Evaluation of satellite Leaf Area Index in California vineyards for improving water use estimation.

Remote sensing estimation of evapotranspiration (ET) directly quantifies plant water consumption and provides essential information for irrigation scheduling, which is a pressing need for California vineyards as extreme droughts become more frequent. Many ET models take satellite-derived Leaf Area Index (LAI) as a major input, but how uncertainties of LAI estimations propagate to ET and the partitioning between evaporation and transpiration is poorly understood. Here we assessed six satellite-based LAI estimation approaches using Landsat and Sentinel-2 images against ground measurements from four vineyards in California and evaluated ET sensitivity to LAI in the thermal-based two-source energy balance (TSEB) model. We found that radiative transfer modeling-based approaches predicted low to medium LAI well, but they significantly underestimated high LAI in highly clumped vine canopies (RMSE ~ 0.97 to 1.27). Cubist regression models trained with ground LAI measurements from all vineyards achieved high accuracy (RMSE ~ 0.3 to 0.48), but these empirical models did not generalize well between sites. Red edge bands and the related vegetation index (VI) from the Sentinel-2 satellite contain complementary information of LAI to VIs based on near-infrared and red bands. TSEB ET was more sensitive to positive LAI biases than negative ones. Positive LAI errors of 50% resulted in up to 50% changes in ET, while negative biases of 50% in LAI caused less than 10% deviations in ET. However, even when ET changes were minimal, negative LAI errors of 50% led to up to a 40% reduction in modeled transpiration, as soil evaporation and plant transpiration responded to LAI change divergently. These findings call for careful consideration of satellite LAI uncertainties for ET modeling, especially for the partitioning of water loss between vine and soil or cover crop for effective vineyard irrigation management.

Improving the spatiotemporal resolution of remotely sensed ET information for water management through Landsat, Sentinel-2, ECOSTRESS and VIIRS data fusion.

Robust information on consumptive water use (evapotranspiration, ET) derived from remote sensing can significantly benefit water decision-making in agriculture, informing irrigation schedules and water management plans over extended regions. To be of optimal utility for operational usage, these remote sensing ET data should be generated at the sub-field spatial resolution and daily-to-weekly timesteps commensurate with the scales of water management activities. However, current methods for field-scale ET retrieval based on thermal infrared (TIR) imaging, a valuable diagnostic of canopy stress and surface moisture status, are limited by the temporal revisit of available medium-resolution (100 m or finer) thermal satellite sensors. This study investigates the efficacy of a data fusion method for combining information from multiple medium-resolution sensors toward generating high spatiotemporal resolution ET products for water management. TIR data from Landsat and ECOSTRESS (both at ~ 100-m native resolution), and VIIRS (375-m native) are sharpened to a common 30-m grid using surface reflectance data from the Harmonized Landsat-Sentinel dataset. Periodic 30-m ET retrievals from these combined thermal data sources are fused with daily retrievals from unsharpened VIIRS to generate daily, 30-m ET image timeseries. The accuracy of this mapping method is tested over several irrigated cropping systems in the Central Valley of California in comparison with flux tower observations, including measurements over irrigated vineyards collected in the GRAPEX campaign. Results demonstrate the operational value added by the augmented TIR sensor suite compared to Landsat alone, in terms of capturing daily ET variability and reduced latency for real-time applications. The method also provides means for incorporating new sources of imaging from future planned thermal missions, further improving our ability to map rapid changes in crop water use at field scales.

Aetiology and incidence of sudden cardiac arrest and death in young competitive athletes in the USA: a 4-year prospective study.

OBJECTIVE: To investigate the aetiology and incidence of sudden cardiac arrest and death (SCA/D) in US competitive athletes. METHODS: Prospective surveillance was conducted from 1 July 2014 to 30 June 2018 through the National Center for Catastrophic Sports Injury Research in collaboration with national sports organisations. Autopsy reports, death certificates, and medical records were reviewed by an expert panel to determine aetiology. Athlete participation statistics from the National Federation of State High School Associations and the National Collegiate Athletic Association (NCAA) were used to calculate incidence rates per athlete-years (AY). Comparisons of incidence rates were calculated using incidence rate ratios (IRR) with 95% CIs. RESULTS: 331 cases of confirmed SCA/D (158 survivors; 173 fatalities) were identified; 15.4% in middle school, 61.6% in high school and 16.6% in college and professional athletes. Average age was 16.7 (11-29) years, and the majority were in male (83.7%), basketball (28.7%) or American football (25.4%) athletes. Common causes included hypertrophic cardiomyopathy (20.6%), idiopathic left ventricular hypertrophy (13.4%), coronary artery anomalies (12.0%) and autopsy-negative sudden unexplained death (9.6%). Coronary anomalies were more common in middle school athletes (28%), while cardiomyopathies (hypertrophic, arrhythmogenic, dilated, non-compaction or restricted) accounted for 47% of cases in college and professional athletes. Incidence was higher in male versus female athletes at the high school (1:43 932 AY (95% CI 1:38 101 to 1:50 907) vs 1:203 786 AY (95% CI 1:145 251 to 1:293 794); IRR 4.6 (95% CI 3.1 to 7.2)) and NCAA (1:34 906 AY (95% CI 1:25 385 to 1:49 173) vs 1:123 278 AY (95% CI 1:66 078 to 1:249 853); IRR 3.5 (95% CI 1.5 to 9.5)) levels. African American male NCAA Division I basketball players had the highest annual incidence rate of SCA/D (1:2087 AY (95% CI 1:1073 to 1:4 450)). CONCLUSIONS: Cardiomyopathies account for nearly half of SCA/D cases in college and professional athletes, while coronary artery anomalies play a more prominent role than expected in middle school athletes. Over half of SCA cases in athletes result in sudden death, calling for improved prevention strategies.

An in Vitro Assay Using Cultured Kupffer Cells Can Predict the Impact of Drug Conjugation on in Vivo Antibody Pharmacokinetics.

While antibody-drug conjugates (ADCs) are advancing through clinical testing and receiving new marketing approvals, improvements to the technology continue to be developed in both academic and industrial laboratories. Among the key ADC attributes that can be improved upon with new technology are their biodistribution and pharmacokinetic properties. During the course of ADC development, it has become apparent that conjugation of drugs to the surface of a monoclonal antibody can alter its physicochemical characteristics in a manner that results in increased nonspecific interactions and more rapid elimination from plasma. Researchers in the field have typically relied upon in vivo studies in preclinical models to understand how a particular ADC chemistry will impact these biological characteristics. In previous work, we described how animal studies have revealed a relationship between ADC hydrophobicity, pharmacokinetics, and nonspecific hepatic clearance, particularly by sinusoidal endothelium and Kupffer cells. Here, we describe a fluorescence-based assay using cultured Kupffer cells to recapitulate the nonspecific interactions that lead to ADC clearance in an in vitro setting with the aim of developing a tool for predicting the pharmacokinetics of novel ADC designs. Output from this assay has demonstrated an excellent correlation with plasma clearance for a series of closely related ADCs bearing discrete PEG chains of varying length and has proven useful in interrogating the mechanism of the interactions between ADCs and Kupffer cells.

Sharpening ECOSTRESS and VIIRS land surface temperature using harmonized Landsat-Sentinel surface reflectances.

Land surface temperature (LST) is a key diagnostic indicator of agricultural water use and crop stress. LST data retrieved from thermal infrared (TIR) band imagery, however, tend to have a coarser spatial resolution (e.g., 100 m for Landsat 8) than surface reflectance (SR) data collected from shortwave bands on the same instrument (e.g., 30 m for Landsat). Spatial sharpening of LST data using the higher resolution multi-band SR data provides an important path for improved agricultural monitoring at sub-field scales. A previously developed Data Mining Sharpener (DMS) approach has shown great potential in the sharpening of Landsat LST using Landsat SR data co-collected over various landscapes. This work evaluates DMS performance for sharpening ECOsystem Spaceborne Thermal Radiometer Experiment on Space Station (ECOSTRESS) LST (~70 m native resolution) and Visible Infrared Imaging Radiometer Suite (VIIRS) LST (375 m) data using Harmonized Landsat and Sentinel-2 (HLS) SR data, providing the basis for generating 30-m LST data at a higher temporal frequency than afforded by Landsat alone. To account for the misalignment between ECOSTRESS/VIIRS and Landsat/HLS caused by errors in registration and orthorectification, we propose a modified version of the DMS approach that employs a relaxed box size for energy conservation (EC). Sharpening experiments were conducted over three study sites in California, and results were evaluated visually and quantitatively against LST data from unmanned aerial vehicles (UAV) flights and from Landsat 8. Over the three sites, the modified DMS technique showed improved sharpening accuracy over the standard DMS for both ECOSTRESS and VIIRS, suggesting the effectiveness of relaxing EC box in relieving misalignment-induced errors. To achieve reasonable accuracy while minimizing loss of spatial detail due to the EC box size increase, an optimal EC box size of 180-270 m was identified for ECOSTRESS and about 780 m for VIIRS data based on experiments from the three sites. Results from this work will facilitate the development of a prototype system that generates high spatiotemporal resolution LST products for improved agricultural water use monitoring by synthesizing multi-source remote sensing data.

Data Assimilation of High-Resolution Thermal and Radar Remote Sensing Retrievals for Soil Moisture Monitoring in a Drip-Irrigated Vineyard.

Efficient water use assessment and irrigation management is critical for the sustainability of irrigated agriculture, especially under changing climate conditions. Due to the impracticality of maintaining ground instrumentation over wide geographic areas, remote sensing and numerical model-based fine-scale mapping of soil water conditions have been applied for water resource applications at a range of spatial scales. Here, we present a prototype framework for integrating high-resolution thermal infrared (TIR) and synthetic aperture radar (SAR) remote sensing data into a soil-vegetation-atmosphere-transfer (SVAT) model with the aim of providing improved estimates of surface- and root-zone soil moisture that can support optimized irrigation management strategies. Specifically, remotely-sensed estimates of water stress (from TIR) and surface soil moisture retrievals (from SAR) are assimilated into a 30-m resolution SVAT model over a vineyard site in the Central Valley of California, U.S. The efficacy of our data assimilation algorithm is investigated via both the synthetic and real data experiments. Results demonstrate that a particle filtering approach is superior to an ensemble Kalman filter for handling the nonlinear relationship between model states and observations. In addition, biophysical conditions such as leaf area index are shown to impact the relationship between observations and states and must therefore be represented accurately in the assimilation model. Overall, both surface and root-zone soil moisture predicted via the SVAT model are enhanced through the assimilation of thermal and radar-based retrievals, suggesting the potential for improving irrigation management at the agricultural sub-field scale using a data assimilation strategy.

Etiology of Sudden Cardiac Arrest and Death in US Competitive Athletes: A 2-Year Prospective Surveillance Study.

OBJECTIVE: To determine the etiology of sudden cardiac arrest and death (SCA/D) in competitive athletes through a prospective national surveillance program. DESIGN: Sudden cardiac arrest and death cases in middle school, high school, college, and professional athletes were identified from July 2014 to June 2016 through traditional and social media searches, reporting to the National Center for Catastrophic Sports Injury Research, communication with state and national high school associations, review of the Parent Heart Watch database, and search of student-athlete deaths on the NCAA Resolutions List. Autopsy reports and medical records were reviewed by a multidisciplinary panel to determine the underlying cause. SETTING AND PARTICIPANTS: US competitive athletes with SCA/D. MAIN OUTCOME MEASURES: Etiology of SCA/D. RESULTS: A total of 179 cases of SCA/D were identified (74 arrests with survival, 105 deaths): average age 16.6 years (range 11-29), 149 (83.2%) men, 94 (52.5%) whites, and 54 (30.2%) African American. One hundred seventeen (65.4%) had an adjudicated diagnosis, including 83 deaths and 34 survivors. The most common etiologies included hypertrophic cardiomyopathy (19, 16.2%), coronary artery anomalies (16, 13.7%), idiopathic left ventricular hypertrophy/possible cardiomyopathy (13, 11.1%), autopsy-negative sudden unexplained death (8, 6.8%), Wolff-Parkinson-White (8, 6.8%), and long QT syndrome (7, 6.0%). Hypertrophic cardiomyopathy was more common in male basketball (23.3%), football (25%), and African American athletes (30.3%). An estimated 56.4% of cases would likely demonstrate abnormalities on an electrocardiogram. CONCLUSIONS: The etiology of SCA/D in competitive athletes involves a wide range of clinical disorders. More robust reporting mechanisms, standardized autopsy protocols, and accurate etiology data are needed to better inform prevention strategies.

Neonatal Organ and Tissue Donation for Research: Options Following Death by Natural Causes.

The donation of organs and tissues from neonates (birth to 28 days) for transplantation has been a relatively infrequent occurrence. Less common has been the use of neonatal organs and tissues for research. Specific ethical and legal questions beg for rational and transparent guidelines with which to evaluate referrals of potential donors. Donation of organs and tissues from a neonate can play a key role in the care and support provided to families by health care professionals around the time of a neonate's death. We report on the recovery of neonatal organs and tissues for research. A working group made up of bioethicists, neonatologists, lawyers, obstetric practioners as well as organ procurement and tissue banking professionals evaluated legal, ethical and medical issues. Neonatal donor family members were also consulted. Our primary goals were (a) to ensure that referrals were made in compliance with all applicable federal and state laws, regulations and institutional protocols, and (b) to follow acceptable ethical standards. Algorithms and policies designed to assist in the evaluation of potential neonatal donors were developed. Neonatal donation is proving increasingly valuable for research into areas including diabetes, pulmonary, gastrointestinal, genitourinary and neurological development, rheumatoid arthritis, autism, childhood psychiatric and neurologic disorders, treatment of MRSA infection and pediatric emergency resuscitation. The development of policies and procedures will assist medical professionals who wish to offer the option of donation to family members anticipating the death of a neonate.

Evaluation of TSEB turbulent fluxes using different methods for the retrieval of soil and canopy component temperatures from UAV thermal and multispectral imagery.

The thermal-based Two-Source Energy Balance (TSEB) model partitions the evapotranspiration (ET) and energy fluxes from vegetation and soil components providing the capability for estimating soil evaporation (E) and canopy transpiration (T). However, it is crucial for ET partitioning to retrieve reliable estimates of canopy and soil temperatures and net radiation, as the latter determines the available energy for water and heat exchange from soil and canopy sources. These two factors become especially relevant in row crops with wide spacing and strongly clumped vegetation such as vineyards and orchards. To better understand these effects, very high spatial resolution remote-sensing data from an unmanned aerial vehicle were collected over vineyards in California, as part of the Grape Remote sensing and Atmospheric Profile and Evapotranspiration eXperiment and used in four different TSEB approaches to estimate the component soil and canopy temperatures, and ET partitioning between soil and canopy. Two approaches rely on the use of composite T rad, and assume initially that the canopy transpires at the Priestley-Taylor potential rate. The other two algorithms are based on the contextual relationship between optical and thermal imagery partition T rad into soil and canopy component temperatures, which are then used to drive the TSEB without requiring a priori assumptions regarding initial canopy transpiration rate. The results showed that a simple contextual algorithm based on the inverse relationship of a vegetation index and T rad to derive soil and canopy temperatures yielded the closest agreement with flux tower measurements. The utility in very high-resolution remote-sensing data for estimating ET and E and T partitioning at the canopy level is also discussed.

The Second Annual Think Tank on Prevention of Sudden Cardiac Death in the Young: Developing a rational, reliable, and sustainable national health care resource. A report from the Cardiac Safety Research Consortium.

Sudden cardiac death in the young (SCDY) spans gender, race, ethnicity, and socioeconomic class. The loss of any pediatric patient is a matter of national and international public health concern, and focused efforts should be aimed at preventing these burdensome tragedies. Prepared by members of the Cardiac Safety Research Consortium, this White Paper summarizes and reports the dialogue at the second Think Tank related to the issues and the proposed solutions for the development of a national resource for screening and prevention of SCDY. This Think Tank, sponsored by the Cardiac Safety Research Consortium and the United States Food and Drug Administration, convened on February 18, 2016, in Miami, FL, to identify and resolve the barriers that prevent early identification of patients at risk for SCDY. All potential stakeholders including national and international experts from industry, medicine, academics, engineering, and community advocacy leaders had an opportunity to share ideas and collaborate.

Global relationships among traditional reflectance vegetation indices (NDVI and NDII), evapotranspiration (ET), and soil moisture variability on weekly timescales.

Monitoring the effects of water availability on vegetation globally using satellites is important for applications such as drought early warning, precision agriculture, and food security as well as for more broadly understanding relationships between water and carbon cycles. In this global study, we examine how quickly several satellite-based indicators, assumed to have relationships with water availability, respond, on timescales of days to weeks, in comparison with variations in root-zone soil moisture (RZM) that extends to about 1 m depth. The satellite indicators considered are the normalized difference vegetation and infrared indices (NDVI and NDII, respectively) derived from reflectances obtained with moderately wide (20-40 nm) spectral bands in the visible and near-infrared (NIR) and evapotranspiration (ET) estimated from thermal infrared observations and normalized by a reference ET. NDVI is primarily sensitive to chlorophyll contributions and vegetation structure while NDII may contain additional information on water content in leaves and canopy. ET includes both the loss of root zone soil water through transpiration (modulated by stomatal conductance) as well as evaporation from bare soil. We find that variations of these satellite-based drought indicators on time scales of days to weeks have significant correlations with those of RZM in the same water-limited geographical locations that are dominated by grasslands, shrublands, and savannas whose root systems are generally contained within the 1 m RZM layer. Normalized ET interannual variations show generally a faster response to water deficits and enhancements as compared with those of NDVI and NDII, particularly in sparsely vegetated regions.

Global Investigation of Soil Moisture and Latent Heat Flux Coupling Strength.

As a key variable in the climate system, soil moisture (SM) plays a central role in the earth's terrestrial water, energy, and biogeochemical cycles through its coupling with surface latent heat flux (LH). Despite the need to accurately represent SM/LH coupling in earth system models, we currently lack quantitative, observation-based, and unbiased estimates of its strength. Here, we utilize the triple collocation (TC) approach introduced in Crow et al. (2015) to SM and LH products obtained from multiple satellite remote sensing platforms and land surface models (LSMs) to obtain unbiased global maps of SM/LH coupling strength. Results demonstrate that, relative to coupling strength estimates acquired directly from remote sensing-based datasets, the application of TC generally enhances estimates of warm-season SM/LH coupling, especially in the western United States, the Sahel, Central Asia, and Australia. However, relative to triple collocation estimates, LSMs (still) over-predict SM/LH coupling strength along transitional climate regimes between wet and dry climates, such as the central Great Plains of North America, India, and coastal Australia. Specific climate zones with biased relations in LSMs are identified to geographically focus the re-examination of LSM parameterizations. TC-based coupling strength estimates are robust to our choice of LSM contributing SM and LH products to the TC analysis. Given their robustness, TC-based coupling strength estimates can serve as an objective benchmark for investigating model predicted SM/LH coupling.

Prevention of sudden cardiac death in the young: Developing a rational, reliable, and sustainable national health care resource. A report from the Cardiac Safety Research Consortium.

This White Paper, prepared by members of the Cardiac Safety Research Consortium, discusses important issues regarding sudden cardiac death in the young (SCDY), a problem that does not discriminate by gender, race, ethnicity, education, socioeconomic level, or athletic status. The occurrence of SCDY has devastating impact on families and communities. Sudden cardiac death in the young is a matter of national and international public health, and its prevention has generated deep interest from multiple stakeholders, including families who have lost children, advocacy groups, academicians, regulators, and the medical industry. To promote scientific and clinical discussion of SCDY prevention and to germinate future initiatives to move this field forward, a Cardiac Safety Research Consortium-sponsored Think Tank was held on February 21, 2015 at the US Food and Drug Administration's White Oak facilities, Silver Spring, MD. The ultimate goal of the Think Tank was to spark initiatives that lead to the development of a rational, reliable, and sustainable national health care resource focused on SCDY prevention. This article provides a detailed summary of discussions at the Think Tank and descriptions of related multistakeholder initiatives now underway: it does not represent regulatory guidance.

Estimating Morning Change in Land Surface Temperature from MODIS Day/Night Observations: Applications for Surface Energy Balance Modeling.

Observations of land surface temperature (LST) are crucial for the monitoring of surface energy fluxes from satellite. Methods that require high temporal resolution LST observations (e.g., from geostationary orbit) can be difficult to apply globally because several geostationary sensors are required to attain near-global coverage (60°N to 60°S). While these LST observations are available from polar-orbiting sensors, providing global coverage at higher spatial resolutions, the temporal sampling (twice daily observations) can pose significant limitations. For example, the Atmosphere Land Exchange Inverse (ALEXI) surface energy balance model, used for monitoring evapotranspiration and drought, requires an observation of the morning change in LST - a quantity not directly observable from polar-orbiting sensors. Therefore, we have developed and evaluated a data-mining approach to estimate the mid-morning rise in LST from a single sensor (2 observations per day) of LST from the Moderate Resolution Imaging Spectroradiometer (MODIS) sensor on the Aqua platform. In general, the data-mining approach produced estimates with low relative error (5 to 10%) and statistically significant correlations when compared against geostationary observations. This approach will facilitate global, near real-time applications of ALEXI at higher spatial and temporal coverage from a single sensor than currently achievable with current geostationary datasets.

Development of orally active inhibitors of protein and cellular fucosylation.

The key role played by fucose in glycoprotein and cellular function has prompted significant research toward identifying recombinant and biochemical strategies for blocking its incorporation into proteins and membrane structures. Technologies surrounding engineered cell lines have evolved for the inhibition of in vitro fucosylation, but they are not applicable for in vivo use and drug development. To address this, we screened a panel of fucose analogues and identified 2-fluorofucose and 5-alkynylfucose derivatives that depleted cells of GDP-fucose, the substrate used by fucosyltransferases to incorporate fucose into protein and cellular glycans. The inhibitors were used in vitro to generate fucose-deficient antibodies with enhanced antibody-dependent cellular cytotoxicity activities. When given orally to mice, 2-fluorofucose inhibited fucosylation of endogenously produced antibodies, tumor xenograft membranes, and neutrophil adhesion glycans. We show that oral 2-fluorofucose treatment afforded complete protection from tumor engraftment in a syngeneic tumor vaccine model, inhibited neutrophil extravasation, and delayed the outgrowth of tumor xenografts in immune-deficient mice. The results point to several potential therapeutic applications for molecules that selectively block the endogenous generation of fucosylated glycan structures.

TP53 mutations in human cancer: database reassessment and prospects for the next decade.

More than 50% of human tumors carry TP53 gene mutations and in consequence more than 45,000 somatic and germline mutations have been gathered in the UMD TP53 database (http://p53.fr). Analyses of these mutations have been invaluable for bettering our knowledge on the structure-function relationships within the TP53 protein and the high degree of heterogeneity of the various TP53 mutants in human cancer. In this review, we discuss how with the release of the sequences of thousands of tumor genomes issued from high-throughput sequencing, the description of novel TP53 mutants is now reaching a plateau indicating that we are close to the full set of mutants that target the elusive tumor-suppressive activity of this protein. We performed an extensive and thorough analysis of the TP53 mutation database, focusing particularly on specific sets of mutations that were overlooked in the past because of their low frequencies, for example, synonymous mutations, splice mutations, or mutations-targeting residues subject to posttranslational modifications. We also discuss the evolution of the statistical methods used to differentiate TP53 passenger mutations and artifactual data from true mutations, a process vital to the release of an accurate TP53 mutation database that will in turn be an invaluable tool for both clinicians and researchers.

Brentuximab Vedotin-Driven Microtubule Disruption Results in Endoplasmic Reticulum Stress Leading to Immunogenic Cell Death and Antitumor Immunity.

Brentuximab vedotin, a CD30-directed antibody-drug conjugate (ADC), is approved for clinical use in multiple CD30-expressing lymphomas. The cytotoxic payload component of brentuximab vedotin is monomethyl auristatin E (MMAE), a highly potent microtubule-disrupting agent. Preclinical results provided here demonstrate that treatment of cancer cells with brentuximab vedotin or free MMAE leads to a catastrophic disruption of the microtubule network eliciting a robust endoplasmic reticulum (ER) stress response that culminates in the induction of the classic hallmarks of immunogenic cell death (ICD). In accordance with the induction of ICD, brentuximab vedotin-killed lymphoma cells drove innate immune cell activation in vitro and in vivo. In the "gold-standard" test of ICD, vaccination of mice with brentuximab vedotin or free MMAE-killed tumor cells protected animals from tumor rechallenge; in addition, T cells transferred from previously vaccinated animals slowed tumor growth in immunodeficient mice. Immunity acquired from killed tumor cell vaccination was further amplified by the addition of PD-1 blockade. In a humanized model of CD30+ B-cell tumors, treatment with brentuximab vedotin drove the expansion and recruitment of autologous Epstein-Barr virus-reactive CD8+ T cells potentiating the activity of anti-PD-1 therapy. Together, these data support the ability of brentuximab vedotin and MMAE to drive ICD in tumor cells resulting in the activation of antigen-presenting cells and augmented T-cell immunity. These data provide a strong rationale for the clinical combination of brentuximab vedotin and other MMAE-based ADCs with checkpoint inhibitors.

Spatial calibration and uncertainty reduction of the SWAT model using multiple remotely sensed data.

Remotely sensed products are often used in watershed modeling as additional constraints to improve model predictions and reduce model uncertainty. Remotely sensed products also enabled the spatial evaluation of model simulations due to their spatial and temporal coverage. However, their usability is not extensively explored in various regions. This study evaluates the effectiveness of incorporating remotely sensed evapotranspiration (RS-ET) and leaf area index (RS-LAI) products to enhance watershed modeling predictions. The objectives include reducing parameter uncertainty at the watershed scale and refining the model's capability to predict the spatial distribution of ET and LAI at sub-watershed scale. Using the Soil and Water Assessment Tool (SWAT) model, a systematic calibration procedure was applied. Initially, solely streamflow data was employed as a constraint, gradually incorporating RS-ET and RS-LAI thereafter. The results showed that while 14 parameter sets exhibit satisfactory performance for streamflow and RS-ET, this number diminishes to six with the inclusion of RS-LAI as an additional constraint. Furthermore, among these six sets, only three effectively captured the spatial patterns of ET and LAI at the sub-watershed level. Our findings showed that leveraging multiple remotely sensed products has the potential to diminish parameter uncertainty and increase the credibility of intra-watershed process simulations. These results contributed to broadening the applicability of remotely sensed products in watershed modeling, enhancing their usefulness in this field.

A potent anti-CD70 antibody-drug conjugate combining a dimeric pyrrolobenzodiazepine drug with site-specific conjugation technology.

A highly cytotoxic DNA cross-linking pyrrolobenzodiazepine (PBD) dimer with a valine-alanine dipeptide linker was conjugated to the anti-CD70 h1F6 mAb either through endogenous interchain cysteines or, site-specifically, through engineered cysteines at position 239 of the heavy chains. The h1F6239C-PBD conjugation strategy proved to be superior to interchain cysteine conjugation, affording an antibody-drug conjugate (ADC) with high uniformity in drug-loading and low levels of aggregation. In vitro cytotoxicity experiments demonstrated that the h1F6239C-PBD was potent and immunologically specific on CD70-positive renal cell carcinoma (RCC) and non-Hodgkin lymphoma (NHL) cell lines. The conjugate was resistant to drug loss in plasma and in circulation, and had a pharmacokinetic profile closely matching that of the parental h1F6239C antibody capped with N-ethylmaleimide (NEM). Evaluation in CD70-positive RCC and NHL mouse xenograft models showed pronounced antitumor activities at single or weekly doses as low as 0.1 mg/kg of ADC. The ADC was tolerated at 2.5 mg/kg. These results demonstrate that PBDs can be effectively used for antibody-targeted therapy.

Global patterns of water storage in the rooting zones of vegetation.

The rooting-zone water-storage capacity-the amount of water accessible to plants-controls the sensitivity of land-atmosphere exchange of water and carbon during dry periods. How the rooting-zone water-storage capacity varies spatially is largely unknown and not directly observable. Here we estimate rooting-zone water-storage capacity globally from the relationship between remotely sensed vegetation activity, measured by combining evapotranspiration, sun-induced fluorescence and radiation estimates, and the cumulative water deficit calculated from daily time series of precipitation and evapotranspiration. Our findings indicate plant-available water stores that exceed the storage capacity of 2-m-deep soils across 37% of Earth's vegetated surface. We find that biome-level variations of rooting-zone water-storage capacities correlate with observed rooting-zone depth distributions and reflect the influence of hydroclimate, as measured by the magnitude of annual cumulative water-deficit extremes. Smaller-scale variations are linked to topography and land use. Our findings document large spatial variations in the effective root-zone water-storage capacity and illustrate a tight link among the climatology of water deficits, rooting depth of vegetation and its sensitivity to water stress.