Earth's terrestrial near‐subsurface environment can be divided into relatively porous layers of soil, intact regolith, and sedimentary deposits above unweathered bedrock. Variations in the ...thicknesses of these layers control the hydrologic and biogeochemical responses of landscapes. Currently, Earth System Models approximate the thickness of these relatively permeable layers above bedrock as uniform globally, despite the fact that their thicknesses vary systematically with topography, climate, and geology. To meet the need for more realistic input data for models, we developed a high‐resolution gridded global data set of the average thicknesses of soil, intact regolith, and sedimentary deposits within each 30 arcsec (∼1 km) pixel using the best available data for topography, climate, and geology as input. Our data set partitions the global land surface into upland hillslope, upland valley bottom, and lowland landscape components and uses models optimized for each landform type to estimate the thicknesses of each subsurface layer. On hillslopes, the data set is calibrated and validated using independent data sets of measured soil thicknesses from the U.S. and Europe and on lowlands using depth to bedrock observations from groundwater wells in the U.S. We anticipate that the data set will prove useful as an input to regional and global hydrological and ecosystems models.
Key Points:
We have quantified the thicknesses of permeable layers above bedrock for Earth System Models
We distinguish among uplands and lowlands, using optimal models for each to predict depth to bedrock
The data set honors the geologic, topographic, and climatic controls on permeable layer thicknesses
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.
The synthesis of antibody–drug conjugates (ADCs) using the interchain cysteines of the antibody inherently gives a mixture of proteins with varying drug-to-antibody ratio. The drug distribution ...profiles of ADCs are routinely characterized by hydrophobic interaction chromatography (HIC). Because HIC is not in-line compatible with mass spectrometry (MS) due to the high salt levels, it is laborious to identify the constituents of HIC peaks. An MS-compatible alternative to HIC is reported here: native reversed phase liquid chromatography (nRPLC). This novel technique employs a mobile phase 50 mM ammonium acetate for high sensitivity in MS and elution with a gradient of water/isopropanol. The key to the enhancement is a bonded phase giving weaker drug–surface interactions compared to the noncovalent interactions holding the antibody–drug conjugates together. The hydrophobicity of the bonded phase is varied, and the least hydrophobic bonded phase in the series, poly(methyl methacrylate), is found to resolve the intact constituents of a model ADC (Ab095-PZ) and a commercial ADC (brentuximab vedotin) under the MS-compatible conditions. The nRPLC-MS data show that all species, ranging from drug-to-antibody ratios of 1 to 8, remained intact in the column. Another desired advantage of the nRPLC is the ability of resolving multiple positional isomers of ADC that are not well-resolved in other chromatographic modes. This supports the premise that lower hydrophobicity of the bonded phase is the key to enabling online nRPLC-MS analysis of antibody–drug conjugates.
The Wnt/β‐catenin signalling and autophagy pathways each play important roles during development, adult tissue homeostasis and tumorigenesis. Here we identify the Wnt/β‐catenin signalling pathway as ...a negative regulator of both basal and stress‐induced autophagy. Manipulation of β‐catenin expression levels in vitro and in vivo revealed that β‐catenin suppresses autophagosome formation and directly represses p62/SQSTM1 (encoding the autophagy adaptor p62) via TCF4. Furthermore, we show that during nutrient deprivation β‐catenin is selectively degraded via the formation of a β‐catenin–LC3 complex, attenuating β‐catenin/TCF‐driven transcription and proliferation to favour adaptation during metabolic stress. Formation of the β‐catenin–LC3 complex is mediated by a W/YXXI/L motif and LC3‐interacting region (LIR) in β‐catenin, which is required for interaction with LC3 and non‐proteasomal degradation of β‐catenin. Thus, Wnt/β‐catenin represses autophagy and p62 expression, while β‐catenin is itself targeted for autophagic clearance in autolysosomes upon autophagy induction. These findings reveal a regulatory feedback mechanism that place β‐catenin at a key cellular integration point coordinating proliferation with autophagy, with implications for targeting these pathways for cancer therapy.
This paper describes a novel and direct interplay of beta‐catenin with crucial regulators of autophagy, establishing Wnt/β‐catenin signals as central hub in the coordination of cellular proliferation and autophagy.
Mass spectrometry (MS) detection can offer unmatched selectivity and sensitivity. The use of MS without chromatography greatly increases the throughput, making it suitable for high throughput ...screening. However, the trade-offs of direct MS detection need to be carefully evaluated along with the development of novel strategies to ensure successful implementation. In this review, we will discuss the pros and cons of chromatography-free MS and discuss some of the currently used and future technologies being investigated to enable high-throughput MS.
Primary care providers have important roles across the cancer continuum, from encouraging screening and accurate diagnosis to providing care during and after treatment for both the cancer and any ...comorbid conditions. Evidence shows that higher cancer screening participation rates are associated with greater involvement of primary care. Primary care providers are pivotal in reducing diagnostic delay, particularly in health systems that have long waiting times for outpatient diagnostic services. However, so-called fast-track systems designed to speed up hospital referrals are weakened by significant variation in their use by general practitioners (GPs), and affect the associated conversion and detection rates. Several randomized controlled trials have shown primary care-led follow-up care to be equivalent to hospital-led care in terms of patient wellbeing, recurrence rates and survival, and might be less costly. For primary care-led follow-up to be successful, appropriate guidelines must be incorporated, clear communication must be provided and specialist care must be accessible if required. Finally, models of long-term cancer follow-up are needed that provide holistic care and incorporate management of co-morbid conditions. We discuss all these aspects of primary care, focusing on the most common cancers managed at the GP office-breast, colorectal, prostate, lung and cervical cancers.
Mass spectrometry (MS) is the primary analytical tool used to characterize proteins within the biopharmaceutical industry. Electrospray ionization (ESI) coupled to liquid chromatography (LC) is the ...current gold standard for intact protein analysis. However, inherent speed limitations of LC/MS prevent analysis of large sample numbers (>1000) in a day. Infrared matrix-assisted laser desorption electrospray ionization (IR-MALDESI-MS), an ambient ionization MS technology, has recently been established as a platform for high-throughput small molecule analysis. Here, we report the applications of such a system for the analysis of intact proteins commonly performed within the drug discovery process. A wide molecular weight range of proteins 10–150 kDa was detected on the system with improved tolerance to salts and buffers compared to ESI. With high concentrations and model proteins, a sample rate of up to 22 Hz was obtained. For proteins at low concentrations and in buffers used in commonly employed assays, robust data at a sample rate of 1.5 Hz were achieved, which is ∼22× faster than current technologies used for high-throughput ESI-MS-based protein assays. In addition, two multiplexed plate-based high-throughput sample cleanup methods were coupled to IR-MALDESI-MS to enable analysis of samples containing excessive amounts of salts and buffers without fully compromising productivity. Example experiments, which leverage the speed of the IR-MALDESI-MS system to monitor NISTmAb reduction, protein autophosphorylation, and compound binding kinetics in near real time, are demonstrated.
Gun violence disproportionately affects young Black men, but the impact extends to families and communities. Those at highest risk are teens delinquent of gun crimes. While there is no nationally ...accepted juvenile rate of recidivism, previous literature reveals rearrest rates from 50% to 80% in high-risk youth, and some reports show that up to 40% of delinquent juveniles are incarcerated in adult prisons before the age of 25 years. We hypothesize that Project Inspire, a hospital-led comprehensive intervention, reduces recidivism among high-risk teens.
Led by a level 1 trauma center, key community stakeholders including the juvenile court, city, and city police department joined forces to create a community-wide program aimed at curbing gun violence in high-risk individuals. Participants, aged 13 to 18 years, are selected by the juvenile gun court. They underwent a rigorous 3-week program with a curriculum incorporating the following: trauma-informed training and confidence building, educational/professional development, financial literacy, entrepreneurship, and career-specific job shadowing and mentorship. Rates of recidivism were measured annually.
Project Inspire has hosted two classes in 2018 and 2019, graduating nine participants aged 14 to 17 years. Sixty-seven percent were Black. All were males. At 1 year, none of the graduates reoffended. At 2 years, one participant reoffended. At 3 years, no additional participants reoffended. No graduate reoffended as a juvenile. Thus, the overall rate of recidivism for Project Inspire is 11% to date. Eighty-nine percent of graduates received a diploma, general educational development, or obtained employment.
Project Inspire is a hospital-led initiative that effectively reduces recidivism among juveniles delinquent of gun crimes. This sets the framework for trauma centers nationwide to lead in establishing impactful, comprehensive, gun-violence intervention strategies.
Prognostic and Epidemiological; Level V.
Antibody–drug conjugates (ADCs) are an increasingly prevalent drug class utilized as chemotherapeutic agents. The complexity of ADCs, including their large size, array of drug conjugation sites, and ...heterogeneous compositions containing from zero to several payloads, demands the use of advanced analytical characterization methods. Tandem mass spectrometry (MS/MS) strategies, including a variety of bottom-up, middle-down, and even top-down approaches, frequently applied for the analysis of antibodies are increasingly being adapted for antibody–drug conjugates. Middle-down tandem mass spectrometry, often focusing on the analysis of ∼25 kDa protein subunits, offers the potential for complete sequence confirmation as well as the identification of multiple conjugation states. While middle-down studies have been extensively developed for monoclonal antibodies, middle-down characterization of ADCs has been limited by the high complexity of the drug molecules. This study seeks to bridge the gap by utilizing a combination of 193 nm ultraviolet photodissociation (UVPD), electron-transfer dissociation (ETD), and electron-transfer/higher-energy collision dissociation (EThcD). The compilation of these MS/MS methods leads to high sequence coverages of 60–80% for each subunit of the ADC. Moreover, the combined fragmentation patterns provide sufficient information to allow confirmation of both the sequence of the complementarity-determining regions and the payload conjugation sites.
Blunt cerebrovascular injury (BCVI) results from blunt trauma causing injury to the carotid and/or vertebral arteries. Its most severe manifestation is stroke. The purpose of this study was to ...evaluate the incidence, management, and outcomes of BCVI at a level one trauma/stroke center. Data on patients diagnosed with BCVI from 2016 to 2021 were extracted from the USA Health trauma registry with associated intervention performed and patient outcomes. Of the 97 patients identified, 16.5% presented with stroke-like symptoms (SS). Medical management was employed for 75%. Intravascular stent alone was utilized for 18.8%. The mean age of symptomatic BCVI patients was 37.6 with a mean injury severity score (ISS) of 38.2. Within the asymptomatic population, 58% received medical management and 3.7% underwent combination therapy. The mean age of asymptomatic BCVI patients was 46.9 with a mean ISS of 20.3. There were 6 mortalities, only one BCVI related.
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