A two-step sensitivity analysis for hydrological signatures in Jinhua River Basin, East China

This is the author accepted manuscript. The final version is available from Taylor & Francis via the DOI in this record.Parameter calibration and sensitivity analysis are usually not straightforward tasks for distributed hydrological models, owing to the complexity of model and large number of parameters. A two-step sensitivity analysis approach is proposed for analyzing the hydrological signatures based on the Distributed Hydrology-Soil-Vegetation Model in Jinhua River Basin, East China. A preliminary sensitivity analysis is conducted to obtain influential parameters via Analysis of Variance. These parameters are further analyzed through a variance-based global sensitivity analysis method to achieve robust rankings and parameter contributions. Parallel computing is designed to reduce computational burden. The results reveal that only a few parameters are significantly sensitive and the interactions between parameters could not be ignored. When analyzing hydrological signatures, it is found that water yield was simulated very well for most samples. Small and medium floods are simulated very well while slight underestimations happen to large floods.This work was supported by National Natural Science Foundation of China (91547106 and 51379183), Zhejiang Provincial Natural Science Foundation of China (LR14E090001), and National Key Research and Development Plan "Inter-governmental Cooperation in International Scientific and Technological Innovation"(2016YFE0122100)

The Role of Nonphotosynthetic Microbes in the Recovery of Biological Soil Crusts in the Gurbantunggut Desert, Northwestern China

The mechanisms regulating the recovery of biological soil crusts (BSCs) due to the presence of nonphotosynthetic microbes were investigated using a soil scalping technique. Microscopic examinations identified the oglueo and oropeo action of bacteria and fungi at the initial stages of recovery of BSCs prior to the appearance of cyanobacteria. Extracellular polymeric substances (EPS) excreted by bacteria principally contained glucose and mannose. The optimum conditions for EPS production included the availability of glucose as the carbon source, the presence of CaCO3 (2g/L), KH2PO4 (0.3g/L), and MgSO4 (0.1g/L), a pH of 7 and incubation at 37 degrees C for 72h. Crust-forming tests in the laboratory and in the field demonstrated that inoculation of bare sand with oligotrophic bacteria was effective in accelerating the recovery of BSCs. The number of nonphotosynthetic microbes (especially actinomycetes and fungi) recorded in both the crust layer (0-2cm) and subsurface layer (2-5cm) was higher after 3 years than after 1 year. Microbial spatial variability of BSCs was related to nutrient status, especially available N

Clinical, Virological and Immunological Features from Patients Infected with Re-Emergent Avian-Origin Human H7N9 Influenza Disease of Varying Severity in Guangdong Province

The second wave of avian influenza H7N9 virus outbreak in humans spread to the Guangdong province of China by August of 2013 and this virus is now endemic in poultry in this region.Background The second wave of avian influenza H7N9 virus outbreak in humans spread to the Guangdong province of China by August of 2013 and this virus is now endemic in poultry in this region. Methods Five patients with H7N9 virus infection admitted to our hospital during August 2013 to February 2014 were intensively investigated. Viral load in the respiratory tract was determined by quantitative polymerase chain reaction (Q-PCR) and cytokine levels were measured by bead-based flow cytometery. Results Four patients survived and one died. Viral load in different clinical specimens was correlated with cytokine levels in plasma and broncho-alveolar fluid (BALF), therapeutic modalities used and clinical outcome. Intravenous zanamivir appeared to be better than peramivir as salvage therapy in patients who failed to respond to oseltamivir. Higher and more prolonged viral load was found in the sputum or endotracheal aspirates compared to throat swabs. Upregulation of proinflammatory cytokines IP-10, MCP-1, MIG, MIP-1α/β, IL-1β and IL-8 was found in the plasma and BALF samples. The levels of cytokines in the plasma and viral load were correlated with disease severity. Reactivation of herpes simplex virus type 1(HSV-1) was found in three out of five patients (60%). Conclusion Expectorated sputum or endotracheal aspirate specimens are preferable to throat swabs for detecting and monitoring H7N9 virus. Severity of the disease was correlated to the viral load in the respiratory tract as well as the extents of cytokinemia. Reactivation of HSV-1 may contribute to clinical outcome.published_or_final_versio

Identification of an Imidazopyridine-based Compound as an Oral Selective Estrogen Receptor Degrader for Breast Cancer Therapy.

UNLABELLED: The pro-oncogenic activities of estrogen receptor alpha (ERα) drive breast cancer pathogenesis. Endocrine therapies that impair the production of estrogen or the action of the ERα are therefore used to prevent primary disease metastasis. Although recent successes with ERα degraders have been reported, there is still the need to develop further ERα antagonists with additional properties for breast cancer therapy. We have previously described a benzothiazole compound A4B17 that inhibits the proliferation of androgen receptor-positive prostate cancer cells by disrupting the interaction of the cochaperone BAG1 with the AR. A4B17 was also found to inhibit the proliferation of estrogen receptor-positive (ER+) breast cancer cells. Using a scaffold hopping approach, we report here a group of small molecules with imidazopyridine scaffolds that are more potent and efficacious than A4B17. The prototype molecule X15695 efficiently degraded ERα and attenuated estrogen-mediated target gene expression as well as transactivation by the AR. X15695 also disrupted key cellular protein-protein interactions such as BAG1-mortalin (GRP75) interaction as well as wild-type p53-mortalin or mutant p53-BAG2 interactions. These activities together reactivated p53 and resulted in cell-cycle block and the induction of apoptosis. When administered orally to in vivo tumor xenograft models, X15695 potently inhibited the growth of breast tumor cells but less efficiently the growth of prostate tumor cells. We therefore identify X15695 as an oral selective ER degrader and propose further development of this compound for therapy of ER+ breast cancers. SIGNIFICANCE: An imidazopyridine that selectively degrades ERα and is orally bioavailable has been identified for the development of ER+ breast cancer therapeutics. This compound also activates wild-type p53 and disrupts the gain-of-function tumorigenic activity of mutant p53, resulting in cell-cycle arrest and the induction of apoptosis

Architecture of Pol II(G) and molecular mechanism of transcription regulation by Gdown1.

Tight binding of Gdown1 represses RNA polymerase II (Pol II) function in a manner that is reversed by Mediator, but the structural basis of these processes is unclear. Although Gdown1 is intrinsically disordered, its Pol II interacting domains were localized and shown to occlude transcription factor IIF (TFIIF) and transcription factor IIB (TFIIB) binding by perfect positioning on their Pol II interaction sites. Robust binding of Gdown1 to Pol II is established by cooperative interactions of a strong Pol II binding region and two weaker binding modulatory regions, thus providing a mechanism both for tight Pol II binding and transcription inhibition and for its reversal. In support of a physiological function for Gdown1 in transcription repression, Gdown1 co-localizes with Pol II in transcriptionally silent nuclei of early Drosophila embryos but re-localizes to the cytoplasm during zygotic genome activation. Our study reveals a self-inactivation through Gdown1 binding as a unique mode of repression in Pol II function

ALMaQUEST. IV. The ALMA-MaNGA QUEnching and STar Formation (ALMaQUEST) Survey

The ALMaQUEST (ALMA-MaNGA QUEnching and STar formation) survey is a program with spatially-resolved $^{12}$CO(1-0) measurements obtained with the Atacama Large Millimeter Array (ALMA) for 46 galaxies selected from the Mapping Nearby Galaxies at Apache Point Observatory (MaNGA) DR15 optical integral-field spectroscopic survey. The aim of the ALMaQUEST survey is to investigate the dependence of star formation activity on the cold molecular gas content at kpc scales in nearby galaxies. The sample consists of galaxies spanning a wide range in specific star formation rate (sSFR), including starburst (SB), main-sequence (MS), and green valley (GV) galaxies. In this paper, we present the sample selection and characteristics of the ALMA observations, and showcase some of the key results enabled by the combination of spatially-matched stellar populations and gas measurements. Considering the global (aperture-matched) stellar mass, molecular gas mass, and star formation rate of the sample, we find that the sSFR depends on both the star formation efficiency (SFE) and the molecular gas fraction ($f_{\rm H_{2}}$), although the correlation with the latter is slightly weaker. Furthermore, the dependence of sSFR on the molecular gas content (SFE or $f_{\rm H_{2}}$) is stronger than that on either the atomic gas fraction or the molecular-to-atomic gas fraction, albeit with the small HI sample size. On kpc scales, the variations in both SFE and $f_{\rm H_{2}}$ within individual galaxies can be as large as 1-2 dex thereby demonstrating that the availability of spatially-resolved observations is essential to understand the details of both star formation and quenching processes.STFC ER

Cryptococcus neoformans-infected macrophages release proinflammatory extracellular vesicles: Insight into their components by multi-omics

This is the final version. Available on open access from the American Society for Microbiology via the DOI in this recordCryptococcus neoformans causes deadly mycosis in immunocompromised individuals. Macrophages are key cells fighting against microbes. Extracellular vesicles (EVs) are cell-to-cell communication mediators. The roles of EVs from infected host cells in the interaction with Cryptococcus remain uninvestigated. Here, EVs from viable C. neo-formans-infected macrophages reduced fungal burdens but led to shorter survival of infected mice. In vitro, EVs induced naive macrophages to an inflammatory phenotype. Transcriptome analysis showed that EVs from viable C. neoformans-infected macro-phages activated immune-related pathways, including p53 in naive human and murine macrophages. Conserved analysis demonstrated that basic cell biological processes, including cell cycle and division, were activated by infection-derived EVs from both murine and human infected macrophages. Combined proteomics, lipidomics, and metabo-lomics of EVs from infected macrophages showed regulation of pathways such as extracellular matrix (ECM) receptors and phosphatidylcholine. This form of intermacro-phage communication could serve to prepare cells at more distant sites of infection to resist C. neoformans infection. IMPORTANCE Cryptococcus neoformans causes cryptococcal meningitis, which is frequent in patients with HIV/AIDS, especially in less-developed countries. The incidence of cryp-tococcal meningitis is close to 1 million each year globally. Macrophages are key cells that protect the body against microbes, including C. neoformans. Extracellular vesicles are a group of membrane structures that are released from cells such as macrophages that modulate cell activities via the transfer of materials such as proteins, lipids, and RNAs. In this study, we found that Cryptococcus neoformans-infected macrophages pro-duce extracellular vesicles that enhance the inflammatory response in Cryptococcus-infected mice. These Cryptococcus neoformans-infected macrophage vesicles also showed higher fungicidal biological effects on inactivated macrophages. Using omics technology, unique protein and lipid signatures were identified in these extracellular vesicles. Transcriptome analysis showed that these vesicles activated immune-related pathways like p53 in naive macrophages. The understanding of this intermacrophage communication could provide potential targets for the design of therapeutic agents to fight this deadly mycosis.Major National R&D Projects of the National Health DepartmentNational Natural Science Foundation of ChinaShanghai Science and Technology CommitteeChinese Academy of EngineeringShanghai Municipal Commission of Health and Family PlanningShanghai Sailing ProgramNI