Sagittal Abdominal Diameter as a Screening Tool in Clinical Research: Cutoffs for Cardiometabolic Risk

Background. Waist girth and BMI are commonly used as markers of cardiometabolic risk. Accumulating data however suggest that sagittal abdominal diameter (SAD) or “abdominal height” may be a better marker of intra-abdominal adiposity and cardiometabolic risk. We aimed to identify cutoffs for SAD using a cardiometabolic risk score. Design. A population-based cross-sectional study. Methods. In 4032 subjects (1936 men and 2096 women) at age 60, different anthropometric variables (SAD, BMI, waist girth, and waist-to-hip ratio) were measured and cardiometabolic risk score calculated. ROC curves were used to assess cutoffs. Results. Among men SAD showed the strongest correlations to the majority of the individual risk factors; whereas in women SAD was equal to that of waist girth. In the whole sample, the area under the ROC curve was highest for SAD. The optimal SAD cutoff for an elevated cardiometabolic risk score in men was ∼22 cm (95%CI; 21.6 to 22.8) and in women ∼20 cm (95%CI; 19.4 to 20.8). These cutoffs were similar if the Framingham risk score was used. Conclusions. These cutoffs may be used in research and screening to identify “metabolically obese” men who would benefit from lifestyle and pharmacological interventions. These results need to be verified in younger age groups

Observation of emission from chaotic lasing modes in deformed microspheres: displacement by the stable orbit modes

By combining detailed imaging measurements at different tilt angles with simulations of ray emission from prolate deformed lasing micro-droplets, we conclude that the probability density for the lasing modes in a three-dimensional dielectric microcavity must reside in the chaotic region of the ray phase space. In particular, maximum emission from such chaotic lasing modes is not from tangent rays emerging from the highest curvature part of the rim. The laser emission is observed and calculated to be non-tangent and displaced from the highest curvature due to the presence of stable orbits. In this Letter we present the first experimental evidence for this phenomenon of ``dynamical eclipsing''.Comment: 4 figure

Mutations in cancer cause gain of cysteine, histidine, and tryptophan at the expense of a net loss of arginine on the proteome level

Accumulation of somatic mutations is critical for the transition of a normal cell to become cancerous. Mutations cause amino acid substitutions that change properties of proteins. However, it has not been studied as to what extent the composition and accordingly chemical properties of the cell proteome is altered as a result of the increased mutation load in cancer. Here, we analyzed data on amino acid substitutions caused by mutations in about 2000 protein coding genes from the Cancer Cell Line Encyclopedia that contains information on nucleotide and amino acid alterations in 782 cancer cell lines, and validated the analysis with information on amino acid substitutions for the same set of proteins in the Catalogue of Somatic Mutations in Cancer (COSMIC; v78) in circa 18,000 tumor samples. We found that nonsynonymous single nucleotide substitutions in the analyzed proteome subset ultimately result in a net gain of cysteine, histidine, and tryptophan at the expense of a net loss of arginine. The extraordinary loss of arginine may be attributed to some extent to composition of its codons as well as to the importance of arginine in the functioning of prominent tumor suppressor proteins like p53

In silico druggability assessment of the NUDIX hydrolase protein family as a workflow for target prioritization

Computational chemistry has now been widely accepted as a useful tool for shortening lead times in early drug discovery. When selecting new potential drug targets, it is important to assess the likelihood of finding suitable starting points for lead generation before pursuing costly high-throughput screening campaigns. By exploiting available high-resolution crystal structures, an in silico druggability assessment can facilitate the decision of whether, and in cases where several protein family members exist, which of these to pursue experimentally. Many of the algorithms and software suites commonly applied for in silico druggability assessment are complex, technically challenging and not always user-friendly. Here we applied the intuitive open access servers of DoGSite, FTMap and CryptoSite to comprehensively predict ligand binding pockets, druggability scores and conformationally active regions of the NUDIX protein family. In parallel we analyzed potential ligand binding sites, their druggability and pocket parameter using Schrödinger's SiteMap. Then an in silico docking cascade of a subset of the ZINC FragNow library using the Glide docking program was performed to assess identified pockets for large-scale small-molecule binding. Subsequently, this initial dual ranking of druggable sites within the NUDIX protein family was benchmarked against experimental hit rates obtained both in-house and by others from traditional biochemical and fragment screening campaigns. The observed correlation suggests that the presented user-friendly workflow of a dual parallel in silico druggability assessment is applicable as a standalone method for decision on target prioritization and exclusion in future screening campaigns

Large-Eddy Simulation: Current Capabilities, Recommended Practices, and Future Research

This paper presents the results of an activity by the Large Eddy Simulation (LES) Working Group of the AIAA Fluid Dynamics Technical Committee to (1) address the current capabilities of LES, (2) outline recommended practices and key considerations for using LES, and (3) identify future research needs to advance the capabilities and reliability of LES for analysis of turbulent flows. To address the current capabilities and future needs, a survey comprised of eleven questions was posed to LES Working Group members to assemble a broad range of perspectives on important topics related to LES. The responses to these survey questions are summarized with the intent not to be a comprehensive dictate on LES, but rather the perspective of one group on some important issues. A list of recommended practices is also provided, which does not treat all aspects of a LES, but provides guidance on some of the key areas that should be considered

AXL and CAV-1 play a role for MTH1 inhibitor TH1579 sensitivity in cutaneous malignant melanoma

Cutaneous malignant melanoma (CMM) is the deadliest form of skin cancer and clinically challenging due to its propensity to develop therapy resistance. Reactive oxygen species (ROS) can induce DNA damage and play a significant role in CMM. MTH1 protein protects from ROS damage and is often overexpressed in different cancer types including CMM. Herein, we report that MTH1 inhibitor TH1579 induced ROS levels, increased DNA damage responses, caused mitotic arrest and suppressed CMM proliferation leading to cell death both in vitro and in an in vivo xenograft CMM zebrafish disease model. TH1579 was more potent in abrogating cell proliferation and inducing cell death in a heterogeneous co-culture setting when compared with CMM standard treatments, vemurafenib or trametinib, showing its broad anticancer activity. Silencing MTH1 alone exhibited similar cytotoxic effects with concomitant induction of mitotic arrest and ROS induction culminating in cell death in most CMM cell lines tested, further emphasizing the importance of MTH1 in CMM cells. Furthermore, overexpression of receptor tyrosine kinase AXL, previously demonstrated to contribute to BRAF inhibitor resistance, sensitized BRAF mutant and BRAF/NRAS wildtype CMM cells to TH1579. AXL overexpression culminated in increased ROS levels in CMM cells. Moreover, silencing of a protein that has shown opposing effects on cell proliferation, CAV-1, decreased sensitivity to TH1579 in a BRAF inhibitor resistant cell line. AXL-MTH1 and CAV-1-MTH1 mRNA expressions were correlated as seen in CMM clinical samples. Finally, TH1579 in combination with BRAF inhibitor exhibited a more potent cell killing effect in BRAF mutant cells both in vitro and in vivo. In summary, we show that TH1579-mediated efficacy is independent of BRAF/NRAS mutational status but dependent on the expression of AXL and CAV-1

A criterion for admissible singularities in brane world

When gravity couples to scalar fields in Anti-de Sitter space, the geometry becomes non-AdS and develops singularities generally. We propose a criterion that the singularity is physically admissible if the integral of the on-shell Lagrangian density over the finite range is finite everywhere. For all classes of the singularities studied here, the criterion suggested in this paper coincides with an independent proposal made by Gubser that the potential should be bounded from above in the solution. This gives a reason why Gubser's conjecture works.Comment: 14 pages, revtex, 1 table, references added, two other criteria include

Deltagande Forskning – Lärdomar, resultat och erfarenheter från Växthusgruppens arbete 1999–2000

Centrum för uthålligt lantbruk (CUL) vid SLU har initierat ett pionjärarbete att få igång deltagande forskning inom lantbrukssektorn i Sverige. I denna rapport beskrivs den läro- och förändringsprocess, de framgångar och svårigheter, som en av de grupper som ingår i CUL:s satsning genomgått och mött under sitt arbete med deltagande forskning. De resultat gruppens försök och praktiska arbete lett fram till presenteras också. Rapporten är skriven av gruppens facilitator (Karin Eksvärd) efter att ha samtalat med gruppmedlemmarna enskilt och tillsammans om deltagarnas åsikter kring gruppens arbete och arbetsformer. Några av gruppdeltagarnas åsikter och uttalanden finns inlagda som citat i rapporten. Deltagarna har även haft möjlighet att kommentera rapporten under dess framtagande. Gruppens arbete har möjliggjorts genom att rådgivarna har arrangerat gruppens möten som kurser inom miljöstödsprogrammet. Det har varit ett givande och lärorikt arbete som fortsätter att öka vårt kunnande om ekologisk tomatodling, oss själva som grupp och sättet att arbeta. Vi hoppas att denna rapport skall inspirera fler lantbrukare, rådgivare och forskare att i högre grad samverka med varandra och att på detta sätt vidareutveckla svenskt lantbruk