Cyclin E1/CDK2 activation defines a key vulnerability to WEE1 kinase inhibition in gynecological cancers.

Upregulation of Cyclin E1 and subsequent activation of CDK2 accelerates cell cycle progression from G1 to S phase and is a common oncogenic driver in gynecological malignancies. WEE1 kinase counteracts the effects of Cyclin E1/CDK2 activation by regulating multiple cell cycle checkpoints. Here we characterized the relationship between Cyclin E1/CDK2 activation and sensitivity to the selective WEE1 inhibitor azenosertib.

Produced water geochemistry from hydraulically stimulated Niobrara Formation petroleum wells: Origin of salinity and temporal perspectives on treatment and reuse.

Produced water (i.e., a mixture of returned injection fluids and geologic formation brines) represents the largest volumetric waste stream associated with petroleum production in the United States.

Cathodoluminescence differentiates sedimentary organic matter types.

High-resolution scanning electron microscopy (SEM) visualization of sedimentary organic matter is widely utilized in the geosciences for evaluating microscale rock properties relevant to depositional environment, diagenesis, and the processes of fluid generation, transport, and storage. However, despite thousands of studies which have incorporated SEM methods, the inability of SEM to differentiate sedimentary organic matter types has hampered the pace of scientific advancement. In this study, we show that SEM-cathodoluminescence (CL) properties can be used to identify and characterize sedimentary organic matter at low thermal maturity conditions.

Co-infection and ICU-acquired infection in COIVD-19 ICU patients: a secondary analysis of the UNITE-COVID data set.

Background: The COVID-19 pandemic presented major challenges for critical care facilities worldwide. Infections which develop alongside or subsequent to viral pneumonitis are a challenge under sporadic and pandemic conditions; however, data have suggested that patterns of these differ between COVID-19 and other viral pneumonitides. This secondary analysis aimed to explore patterns of co-infection and intensive care unit-acquired infections (ICU-AI) and the relationship to use of corticosteroids in a large, international cohort of critically ill COVID-19 patients.

Dissolved organic matter within oil and gas associated wastewaters from U.S. unconventional petroleum plays: Comparisons and consequences for disposal and reuse.

Wastewater generated during petroleum extraction (produced water) may contain high concentrations of dissolved organics due to their intimate association with organic-rich source rocks, expelled petroleum, and organic additives to fluids used for hydraulic fracturing of unconventional (e.g., shale) reservoirs.

Clinical and organizational factors associated with mortality during the peak of first COVID-19 wave: the global UNITE-COVID study.

Purpose: To accommodate the unprecedented number of critically ill patients with pneumonia caused by coronavirus disease 2019 (COVID-19) expansion of the capacity of intensive care unit (ICU) to clinical areas not previously used for critical care was necessary. We describe the global burden of COVID-19 admissions and the clinical and organizational characteristics associated with outcomes in critically ill COVID-19 patients.

Methods: Multicenter, international, point prevalence study, including adult patients with SARS-CoV-2 infection confirmed by polymerase chain reaction (PCR) and a diagnosis of COVID-19 admitted to ICU between February 15th and May 15th, 2020.

Water-rock interaction and the concentrations of major, trace, and rare earth elements in hydrocarbon-associated produced waters of the United States.

Studies of co-produced waters from hydrocarbon extraction across multiple energy-producing basins have generally focused on major ions or a few select tracers, and studies that examine trace elements and involve laboratory experiments have generally been basin specific. Here, new perspective is sought through a broad analysis of concentration data for 26 elements from three hydrocarbon well types using the U.S.

Advancing drug discovery using the power of the human genome.

Human genetics plays an increasingly important role in drug development and population health. Here we review the history of human genetics in the context of accelerating the discovery of therapies, present examples of how human genetics evidence supports successful drug targets, and discuss how polygenic risk scores could be beneficial in various clinical settings. We highlight the value of direct-to-consumer platforms in the era of fast-paced big data biotechnology, and how diverse genetic and health data can benefit society.

Utica Shale Play Oil and Gas Brines: Geochemistry and Factors Influencing Wastewater Management.

The Utica and Marcellus Shale Plays in the Appalachian Basin are the fourth and first largest natural gas producing plays in the United States, respectively. Hydrocarbon production generates large volumes of brine ("produced water") that must be disposed of, treated, or reused. Though Marcellus brines have been studied extensively, there are few studies from the Utica Shale Play.

Repetitive Sampling and Control Threshold Improve 16S rRNA Gene Sequencing Results From Produced Waters Associated With Hydraulically Fractured Shale.

Sequencing microbial DNA from deep subsurface environments is complicated by a number of issues ranging from contamination to non-reproducible results. Many samples obtained from these environments - which are of great interest due to the potential to stimulate microbial methane generation - contain low biomass. Therefore, samples from these environments are difficult to study as sequencing results can be easily impacted by contamination.

Visualizing Genome Reorganization Using 3D DNA FISH.

Understanding how the genome is organized within the cell nucleus is increasingly recognized to be important to understand gene regulation. In 3D DNA fluorescence in situ hybridization (3D DNA FISH) labeled probes complementary to specific loci of interest are hybridized to the genome. The samples are then imaged using fluorescence microscopy, collecting z-stacks through the nuclei, and the relative positions of the hybridized probes are analyzed in the reconstructed 3D images.

Effect of copper salts on hydrothermal oxidative decarboxylation: a study of phenylacetic acid.

Decarboxylation of carboxylic acids is favored under hydrothermal conditions, and can be influenced by dissolved metals. Here, we use phenylacetic acid as a model compound to study its hydrothermal decarboxylation in the presence of copper(ii) salts but no O. Our results showed a strong oxidizing role of copper in facilitating oxidative decarboxylation.

Potent LpxC Inhibitors with Activity against Multidrug-Resistant Pseudomonas aeruginosa.

New drugs with novel mechanisms of resistance are desperately needed to address both community and nosocomial infections due to Gram-negative bacteria. One such potential target is LpxC, an essential enzyme that catalyzes the first committed step of lipid A biosynthesis. Achaogen conducted an extensive research campaign to discover novel LpxC inhibitors with activity against We report here the antibacterial activity and pharmacodynamics of ACHN-975, the only molecule from these efforts and the first ever LpxC inhibitor to be evaluated in phase 1 clinical trials.

Optimization of LpxC Inhibitors for Antibacterial Activity and Cardiovascular Safety.

UDP-3-O-(R-3-hydroxymyristoyl)-N-acetylglucosamine deacetylase (LpxC) is a Zn deacetylase that is essential for the survival of most pathogenic Gram-negative bacteria. ACHN-975 (N-((S)-3-amino-1-(hydroxyamino)-3-methyl-1-oxobutan-2-yl)-4-(((1R,2R)-2-(hydroxymethyl)cyclopropyl)buta-1,3-diyn-1-yl)benzamide) was the first LpxC inhibitor to reach human clinical testing and was discovered to have a dose-limiting cardiovascular toxicity of transient hypotension without compensatory tachycardia. Herein we report the effort beyond ACHN-975 to discover LpxC inhibitors optimized for enzyme potency, antibacterial activity, pharmacokinetics, and cardiovascular safety.

Accuracy of methods for reporting inorganic element concentrations and radioactivity in oil and gas wastewaters from the Appalachian Basin, U.S. based on an inter-laboratory comparison.

Accurate and precise analyses of oil and gas (O&G) wastewaters and solids (e.g., sediments and sludge) are important for the regulatory monitoring of O&G development and tracing potential O&G contamination in the environment.

Characterization of iron oxide nanoparticle films at the air-water interface in Arctic tundra waters.

Massive amounts of organic carbon have accumulated in Arctic permafrost and soils due to anoxic and low temperature conditions that limit aerobic microbial respiration. Alternative electron acceptors are thus required for microbes to degrade organic carbon in these soils. Iron or iron oxides have been recognized to play an important role in carbon cycle processes in Arctic soils, although the exact form and role as an electron acceptor or donor remain poorly understood.

Glucocorticoid Receptor Binding Induces Rapid and Prolonged Large-Scale Chromatin Decompaction at Multiple Target Loci.

Glucocorticoids act by binding to the glucocorticoid receptor (GR), which binds to specific motifs within enhancers of target genes to activate transcription. Previous studies have suggested that GRs can promote interactions between gene promoters and distal elements within target loci. In contrast, we demonstrate here that glucocorticoid addition to mouse bone-marrow-derived macrophages produces very rapid chromatin unfolding detectable by fluorescence in situ hybridization (FISH) at loci associated with GR binding.

Hypoxia-related biological markers as predictors of epirubicin-based treatment responsiveness and resistance in locally advanced breast cancer.

Purpose: To identify hypoxia-related biomarkers indicative of response and resistance to epirubicin treatment in patients with locally advanced breast cancer.

Patients And Methods: One hundred seventy-six women with T2-4 N0-1 breast tumours were randomly assigned to receive epirubicin 120 mg/m2/1-21 (EPI ARM), epirubicin 120 mg/m2/1-21 + erythropoietin 10.000 IU sc three times weekly (EPI-EPO ARM) and epirubicin 40 mg/m2/w-q21 (EPI-W ARM).

Photochemical reactions between mercury (Hg) and dissolved organic matter decrease Hg bioavailability and methylation.

Atmospheric deposition of mercury (Hg) to surface water is one of the dominant sources of Hg in aquatic environments and ultimately drives methylmercury (MeHg) toxin accumulation in fish. It is known that freshly deposited Hg is more readily methylated by microorganisms than aged or preexisting Hg; however the underlying mechanism of this process is unclear. We report that Hg bioavailability is decreased by photochemical reactions between Hg and dissolved organic matter (DOM) in water.