The Community Land Model (CLM) is the land component of the Community Earth System Model (CESM) and is used in several global and regional modeling systems. In this paper, we introduce model developments included in CLM version 5 (CLM5), which is the default land component for CESM2. We assess an ensemble of simulations, including prescribed and prognostic vegetation state, multiple forcing data sets, and CLM4, CLM4.5, and CLM5, against a range of metrics including from the International Land Model Benchmarking (ILAMBv2) package. CLM5 includes new and updated processes and Key Points: • Updated Community Land Model has more hydrological and ecological process fidelity and more comprehensive representation of land management. • The model is systematically evaluated using International Land Model Benchmarking system and shows marked improvement over prior versions. parameterizations: (1) dynamic land units, (2) updated parameterizations and structure for hydrology and snow (spatially explicit soil depth, dry surface layer, revised groundwater scheme, revised canopy interception and canopy snow processes, updated fresh snow density, simple firn model, and Model for Scale Adaptive River Transport), (3) plant hydraulics and hydraulic redistribution, (4) revised nitrogen cycling (flexible leaf stoichiometry, leaf N optimization for photosynthesis, and carbon costs for plant nitrogen uptake), (5) global crop model with six crop types and time-evolving irrigated areas and fertilization rates, (6) updated urban building energy, (7) carbon isotopes, and (8) updated stomatal physiology. New optional features include demographically structured dynamic vegetation model (Functionally Assembled Terrestrial Ecosystem Simulator), ozone damage to plants, and fire trace gas emissions coupling to the atmosphere. Conclusive establishment of improvement or degradation of individual variables or metrics is challenged by forcing uncertainty, parametric uncertainty, and model structural complexity, but the multivariate metrics presented here suggest a general broad improvement from CLM4 to CLM5. Plain Language Summary The Community Land Model (CLM) is the land component of the widely used Community Earth System Model (CESM). Here, we introduce model developments included in CLM version 5 (CLM5), the default land component for CESM2 which will be used for the Coupled Model Intercomparison Project (CMIP6). CLM5 includes many new and updated processes including (1) hydrology and snow features such as spatially explicit soil depth, canopy snow processes, a simple firn model, and a more mechanistic river model, (2) plant hydraulics and hydraulic redistribution, (3) revised nitrogen cycling with flexible leaf stoichiometry, leaf N optimization for photosynthesis, and carbon costs for plant nitrogen uptake, (4) expansion to six crop types (global) and time-evolving irrigated areas and fertilization rates, (5) improved urban building energy model, and (6) carbon isotopes. New optional features include a demographically structured dynamic vegetat...

Based on engineered or bacterial nucleases, the development of genome editing technologies has opened up the possibility of directly targeting and modifying genomic sequences in almost all eukaryotic cells. Genome editing has extended our ability to elucidate the contribution of genetics to disease by promoting the creation of more accurate cellular and animal models of pathological processes and has begun to show extraordinary potential in a variety of fields, ranging from basic research to applied biotechnology and biomedical research. Recent progress in developing programmable nucleases, such as zinc-finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs) and clustered regularly interspaced short palindromic repeat (CRISPR)-Cas-associated nucleases, has greatly expedited the progress of gene editing from concept to clinical practice. Here, we review recent advances of the three major genome editing technologies (ZFNs, TALENs, and CRISPR/Cas9) and discuss the applications of their derivative reagents as gene editing tools in various human diseases and potential future therapies, focusing on eukaryotic cells and animal models. Finally, we provide an overview of the clinical trials applying genome editing platforms for disease treatment and some of the challenges in the implementation of this technology.

Esophageal squamous cell carcinoma (ESCC) is one of the most common cancers worldwide and the fourth most lethal cancer in China. However, although genomic studies have identified some mutations associated with ESCC, we know little of the mutational processes responsible. To identify genome-wide mutational signatures, we performed either whole-genome sequencing (WGS) or whole-exome sequencing (WES) on 104 ESCC individuals and combined our data with those of 88 previously reported samples. An APOBEC-mediated mutational signature in 47% of 192 tumors suggests that APOBEC-catalyzed deamination provides a source of DNA damage in ESCC. Moreover, PIK3CA hotspot mutations (c.1624G>A [p.Glu542Lys] and c.1633G>A [p.Glu545Lys]) were enriched in APOBEC-signature tumors, and no smoking-associated signature was observed in ESCC. In the samples analyzed by WGS, we identified focal (<100 kb) amplifications of CBX4 and CBX8. In our combined cohort, we identified frequent inactivating mutations in AJUBA, ZNF750, and PTCH1 and the chromatin-remodeling genes CREBBP and BAP1, in addition to known mutations. Functional analyses suggest roles for several genes (CBX4, CBX8, AJUBA, and ZNF750) in ESCC. Notably, high activity of hedgehog signaling and the PI3K pathway in approximately 60% of 104 ESCC tumors indicates that therapies targeting these pathways might be particularly promising strategies for ESCC. Collectively, our data provide comprehensive insights into the mutational signatures of ESCC and identify markers for early diagnosis and potential therapeutic targets.

A major research plan entitled “Integrated research on the ecohydrological process of the Heihe River Basin” was launched by the National Natural Science Foundation of China in 2010. One of the key aims of this research plan is to establish a research platform that integrates observation, data management, and model simulation to foster twenty-first-century watershed science in China. Based on the diverse needs of interdisciplinary studies within this research plan, a program called the Heihe Watershed Allied Telemetry Experimental Research (HiWATER) was implemented. The overall objective of HiWATER is to improve the observability of hydrological and ecological processes, to build a world-class watershed observing system, and to enhance the applicability of remote sensing in integrated ecohydrological studies and water resource management at the basin scale. This paper introduces the background, scientific objectives, and experimental design of HiWATER. The instrumental setting and airborne mission plans are also outlined. The highlights are the use of a flux observing matrix and an eco-hydrological wireless sensor network to capture multiscale heterogeneities and to address complex problems, such as heterogeneity, scaling, uncertainty, and closing water cycle at the watershed scale. HiWATER was formally initialized in May 2012 and will last four years until 2015. Data will be made available to the scientific community via the Environmental and Ecological Science Data Center for West China. International scientists are welcome to participate in the field campaign and use the data in their analyses.

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