Patient-Customized Oligonucleotide Therapy for a Rare Genetic Disease.

Genome sequencing is often pivotal in the diagnosis of rare diseases, but many of these conditions lack specific treatments. We describe how molecular diagnosis of a rare, fatal neurodegenerative condition led to the rational design, testing, and manufacture of milasen, a splice-modulating antisense oligonucleotide drug tailored to a particular patient. Proof-of-concept experiments in cell lines from the patient served as the basis for launching an "N-of-1" study of milasen within 1 year after first contact with the patient. There were no serious adverse events, and treatment was associated with objective reduction in seizures (determined by electroencephalography and parental reporting). This study offers a possible template for the rapid development of patient-customized treatments. (Funded by Mila's Miracle Foundation and others.).

The floodplain inundation history of the Murray-Darling Basin through two-monthly maximum water depth maps.

With growing concerns over water management in rivers worldwide, researchers are seeking innovative solutions to monitor and understand changing flood patterns. In a noteworthy advancement, stakeholders interested in the changing flood patterns of the Murray Darling Basin (MDB) in Australia, covering an area of 1 million km2, can now access a consistent timeseries of water depth maps for the entire basin. The dataset covers the period from 1988 to 2022 at two-monthly timestep and was developed using remotely sensed imagery and a flood depth estimation model at a spatial resolution of ≈30 m, providing a comprehensive picture of maximum observed inundation depth across the MDB. Validation against 13 hydrodynamic model outputs for different parts of the MDB yielded a mean absolute error of 0.49 m, demonstrating reasonable accuracy and reliability of the dataset. The resulting dataset is best suited to system-wide analysis but might also be useful for those interested in the history of flooding at specific locations in the system. We provide the dataset, visualization tools, and examples to support ongoing research.

Assessing irrigated agriculture's surface water and groundwater consumption by combining satellite remote sensing and hydrologic modelling.

Globally, irrigation accounts for more than two thirds of freshwater demand. Recent regional and global assessments indicate that groundwater extraction (GWE) for irrigation has increased more rapidly than surface water extraction (SWE), potentially resulting in groundwater depletion. Irrigated agriculture in semi-arid and arid regions is usually from a combination of stored surface water and groundwater. This paper assesses the usefulness of remotely-sensed (RS) derived information on both irrigation dynamics and rates of actual evapotranspiration which are both input to a river-reach water balance model in order to quantify irrigation water use and water provenance (either surface water or groundwater). The assessment is implemented for the water-years 2004/05-2010/11 in five reaches of the Murray-Darling Basin (Australia); a heavily regulated basin with large irrigated areas and periodic droughts and floods. Irrigated area and water use are identified each water-year (from July to June) through a Random Forest model which uses RS vegetation phenology and actual evapotranspiration as predicting variables. Both irrigated areas and actual evapotranspiration from irrigated areas were compared against published estimates of irrigated areas and total water extraction (SWE+GWE).The river-reach model determines the irrigated area that can be serviced with stored surface water (SWE), and the remainder area (as determined by the Random Forest Model) is assumed to be supplemented by groundwater (GWE). Model results were evaluated against observed SWE and GWE. The modelled SWE generally captures the observed interannual patterns and to some extent the magnitudes, with Pearson's correlation coefficients >0.8 and normalised root-mean-square-error<30%. In terms of magnitude, the results were as accurate as or better than those of more traditional (i.e., using areas that fluctuate based on water resource availability and prescribed crop factors) irrigation modelling. The RS irrigated areas and actual evapotranspiration can be used to: (i) understand irrigation dynamics, (ii) constrain irrigation models in data scarce regions, as well as (iii) pinpointing areas that require better ground-based monitoring.

Multi-decadal trends in global terrestrial evapotranspiration and its components.

Evapotranspiration (ET) is the process by which liquid water becomes water vapor and energetically this accounts for much of incoming solar radiation. If this ET did not occur temperatures would be higher, so understanding ET trends is crucial to predict future temperatures. Recent studies have reported prolonged declines in ET in recent decades, although these declines may relate to climate variability. Here, we used a well-validated diagnostic model to estimate daily ET during 1981-2012, and its three components: transpiration from vegetation (Et), direct evaporation from the soil (Es) and vaporization of intercepted rainfall from vegetation (Ei). During this period, ET over land has increased significantly (p < 0.01), caused by increases in Et and Ei, which are partially counteracted by Es decreasing. These contrasting trends are primarily driven by increases in vegetation leaf area index, dominated by greening. The overall increase in Et over land is about twofold of the decrease in Es. These opposing trends are not simulated by most Coupled Model Intercomparison Project phase 5 (CMIP5) models, and highlight the importance of realistically representing vegetation changes in earth system models for predicting future changes in the energy and water cycle.