In contrast to studies on class I histone deacetylase (HDAC) inhibitors, the elucidation of the molecular mechanisms and therapeutic potential of class IIa HDACs (HDAC4, HDAC5, HDAC7 and HDAC9) is impaired by the lack of potent and selective chemical probes. Here we report the discovery of inhibitors that fill this void with an unprecedented metal-binding group, trifluoromethyloxadiazole (TFMO), which circumvents the selectivity and pharmacologic liabilities of hydroxamates. We confirm direct metal binding of the TFMO through crystallographic approaches and use chemoproteomics to demonstrate the superior selectivity of the TFMO series relative to a hydroxamate-substituted analog. We further apply these tool compounds to reveal gene regulation dependent on the catalytic active site of class IIa HDACs. The discovery of these inhibitors challenges the design process for targeting metalloenzymes through a chelating metal-binding group and suggests therapeutic potential for class IIa HDAC enzyme blockers distinct in mechanism and application compared to current HDAC inhibitors.

This study investigates global changes in indicators of mean and extreme streamflow. The assessment is based on the Global Streamflow Indices and Metadata archive and focuses on time series of the annual minimum, the 10th, 50th, and 90th percentiles, the annual mean, and the annual maximum of daily streamflow. Trends are estimated using the Sen‐Theil slope, and the significance of mean regional trends is established through bootstrapping. Changes in the indices are often regionally consistent, showing that the entire flow distribution is moving either upward or downward. In addition, the analysis confirms the complex nature of hydrological change where drying in some regions (e.g., in the Mediterranean) is contrasted by wetting in other regions (e.g., North Asia). Observed changes are discussed in the context of previous results and with respect to model estimates of the impacts of anthropogenic climate change and human water management.

This is the first part of a two-paper series presenting the Global Streamflow Indices and Metadata archive (GSIM), a worldwide collection of metadata and indices derived from more than 35 000 daily streamflow time series. This paper focuses on the compilation of the daily streamflow time series based on 12 free-toaccess streamflow databases (seven national databases and five international collections). It also describes the development of three metadata products (freely available at https://doi.pangaea.de/10.1594/PANGAEA.887477):(1) a GSIM catalogue collating basic metadata associated with each time series, (2) catchment boundaries for the contributing area of each gauge, and (3) catchment metadata extracted from 12 gridded global data products representing essential properties such as land cover type, soil type, and climate and topographic characteristics. The quality of the delineated catchment boundary is also made available and should be consulted in GSIM application. The second paper in the series then explores production and analysis of streamflow indices. Having collated an unprecedented number of stations and associated metadata, GSIM can be used to advance large-scale hydrological research and improve understanding of the global water cycle. flow archive. Firstly, there are threats to the quantity of data, such as political sensitivities (Nelson, 2009), cost recovery and strict access policies (Hannah et al., 2011), unavailability in an electronic format, consistency of data formats, limited documentation, missing metadata, and a lack of resources for database maintenance and updating. Secondly, there are difficulties associated with the quality of the data in many regions, such as poor spatial coverage, poor quality control, variable quality control between regions, inconsistent metadata, imprecise geographic coordinates of the site, changes in the density of stream gauges, and variable record lengths. Lastly, even in locations where there are abundant and highquality streamflow observations, there can be questions over its utility in specific research such as climate sensitivity analysis due to the manifestation of human impacts -for example, urbanization, land-use changes, channelization, and upstream dams (Hannah et al., 2011).Published by Copernicus Publications.

Abstract. This is Part 2 of a two-paper series presenting the Global Streamflow Indices and Metadata Archive (GSIM), which is a collection of daily streamflow observations at more than 30 000 stations around the world. While Part 1 (Do et al., 2018a) describes the data collection process as well as the generation of auxiliary catchment data (e.g. catchment boundary, land cover, mean climate), Part 2 introduces a set of quality controlled time-series indices representing (i) the water balance, (ii) the seasonal cycle, (iii) low flows and (iv) floods. To this end we first consider the quality of individual daily records using a combination of quality flags from data providers and automated screening methods. Subsequently, streamflow time-series indices are computed for yearly, seasonal and monthly resolution. The paper provides a generalized assessment of the homogeneity of all generated streamflow time-series indices, which can be used to select time series that are suitable for a specific task. The newly generated global set of streamflow time-series indices is made freely available with an digital object identifier at https://doi.pangaea.de/10.1594/PANGAEA.887470 and is expected to foster global freshwater research, by acting as a ground truth for model validation or as a basis for assessing the role of human impacts on the terrestrial water cycle. It is hoped that a renewed interest in streamflow data at the global scale will foster efforts in the systematic assessment of data quality and provide momentum to overcome administrative barriers that lead to inconsistencies in global collections of relevant hydrological observations.