2,273 research outputs found

    A Biochemical Genomics Screen for Substrates of Ste20p Kinase Enables the In Silico Prediction of Novel Substrates

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    The Ste20/PAK family is involved in many cellular processes, including the regulation of actin-based cytoskeletal dynamics and the activation of MAPK signaling pathways. Despite its numerous roles, few of its substrates have been identified. To better characterize the roles of the yeast Ste20p kinase, we developed an in vitro biochemical genomics screen to identify its substrates. When applied to 539 purified yeast proteins, the screen reported 14 targets of Ste20p phosphorylation. We used the data resulting from our screen to build an in silico predictor to identify Ste20p substrates on a proteome-wide basis. Since kinase-substrate specificity is often mediated by additional binding events at sites distal to the phosphorylation site, the predictor uses the presence/absence of multiple sequence motifs to evaluate potential substrates. Statistical validation estimates a threefold improvement in substrate recovery over random predictions, despite the lack of a single dominant motif that can characterize Ste20p phosphorylation. The set of predicted substrates significantly overrepresents elements of the genetic and physical interaction networks surrounding Ste20p, suggesting that some of the predicted substrates are in vivo targets. We validated this combined experimental and computational approach for identifying kinase substrates by confirming the in vitro phosphorylation of polarisome components Bni1p and Bud6p, thus suggesting a mechanism by which Ste20p effects polarized growth

    Revealing the electroweak properties of a new scalar resonance

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    One or more new heavy resonances may be discovered in experiments at the CERN Large Hadron Collider. In order to determine if such a resonance is the long-awaited Higgs boson, it is essential to pin down its spin, CP, and electroweak quantum numbers. Here we describe how to determine what role a newly-discovered neutral CP-even scalar plays in electroweak symmetry breaking, by measuring its relative decay rates into pairs of electroweak vector bosons: WW, ZZ, \gamma\gamma, and Z\gamma. With the data-driven assumption that electroweak symmetry breaking respects a remnant custodial symmetry, we perform a general analysis with operators up to dimension five. Remarkably, only three pure cases and one nontrivial mixed case need to be disambiguated, which can always be done if all four decay modes to electroweak vector bosons can be observed or constrained. We exhibit interesting special cases of Higgs look-alikes with nonstandard decay patterns, including a very suppressed branching to WW or very enhanced branchings to \gamma\gamma and Z\gamma. Even if two vector boson branching fractions conform to Standard Model expectations for a Higgs doublet, measurements of the other two decay modes could unmask a Higgs imposter.Comment: 23 pages, two figures; v2: minor revision and version to appear in JHE

    Psychometric evaluation of the Chinese version of the subjective happiness scale: Evidence from the Hong Kong FAMILY cohort

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    BACKGROUND: With China's rapid economic growth in the past few decades, there is currently an emerging focus on happiness. Cross-cultural validity studies have indicated that the four-item Subjective Happiness Scale (SHS) has high internal consistency and stable reliability. However, the psychometric characteristics of the SHS in broader Chinese community samples are unknown. PURPOSE: We evaluated the factor structure and psychometric properties of the SHS in the Hong Kong general population. METHODS: The Chinese SHS was derived using forward-backward translation. Of the Cantonese-speaking participants aged >/=15 years, 2,635 were randomly selected from the random sample component of the FAMILY Cohort, a territory-wide cohort study in Hong Kong. In addition to the SHS, a single-item overall happiness scale, the Patient Health Questionnaire-9 (PHQ-9), the Family Adaptation, Partnership, Growth, Affection, Resolve (APGAR) scale, and the Medical Outcomes Study 12-item short-form version 2 (SF-12) mental and physical health scales were administered. RESULTS: Exploratory and confirmatory factor analyses supported a single factor with high loadings for the four SHS items. Multiple group analyses indicated factor invariance across sex and age groups. Cronbach's alpha was 0.82, and 2-week test-retest reliability (n = 191) was 0.70. The SHS correlated significantly with single-item overall happiness (Spearman's rho [rho] = 0.57), Family APGAR (rho = 0.26), PHQ-9 (rho = -0.34), and mental health-related quality of life (rho = 0.40) but showed a lower correlation with physical health (rho = 0.15). A regression model that included the PHQ-9 and Family APGAR scores explained 37 % of the variance in SF-12 mental health scores; adding the SHS raised the variance explained to 41 %. CONCLUSIONS: Our results support the reliability and validity of the SHS as a relevant component in the measurement battery for mental well-being in a Chinese general population.published_or_final_versio

    Mixed Bino-Wino-Higgsino Dark Matter in Gauge Messenger Models

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    Almost degenerate bino and wino masses at the weak scale is one of unique features of gauge messenger models. The lightest neutralino is a mixture of bino, wino and higgsino and can produce the correct amount of the dark matter density if it is the lightest supersymmetric particle. Furthermore, as a result of squeezed spectrum of superpartners which is typical for gauge messenger models, various co-annihilation and resonance regions overlap and very often the correct amount of the neutralino relic density is generated as an interplay of several processes. This feature makes the explanation of the observed amount of the dark matter density much less sensitive to fundamental parameters. We calculate the neutralino relic density assuming thermal history and present both spin independent and spin dependent cross sections for the direct detection. We also discuss phenomenological constraints from b to s gamma and muon g-2 and compare results of gauge messenger models to well known results of the mSUGRA scenario.Comment: 27 pages, 9 figures, references added, version to appear at JCA

    Staged Laser Interstitial Thermal Therapy for the Surgical Treatment of Insular Glioma: a Case Series

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    Staged Laser Interstitial Thermal Therapy for the Surgical Treatment of Insular Glioma: a Case Series Introduction Insular gliomas pose one of the most significant challenges in neurosurgical oncology due to the complexity of the surrounding functional and microvascular anatomy. Despite current surgical and technological advancements, resection of insular gliomas can lead to potentially severe neurological morbidities. Laser Interstitial Thermal Therapy (LITT), either alone or combined with surgery, presents a less invasive cytoreductive approach for treating insular gliomas. Objective In this work we describe the first-ever reported series of patients with insular gliomas treated with staged LITT operations with or without subsequent craniotomy. Methods We reviewed a retrospective institutional database to identify patients with insular glioma who underwent staged LITT operations with or without subsequent craniotomy. From the compiled list of 11 patients, we obtained clinical, histopathological and volumetric lesion characteristics for each patient. Procedural characteristics, morbidity, overall survival (OS) and progression-free survival (PFS) were further assessed. Results From the 11 insular glioma patients included in this study the average age was 42 (SD = 12.5 years) with 8 (73%) patients that had left sided tumors and 6 (55%) patients had high grade insular gliomas. A total of 26 surgical procedures were performed with 21 ablations and 5 ablations that were followed by subsequent craniotomy. With regards to operative outcomes, the median tumor volume (cc) of our patient group was 31.5 (9.58-97) and the extent of tumor resection with laser ablation was on average 96.2% (SD = 8.5). Assessing post-operative morbidities, our group found OS to be 15.7 months (SD=10.3) and PFS to be 11.7 months (SD=7.5). Of the 21 ablation-only procedures performed, in the peri-operative period (3-5 days) neurological deficits were found in 9 (43%) post-ablation cases however there were 0 post-ablation cases with neurological deficits in the long-term (\u3e3months). Of the 5 procedures where laser ablation was followed with subsequent craniotomy, neurological deficits were found in the peri-operative period in all 5 post-resection cases (100%) and there were neurological deficits in the long-term period found in 2 of them (40%). Conclusions We present the first ever reported series of insular gliomas treated with staged LITT operations. Through conducting this study our group found that staged treatment of insular gliomas with LITT is safe, effective and a minimally invasive option that avoids the potentially severe neurological compromises associated with conventional surgical resection approaches. Usage of stages of LITT to directly target high-risk insular glioma regions presents a novel treatment approach that may facilitate the maximal safe treatment of these otherwise significantly surgically challenging lesions

    Risk stratification of cardiac arrhythmias and sudden cardiac death in type 2 diabetes mellitus patients receiving insulin therapy: A population-based cohort study

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    Introduction Metabolic abnormalities may exacerbate the risk of adverse outcomes in patients with type 2 diabetes mellitus. The present study aims to assess the predictive value of HbA1c and lipid variability on the risks of sudden cardiac death (SCD) and incident atrial fibrillation (AF). Methods The retrospective observational study consists of type 2 diabetic patients prescribed with insulin, who went to publicly funded clinics and hospitals in Hong Kong between January 1, 2009 and December 31, 2009. Variability in total cholesterol, low-density lipoprotein-cholesterol (LDL-C), high-density lipoprotein-cholesterol (HDL-C), triglyceride, and HbA1c were assessed through their SD and coefficient of variation. The primary outcomes were incident (1) ventricular tachycardia/ventricular fibrillation, actual or aborted SCD and (2) AF. Results A total of 23 329 patients (mean ± SD age: 64 ± 14 years old; 51% male; mean HbA1c 8.6 ± 1.3%) were included. On multivariable analysis, HbA1c, total cholesterol, LDL-C and triglyceride variability were found to be predictors of SCD (p < .05). Conclusion HbA1c and lipid variability were predictive of SCD. Therefore, poor glucose control and variability in lipid parameters in diabetic patients are associated with aborted or actual SCD. These observations suggest the need to re-evaluate the extent of glycemic control required for outcome optimization

    Experimental observation of autosoliton propagation in a dispersion-managed system guided by nonlinear optical loop mirrors

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    Observation of autosoliton propagation in a dispersion-managed optical transmission system controlled by in-line nonlinear fiber loop switches is reported for what is believed to be the first time. The system is based on a strong dispersion map with large amplifier spacing. Operation at transmission rates of 10 and 40 Gbits/s is demonstrated. ©2004 Optical Society of America

    Osteological and Biomolecular Evidence of a 7000-Year Old Case of Hypertrophic Pulmonary Osteopathy Secondary to Tuberculosis from Neolithic Hungary

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    Seventy-one individuals from the late Neolithic population of the 7000-year-old site of Hódmezővásárhely-Gorzsa were examined for their skeletal palaeopathology. This revealed numerous cases of infections and non-specific stress indicators in juveniles and adults, metabolic diseases in juveniles, and evidence of trauma and mechanical changes in adults. Several cases showed potential signs of tuberculosis, particularly the remains of the individual HGO-53. This is an important finding that has significant implications for our understanding of this community. The aim of the present study was to seek biomolecular evidence to confirm this diagnosis. HGO-53 was a young male with a striking case of hypertrophic pulmonary osteopathy (HPO), revealing rib changes and cavitations in the vertebral bodies. The initial macroscopic diagnosis of HPO secondary to tuberculosis was confirmed by analysis of Mycobacterium tuberculosis complex specific cell wall lipid biomarkers and corroborated by ancient DNA (aDNA) analysis. This case is the earliest known classical case of HPO on an adult human skeleton and is one of the oldest palaeopathological and palaeomicrobiological tuberculosis cases to date

    Dietary garlic and hip osteoarthritis: evidence of a protective effect and putative mechanism of action

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    Background Patterns of food intake and prevalent osteoarthritis of the hand, hip, and knee were studied using the twin design to limit the effect of confounding factors. Compounds found in associated food groups were further studied in vitro. Methods Cross-sectional study conducted in a large population-based volunteer cohort of twins. Food intake was evaluated using the Food Frequency Questionnaire; OA was determined using plain radiographs. Analyses were adjusted for age, BMI and physical activity. Subsequent in vitro studies examined the effects of allium-derived compounds on the expression of matrix-degrading proteases in SW1353 chondrosarcoma cells. Results Data were available, depending on phenotype, for 654-1082 of 1086 female twins (median age 58.9 years; range 46-77). Trends in dietary analysis revealed a specific pattern of dietary intake, that high in fruit and vegetables, showed an inverse association with hip OA (p = 0.022). Consumption of 'non-citrus fruit' (p = 0.015) and 'alliums' (p = 0.029) had the strongest protective effect. Alliums contain diallyl disulphide which was shown to abrogate cytokine-induced matrix metalloproteinase expression. Conclusions Studies of diet are notorious for their confounding by lifestyle effects. While taking account of BMI, the data show an independent effect of a diet high in fruit and vegetables, suggesting it to be protective against radiographic hip OA. Furthermore, diallyl disulphide, a compound found in garlic and other alliums, represses the expression of matrix-degrading proteases in chondrocyte-like cells, providing a potential mechanism of action
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