A Multi-scale Approach for Simulating Tidal Marsh Evolution

This study presents a new approach to modeling marsh evolution. The Tidal Marsh Model (TMM) has been developed as a module within the SCHISM (Semi-implicit Cross-scale Hydroscience Integrated System Model) framework. Some unique features of the TMM are dynamic rates, cross-scale simulations, and incorporation of anthropogenic stressors, which allow it to overcome many limitations that current marsh models possess. To evaluate model performance, the TMM was applied in Carter Creek and Taskinas Creek within the York River system (Virginia, USA). We assessed model outputs against field observations focusing on two main aspects: marsh boundary evolution and distribution of marsh sediments. Marsh change is captured with an accuracy of 81% in Carter Creek and an accuracy of 78% in Taskinas Creek. Different statistical descriptors were used to evaluate the model’s ability to reproduce the distribution of observed marsh sediment fractions. Results in both study areas show a satisfactory agreement between sediment model outputs and field observations. This innovative modeling approach will help close some critical knowledge gaps in the current understanding of the system dynamics and allow better implementation of management actions to preserve these ecosystems and their services. https://rdcu.be/b5j0C Read only

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

Explaining the resistomes in a megacity's water supply catchment: Roles of microbial assembly-dominant taxa, niched environments and pathogenic bacteria

Antibiotic resistance genes (ARGs) in drinking water sources suggest the possible presence of resistant microorganisms that jeopardize human health. However, explanations for the presence of specific ARGs in situ are largely unknown, especially how their prevalence is affected by local microbial ecology, taxa assembly and community-wide gene transfer. Here, we characterized resistomes and bacterial communities in the Taipu River catchment, which feeds a key drinking water reservoir to a global megacity, Shanghai. Overall, ARG abundances decreased significantly as the river flowed downstream towards the reservoir (P 2.0) as a function of temperature and dissolved oxygen conditions with the assembly-dominant taxa (e.g. Ilumatobacteraceae and Cyanobiaceae) defining local resistomes (P < 0.01, Cohen's D = 4.22). Bacterial hosts of intragenomic ARGs stayed at the same level across the catchment (60 ∼ 70 genome copies per million reads). Among them, the putative resistant pathogens (e.g. Burkholderiaceae) carried mixtures of ARGs that exhibited high transmission probability (transfer counts = 126, P < 0.001), especially with the microbial assembly-dominant taxa. These putative resistant pathogens had densities ranging form 3.0 to 4.0 × 106 cell/L, which was more pronouncedly affected by resistome and microbial assembly structures than environmental factors (SEM, std-coeff β = 0.62 vs. 0.12). This work shows that microbial assembly and resistant pathogens play predominant roles in prevelance and dissemination of resistomes in receiving water, which deserves greater attention in devisng control strategies for reducing in-situ ARGs and resistant strains in a catchment

MetalOrganic Framework Derived Multicomponent Nanoagent as a Reactive Oxygen Species Amplifier for Enhanced Photodynamic Therapy

Intracellular antioxidants such as glutathione (GSH) play a critical role in protecting malignant tumor cells from apoptosis induced by reactive oxygen species (ROS) and in mechanisms of multidrug and radiation resistance. Herein, we rationally design two multicomponent self-assembled photodynamic therapy (PDT) nanoagents, that is, Glup-MFi-c and Glud-MFo-c, which consist of respective GSH-passivation and GSH-depletion linkers in metal−organic frameworks encapsulated with photosensitizers for a deeply comprehensive understanding of GSH-based tumor PDT. Multicomponent coordination, π−π stacking, and electrostatic interactions among metal ions, photosensitizers, and bridging linkers under the protection of a biocompatible polymer generate homogeneous nanoparticles with satisfied size, good colloid stability, and ultrahigh loading capacity. Compared to the GSH-passivated Glup-MFi-c, the GSH-depleted Glud-MFo-c shows pH-responsive release of photosensitizer and [FeIII(CN)6] linker in tumor cells to efficiently deplete intracellular GSH, thus amplifying the cell-killing efficiency of ROS and suppressing the tumor growth in vivo. This study demonstrates that Glud-MFo-c acts as a ROS amplifier, providing a useful strategy to deeply understand the role of GSH in combating cancer.Ministry of Education (MOE)National Research Foundation (NRF)Accepted versionThis research is supported by the Singapore National Research Foundation Investigatorship (NRF-NRFI2018-03), the Singapore Academic Research Fund (RT12/19), the National Natural Science Foundation of China (31471268), and the National Key Research and Development Program of China (Stem Cell and Translational Research, 2016YFA0101202)

Pharmacological hallmarks of allostery at the M4 muscarinic receptor elucidated through structure and dynamics

Allosteric modulation of G protein-coupled receptors (GPCRs) is a major paradigm in drug discovery. Despite decades of research, a molecular-level understanding of the general principles that govern the myriad pharmacological effects exerted by GPCR allosteric modulators remains limited. The M4 muscarinic acetylcholine receptor (M4 mAChR) is a validated and clinically relevant allosteric drug target for several major psychiatric and cognitive disorders. In this study, we rigorously quantified the affinity, efficacy, and magnitude of modulation of two different positive allosteric modulators, LY2033298 (LY298) and VU0467154 (VU154), combined with the endogenous agonist acetylcholine (ACh) or the high-affinity agonist iperoxo (Ipx), at the human M4 mAChR. By determining the cryo-electron microscopy structures of the M4 mAChR, bound to a cognate Gi1 protein and in complex with ACh, Ipx, LY298-Ipx, and VU154-Ipx, and applying molecular dynamics simulations, we determine key molecular mechanisms underlying allosteric pharmacology. In addition to delineating the contribution of spatially distinct binding sites on observed pharmacology, our findings also revealed a vital role for orthosteric and allosteric ligand–receptor–transducer complex stability, mediated by conformational dynamics between these sites, in the ultimate determination of affinity, efficacy, cooperativity, probe dependence, and species variability. There results provide a holistic framework for further GPCR mechanistic studies and can aid in the discovery and design of future allosteric drugs

The Chesapeake Bay Program Modeling System: Overview and Recommendations For Future Development

The Chesapeake Bay is the largest, most productive, and most biologically diverse estuary in the continental United States providing crucial habitat and natural resources for culturally and economically important species. Pressures from human population growth and associated development and agricultural intensification have led to excessive nutrient and sediment inputs entering the Bay, negatively affecting the health of the Bay ecosystem and the economic services it provides. The Chesapeake Bay Program (CBP) is a unique program formally created in 1983 as a multi-stakeholder partnership to guide and foster restoration of the Chesapeake Bay and its watershed. Since its inception, the CBP Partnership has been developing, updating, and applying a complex linked modeling system of watershed, airshed, and estuary models as a planning tool to inform strategic management decisions and Bay restoration efforts. This paper provides a description of the 2017 CBP Modeling System and the higher trophic level models developed by the NOAA Chesapeake Bay Office, along with specific recommendations that emerged from a 2018 workshop designed to inform future model development. Recommendations highlight the need for simulation of watershed inputs, conditions, processes, and practices at higher resolution to provide improved information to guide local nutrient and sediment management plans. More explicit and extensive modeling of connectivity between watershed landforms and estuary sub-areas, estuarine hydrodynamics, watershed and estuarine water quality, the estuarine-watershed socioecological system, and living resources will be important to broaden and improve characterization of responses to targeted nutrient and sediment load reductions. Finally, the value and importance of maintaining effective collaborations among jurisdictional managers, scientists, modelers, support staff, and stakeholder communities is emphasized. An open collaborative and transparent process has been a key element of successes to date and is vitally important as the CBP Partnership moves forward with modeling system improvements that help stakeholders evolve new knowledge, improve management strategies, and better communicate outcomes