Using temperature sensitivity to estimate shiftable electricity demand.

The growth of intermittent renewable energy and climate change makes it increasingly difficult to manage electricity demand variability. Centralized storage can help but is costly. An alternative is to shift demand.

Interannual monsoon wind variability as a key driver of East African small pelagic fisheries.

Small pelagic fisheries provide food security, livelihood support and economic stability for East African coastal communities-a region of least developed countries. Using remotely- sensed and field observations together with modelling, we address the biophysical drivers of this important resource. We show that annual variations of fisheries yield parallel those of chlorophyll-a (an index of phytoplankton biomass).

From global to regional and back again: common climate stressors of marine ecosystems relevant for adaptation across five ocean warming hotspots.

Ocean warming 'hotspots' are regions characterized by above-average temperature increases over recent years, for which there are significant consequences for both living marine resources and the societies that depend on them. As such, they represent early warning systems for understanding the impacts of marine climate change, and test-beds for developing adaptation options for coping with those impacts. Here, we examine five hotspots off the coasts of eastern Australia, South Africa, Madagascar, India and Brazil.

Insulation Failure of the Linox Defibrillator Lead: A Case Report and Retrospective Review of a Single Center Experience.

Implantable cardioverter defibrillator (ICD) lead insulation failure and conductor externalization have been increasingly reported. The 7.8F silicon-insulated Linox SD and Linox S ICD leads (Biotronik, Berlin, Germany) were released in 2006 and 2007, respectively, with an estimated 85,000 implantations worldwide.

Fluoroscopic and electrical assessment of implantable cardioverter defibrillator leads: a prospective observational study.

Background: Insulation defects resulting in conductor externalization (CE) have been reported in the Riata family of implantable cardioverter defibrillator (ICD) leads (St. Jude Medical, Sylmar, CA, USA). The aim of this study was to identify, prospectively, the rate of CE and outcomes following this, within a group of patients with a Riata ICD lead.

Greater sensitivity to drought accompanies maize yield increase in the U.S. Midwest.

A key question for climate change adaptation is whether existing cropping systems can become less sensitive to climate variations. We use a field-level data set on maize and soybean yields in the central United States for 1995 through 2012 to examine changes in drought sensitivity. Although yields have increased in absolute value under all levels of stress for both crops, the sensitivity of maize yields to drought stress associated with high vapor pressure deficits has increased.

Multi-targeted therapy of cancer by niclosamide: A new application for an old drug.

The rapid development of new anticancer drugs that are safe and effective is a common goal shared by basic scientists, clinicians and patients. The current review discusses one such agent, namely niclosamide, which has been used in the clinic for the treatment of intestinal parasite infections. Recent studies repeatedly identified niclosamide as a potential anticancer agent by various high-throughput screening campaigns.

Fluoroscopic and electrical assessment of a series of defibrillation leads: prevalence of externalized conductors.

Introduction: Insulation defects with externalized conductors have been reported in the St. Jude Riata(®)  family of defibrillation leads (St. Jude Medical, Sylmar, CA, USA).

Niclosamide suppresses cancer cell growth by inducing Wnt co-receptor LRP6 degradation and inhibiting the Wnt/β-catenin pathway.

The Wnt/β-catenin signaling pathway is important for tumor initiation and progression. The low density lipoprotein receptor-related protein-6 (LRP6) is an essential Wnt co-receptor for Wnt/β-catenin signaling and represents a promising anticancer target. Recently, the antihelminthic drug, niclosamide was found to inhibit Wnt/β-catenin signaling, although the mechanism was not well defined.

Development and validation of a comparative genomic fingerprinting method for high-resolution genotyping of Campylobacter jejuni.

Campylobacter spp. are a leading cause of bacterial gastroenteritis worldwide. The need for molecular subtyping methods with enhanced discrimination in the context of surveillance- and outbreak-based epidemiologic investigations of Campylobacter spp.

Nonlinear temperature effects indicate severe damages to U.S. crop yields under climate change.

The United States produces 41% of the world's corn and 38% of the world's soybeans. These crops comprise two of the four largest sources of caloric energy produced and are thus critical for world food supply. We pair a panel of county-level yields for these two crops, plus cotton (a warmer-weather crop), with a new fine-scale weather dataset that incorporates the whole distribution of temperatures within each day and across all days in the growing season.

Assessment of the environmental toxicity and carcinogenicity of tungsten-based shot.

The toxicity of elemental tungsten released from discharged shot was assessed against previous studies that established a 1% toxic threshold for soil organisms. Extremely heavy theoretical shot loadings of 69,000shot/ha were used to generate estimated environmental concentrations (EEC) for two brands of tungsten-based shot containing 51% and 95% tungsten. The corresponding tungsten EEC values were 6.

Discovery and biological evaluation of benzo[a]carbazole-based small molecule agonists of the thrombopoietin (Tpo) receptor.

A novel series of benzo[a]carbazole-based small molecule agonists of the thrombopoietin (Tpo) receptor is reported. Starting from a 3.4 microM high throughput screen hit, members of this series have been identified which are full agonists with functional potency <50 nM and oral bioavailability in mice.

Discovery of inhibitors of the channel-activating protease prostasin (CAP1/PRSS8) utilizing structure-based design.

Structure-based design was utilized to guide the early stage optimization of a substrate-like inhibitor to afford potent peptidomimetic inhibitors of the channel-activating protease prostasin. The first X-ray crystal structures of prostasin with small molecule inhibitors bound to the active site are also reported.

A pilot study of a low-tilt biphasic waveform for transvenous cardioversion of atrial fibrillation: improved efficacy compared with conventional capacitor-based waveforms in patients.

Background: The optimal waveform tilt for defibrillation is not known. Most modern defibrillators used for the cardioversion of atrial fibrillation (AF) employ high-tilt, capacitor-based biphasic waveforms.

Methods: We have developed a low-tilt biphasic waveform for defibrillation.

The vulvalgesiometer as a device to measure genital pressure-pain threshold.

The construction and application of the vulvalgesiometer are described. This manually-applied device allows for the quantifiable measurement of pressure-pain thresholds in the external female genital region. A set of five vulvalgesiometers exerting pressures from 3 to 950 g was used in two studies.

Activation patterns during selective pacing of the left ventricle can be characterized using noninvasive electrocardiographic imaging.

Background: Noncontact endocardial mapping allows accurate beat-to-beat reconstruction of the reentrant pathway of ventricular tachycardia and improves outcomes after ablation. Several studies support electrocardiographic imaging (ECGI) as a means of noninvasively outlining epicardial activation despite constraints of internal geometry. However, few have explored its clinical application.

Hydrophilic anilinogeranyl diphosphate prenyl analogues are Ras function inhibitors.

Sequential processing of H-Ras by protein farnesyl transferase (FTase), Ras converting enzyme (Rce1), and protein-S-isoprenylcysteine O-methyltransferase (Icmt) to give H-Ras C-terminal farnesyl-S-cysteine methyl ester is required for appropriate H-Ras membrane localization and function, including activation of the mitogen-activated protein kinase (MAPK) cascade. We employed a Xenopus laevis oocyte whole-cell model system to examine whether anilinogeranyl diphosphate analogues of similar shape and size, but with a hydrophobicity different from that of the FTase substrate farnesyl diphosphate (FPP), could ablate biological function of H-Ras. Analysis of oocyte maturation kinetics following microinjection of in vitro analogue-modified H-Ras into isoprenoid-depleted oocytes revealed that analogues with a hydrophobicity near that of FPP supported H-Ras biological function, while the analogues p-nitroanilinogeranyl diphosphate (p-NO2-AGPP), p-cyanoanilinogeranyl diphosphate (p-CN-AGPP), and isoxazolaminogeranyl diphosphate (Isox-GPP) with hydrophobicities 2-5 orders of magnitude lower than that of FPP did not.

Integration of cardiac imaging and electrophysiology during catheter ablation procedures for atrial fibrillation.

As nonpharmacologic therapies for atrial fibrillation expand, the complexity of the anatomical and electrical substrates of atrial fibrillation requires integration of multiple imaging modalities for successful treatment. Combining chamber-specific imaging and electrophysiologic data points during ablation therapy has improved pulmonary vein isolation accuracy while diminishing risk. Merging 3-dimensional computed tomography left atrial renditions, intracardiac echocardiography, and electroanatomical mapping during pulmonary vein isolation is a reality that relates the complex anatomy of the left atrium to its often variable electrical targets.

Usefulness of body surface maps to demonstrate ventricular activation patterns during left ventricular pacing and reentrant activation during ventricular tachycardia in men with coronary heart disease and left ventricular dysfunction.

Epicardial electrical events were reconstructed using an inverse model for left ventricular (LV) pacing and during ventricular tachycardia (VT) induced during implantation of a biventricular pacemaker and/or internal defibrillator. The electrocardiographic position of the pacing lead, determined from the region of most negative potential 30 ms after the pacing spike, was compared with the radiographic position. Activation characterized by isochronal maps was correlated with the echocardiographic/myocardial scintigraphic data.

Arylaminoethyl carbamates as a novel series of potent and selective cathepsin S inhibitors.

We report a novel series of noncovalent inhibitors of cathepsin S. The synthesis of the peptidomimetic scaffold is described and structure-activity relationships of P3, P1, and P1' subunits are discussed. Lead optimization to a non-peptidic scaffold has resulted in a new class of potent, highly selective, and orally bioavailable cathepsin S inhibitors.

Synthesis and SAR of arylaminoethyl amides as noncovalent inhibitors of cathepsin S: P3 cyclic ethers.

The synthesis and structure-activity relationship of a series of arylaminoethyl amide cathepsin S inhibitors are reported. Optimization of P3 and P2 groups to improve overall physicochemical properties resulted in significant improvements in oral bioavailability over early lead compounds. An X-ray structure of compound 37 bound to the active site of cathepsin S is also reported.

Validation of an HPLC method for analysis of DB-67 and its water soluble prodrug in mouse plasma.

A method for the quantitation of DB-67 ((20S)-10-hydroxy-7-tert-butyldimethylsilylcamptothecin) lactone and carboxylate in mouse plasma has been developed, validated, and applied in pharmacokinetic studies. The analytes were separated by reversed-phase chromatography with fluorescence detection. Validation demonstrated the selectivity and specificity for the carboxylate and lactone, with linearity between 1-300ng/mL and 2.

Synthesis and evaluation of arylaminoethyl amides as noncovalent inhibitors of cathepsin S. Part 3: heterocyclic P3.

A series of N(alpha)-2-benzoxazolyl-alpha-amino acid-(arylaminoethyl)amides were identified as potent, selective, and noncovalent inhibitors of cathepsin S. Structure-activity relationships including strategies for modulating the selectivities among cathepsins S, K, and L, and in vivo pharmacokinetics are discussed. A X-ray structure of compound 3 bound to the active site of cathepsin S is also reported.

Dependence of nelfinavir brain uptake on dose and tissue concentrations of the selective P-glycoprotein inhibitor zosuquidar in rats.

Most reverse transcriptase and protease inhibitors used in highly active antiretroviral therapy for treating human immunodeficiency virus (HIV) infections exhibit poor penetration into the brain, raising the concern that the brain may be a sanctuary site for the development of resistant HIV variants. This study explores the relationship between the dose and plasma and brain concentrations of zosuquidar and the effect of this selective P-glycoprotein inhibitor on central nervous system penetration of the HIV protease inhibitor nelfinavir maintained at steady state by intravenous infusions in rats. Nelfinavir was infused (10 mg/kg/h) for up to 10 h with or without concurrent administration of an intravenous bolus dose of 2, 6, or 20 mg/kg zosuquidar given at 4 h.