compared with controls, overexpression of AEP increased lung metastatic foci and area, as well as vascular instability in primary tumors or lung metastatic sites. Moreover, endothelial ZO-1 was decreased in the AEP-overexpressing group. Taken together, our data show that tumor cell-derived AEP increases the permeability of endothelial barriers. Interactions between RGD and endothelial integrin αvβ3 mediate this effect by downregulating ZO-1.

Telomere length maintenance is essential for cell proliferation, which is particularly prominent in cancer. We validate that the primary colorectal tumors exhibit heterogeneous telomere lengths but mostly (90%) short telomeres relative to normal tissues. Intriguingly, relatively short telomeres are associated with tumor malignancy as indicated by poorly differentiated state, and these tumors contain more cancer stem-like cells (CSLCs) identified by several commonly used markers CD44, EPHB2 or LGR5. Moreover, promyelocytic leukemia (PML) and ALT-associated PML nuclear bodies (APBs) are frequently found in tumors with short telomeres and high proliferation. In contrast, distant normal tissues rarely or only minimally express PML. Inhibition of PML and APBs by an ATR inhibitor decreases proliferation of CSLCs and organoids, suggesting a potential therapeutic target to progressive colorectal tumors. Together, telomere maintenance underling tumor progression is connected with CSLCs.

Summary The structure-specific endonuclease ERCC1/XPF plays an important role in nucleotide excision repair and interstrand cross-link repair. In this study, we identified new functions of ERCC1/XPF in DNA double-strand break (DSB) repair. We found that the conserved function of ERCC1/XPF to remove non-homologous sequences at DSBs is a rate-limiting step for homologous recombination in mammalian cells, and more importantly, we uncovered an indispensable role of ERCC1/XPF in repair of DSBs containing DNA secondary structures, including the structure-prone AT-rich DNA sequences derived from common fragile sites and G-quadruplexes (G4s). We also demonstrated a synthetic lethal interaction of XPF with DNA translocase FANCM that is involved in removing DNA secondary structures. Furthermore, inactivation of XPF sensitizes FANCM-deficient cells to G4-interacting compounds. These results suggest an important function of ERCC1/XPF in protecting DNA secondary structures and provide a rationale for targeted treatment of FANCM-deficient tumors through inhibition of XPF., Graphical Abstract, Highlights • ERCC1/XPF has a conserved role in removing non-homologous tails at DSBs during HR • ERCC1/XPF is required for repairing DSBs containing DNA secondary structures by HR • XPF is synthetic lethal with FANCM • XPF deficiency causes sensitivity to G4-interacting compounds, Biological Sciences; Molecular Biology; Cell Biology

Toll‐like receptor 4 (TLR4) plays an essential role in cancer progress. Here, we find that the expression of TLR4 in relapsed human hepatocellular carcinoma (HCC) clinical samples is higher than that in the non‐relapsed ones, which leads us to explore the role of TLR4 in cancer stemness. We reported that TLR4‐AKT signaling pathway was activated by lipopolysaccharides (LPS) in HCC cell lines to enhance the cancer stemness capacity, which was reflected by the increased percentage of CD133+ CD49f+ population and side population, enhanced sphere formation, and the upregulation of stemness marker gene‐SOX2. Downregulation of SOX2 attenuated the enhanced HCC stemness induced by LPS, indicating SOX2 as a downstream mediator of LPS‐TLR4 signaling. The role of LPS‐TLR4 signaling in inducing HCC stemness was further confirmed by tumor xenograft experiment in vivo. Taken together, our findings provide a novel therapeutic target to prevent the recurrence of HCC.

Manure belt poultry houses were widely used for egg production. However, reliable spatial distribution of airborne bacteria data from long-term on-farm monitoring in manure belt houses are scarce. In this study, the airborne bacteria were collected by the Andersen air microorganism sampler in a 4 tiers and an 8 tiers layer house, respectively. Results revealed that the airborne bacteria concentration range from 565 ± 247 CFU/m3 to 12,118 ± 883 CFU/m3 inside the 4 tiers poultry farmhouse and 459 ± 247 to 12,966 ± 884 CFU/m3 inside 8 tiers poultry farmhouse, respectively. The average airborne bacterial concentrations in the 4 and 8 tiers manure belt houses were 4,527 ± 2,509 and 5,489 ± 2,579 CFU/m3, respectively. Significant spatial variations of airborne bacteria concentration were observed for both houses. Spatial distribution of airborne bacteria concentration along the long axis direction can be divided into 3 regions: the low concentration region ( 10,000 CFU/m3), and airborne bacteria concentration was symmetrically distributed along the short axis direction inside both houses. We used 5 and 3 sampling locations to assess the average and maximum airborne bacterial concentration inside the manure belt houses, respectively. The average airborne bacteria concentration of 3 sampling locations was closest to the maximum concentration of both houses. It is more useful to use 3 sampling locations to monitor the change of the maximum airborne bacterial concentration inside the manure belt houses.

The South China Sea (SCS) is an important moisture and heat source in the Asian monsoon system, and its environmental changes influence economic and social stability in Southeast Asia and East Asian. Previous records on sea surface temperature (SST) and salinity (SSS) were mostly from one sediment core, and/or only showed fragmentary information. It is hard to provide insights into the mechanisms of the overall paleoceanographical environmental variability in the northern SCS. In this study, paired δ18O and Mg/Ca records of planktonic foraminifer Globigerinoides ruber from Core S0204B nearby the Luzon Strait (21°13.818′N, 118°3.077′, water depth 1822 m), and Core GHE 27L (19.85°N, 115.34°E, water depth of 1533 m) in the central northern SCS, were analyzed, so as to better understand the physical process of the SST and SSS changes in the northern SCS and its relationship with the tropical Pacific. The results demonstrate that the SST is relatively stable and seawater δ18O (δ18Osw) values, a salinity proxy, shows a decrease trend since 7.0 ka BP in Core S0204B. By contrast, SST and δ18Osw in Core GHE 27L exhibit an overall increasing trend at the same time, indicating apparent regional discrepancy on the changing trend of the SST and SSS in the northern SCS. We suggest that the thermal and hydrographic conditions in Core S0204B were primarily influenced by the outer western Pacific water. However, the thermal and hydrographic conditions in Core GHE 27L may be predominantly controlled by the weakened Asian monsoon during the mid-late Holocene, which was induced by the southern migration of Intertropical Convergence Zone (ITCZ) and stronger EI Nino Southern Oscillation.

Objective To study the role and mechanism of microRNA 19b (miR-19b) in hypoxia/reoxygenation (H/R)-induced injury by targeting PTEN. Methods PC12 and BV2 cells induced by H/R were treated with miR-19b mimics/inhibitors or small interfering PTEN (si-PTEN), respectively. Lactate dehydrogenase (LDH) level, malondialdehyde (MDA), and superoxide dismutase (SOD) content was detected. Besides, cell viability and apoptosis were determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, Hoechst33342 staining, and flow cytometry, whereas mitochondrial membrane potential (MMP) tested by JC-1 assay, and reactive oxygen species (ROS) evaluated by the dichloro-dihydro-fluorescein diacetate assay. The ischemia/reperfusion (I/R) rats model was used to investigate the effects of miR-19b in vivo test. The infarct area and apoptosis rates in brain tissues were detected by 2,3,5-triphenyltetrazolium chloride and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling staining, respectively. miR-19b and PTEN/PI3K/Akt pathway-related proteins were detected by quantitative reverse-transcription polymerase chain reaction and western blot analysis. Results miR-19b mimics could reduce LDH, MDA, and ROS levels and decline cell apoptosis, but enhance the viability, MMP, and SOD activity with decreased PTEN and cleaved caspase, as well as increased p-Akt/Akt and Bcl-2/Bax ratios in H/R-induced PC12 and BV2 cells. However, miR-19b inhibitors led to completely opposite results to aggravate H/R-induced cell injury. Meanwhile, si-PTEN could reverse the effect of miR-19b inhibitors on H/R-induced injury. Moreover, treatment with miR-19b agomir after I/R in vivo sufficiently decreased infarct area and reduced apoptosis rates by targeting PTEN through the regulation of the PI3K/Akt pathway. Conclusion miR-19b could inhibit oxidative stress, enhance cell MMP, promote cell survival, and inhibit cell apoptosis by targeting PTEN via the regulation of the PI3K/Akt pathway, thus playing the neuronal protective effects.

The altered metabolism and acidic microenvironment plays an important role in promoting tumor malignant characteristics. A small population of cancer stem cells (CSCs) were considered as a therapy target to reserve tumor relapse, resistance, and metastasis. However, the molecular mechanism that regulates CSCs metabolism remains poorly understood. In this study, we demonstrate a fundamental role of stemness gene LIN28B in maintaining CSCs glycolysis metabolism. Using LIN28B-expressing cancer cell lines, we found that the rate of extracellular acidification, glucose uptake, and lactate secretion are all suppressed by LIN28B knockdown in vitro and in vivo. Importantly, metabolic analyses reveal that CSCs have enhanced aerobic glycolysis metabolic characteristics and the glycolytic product lactate further promotes cancer associated stemness properties. LIN28B silencing suppresses MYC expression that further increases miR-34a-5p level. Furthermore, the glycolysis metabolism of human breast cancer cell line MDA-MB-231 is suppressed by either MYC siRNA or miR-34a-5p mimic. Clinically, high MYC and low miR-34a-5p level are correlated with high LIN28B expression and poor prognosis in human breast cancer patients. Notably, blocking LIN28B/MYC/miR-34a-5p signaling pathway by LIN28B-specific inhibitor causes dramatic inhibition of tumor growth and metastasis in immunodeficient orthotopic mouse models of human breast cancer cell MDA-MB-231. Taken together, our findings offer a preclinical investigation of targeting LIN28B to suppress CSCs glycolysis metabolism and tumor progression that may improve the therapeutic benefit for cancer patients.

Dilated cardiomyopathy (DCM) is a severe cardiovascular disease which can lead to heart failure and sudden cardiac death (SCD). The typical feature of DCM is left ventricular enlargement or dilatation. In some conditions, DCM and arrhythmia can occur concurrently, apparently promoting the prevalence of SCD. According to previous studies, mutations in more than 100 genes have been detected in DCM and/or arrhythmia patients. Here, we report a Chinese family with typical DCM, ventricular tachycardia, syncope, and SCD. Using whole-exome sequencing, a novel, likely pathogenic mutation (c.959T>G/p.L320R) of actinin alpha 2 (ACTN2) was identified in all affected family members. This novel mutation was also predicted to be disease-causing by MutationTaster, SIFT, and Polyphen-2. Our study not only expands the spectrum of ACTN2 mutations and contributes to the genetic diagnosis and counseling of the family, but also provides a new case with overlap phenotype that may be caused by the ACTN2 variant.

Planktic foraminifera-bound organic nitrogen isotopes (FB-δ 15 N) archived in sediments provide an opportunity to reveal past changes in marine nitrogen cycling in the upper water column. However, detailed knowledge about living foraminifera FB-δ 15 N is still critically lacking. This study presents the FB-δ 15 N analysis of planktic foraminifera collected from plankton tows and sediment traps in the South China Sea and the Bay of Bengal. Tests of Globigerinoides sacculifer with- and without-sac like chamber from plankton tows showed almost identical FB-δ 15 N values, suggesting that high thermocline δ 15 N is not incorporated into the carbonate tests during gametogenic calcification. Sediment trap samples revealed that species dwelling in the upper euphotic zone, such as Globigerinoides sacculifer , contained slightly depleted FB-δ 15 N relative to the deeper-dwelling species, such as Orbulina universa and Globigerinella siphonifera . The three species also contained FB-δ 15 N similar to δ 15 N of the suspended particulate organic matter at corresponding dwelling depths. Our results confirm the increase in FB-δ 15 N from shallower-dwelling species to deeper-dwelling species and these FB-δ 15 N differences (Δ 15 N vertical ) between shallower- and deeper-dwelling species may shed light on the nitrogen dynamics of the euphotic zone in the South China Sea, which is under the influence of the East Asian winter monsoon.

Long QT syndrome (LQTS) is a rare inherited arrhythmia disease characterized by a prolonged QT interval on 12-lead electrocardiograms. It is the crucial factor to induce syncope, ventricular fibrillation, and even sudden cardiac death. Previous studies have proved that mutations of ion channels-related genes play an important role in LQTS patients. In this study, we enrolled a Chinese family with LQTS and syncope. With the help of whole-exome sequencing, we identified a novel nonsense mutation (c.439C>T/p.Q147X) of Ring Finger Protein 207 (RNF207) in this family. The novel mutation, resulting in a premature stop codon in exon 4 of the RNF207 gene, co-segregated with the affected individuals. Bioinformatics analysis and real-time PCR further proved that the newly identified mutation might induce nonsense-mediated mRNA decay. In mutation carriers, the level of RNF207 mRNA expression was much lower than controls, which may affect potassium channel KCNH2 and lead to LQTS and syncope. In this research, we reported a rare novel mutation of RNF207 in LQTS and syncope patients which further supports the significant role of RNF207 in potassium channel activation and expanded the spectrum of RNF207 mutations. These data may contribute to the genetic diagnosis and counseling of families with LQTS and syncope.

Morganella morganii is a member of Morganellaceae that shares closest features with Proteus and Providencia genera (1) and is widespread in the environment and the intestinal tracts of animals and humans.….

Histone lysine demethylase 4D (KDM4D), also known as JMJD2D, plays an important role in cell proliferation and survival and has been associated with several tumor types. KDM4D has emerged as a potential target for the treatment of human cancer. Here, we reported crystal complex structures for two KDM4D inhibitors, OWS [2-(1H-pyrazol-3-yl)isonicotinic acid] and 10r (5-hydroxy-2-methylpyrazolo[1,5-a]pyrido[3,2-e]pyrimidine-3-carbonitrile), which were both determined to 2.0 A. OWS is a newly discovered KDM4D inhibitor (IC50 = 4.28 μM) and the critical pharmacophores of this compound are confirmed by the complex structure. Compound 10r is a KDM4D inhibitor reported by us previously. To clarify the binding mode in more detail, the crystal structure was determined and the comparison analysis revealed unique interactions that had never been observed before. Overall, our data provide new structural insights for rational design and offer an opportunity for optimization of KDM4D inhibitors.

Pseudoachondroplasia (PSACH) is an autosomal dominant skeletal dysplasia with an estimated incidence of ~1/60000 that is characterized by disproportionate short stature, brachydactyly, joint laxity, and early-onset osteoarthritis. COMP encodes the cartilage oligomeric matrix protein, which is expressed predominantly in the extracellular matrix (ECM) surrounding the cells that make up cartilage, ligaments, and tendons. Mutations in COMP are known to give rise to PSACH. In this study, we identified a novel nucleotide mutation (NM_000095.2: c.1317C>G, p.D439E) in COMP responsible for PSACH in a Chinese family by employing whole-exome sequencing (WES) and built the structure model of the mutant protein to clarify its pathogenicity. The novel mutation cosegregated with the affected individuals. Our study expands the spectrum of COMP mutations and further provides additional genetic testing information for other PSACH patients.

Besides being an important pest in agriculture and forestry, the Himalayan field rat (Rattus nitidus) can be the reservoir host of many zoonoses. Some ectoparasitic gamasid mites on rodents (rats, mice and voles, etc.) are associated with some zoonoses. A field investigation was made in 39 counties in Yunnan Province of southwestern China between 1990 and 2015, and a total of 928 R. nitidus were collected. Based on some strategies of “data mining”, the present paper analyzed the infestation and distribution of gamasid mites on the body surface of R. nitidus in Yunnan for the first time. There were 19,585 individuals of gamasid mites collected, and 18.971 of them were identified as 54 species and 19 genera under seven families. The results indicated that R. nitidus has a high potential to harbor abundant gamasid mites of diverse species. The two dominant mite species, Laelaps nuttalli and Laelaps echidninus, had an aggregated distribution among different individuals of R. nitidus. The identified 54 species of gamasid mites showed a high species diversity on a single rat species (R. nitidus), and the diversity index at the family level was higher than that at the genus level. The infestation of R. nitidus with gamasid mites in the different habitats and altitude gradients was uneven and heterogenic, which reflects the infestation bias in different environments. Most gamasid mites tended to infest male and adult rats rather than female and juvenile ones, which reflects the infestation bias on different sexes and ages. Based on Chao1’s formula, the total number of gamasid mite species on R. nitidus was estimated to be 66.

In order to evaluate the identification ability of nrDNA ITS sequences on Torreya , this study used ITS sequence and four different analysis methods (BLAST, K2P genetic distance, SNP analysis, NJ tree) to identify species of Torreya , and established phylogenetic trees to discuss their phylogenetic relationships. The results showed that the length of 48 ITS sequences was 1 095 bp~1 105 bp, the average intraspecies genetic distance was 0.001 6 and the average interspecies genetic distance was 0.015 0. At the species level, BLAST alignment and NJ tree had the highest efficiency in Torreya . The SNP loci analysis could effectively identify T. grandis cv . ‘ Merrillii ’ and T. grandis . The analysis of genetic relationship showed that all the other species of Torreya were single-line branches, but the quince tree of T. yunnanensis and T. fargesii were clustered into a cluster in the ML tree, indicating that the two were closely related. This provided evidence for the nuclear genome sequence proposed the incorporation of T. yunnanensis and T. fargesii . This study showed that ITS sequence could be used as a DNA barcode for the identification of Torreya , and providing reference for the identification and systematic relationship of Torreya.

Metabolic reprogramming to fulfill the biosynthetic and bioenergetic demands of cancer cells has aroused great interest in recent years. However, metabolic reprogramming for cancer metastasis has not been well elucidated. Here, we screened a subpopulation of breast cancer cells with highly metastatic capacity to the lung in mice and investigated the metabolic alternations by analyzing the metabolome and the transcriptome, which were confirmed in breast cancer cells, mouse models, and patients’ tissues. The effects and the mechanisms of nucleotide de novo synthesis in cancer metastasis were further evaluated in vitro and in vivo. In our study, we report an increased nucleotide de novo synthesis as a key metabolic hallmark in metastatic breast cancer cells and revealed that enforced nucleotide de novo synthesis was enough to drive the metastasis of breast cancer cells. An increased key metabolite of de novo synthesis, guanosine-5'-triphosphate (GTP), is able to generate more cyclic guanosine monophosphate (cGMP) to activate cGMP-dependent protein kinases PKG and downstream MAPK pathway, resulting in the increased tumor cell stemness and metastasis. Blocking de novo synthesis by silencing phosphoribosylpyrophosphate synthetase 2 (PRPS2) can effectively decrease the stemness of breast cancer cells and reduce the lung metastasis. More interestingly, in breast cancer patients, the level of plasma uric acid (UA), a downstream metabolite of purine, is tightly correlated with patient’s survival. Our study uncovered that increased de novo synthesis is a metabolic hallmark of metastatic breast cancer cells and its metabolites can regulate the signaling pathway to promote the stemness and metastasis of breast cancer., Metabolic reprogramming to fulfil the biosynthetic and bioenergetic demands of cancer cells is well known, but a role in metastasis is less clear. This study shows that nucleotide metabolic reprogramming leads to an enhancement of the cGMP-PKG-MAPK axis, enabling breast cancer cells to effectively colonize and grow in the lung.

Phycosphere hosts the boundary of unique holobionts harboring dynamic algae-bacteria interactions. During our investigating the microbial consortia composition of phycosphere microbiota (PM) derived from diverse harmful algal blooms (HAB) dinoflagellates, a novel rod-shaped, motile and faint yellow-pigmented bacterium, designated as strain LZ-6 T, was isolated from HAB Alexandrium catenella LZT09 which produces high levels paralytic shellfish poisoning toxins. Phylogenetic analysis based on 16S rRNA gene and two housekeeping genes, rpoA and pheS sequences showed that the novel isolate shared the highest gene similarity with Marinobacter shengliensis CGMCC 1.12758 T (99.6%) with the similarity values of 99.6%, 99.9% and 98.5%, respectively. Further phylogenomic calculations of average nucleotide identity (ANI), average amino acid identity (AAI) and digital DNA-DNA hybridization (dDDH) values between strains LZ-6 T and the type strain of M. shengliensis were 95.9%, 96.4% and 68.5%, respectively. However, combined phenotypic and chemotaxonomic characterizations revealed that the new isolate was obviously different from the type strain of M. shengliensis. The obtained taxonomic evidences supported that strain LZ-6 T represents a novel subspecies of M. shengliensis, for which the name is proposed, Marinobacter shengliensis subsp. alexandrii subsp. nov. with the type strain LZ-6 T (= CCTCC AB 2018388TT = KCTC 72197 T). This proposal automatically creates Marinobacter shengliensis subsp. shengliensis for which the type strain is SL013A34A2T (= LMG 27740 T = CGMCC 1.12758 T).

Background The widely recognized anti-cancer potential of aspirin has created a broad interest to explore the clinical benefits of aspirin in cancer therapy. However, the current understanding of the molecular mechanisms involved in the anti-cancer potential of aspirin remains limited. Methods Cancer stemness assays which contained ALDH, side population, chemo-resistance, sphere formation, and tumorigenesis were performed to validate aspirin function in vitro and in vivo. Histone modification assay was performed to check the effect of aspirin on histone methylation as well as the activity of HDAC and KDM6A/B. Inhibitor in vivo assay was performed to evaluate therapeutic effects of various inhibitor combination manners. Results In regards to in vitro studies, aspirin diminishes cancer cell stemness properties which include reducing the ALDH+ subpopulation, side population, chemo-resistance, and sphere formation in three cancer types. In regards to in vivo studies, aspirin decreases tumor growth and metastasis and prolongs survival. In addition, our results showed that aspirin inhibits inflammation-related stemness gene expression (especially ICAM3) identified by a high-throughput siRNA platform. In regards to the underlying molecular mechanism of action, aspirin reduces histone demethylase (KDM6A/B) expression that mediates histone methylation and suppresses gene expression via a COX-independent manner. In regards to therapeutic strategies, aspirin combined HDM inhibitors, ICAM3 downstream signaling Src/PI3K inhibitors, or ICAM3 inhibitor Lifitigrast prevents cancer progression in vivo. Conclusions The aforementioned findings suggest a molecular model that explains how aspirin diminishes cancer cell stemness properties. These findings may provide novel targets for therapeutic strategies involving aspirin in the prevention of cancer progression.

The outbreaks of severe acute respiratory syndrome (SARS) and Coronavirus Disease 2019 (COVID-19) caused by SARS-CoV and SARS-CoV-2, respectively, have posed severe threats to global public health and the economy. Treatment and prevention of these viral diseases call for the research and development of human neutralizing monoclonal antibodies (NMAbs). Scientists have screened neutralizing antibodies using the virus receptor-binding domain (RBD) as an antigen, indicating that RBD contains multiple conformational neutralizing epitopes, which are the main structural domains for inducing neutralizing antibodies and T-cell immune responses. This review summarizes the structure and function of RBD and RBD-specific NMAbs against SARS-CoV and SARS-CoV-2 currently under development.

A few animals have been suspected to be intermediate hosts of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, a large-scale single-cell screening of SARS-CoV-2 target cells on a wide variety of animals is missing. Here, we constructed the single-cell atlas for 11 representative species in pets, livestock, poultry, and wildlife. Notably, the proportion of SARS-CoV-2 target cells in cat was found considerably higher than other species we investigated and SARS-CoV-2 target cells were detected in multiple cell types of domestic pig, implying the necessity to carefully evaluate the risk of cats during the current COVID-19 pandemic and keep pigs under surveillance for the possibility of becoming intermediate hosts in future coronavirus outbreak. Furthermore, we screened the expression patterns of receptors for 144 viruses, resulting in a comprehensive atlas of virus target cells. Taken together, our work provides a novel and fundamental strategy to screen virus target cells and susceptible species, based on single-cell transcriptomes we generated for domesticated animals and wildlife, which could function as a valuable resource for controlling current pandemics and serve as an early warning system for coping with future infectious disease threats.

Influenza continues to be a significant public health challenge. Two glycoproteins on the surface of influenza virus, hemagglutinin and neuraminidase, play a prominent role in the process of influenza virus infection and release. Monoclonal antibodies targeting glycoproteins can effectively prevent the spread of the virus. In this review, we summarized currently reported human monoclonal antibodies targeting glycoproteins of influenza A and B viruses.

Background: A hallmark of eosinophilic chronic rhinosinusitis with nasal polyps (eCRSwNP) is mucosal eosinophil-predominant inflammation. Nasal nitric oxide (nNO) is a known biomarker of eosinophilic inflammation in the upper airway. However, the utility of nNO measurement in the upper airway remains controversial. The present study aimed to compare the use of other clinical parameters with nNO to prediagnose patients with eCRSwNP from Central China. Methods: From June 2019 to December 2019, 70 patients with CRSwNP undergoing endoscopic sinus surgery and 30 healthy subjects were enrolled. nNO measurements were performed in all of these subjects. Computed tomography scans, full blood count with differential analysis, and determination of total immunoglobulin E (total IgE) and plasma cytokines were performed before surgery. Receiver operating characteristic curves and logistic regression analysis were used to assess the predictive potential of the clinical parameters. Results: We recruited 24 patients with eCRSwNP and 46 with noneosinophilic CRSwNP (non-eCRSwNP). In patients with eCRSwNP, nNO levels were significantly higher than those in patients with non-eCRSwNP (p < 0.0001). Blood eosinophil percentages and counts, total IgE, and CT-derived ethmoid sinus and maxillary sinus ratio (E/M ratio) were all significantly higher compared with those in patients with non-eCRSwNP (p < 0.05). To diagnose eCRSwNP, the highest area under the curve (0.803) was determined for nNO. At a cutoff of >329 parts per billion (ppb), the sensitivity was 83.30% and the specificity was 71.70%. However, the levels of plasma cytokines Th1/Th2 were not significantly different between the histological types of CRSwNP (p > 0.05). Conclusion: Measurement of nNO is useful for the early diagnosis of eCRSwNP.

Hantavirus (HV), a pathogen of animal infectious diseases that poses a threat to humans, has attracted extensive attention. Clinically, HV can cause hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS), between which HFRS is mostly in Eurasia, and HPS is mostly in the Americas. This paper reviews the research progress of small-molecule inhibitors of HV.