A Gpr120-selective agonist improves insulin resistance and chronic inflammation in obese mice.

It is well known that the ω-3 fatty acids (ω-3-FAs; also known as n-3 fatty acids) can exert potent anti-inflammatory effects. Commonly consumed as fish products, dietary supplements and pharmaceuticals, ω-3-FAs have a number of health benefits ascribed to them, including reduced plasma triglyceride levels, amelioration of atherosclerosis and increased insulin sensitivity. We reported that Gpr120 is the functional receptor for these fatty acids and that ω-3-FAs produce robust anti-inflammatory, insulin-sensitizing effects, both in vivo and in vitro, in a Gpr120-dependent manner. Indeed, genetic variants that predispose to obesity and diabetes have been described in the gene encoding GPR120 in humans (FFAR4). However, the amount of fish oils that would have to be consumed to sustain chronic agonism of Gpr120 is too high to be practical, and, thus, a high-affinity small-molecule Gpr120 agonist would be of potential clinical benefit. Accordingly, Gpr120 is a widely studied drug discovery target within the pharmaceutical industry. Gpr40 is another lipid-sensing G protein-coupled receptor, and it has been difficult to identify compounds with a high degree of selectivity for Gpr120 over Gpr40 (ref. 11). Here we report that a selective high-affinity, orally available, small-molecule Gpr120 agonist (cpdA) exerts potent anti-inflammatory effects on macrophages in vitro and in obese mice in vivo. Gpr120 agonist treatment of high-fat diet-fed obese mice causes improved glucose tolerance, decreased hyperinsulinemia, increased insulin sensitivity and decreased hepatic steatosis. This suggests that Gpr120 agonists could become new insulin-sensitizing drugs for the treatment of type 2 diabetes and other human insulin-resistant states in the future

Nonlinear fractional differential equations in nonreflexive Banach spaces and fractional calculus

The aim of this paper is to correct some ambiguities and inaccuracies in Agarwal et al. (Commun. Nonlinear Sci. Numer. Simul. 20(1): 59-73, 2015; Adv. Differ. Equ. 2013: 302, 2013, doi:10.1186/1687-1847-2013-302) and to present new ideas and approaches for fractional calculus and fractional differential equations in nonreflexive Banach spaces

Estrogen-dependent dynamic profile of eNOS-DNA associations in prostate cancer

In previous work we have documented the nuclear translocation of endothelial NOS (eNOS) and its participation in combinatorial complexes with Estrogen Receptor Beta (ERβ) and Hypoxia Inducible Factors (HIFs) that determine localized chromatin remodeling in response to estrogen (E2) and hypoxia stimuli, resulting in transcriptional regulation of genes associated with adverse prognosis in prostate cancer (PCa). To explore the role of nuclear eNOS in the acquisition of aggressive phenotype in PCa, we performed ChIP-Sequencing on chromatin-associated eNOS from cells from a primary tumor with poor outcome and from metastatic LNCaP cells. We found that: 1. the eNOS-bound regions (peaks) are widely distributed across the genome encompassing multiple transcription factors binding sites, including Estrogen Response Elements. 2. E2 increased the number of peaks, indicating hormone-dependent eNOS re-localization. 3. Peak distribution was similar with/without E2 with ≈ 55% of them in extragenic DNA regions and an intriguing involvement of the 5′ domain of several miRs deregulated in PCa. Numerous potentially novel eNOS-targeted genes have been identified suggesting that eNOS participates in the regulation of large gene sets. The parallel finding of downregulation of a cluster of miRs, including miR-34a, in PCa cells associated with poor outcome led us to unveil a molecular link between eNOS and SIRT1, an epigenetic regulator of aging and tumorigenicity, negatively regulated by miR-34a and in turn activating eNOS. E2 potentiates miR-34a downregulation thus enhancing SIRT1 expression, depicting a novel eNOS/SIRT1 interplay fine-tuned by E2-activated ER signaling, and suggesting that eNOS may play an important role in aggressive PCa

SWIFT Code Assessment for Two Similar Transonic Compressors

One goal of the NASA Fundamental Aeronautics Program is the assessment of computational fluid dynamic (CFD) codes used for the design and analysis of many aerospace systems. This paper describes the assessment of the SWIFT turbomachinery analysis code for two similar transonic compressors, NASA rotor 37 and stage 35. The two rotors have identical blade profiles on the front, transonic half of the blade but rotor 37 has more camber aft of the shock. Thus the two rotors have the same shock structure and choking flow but rotor 37 produces a higher pressure ratio. The two compressors and experimental data are described here briefly. Rotor 37 was also used for test cases organized by ASME, IGTI, and AGARD in 1994-1998. Most of the participating codes over predicted pressure and temperature ratios, and failed to predict certain features of the downstream flowfield. Since then the AUSM+ upwind scheme and the k- turbulence model have been added to SWIFT. In this work the new capabilities were assessed for the two compressors. Comparisons were made with overall performance maps and spanwise profiles of several aerodynamic parameters. The results for rotor 37 were in much better agreement with the experimental data than the original blind test case results although there were still some discrepancies. The results for stage 35 were in very good agreement with the data. The results for rotor 37 were very sensitive to turbulence model parameters but the results for stage 35 were not. Comparison of the rotor solutions showed that the main difference between the two rotors was not blade camber as expected, but shock/boundary layer interaction on the casing

Description of Goussia kuehae n. sp. (Apicomplexa: Eimeriidae) infecting the Asian seabass, Lates calcarifer (Bloch)(Perciformes: Latidae), cultured in Malaysian fish farms

Culturing fishes in marine cages is a rapidly developing area of marine aquaculture. The Asian seabass Lates calcarifer (Bloch) is a fast growing good quality fish that is readily cultured in intensive systems in the South Asian region and in Malaysia in particular. Although several papers have been published to date on viral, bacterial, parasitic and fungal organisms causing diseases in the Asian seabass, the occurrence of a coccidian infection in this species has only recently been recorded. We collected sporulated and unsporulated oo¨cysts of a new species of Goussia Labbe´, 1986, from the mucus covering the epithelium of the intestine of L. calcarifer. This paper provides a description of Goussia kuehae n. sp. Sporulated oo¨cysts of this species are ellipsoidal, 37–40 lm in length and 28–30 lm in width. The ellipsoidal sporocysts are relatively small, 15.2–17 9 5.7–8 lm, and located loosely in the oo¨cyst. There are residual bodies both in the oo¨cysts and the sporocysts. Goussia kuehae n. sp. differs from all known species of Goussia in the large size of the oo¨cysts and in having two types of oo¨cyst residuum

Detection of Adriamycin–DNA adducts by accelerator mass spectrometry at clinically relevant Adriamycin concentrations

Limited sensitivity of existing assays has prevented investigation of whether Adriamycin–DNA adducts are involved in the anti-tumour potential of Adriamycin. Previous detection has achieved a sensitivity of a few Adriamycin–DNA adducts/104 bp DNA, but has required the use of supra-clinical drug concentrations. This work sought to measure Adriamycin–DNA adducts at sub-micromolar doses using accelerator mass spectrometry (AMS), a technique with origins in geochemistry for radiocarbon dating. We have used conditions previously validated (by less sensitive decay counting) to extract [14C]Adriamycin–DNA adducts from cells and adapted the methodology to AMS detection. Here we show the first direct evidence of Adriamycin–DNA adducts at clinically-relevant Adriamycin concentrations. [14C]Adriamycin treatment (25 nM) resulted in 4.4 ± 1.0 adducts/107 bp (∼1300 adducts/cell) in MCF-7 breast cancer cells, representing the best sensitivity and precision reported to date for the covalent binding of Adriamycin to DNA. The exceedingly sensitive nature of AMS has enabled over three orders of magnitude increased sensitivity of Adriamycin–DNA adduct detection and revealed adduct formation within an hour of drug treatment. This method has been shown to be highly reproducible for the measurement of Adriamycin–DNA adducts in tumour cells in culture and can now be applied to the detection of these adducts in human tissues

Collocation of User Request Evaluation Tool, Traffic Management Advisor, and Controller Pilot Data Link Communications: An initial Human Factors Evaluation

This study was a human factors evaluation of collocating User Request Evaluation Tool (URET), Core Capability Limited Deployment, Traffic Management Advisor, and Controller Pilot Data Link Communications (CPDLC), formerly Build 1A. Human Factors Specialists conducted the evaluation in two phases: a \u201cpaper and pencil\u201d study - Phase 1 and a modified cognitive walkthrough - Phase 2. They examined the tools from existing documentation and system design in the context of human factors best practices. Four primary human factors issues emerged from this analysis: 1) Computer-Human Interface (CHI) inconsistencies; 2) Radar Associate (RA)-side collocation and timely access to information; 3) Communication of information between the RA-side and Radar-side controllers; and 4) National Airspace System updates from the different tools. Results include recommendations for human factors engineering for integrating the URET, CPDLC, and Computer Readout Display information on the RA-side, as well as working toward improving CHI consistencies

Physical inactivity is associated with chronic musculoskeletal complaints 11 years later: results from the Nord-Trøndelag Health Study

Background Physical inactivity is associated with several diseases, but studies evaluating the association between chronic musculoskeletal complaints (MSCs) and physical exercise have shown conflicting results. The aim of this large-scale prospective population-based study was to investigate the association between self-reported physical exercise at baseline and the prevalence of chronic musculoskeletal complaints (MSCs) 11 years later. Methods The results are based upon two consecutive public health studies conducted within the county of Nord-Trøndelag, Norway (The HUNT studies). A total of 39,520 (83%) out of 47,556 adults who participated in HUNT 1 and HUNT 2 responded to questions about physical exercise at baseline in 1984–86, and to questions about musculoskeletal complaints 11 years later (1995–97). Chronic MSCs was defined as MSCs ≥ 3 months during the past year, and chronic widespread MSCs such as pain ≥ 15 days during the last month from the axial region, above the waist, and below the waist. Associations were assessed using multiple logistic regression, estimating prevalence odds ratio (OR) with 95% confidence intervals (CIs). All the final analyses were adjusted for age, gender, body mass index, smoking and education level. Results At follow-up 20,223 (51%) reported chronic MSCs, and among these 2,318 (5.9%) reported chronic widespread MSCs. Individuals who exercised at baseline were less likely to report chronic MSCs 11 years later (OR 0.91, 95% CI 0.85–0.97) than inactive persons. Among individuals who exercised more than three times per week, chronic widespread MSCs were 28% less common (OR 0.72, 95% CI 0.59–0.88) compared to inactive individuals. Conclusion In this large-scale population-based study, physical exercise was associated with lower prevalence of chronic MSCs, in particular chronic widespread MSCs. Future studies should try to clarify whether chronic MSCs are a cause or a consequence of inactivity

RNA Polymerase II Pausing Downstream of Core Histone Genes Is Different from Genes Producing Polyadenylated Transcripts

Recent genome-wide chromatin immunoprecipitation coupled high throughput sequencing (ChIP-seq) analyses performed in various eukaryotic organisms, analysed RNA Polymerase II (Pol II) pausing around the transcription start sites of genes. In this study we have further investigated genome-wide binding of Pol II downstream of the 3′ end of the annotated genes (EAGs) by ChIP-seq in human cells. At almost all expressed genes we observed Pol II occupancy downstream of the EAGs suggesting that Pol II pausing 3′ from the transcription units is a rather common phenomenon. Downstream of EAGs Pol II transcripts can also be detected by global run-on and sequencing, suggesting the presence of functionally active Pol II. Based on Pol II occupancy downstream of EAGs we could distinguish distinct clusters of Pol II pause patterns. On core histone genes, coding for non-polyadenylated transcripts, Pol II occupancy is quickly dropping after the EAG. In contrast, on genes, whose transcripts undergo polyA tail addition [poly(A)+], Pol II occupancy downstream of the EAGs can be detected up to 4–6 kb. Inhibition of polyadenylation significantly increased Pol II occupancy downstream of EAGs at poly(A)+ genes, but not at the EAGs of core histone genes. The differential genome-wide Pol II occupancy profiles 3′ of the EAGs have also been confirmed in mouse embryonic stem (mES) cells, indicating that Pol II pauses genome-wide downstream of the EAGs in mammalian cells. Moreover, in mES cells the sharp drop of Pol II signal at the EAG of core histone genes seems to be independent of the phosphorylation status of the C-terminal domain of the large subunit of Pol II. Thus, our study uncovers a potential link between different mRNA 3′ end processing mechanisms and consequent Pol II transcription termination processes

Temporal feedback control of high-intensity laser pulses to optimize ultrafast heating of atomic clusters

We describe how active feedback routines can be applied at a limited repetition rate (5 Hz) to optimize high-power (> 10 TW) laser interactions with clustered gases. Optimization of x-ray production from an argon cluster jet, using a genetic algorithm, approximately doubled the measured energy through temporal modification of the 150 mJ driving laser pulse. This approach achieved an increased radiation yield through exploration of a multi-dimensional parameter space, without requiring detailed a priori knowledge of the complex cluster dynamics. The optimized laser pulses exhibited a slow rising edge to the intensity profile, which enhanced the laser energy coupling into the cluster medium, compared to the optimally compressed FWHM pulse (40 fs). Our work suggests that this technique can be more widely utilized for control of intense pulsed secondary radiation from petawatt-class laser systems