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  1. Zhang D, Gao C, Li R, Zhang L, Tian J
    Arch Pharm Res, 2017 May;40(5):579-591.
    PMID: 28211011 DOI: 10.1007/s12272-017-0899-9
    2α,3α,24-Thrihydroxyurs-12-en-28-oicacid (TEOA), a pentacyclic triterpenoid, isolated from the roots of Actinidia eriantha, exhibits significant cytotoxicity against SW620, BGC-823, HepG-2, A549 and PC-3 cancer cells. In this study, we investigated the underlying molecular mechanism of the anticancer activity of TEOA in SW620 cells. We demonstrated that TEOA induced apoptosis through cleavage of caspase-9 and PARP in SW620 cells. In addition, evidence of TEOA-mediated autophagy included the induction of autophagolysosomes and activation of autophagic markers LC-3B and p62. Further analysis illustrated that TEOA promoted the phosphorylation of PERK and elF2α, followed by up-regulation of the downstream protein CHOP, suggesting the involvement of PERK/eIF2α/CHOP pathway and ER stress in TEOA-induced autophagy in SW620 cells. Meanwhile, TEOA-mediated PINK1, Parkin, ubiquitin and p62 activation revealed that TEOA induced specific autophagy-mitophagy in SW620 cells. Additionally, an antioxidant NAC attenuated the TEOA-induced mitophagy, indicating that TEOA triggers mitophagy via a ROS-dependent pathway. Collectively, our findings revealed a novel cellular mechanism of TEOA in the colon cancer cell line SW620, thus providing a molecular basis for developing TEOA into an anti-tumor candidate.
  2. Yuan Y, Shang J, Gao C, Sommer W, Li W
    Eur J Neurosci, 2024 Jul;60(2):4078-4094.
    PMID: 38777332 DOI: 10.1111/ejn.16422
    Although the attractiveness of voices plays an important role in social interactions, it is unclear how voice attractiveness and social interest influence social decision-making. Here, we combined the ultimatum game with recording event-related brain potentials (ERPs) and examined the effect of attractive versus unattractive voices of the proposers, expressing positive versus negative social interest ("I like you" vs. "I don't like you"), on the acceptance of the proposal. Overall, fair offers were accepted at significantly higher rates than unfair offers, and high voice attractiveness increased acceptance rates for all proposals. In ERPs in response to the voices, their attractiveness and expressed social interests yielded early additive effects in the N1 component, followed by interactions in the subsequent P2, P3 and N400 components. More importantly, unfair offers elicited a larger Medial Frontal Negativity (MFN) than fair offers but only when the proposer's voice was unattractive or when the voice carried positive social interest. These results suggest that both voice attractiveness and social interest moderate social decision-making and there is a similar "beauty premium" for voices as for faces.
  3. Betts JM, Gao C, Brown D, Ikin J, Maniam R, Stub D, et al.
    Aust J Rural Health, 2020 Aug;28(4):399-407.
    PMID: 32463177 DOI: 10.1111/ajr.12634
    OBJECTIVES: Hypertension is a leading risk factor for death and disability. We aimed to estimate the prevalence of hypertension in an older rural Australian cohort and identify predictors of hypertension management.

    DESIGN: Analysis of cross-sectional data collected from participants in a prospective cohort study.

    SETTING: The Victorian rural towns of Morwell and Sale in 2018-2019.

    PARTICIPANTS: A weighted random sample of 1119 eligible participants from Morwell or Sale, aged ≥55-90 years for men and ≥60-90 years for women, was drawn from the Hazelwood Health Study's Adult Survey cohort.

    MAIN OUTCOME MEASURES: Blood pressure, body mass index, left ventricular hypertrophy by electrocardiogram, estimated glomerular filtration rate and glycosylated haemoglobin (HbA1c ) were measured. Participants with hypertension were categorised as managed, undermanaged or unmanaged.

    RESULTS: Testing undertaken of 498 participants estimated the weighted prevalence of hypertension (defined as blood pressure ≥ 140/90 mm Hg, a self-reported doctor diagnosis of hypertension or taking antihypertensive medication) to be 79.9% (95% confidence interval: 75.7-83.4). Of those, 54.5% (49.4-60.0) had managed hypertension (<140/90 mm Hg), 37.1% (32.3-42.1) undermanaged hypertension and 8.4% (5.9-11.9) a new finding of hypertension (unmanaged hypertension). Current employment (relative risk 1.47, 95% confidence interval: 1.06-2.02) and single marital status (relative risk 1.45, 1.4-1.84) were associated with under- or unmanaged hypertension. Compared with no hypertension, the hypertensive groups were more likely to demonstrate markers of end-organ damage such as left ventricular hypertrophy and impaired renal function.

    CONCLUSION: Hypertension is a highly prevalent condition among older rural Australians which is suboptimally identified and managed.

  4. Zhu B, Qian C, Zhou F, Guo J, Chen N, Gao C, et al.
    J Ethnopharmacol, 2020 May 10;253:112663.
    PMID: 32045682 DOI: 10.1016/j.jep.2020.112663
    ETHNOPHARMACOLOGICAL RELEVANCE: Tetrastigma hemsleyanum Diels et Gilg (Sanyeqing) is traditionally used as a folk medicine for the treatments of inflammation, high fever, hepatitis and cancer, and can improve the immune function of the patient. It belongs to the family of Vitaceae, and is mainly distributed in southeast China (Yunnan province) and can be found in India (Andaman Islands), Myanmar, Thailand, Vietnam, Malaysia and Indonesia in the valleys with 1100-1300 m above the sea level.

    AIM OF THE STUDY: The present study aimed to characterize the chemical properties of a purified polysaccharide extracted from the aerial part of Tetrastigma hemsleyanum (SYQP) and investigate its antipyretic and antitumor effects in mice models.

    MATERIALS AND METHODS: Water-soluble crude polysaccharides from the aerial parts of Tetrastigma hemsleyanum were extracted and fractionated by DEAE and gel permeation chromatography. Homogeneity, molecular weight, monosaccharide composition, and FTIR analysis were performed to characterize the SYQP. Antipyretic effect of SYQP was examined using Brewer's yeast induced hyperthermia test. Antitumor effect was investigated using H22 tumor bearing mice. The serum cytokines were determined to evaluated the biological activities of SYQP.

    RESULTS: SYQP was composed of galacturonic acid (GalA), glucose (Glc), mannose (Man), arabinose (Ara), galactose (Gal), and rhamnose (Rha) with a molar ratio of 11.3:7.1:2.5:1.0:0.9:0.5 and it had an average molecular weight of 66.2 kDa. The oral administration of SYQP at 200 and 400 mg/kg could markedly suppress the hyperthermia of mice induced by Brewer's yeast and decrease the production of cytokines especially prostaglandin E2 (PGE2) in the serum of mice. SYQP inhibited the growth of H22 tumor in mice with inhibitory rate of 39.9% at the administration dose of 200 mg/kg and increased the production of cytokines such as tumor necrosis factor-alpha (TNF-a) and interferon γ (IFN-γ). Experimental results showed that the preventive administration of SYQP before lipopolysaccharide (LPS) reduced the high cytokine levels such as IL-6, IL-10 and IFN-γ, indicating that SYQP might act as a competitor with LPS to interact with toll like receptor 4 (TLR4), which further regulated the secretion of cytokines.

    CONCLUSION: The anti-inflammatory and antitumor activities of SYQP might be related to its regulation of host immune function by controlling the secretion of cytokines.

  5. Kawai C, Zhang Y, Lukács G, Chu W, Zheng C, Gao C, et al.
    Psychol Res, 2023 Apr;87(3):704-724.
    PMID: 35838836 DOI: 10.1007/s00426-022-01697-5
    Cultural differences-as well as similarities-have been found in explicit color-emotion associations between Chinese and Western populations. However, implicit associations in a cross-cultural context remain an understudied topic, despite their sensitivity to more implicit knowledge. Moreover, they can be used to study color systems-that is, emotional associations with one color in the context of an opposed one. Therefore, we tested the influence of two different color oppositions on affective stimulus categorization: red versus green and red versus white, in two experiments. In Experiment 1, stimuli comprised positive and negative words, and participants from the West (Austria/Germany), and the East (Mainland China, Macau) were tested in their native languages. The Western group showed a significantly stronger color-valence interaction effect than the Mainland Chinese (but not the Macanese) group for red-green but not for red-white opposition. To explore color-valence interaction effects independently of word stimulus differences between participant groups, we used affective silhouettes instead of words in Experiment 2. Again, the Western group showed a significantly stronger color-valence interaction than the Chinese group in red-green opposition, while effects in red-white opposition did not differ between cultural groups. Our findings complement those from explicit association research in an unexpected manner, where explicit measures showed similarities between cultures (associations for red and green), our results revealed differences and where explicit measures showed differences (associations with white), our results showed similarities, underlining the value of applying comprehensive measures in cross-cultural research on cross-modal associations.
  6. An D, Eggeling J, Zhang L, He H, Sapkota A, Wang YC, et al.
    Sci Rep, 2023 Jul 08;13(1):11068.
    PMID: 37422491 DOI: 10.1038/s41598-023-38317-0
    In the Asia-Pacific region (APR), extreme precipitation is one of the most critical climate stressors, affecting 60% of the population and adding pressure to governance, economic, environmental, and public health challenges. In this study, we analyzed extreme precipitation spatiotemporal trends in APR using 11 different indices and revealed the dominant factors governing precipitation amount by attributing its variability to precipitation frequency and intensity. We further investigated how these extreme precipitation indices are influenced by El Niño-Southern Oscillation (ENSO) at a seasonal scale. The analysis covered 465 ERA5 (the fifth-generation atmospheric reanalysis of the European Center for Medium-Range Weather Forecasts) study locations over eight countries and regions during 1990-2019. Results revealed a general decrease indicated by the extreme precipitation indices (e.g., the annual total amount of wet-day precipitation, average intensity of wet-day precipitation), particularly in central-eastern China, Bangladesh, eastern India, Peninsular Malaysia and Indonesia. We observed that the seasonal variability of the amount of wet-day precipitation in most locations in China and India are dominated by precipitation intensity in June-August (JJA), and by precipitation frequency in December-February (DJF). Locations in Malaysia and Indonesia are mostly dominated by precipitation intensity in March-May (MAM) and DJF. During ENSO positive phase, significant negative anomalies in seasonal precipitation indices (amount of wet-day precipitation, number of wet days and intensity of wet-day precipitation) were observed in Indonesia, while opposite results were observed for ENSO negative phase. These findings revealing patterns and drivers for extreme precipitation in APR may inform climate change adaptation and disaster risk reduction strategies in the study region.
  7. Gao C, Sun X, Wu Z, Yuan H, Han H, Huang H, et al.
    Front Pharmacol, 2020;11:391.
    PMID: 32477104 DOI: 10.3389/fphar.2020.00391
    Introduction: The leaves of Morus alba L is a traditional Chinese medicine widely applied in lung diseases. Moracin N (MAN), a secondary metabolite extracted form the leaves of Morus alba L, is a potent anticancer agent. But its molecular mechanism remains unveiled.

    Objective: In this study, we aimed to examine the effect of MAN on human lung cancer and reveal the underlying molecular mechanism.

    Methods: MTT assay was conducted to measure cell viability. Annexin V-FITC/PI staining was used to detect cell apoptosis. Confocal microscope was performed to determine the formation of autophagosomes and autolysosomes. Flow cytometry was performed to quantify cell death. Western blotting was used to determine the related-signaling pathway.

    Results: In the present study, we demonstrated for the first time that MAN inhibitd cell proliferation and induced cell apoptosis in human non-small-cell lung carcinoma (NSCLC) cells. We found that MAN treatment dysregulated mitochondrial function and led to mitochondrial apoptosis in A549 and PC9 cells. Meanwhile, MAN enhanced autophagy flux by the increase of autophagosome formation, the fusion of autophagsomes and lysosomes and lysosomal function. Moreover, mTOR signaling pathway, a classical pathway regualting autophagy, was inhibited by MAN in a time- and dose-dependent mannner, resulting in autophagy induction. Interestingly, autophagy inhibition by CQ or Atg5 knockdown attenuated cell apoptosis by MAN, indicating that autophagy serves as cell death. Furthermore, autophagy-mediated cell death by MAN can be blocked by reactive oxygen species (ROS) scavenger NAC, indicating that ROS accumulation is the inducing factor of apoptosis and autophagy. In summary, we revealed the molecular mechanism of MAN against lung cancer through apoptosis and autophagy, suggesting that MAN might be a novel therapeutic agent for NSCLC treatment.

  8. Teng ST, Abdullah N, Hanifah AH, Tan SN, Gao C, Law IK, et al.
    Toxicon, 2021 Sep 30;202:132-141.
    PMID: 34600910 DOI: 10.1016/j.toxicon.2021.09.018
    In March 2018, an algal bloom of Pseudo-nitzschia was detected, for the first time, in a semi-enclosed lagoon in Miri, Sarawak, Malaysia Borneo. The plankton samples were collected for cell enumeration and species identification by electron microscopy and molecular characterization. Liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) was performed to detect and quantify the neurotoxin domoic acid (DA) in both the plankton and shellfish samples. The abundance of Pseudo-nitzschia cells ranged from 5.6 × 105 to 3.5 × 106 cell L-1 during the bloom event. Morphological observation of the cells by transmission electron microscopy showed that the plankton samples comprised a single Pseudo-nitzschia morphotype resembling P. cuspidata. The ITS2 sequence-structure phylogenetic inference further supported the species identity as Pseudo-nitzschia cuspidata. Low levels of DA were detected in the plankton samples, with cellular DA, particulate DA, and dissolved DA of 257-504 fg DA cell-1, 676 ng L-1, and 15 ng L-1, respectively. The amount of DA, 8 μg g-1 tissue, was found present in the shellfish sample (Magallana sp.) which is below the regulatory limit of 20 μg DA g-1 tissue. The study documented, for the first time, DA contamination in shellfish that associated with bloom of P. cuspidata in the Western Pacific region.
  9. Adams N, Dhimal M, Mathews S, Iyer V, Murtugudde R, Liang XZ, et al.
    PNAS Nexus, 2022 May;1(2):pgac032.
    PMID: 36713319 DOI: 10.1093/pnasnexus/pgac032
    Climate change is adversely impacting the burden of diarrheal diseases. Despite significant reduction in global prevalence, diarrheal disease remains a leading cause of morbidity and mortality among young children in low- and middle-income countries. Previous studies have shown that diarrheal disease is associated with meteorological conditions but the role of large-scale climate phenomena such as El Niño-Southern Oscillation (ENSO) and monsoon anomaly is less understood. We obtained 13 years (2002-2014) of diarrheal disease data from Nepal and investigated how the disease rate is associated with phases of ENSO (El Niño, La Niña, vs. ENSO neutral) monsoon rainfall anomaly (below normal, above normal, vs. normal), and changes in timing of monsoon onset, and withdrawal (early, late, vs. normal). Monsoon season was associated with a 21% increase in diarrheal disease rates (Incident Rate Ratios [IRR]: 1.21; 95% CI: 1.16-1.27). El Niño was associated with an 8% reduction in risk while the La Niña was associated with a 32% increase in under-5 diarrheal disease rates. Likewise, higher-than-normal monsoon rainfall was associated with increased rates of diarrheal disease, with considerably higher rates observed in the mountain region (IRR 1.51, 95% CI: 1.19-1.92). Our findings suggest that under-5 diarrheal disease burden in Nepal is significantly influenced by ENSO and changes in seasonal monsoon dynamics. Since both ENSO phases and monsoon can be predicted with considerably longer lead time compared to weather, our findings will pave the way for the development of more effective early warning systems for climate sensitive infectious diseases.
  10. Zhou X, Yan Z, Hou J, Zhang L, Chen Z, Gao C, et al.
    Oncogene, 2024 Feb;43(7):495-510.
    PMID: 38168654 DOI: 10.1038/s41388-023-02923-z
    Esophageal squamous cell carcinoma (ESCC) is one of the most lethal malignancies in the world with poor prognosis. Despite the promising applications of immunotherapy, the objective response rate is still unsatisfactory. We have previously shown that Hippo/YAP signaling acts as a powerful tumor promoter in ESCC. However, whether Hippo/YAP signaling is involved in tumor immune escape in ESCC remains largely unknown. Here, we show that YAP directly activates transcription of the "don't eat me" signal CD24, and plays a crucial role in driving tumor cells to avoid phagocytosis by macrophages. Mechanistically, YAP regulates CD24 expression by interacting with TEAD and binding the CD24 promoter to initiate transcription, which facilitates tumor cell escape from macrophage-mediated immune attack. Our animal model data and clinical data show that YAP combined with CD24 in tumor microenvironment redefines the impact of TAMs on the prognosis of ESCC patients which will provide a valuable basis for precision medicine. Moreover, treatment with YAP inhibitor altered the distribution of macrophages and suppressed tumorigenesis and progression of ESCC in vivo. Together, our study provides a novel link between Hippo/YAP signaling and macrophage-mediated immune escape, which suggests that the Hippo-YAP-CD24 axis may act as a promising target to improve the prognosis of ESCC patients. A proposed model for the regulatory mechanism of Hippo-YAP-CD24-signaling axis in the tumor-associated macrophages mediated immune escape.
  11. Zhou X, Li Y, Wang W, Wang S, Hou J, Zhang A, et al.
    Theranostics, 2020;10(21):9443-9457.
    PMID: 32863938 DOI: 10.7150/thno.46078
    Objective: Esophageal squamous cell carcinoma (ESCC) is one of the most commonly diagnosed cancer types in China. Recent genomic sequencing analysis indicated the over-activation of Hippo/YAP signaling might play important roles for the carcinogenic process and progression for ESCC patients. However, little is known about the molecular mechanisms that controls Hippo signaling activity in ESCC. Our previous studies indicated that PLCE1-an important risk factor for ESCC-linked to ESCC progression through snail signaling, during this period, we found PARK2 was an important downstream target of PLCE1-snail axis. PARK2 was decreased in ESCC human samples, and correlated with good prognosis in ESCC patients. Further research showed that PARK2 could inhibit YAP, which functions as key downstream effectors of the Hippo pathway. Here, we aim to reveal the molecular mechanisms of PARK2 modulated Hippo pathway in ESCC. Methods: To evaluate the function of PARK2 in ESCC, we used a tissue microarray (TMA) of 223 human ESCC patients and immunohistochemistry to analyze the correlation between PARK2 expression and clinicopathologic variables. Depletion of endogenous PARK2 and YAP from ESCC cells using CRISPR/Cas9 technologies. Flow cytometry and EdU cell proliferation assay were used to detect proliferation of ESCC cells. Nude mice subcutaneous injection and Ki-67 staining were used to evaluate tumor growth in vivo. Migration and invasion assays were performed. In addition, lung metastasis models in mice were used to validate the function of PARK2 in vivo. Identification of PARK2 involved in hippo pathway was achieved by expression microarray screening, double immunofluorescence staining and co-immunoprecipitation assays. The RNA-seq analysis results were validated through quantitative real-time PCR (qRT-PCR) analysis. The protein half-life of YAP was analyzed by Cycloheximide assay, and the TEAD activity was detected by Luciferase reporter assays. Results: Clinical sample of ESCC revealed that low PARK2 expression correlated with late tumor stage (P < 0.001), poor differentiation (P < 0.04), lymph node (P < 0.001) and distant metastasis (P = 0.0087). Multivariate Cox proportional regression analysis further revealed that PARK2 expression (P = 0.032) is an independent prognostic factor for the overall survival of ESCC patients. Besides, the immunohistochemistry results showed that PARK2 negatively correlated with YAP protein level (P < 0.001). PARK2 depletion promotes ESCC progression both through Hippo/YAP axis, while PARK2 overexpression suppresses ESCC tumor progression by Hippo signaling. Co-IP and ubiquitination assays revealed that PARK2 could interact with YAP in the cytosol and promotes YAP K48-linked ubiquitination at K90 sites. Conclusion: Clinical sample analysis and mechanistic study have validated PARK2 as a tumor suppressor for ESCC. Multivariate Cox proportional regression analysis further revealed that PARK2 is an independent prognostic factor for the overall survival of ESCC patients. Cellular and molecular mechanisms in this study showed that PARK2 associated with YAP protein in the cytosol, promoted YAP ubiquitination and proteasome-dependent degradation in ESCC cells. Therefore, as a novel modulator for Hippo signaling, modulation of PARK2 activity or gene expression level could be an appealing strategy to treat esophageal.
  12. Han M, Sun J, Yang Q, Liang Y, Jiang Y, Gao C, et al.
    mSystems, 2023 Feb 23.
    PMID: 36815859 DOI: 10.1128/msystems.01211-22
    The world's largest macroalgal green tide, caused by Ulva prolifera, has resulted in serious consequences for coastal waters of the Yellow Sea, China. Although viruses are considered to be one of the key factors in controlling microalgal bloom demise, understanding of the relationship between viral communities and the macroalgal green tide is still poor. Here, a Qingdao coastal virome (QDCV) time-series data set was constructed based on the metagenomic analysis of 17 DNA viromes along three coastal stations of the Yellow Sea, covering different stages of the green tide from Julian days 165 to 271. A total of 40,076 viral contigs were detected and clustered into 28,058 viral operational taxonomic units (vOTUs). About 84% of the vOTUs could not be classified, and 62% separated from vOTUs in other ecosystems. Green tides significantly influenced the spatiotemporal dynamics of the viral community structure, diversity, and potential functions. For the classified vOTUs, the relative abundance of Pelagibacter phages declined with the arrival of the bloom and rebounded after the bloom, while Synechococcus and Roseobacter phages increased, although with a time lag from the peak of their hosts. More than 80% of the vOTUs reached peaks in abundance at different specific stages, and the viral peaks were correlated with specific hosts at different stages of the green tide. Most of the viral auxiliary metabolic genes (AMGs) were associated with carbon and sulfur metabolism and showed spatiotemporal dynamics relating to the degradation of the large amount of organic matter released by the green tide. IMPORTANCE To the best of our knowledge, this study is the first to investigate the responses of viruses to the world's largest macroalgal green tide. It revealed the spatiotemporal dynamics of the unique viral assemblages and auxiliary metabolic genes (AMGs) following the variation and degradation of Ulva prolifera. These findings demonstrate a tight coupling between viral assemblages, and prokaryotic and eukaryotic abundances were influenced by the green tide.
  13. Zheng K, Liang Y, Paez-Espino D, Zou X, Gao C, Shao H, et al.
    mSystems, 2023 Sep 13;8(5):e0019723.
    PMID: 37702511 DOI: 10.1128/msystems.00197-23
    The N4-like viruses, which were recently assigned to the novel viral family Schitoviridae in 2021, belong to a podoviral-like viral lineage and possess conserved genomic characteristics and a unique replication mechanism. Despite their significance, our understanding of N4-like viruses is primarily based on viral isolates. To address this knowledge gap, this study has established a comprehensive N4-like viral data sets comprising 342 high-quality N4-like viruses/proviruses (144 viral isolates, 158 uncultured viruses, and 40 integrated N4-like proviruses). These viruses were classified into 97 subfamilies (89 of which are newly identified), 148 genera (100 of which are newly identified), and 253 species (177 of which are newly identified). The study reveals that N4-like viruses inhibit the polar region, oligotrophic open oceans, and the human gut, where they infect various bacterial lineages, such as Alpha/Beta/Gamma/Epsilon-proteobacteria in the Proteobacteria phylum. Although N4-like viral endogenization appears to be prevalent in Proteobacteria, it has also been observed in Firmicutes. Additionally, the phylogenetic analysis has identified evolutionary divergence within the hallmark genes of N4-like viruses, indicating a complex origin of the different conserved parts of viral genomes. Moreover, 1,101 putative auxiliary metabolic genes (AMGs) were identified in the N4-like viral pan-proteome, which mainly participate in nucleotide and cofactor/vitamin metabolisms. Of these AMGs, 27 were found to be associated with virulence, suggesting their potential involvement in the spread of bacterial pathogenicity. IMPORTANCE The findings of this study are significant, as N4-like viruses represent a unique viral lineage with a distinct replication mechanism and a conserved core genome. This work has resulted in a comprehensive global map of the entire N4-like viral lineage, including information on their distribution in different biomes, evolutionary divergence, genomic diversity, and the potential for viral-mediated host metabolic reprogramming. As such, this work significantly contributes to our understanding of the ecological function and viral-host interactions of bacteriophages.
  14. Gu C, Liang Y, Li J, Shao H, Jiang Y, Zhou X, et al.
    iScience, 2021 Dec 17;24(12):103439.
    PMID: 34988389 DOI: 10.1016/j.isci.2021.103439
    The highest plateau on Earth, Qinghai-Tibet Plateau, contains thousands of lakes with broad salinity and diverse and unique microbial communities. However, little is known about their co-occurring viruses. Herein, we identify 4,560 viral Operational Taxonomic Units (vOTUs) from six viromes of three saline lakes on Qinghai-Tibet Plateau, with less than 1% that could be classified. Most of the predicted vOTUs were associated with the dominant bacterial and archaeal phyla. Virus-encoded auxiliary metabolic genes suggest that viruses influence microbial metabolisms of carbon, nitrogen, sulfur, and lipid; the antibiotic resistance mediation; and their salinity adaption. The six viromes clustered together with the ice core viromes and bathypelagic ocean viromes and might represent a new viral habitat. This study has revealed the unique characteristics and potential ecological roles of DNA viromes in the lakes of the highest plateau and established a foundation for the recognition of the viral roles in plateau lake ecosystems.
  15. Gao C, Xia J, Zhou X, Liang Y, Jiang Y, Wang M, et al.
    Appl Environ Microbiol, 2021 10 28;87(22):e0116021.
    PMID: 34469192 DOI: 10.1128/AEM.01160-21
    Nordic Seas are the subarctic seas connecting the Arctic Ocean and North Atlantic Ocean with complex water masses, experiencing an abrupt climate change. Though knowledge of the marine virosphere has expanded rapidly, the diversity of viruses and their relationships with host cells and water masses in the Nordic Seas remain to be fully revealed. Here, we establish the Nordic Sea DNA virome (NSV) data set of 55,315 viral contigs including 1,478 unique viral populations from seven stations influenced by both the warm Atlantic and cold Arctic water masses. Caudovirales dominated in the seven NSVs, especially in the warm Atlantic waters. The major giant nucleocytoplasmic large DNA viruses (NCLDVs) contributed a significant proportion of the classified viral contigs in the NSVs (32.2%), especially in the cold Arctic waters (44.9%). The distribution patterns of Caudovirales and NCLDVs were a reflection of the community structure of their hosts in the corresponding water masses and currents. Latitude, pH, and flow speed were found to be key factors influencing the microbial communities and coinfluencing the variation of viral communities. Network analysis illustrated the tight coupling between the variation of viral communities and microbial communities in the Nordic Seas. This study suggests a probable linkage between viromes, host cells, and surface water masses from both the cool Arctic and warm Atlantic Oceans. IMPORTANCE This is a systematic study of Nordic Sea viromes using metagenomic analysis. The viral diversity, community structure, and their relationships with host cells and the complex water masses from both the cool Arctic and the warm Atlantic oceans were illustrated. The NCLDVs and Caudovirales are proposed as the viral characteristics of the cold Arctic and warm Atlantic waters, respectively. This study provides an important background for the viromes in the subarctic seas connecting the Arctic Ocean and North Atlantic Ocean and sheds light on their responses to abrupt climate change in the future.
  16. Dörk T, Peterlongo P, Mannermaa A, Bolla MK, Wang Q, Dennis J, et al.
    Sci Rep, 2019 08 29;9(1):12524.
    PMID: 31467304 DOI: 10.1038/s41598-019-48804-y
    Fanconi anemia (FA) is a genetically heterogeneous disorder with 22 disease-causing genes reported to date. In some FA genes, monoallelic mutations have been found to be associated with breast cancer risk, while the risk associations of others remain unknown. The gene for FA type C, FANCC, has been proposed as a breast cancer susceptibility gene based on epidemiological and sequencing studies. We used the Oncoarray project to genotype two truncating FANCC variants (p.R185X and p.R548X) in 64,760 breast cancer cases and 49,793 controls of European descent. FANCC mutations were observed in 25 cases (14 with p.R185X, 11 with p.R548X) and 26 controls (18 with p.R185X, 8 with p.R548X). There was no evidence of an association with the risk of breast cancer, neither overall (odds ratio 0.77, 95%CI 0.44-1.33, p = 0.4) nor by histology, hormone receptor status, age or family history. We conclude that the breast cancer risk association of these two FANCC variants, if any, is much smaller than for BRCA1, BRCA2 or PALB2 mutations. If this applies to all truncating variants in FANCC it would suggest there are differences between FA genes in their roles on breast cancer risk and demonstrates the merit of large consortia for clarifying risk associations of rare variants.
  17. Baxter JS, Johnson N, Tomczyk K, Gillespie A, Maguire S, Brough R, et al.
    Am J Hum Genet, 2021 Jul 01;108(7):1190-1203.
    PMID: 34146516 DOI: 10.1016/j.ajhg.2021.05.013
    A combination of genetic and functional approaches has identified three independent breast cancer risk loci at 2q35. A recent fine-scale mapping analysis to refine these associations resulted in 1 (signal 1), 5 (signal 2), and 42 (signal 3) credible causal variants at these loci. We used publicly available in silico DNase I and ChIP-seq data with in vitro reporter gene and CRISPR assays to annotate signals 2 and 3. We identified putative regulatory elements that enhanced cell-type-specific transcription from the IGFBP5 promoter at both signals (30- to 40-fold increased expression by the putative regulatory element at signal 2, 2- to 3-fold by the putative regulatory element at signal 3). We further identified one of the five credible causal variants at signal 2, a 1.4 kb deletion (esv3594306), as the likely causal variant; the deletion allele of this variant was associated with an average additional increase in IGFBP5 expression of 1.3-fold (MCF-7) and 2.2-fold (T-47D). We propose a model in which the deletion allele of esv3594306 juxtaposes two transcription factor binding regions (annotated by estrogen receptor alpha ChIP-seq peaks) to generate a single extended regulatory element. This regulatory element increases cell-type-specific expression of the tumor suppressor gene IGFBP5 and, thereby, reduces risk of estrogen receptor-positive breast cancer (odds ratio = 0.77, 95% CI 0.74-0.81, p = 3.1 × 10-31).
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