Timing and Source of Recharge to the Columbia River Basalt Groundwater System in Northeastern Oregon.

Recharge to and flow within the Columbia River Basalt Group (CRBG) groundwater flow system of northeastern Oregon were characterized using isotopic, gas, and age-tracer samples from wells completed in basalt, springs, and stream base flow. Most groundwater samples were late-Pleistocene to early-Holocene; median age of well samples was 11,100 years. The relation between mean groundwater age and completed well depth across the eastern portion of the study area was similar despite differences in precipitation, topographic position, incision, thickness of the sedimentary overburden, and CRBG geologic unit.

Zetomipzomib (KZR-616) attenuates lupus in mice via modulation of innate and adaptive immune responses.

Zetomipzomib (KZR-616) is a selective inhibitor of the immunoproteasome currently undergoing clinical investigation in autoimmune disorders. Here, we characterized KZR-616 and using multiplexed cytokine analysis, lymphocyte activation and differentiation, and differential gene expression analysis. KZR-616 blocked production of >30 pro-inflammatory cytokines in human peripheral blood mononuclear cells (PBMCs), polarization of T helper (Th) cells, and formation of plasmablasts.

Co-inhibition of immunoproteasome subunits LMP2 and LMP7 enables prevention of transplant arteriosclerosis.

Aims: The loss of vascular wall cells in allotransplanted arteries is the initial event leading to transplant arteriosclerosis (TA) and ensuing loss of allograft function. Pharmacological agents able to prevent TA are currently lacking. We previously showed that selective inhibition of the immunoproteasome prevented the chronic rejection of renal allografts.

(Safe) Sex on My Mind: The Effects of a Safe Sex Prime and an Alcohol Prime on Sex-Related Perceptions and Behavior.

Objective: Previous research suggests that exposure to alcohol primes (i.e., stimuli associated with alcohol) affects drinkers' perceptions and behaviors.

Synthesis and physicochemical characteristics of Ag-doped hydroxyapatite nanoparticles, and their potential biomedical applications.

In this present scenario, hydroxyapatite (HAp) nanostructures were synthesized through green routes for biomedical applications, particularly remediation towards human pathogens and cancer cells. The present study aims at forming non-toxic and eco-friendly silver (Ag) doped HAp using Polyethylene glycol (PEG), Cetyl Trimethyl ammonium bromide (CTAB) and curcumin. Ag doped HAp nanoparticles (NPs) were prepared by the sol-gel method with a cube and rod-like morphology.

Climate impacts on source contributions and evaporation to flow in the Snake River Basin using surface water isoscapes (δH and δO).

Rising global temperatures are expected to decrease the precipitation amount that falls as snow, causing greater risk of water scarcity, groundwater overdraft, and fire in areas that rely on mountain snowpack for their water supply. Streamflow in large river basins varies with the amount, timing, and type of precipitation, evapotranspiration, and drainage properties of watersheds; however, these controls vary in time and space making it difficult to identify the areas contributing most to flow and when. In this study, we separate the evaporative influences from source values of water isotopes from the Snake River Basin in the western United States (US) to relate source area to flow dynamics.

Role of Epoxide Hydrolases and Cytochrome P450s on Metabolism of KZR-616, a First-in-Class Selective Inhibitor of the Immunoproteasome.

KZR-616 is an irreversible tripeptide epoxyketone-based selective inhibitor of the human immunoproteasome. Inhibition of the immunoproteasome results in anti-inflammatory activity in vitro and based on promising therapeutic activity in animal models of rheumatoid arthritis and systemic lupus erythematosus KZR-616 is being developed for potential treatment of multiple autoimmune and inflammatory diseases. The presence of a ketoepoxide pharmacophore presents unique challenges in the study of drug metabolism during lead optimization and clinical candidate profiling.

Dispositional Disinhibition and Alcohol Use Disorders: Personality, Risk Appraisal and Problematic Alcohol Consumption.

The relationship between psychopathic personality and problematic alcohol consumption could be important for understanding risk and potential interventions. This existing work on psychopathy and alcohol abuse is typically conducted in criminal and hospitalized populations and little attention has been paid to investigating the general populations' psychopathic personality and problematic consumption of alcohol. The psychopathy-focused Triarchic Psychopathy Measure (TriPM) and the more general Reinforcement Sensitivity Theory of personality (RST) focus on individual differences related to low self-control and sensation seeking, and could relate to problematic alcohol consumption in non-forensic samples.

Required Immunoproteasome Subunit Inhibition Profile for Anti-Inflammatory Efficacy and Clinical Candidate KZR-616 ((2 S,3 R)- N-(( S)-3-(Cyclopent-1-en-1-yl)-1-(( R)-2-methyloxiran-2-yl)-1-oxopropan-2-yl)-3-hydroxy-3-(4-methoxyphenyl)-2-(( S)-2-(2-morpholinoacetamido)propanamido)propenamide).

Selective immunoproteasome inhibition is a promising approach for treating autoimmune disorders, but optimal proteolytic active site subunit inhibition profiles remain unknown. We reveal here our design of peptide epoxyketone-based selective low molecular mass polypeptide-7 (LMP7) and multicatalytic endopeptidase complex subunit-1 (MECL-1) subunit inhibitors. Utilizing these and our previously disclosed low molecular mass polypeptide-2 (LMP2) inhibitor, we demonstrate a requirement of dual LMP7/LMP2 or LMP7/MECL-1 subunit inhibition profiles for potent cytokine expression inhibition and in vivo efficacy in an inflammatory disease model.

STI-protective self-efficacy and binge drinking in a sample of university students in the United Kingdom.

Objective: Alcohol use has consistently been shown to be related to sexual risk-taking behaviours. To assess what factors may contribute to the sexual risk decision-making process, this study examined the relationships among alcohol use (frequency, quantity, and binge drinking), cognitive appraisals of sexual risk taking, sex-related alcohol expectancies, and STI-protective self-efficacy.

Method: 138 sexually-active university students who drink alcohol completed scales measuring alcohol consumption, appraisals of consequences, sex-related alcohol expectancies, and items regarding STI-protective self-efficacy.

Discovery of Highly Selective Inhibitors of the Immunoproteasome Low Molecular Mass Polypeptide 2 (LMP2) Subunit.

Building upon the success of bortezomib (VELCADE) and carfilzomib (KYPROLIS), the design of a next generation of inhibitors targeting specific subunits within the immunoproteasome is of interest for the treatment of autoimmune disease. There are three catalytic subunits within the immunoproteasome (low molecular mass polypeptide-7, -2, and multicatalytic endopeptidase complex subunit-1; LMP7, LMP2, and MECL-1), and a campaign was undertaken to design a potent and selective LMP2 inhibitor with sufficient properties to allow for sustained inhibition . Screening a focused library of epoxyketones revealed a series of potent dipeptides that were optimized to provide the highly selective inhibitor ().

Exploring the Relationship between Sexual Compulsivity and Attentional Bias to Sex-Related Words in a Cohort of Sexually Active Individuals.

Background/aims: If sexual compulsivity and other addictive behaviours share common aetiology, contemporary proposals about the role of attentional processes in understanding addictive behaviours are relevant.

Methods: To examine attentional biases for sex-related words among sexually active individuals and the relationship between sexual compulsivity and sexual behavioural engagement with attentional bias, 55 sexually active individuals completed a modified Stroop task and the sexual compulsivity scale.

Results: Findings showed attentional bias towards sex-related stimuli among sexually active participants.

Improving patient safety reporting with the common formats: Common data representation for Patient Safety Organizations.

Medical errors and patient safety issues remain a significant problem for the healthcare industry in the United States. The Institute of Medicine report To Err is Human reported that there were as many as 98,000 deaths per year due to medical error as of 1999. Many authors and government officials believe that the first step on the path to improvement in patient safety is more comprehensive collection and analysis of patient safety events.

Discovery of a novel class of highly potent, selective, ATP-competitive, and orally bioavailable inhibitors of the mammalian target of rapamycin (mTOR).

A series of novel, highly potent, selective, and ATP-competitive mammalian target of rapamycin (mTOR) inhibitors based on a benzoxazepine scaffold have been identified. Lead optimization resulted in the discovery of inhibitors with low nanomolar activity and greater than 1000-fold selectivity over the closely related PI3K kinases. Compound 28 (XL388) inhibited cellular phosphorylation of mTOR complex 1 (p-p70S6K, pS6, and p-4E-BP1) and mTOR complex 2 (pAKT (S473)) substrates.

SAR and in vivo evaluation of 4-aryl-2-aminoalkylpyrimidines as potent and selective Janus kinase 2 (JAK2) inhibitors.

We report the discovery of a series of 4-aryl-2-aminoalkylpyrimidine derivatives as potent and selective JAK2 inhibitors. High throughput screening of our in-house compound library led to the identification of hit 1, from which optimization resulted in the discovery of highly potent and selective JAK2 inhibitors. Advanced lead 10d demonstrated a significant dose-dependent pharmacodynamic and antitumor effect in a mouse xenograft model.

Discovery of a novel series of potent and orally bioavailable phosphoinositide 3-kinase γ inhibitors.

The phosphoinositide 3-kinases (PI3Ks) have been linked to an extraordinarily diversified group of cellular functions making these enzymes compelling targets for the treatment of disease. A large body of evidence has linked PI3Kγ to the modulation of autoimmune and inflammatory processes making it an intriguing target for drug discovery. Our high-throughput screening (HTS) campaign revealed two hits that were nominated for further optimization studies.

Surface-Water Nutrient Conditions and Sources in the United States Pacific Northwest.

The SPAtially Referenced Regressions On Watershed attributes (SPARROW) model was used to perform an assessment of surface-water nutrient conditions and to identify important nutrient sources in watersheds of the Pacific Northwest region of the United States (U.S.) for the year 2002.

Trends in Pesticide Concentrations in Streams of the Western United States, 1993-2005.

Trends in pesticide concentrations for 15 streams in California, Oregon, Washington, and Idaho were determined for the organophosphate insecticides chlorpyrifos and diazinon and the herbicides atrazine, s-ethyl diproplythiocarbamate (EPTC), metolachlor, simazine, and trifluralin. A parametric regression model was used to account for flow, seasonality, and antecedent hydrologic conditions and thereby estimate trends in pesticide concentrations in streams arising from changes in use amount and application method in their associated catchments. Decreasing trends most often were observed for diazinon, and reflect the shift to alternative pesticides by farmers, commercial applicators, and homeowners because of use restrictions and product cancelation.

Genetic variation and linkage disequilibrium in Bacillus anthracis.

We performed whole-genome amplification followed by hybridization of custom-designed resequencing arrays to resequence 303 kb of genomic sequence from a worldwide panel of 39 Bacillus anthracis strains. We used an efficient algorithm contained within a custom software program, UniqueMER, to identify and mask repetitive sequences on the resequencing array to reduce false-positive identification of genetic variation, which can arise from cross-hybridization. We discovered a total of 240 single nucleotide variants (SNVs) and showed that B.

Discovery of a novel class of potent and orally bioavailable sphingosine 1-phosphate receptor 1 antagonists.

A series of subtype selective sphingosine 1-phosphate receptor 1 (S1P(1)) antagonists are disclosed. Our high-throughput screening campaign revealed hit 1 for which an increase in potency and mouse oral exposure was achieved with minor modifications to the chemical scaffold. In vivo efficacy revealed that at high doses compounds 12 and 15 inhibited tumor growth.

A polyether biotoxin binding site on the lipid-exposed face of the pore domain of Kv channels revealed by the marine toxin gambierol.

Gambierol is a marine polycyclic ether toxin belonging to the group of ciguatera toxins. It does not activate voltage-gated sodium channels (VGSCs) but inhibits Kv1 potassium channels by an unknown mechanism. While testing whether Kv2, Kv3, and Kv4 channels also serve as targets, we found that Kv3.

Occurrence and fate of pesticides in four contrasting agricultural settings in the United States.

Occurrence and fate of 45 pesticides and 40 pesticide degradates were investigated in four contrasting agricultural settings--in Maryland, Nebraska, California, and Washington. Primary crops included corn at all sites, soybeans in Maryland, orchards in California and Washington, and vineyards in Washington. Pesticides and pesticide degradates detected in water samples from all four areas were predominantly from two classes of herbicides--triazines and chloroacetanilides; insecticides and fungicides were not present in the shallow ground water.

Transport and fate of nitrate at the ground-water/surface-water interface.

Although numerous studies of hyporheic exchange and denitrification have been conducted in pristine, high-gradient streams, few studies of this type have been conducted in nutrient-rich, low-gradient streams. This is a particularly important subject given the interest in nitrogen (N) inputs to the Gulf of Mexico and other eutrophic aquatic systems. A combination of hydrologic, mineralogical, chemical, dissolved gas, and isotopic data were used to determine the processes controlling transport and fate of NO(3)(-) in streambeds at five sites across the USA.

Limited occurrence of denitrification in four shallow aquifers in agricultural areas of the United States.

The ability of natural attenuation to mitigate agricultural nitrate contamination in recharging aquifers was investigated in four important agricultural settings in the United States. The study used laboratory analyses, field measurements, and flow and transport modeling for monitoring well transects (0.5 to 2.

Prostate-cancer-specific survival and clinical progression-free survival in men with prostate cancer treated intermittently with testosterone-inactivating pharmaceuticals.

Objectives: More than 85% of men with prostate cancer die of other causes. An effective method is needed to distinguish fatal forms of prostate cancer from benign variants.

Methods: We performed a retrospective chart review from a medical oncology practice specializing in prostate cancer.