Predicting MHC class I epitopes in large datasets

BACKGROUND: Experimental screening of large sets of peptides with respect to their MHC binding capabilities is still very demanding due to the large number of possible peptide sequences and the extensive polymorphism of the MHC proteins. Therefore, there is significant interest in the development of computational methods for predicting the binding capability of peptides to MHC molecules, as a first step towards selecting peptides for actual screening. RESULTS: We have examined the performance of four diverse MHC Class I prediction methods on comparatively large HLA-A and HLA-B allele peptide binding datasets extracted from the Immune Epitope Database and Analysis resource (IEDB). The chosen methods span a representative cross-section of available methodology for MHC binding predictions. Until the development of IEDB, such an analysis was not possible, as the available peptide sequence datasets were small and spread out over many separate efforts. We tested three datasets which differ in the IC50 cutoff criteria used to select the binders and non-binders. The best performance was achieved when predictions were performed on the dataset consisting only of strong binders (IC50 less than 10 nM) and clear non-binders (IC50 greater than 10,000 nM). In addition, robustness of the predictions was only achieved for alleles that were represented with a sufficiently large (greater than 200), balanced set of binders and non-binders. CONCLUSIONS: All four methods show good to excellent performance on the comprehensive datasets, with the artificial neural networks based method outperforming the other methods. However, all methods show pronounced difficulties in correctly categorizing intermediate binders

Gene expression profile of CD14+ blood monocytes following lifestyle-induced weight loss in individuals with metabolic syndrome.

Lifestyle-induced weight loss is regarded as an efficient therapy to reverse metabolic syndrome (MetS) and to prevent disease progression. The objective of this study was to investigate whether lifestyle-induced weight loss modulates gene expression in circulating monocytes. We analyzed and compared gene expression in monocytes (CD14+ cells) and subcutaneous adipose tissue biopsies by unbiased mRNA profiling. Samples were obtained before and after diet-induced weight loss in well-defined male individuals in a prospective controlled clinical trial (ICTRP Trial Number: U1111-1158-3672). The BMI declined significantly (- 12.6%) in the treatment arm (N = 39) during the 6-month weight loss intervention. This was associated with a significant reduction in hsCRP (- 45.84%) and circulating CD14+ cells (- 21.0%). Four genes were differentially expressed (DEG's) in CD14+ cells following weight loss (ZRANB1, RNF25, RB1CC1 and KMT2C). Comparative analyses of paired CD14+ monocytes and subcutaneous adipose tissue samples before and after weight loss did not identify common genes differentially regulated in both sample types. Lifestyle-induced weight loss is associated with specific changes in gene expression in circulating CD14+ monocytes, which may affect ubiquitination, histone methylation and autophag

Osteocalcin Is Independently Associated with C-Reactive Protein during Lifestyle-Induced Weight Loss in Metabolic Syndrome

Bone-derived osteocalcin has been suggested to be a metabolic regulator. To scrutinize the relation between osteocalcin and peripheral insulin sensitivity, we analyzed changes in serum osteocalcin relative to changes in insulin sensitivity, low-grade inflammation, and bone mineral density following lifestyle-induced weight loss in individuals with metabolic syndrome (MetS). Participants with MetS were randomized to a weight loss program or to a control group. Before and after the 6-month intervention period, clinical and laboratory parameters and serum osteocalcin levels were determined. Changes in body composition were analyzed by dual-energy X-ray absorptiometry (DXA). In participants of the intervention group, weight loss resulted in improved insulin sensitivity and amelioration of inflammation. Increased serum levels of osteocalcin correlated inversely with BMI (r = −0.63; p < 0.001), total fat mass (r = −0.58, p < 0.001), total lean mass (r = −0.45, p < 0.001), C-reactive protein (CRP) (r = −0.37; p < 0.01), insulin (r = −0.4; p < 0.001), leptin (r = −0.53; p < 0.001), triglycerides (r = −0.42; p < 0.001), and alanine aminotransferase (ALAT) (r = −0.52; p < 0.001). Regression analysis revealed that osteocalcin was independently associated with changes in CRP but not with changes in insulin concentration, fat mass, or bone mineral density, suggesting that weight loss-induced higher serum osteocalcin is primarily associated with reduced inflammation

PENGARUH TEKANAN KETAATAN DAN KOMPLEKSITAS TUGAS TERHADAP AUDIT JUDGMENT (Survey Terhadap Lima Kantor AkuntanPublik di Kota Bandung)

ABSTRAK Seperti yang kita ketahui bahwa seorang auditor dalam melakukan tugasnya membuat audit judgment dipengaruhi banyak faktor, baik bersifat teknis dan non teknis. Salah satu faktor non teknis adalah aspek perilaku individual. Aspek perilaku individu, sebagai salah satu faktor yang banyak mempengaruhi pembuatan audit judgment. Pada penelitian ini ada beberapa faktor yang mempengaruhi audit judgment yaitu tekanan ketaatan dan kompleksitas tugas. Dalam penelitian ini penullis ingin mengetahui sejauh mana “tekanan ketaatan dan kompleksitas tugas terhadap audit judgment”. Sedangkan tujuan dari penelitian ini adalah untuk mengetahui dan mempelajari tekanan ketaatan dan kompleksitas tugas terhadap audit judgment. Hipotesis yang diuji dalam penelitian ini adalah “ jika tekanan ketaatan dan kompleksitas tugas baik, maka audit judgment akan meningkat ( baik pula)”. Hipotesis ini berdasarkan asumsi bahwa tekanan ketaatan dan kompleksitas tugas berpengaruh terhadap audit judgment.dalam penelitian ini penulis menggunakan metode deskriptif asosiatif dengan pendekatan survey dan tes statistik. Penelitian ini terdiri dari atas variabel X1 dan X2 dan audit judgment sebagai veriabel Y atau variabel independen. Uji statistik dilakukan dengan mengolah data dari hasil jawaban kuesioner. Dalam penelitian ini, peulis menyebarkan angket kepada 5 Kantor Akuntan Publik di Kota Bandung khusunya untuk para auditor. Pengumpulan data dilakukan dengan cara penyebaran kuesioner yang telah diuji validitasnya dan reabilitasnya. Penelitian ini dilakukan di 5 KAP di Kota Bandung. Pengambilan sampel ini menggunakan purposive sampling berukuran 28 orang responden. Untuk uji hipotesis penelitian, penulis melakukannya dengan uji t untuk masing-masing variabel X1,X2, dan Y. Dari hasil uji tHitung tekanan ketaatan terhadap audit judgment tHitung =4,178>ttabel = 1.705 kompleksitas tugas terhadap audit judgment 5 tHitung = 3.364 > ttabel = 1,705. Maka, dari hasil uji hipotesis tersebut penulis menyimpulkan bahwa hipotesis penelitian diterima (Ho ditolak, Ha diterima) artinya terdapat pengaruh antara terkanan ketaatan terhadap audit judgment dan kompleksitas tugas terhadap audit judgment Untuk mencari besarnya pengaruh Tekanan ketaatan dan Kompleksitas Tugas terhadap Audit Judgment secara simultan penulis melakukannya dengan uji f dengan koefisien determinasi (KD). Dari hasil uji fhitung dan > f table yaitu 16,182>3,370. Kata kunci : Tekanan Ketaatan dan Kompleksitas tugas Terhadap Audit Judgmen

Programme Dementia Prevention (pdp): A Nationwide Program for Personalized Prevention in Luxembourg.

peer reviewedBACKGROUND: With continuously aging societies, an increase in the number of people with cognitive decline is to be expected. Aside from the development of causative treatments, the successful implementation of prevention strategies is of utmost importance to reduce the high societal burden caused by neurodegenerative diseases leading to dementia among which the most common cause is Alzheimer's disease. OBJECTIVE: The aim of the Luxembourgish "programme dementia prevention (pdp)" is to prevent or at least delay dementia in an at-risk population through personalized multi-domain lifestyle interventions. The current work aims to provide a detailed overview of the methodology and presents initial results regarding the cohort characteristics and the implementation process. METHODS: In the frame of the pdp, an extensive neuropsychological evaluation and risk factor assessment are conducted for each participant. Based on the results, individualized multi-domain lifestyle interventions are suggested. RESULTS: A total number of 450 participants (Mean age = 69.5 years; SD = 10.8) have been screened at different recruitment sites throughout the country, among whom 425 participants (94.4%) met the selection criteria. CONCLUSIONS: We provide evidence supporting the feasibility of implementing a nationwide dementia prevention program and achieving successful recruitment of the target population by establishing a network of different healthcare providers.3. Good health and well-bein

Antagonizing Integrin β3 Increases Immunosuppression in Cancer

Integrin β3 is critical for tumor invasion, neoangiogenesis, and inflammation, making it a promising cancer target. However, preclinical and clinical data of integrin β3 antagonists have demonstrated no benefit or worse outcomes. We hypothesized that integrin β3 could affect tumor immunity and evaluated tumors in mice with deletion of integrin β3 in macrophage lineage cells (β3KOM). β3KOM mice had increased melanoma and breast cancer growth with increased tumor-promoting M2 macrophages and decreased CD8+ T cells. Integrin β3 antagonist, cilengitide, also enhanced tumor growth and increased M2 function. We uncovered a negative feedback loop in M2 myeloid cells, wherein integrin β3 signaling favored STAT1 activation, an M1-polarizing signal, and suppressed M2-polarizing STAT6 activation. Finally, disruption of CD8+ T cells, macrophages, or macrophage integrin β3 signaling blocked the tumor-promoting effects of integrin β3 antagonism. These results suggest that effects of integrin β3 therapies on immune cells should be considered to improve outcomes. Cancer Res; 76(12); 3484–95. ©2016 AACR

The Luxembourg Parkinson’s Study: A Comprehensive Approach for Stratification and Early Diagnosis

While genetic advances have successfully defined part of the complexity in Parkinson’s disease (PD), the clinical characterization of phenotypes remains challenging. Therapeutic trials and cohort studies typically include patients with earlier disease stages and exclude comorbidities, thus ignoring a substantial part of the real-world PD population. To account for these limitations, we implemented the Luxembourg PD study as a comprehensive clinical, molecular and device-based approach including patients with typical PD and atypical parkinsonism, irrespective of their disease stage, age, comorbidities, or linguistic background. To provide a large, longitudinally followed, and deeply phenotyped set of patients and controls for clinical and fundamental research on PD, we implemented an open-source digital platform that can be harmonized with international PD cohort studies. Our interests also reflect Luxembourg-specific areas of PD research, including vision, gait, and cognition. This effort is flanked by comprehensive biosampling efforts assuring high quality and sustained availability of body liquids and tissue biopsies. We provide evidence for the feasibility of such a cohort program with deep phenotyping and high quality biosampling on parkinsonism in an environment with structural specificities and alert the international research community to our willingness to collaborate with other centers. The combination of advanced clinical phenotyping approaches including device-based assessment will create a comprehensive assessment of the disease and its variants, its interaction with comorbidities and its progression. We envision the Luxembourg Parkinson’s study as an important research platform for defining early diagnosis and progression markers that translate into stratified treatment approaches

Intensive blood glucose control is safe and effective in diabetic cats using home monitoring and treatment with glargine

Human diabetic patients routinely self-adjust their insulin dose using a protocol and home monitoring, and perform equally well or outperform physician directed adjustments. The objective of this study was to report the outcome of home monitoring of diabetic cats by owners using a protocol aimed at achieving euglycaemia, using ultra-low carbohydrate diets (10 weeks and/or until remission was achieved. Fifty-five cats diagnosed with diabetes mellitus, whose owners joined the online German Diabetes-Katzen Forum, were included. An overall remission rate of 64% was achieved in the cohort. Significantly higher remission rates were observed if good glycaemic control was achieved soon after diagnosis: 84% for cats started on the protocol within 6 months of diagnosis went into remission, and only 35% for cats that began more than 6 months after diagnosis (P<0.001). Only one mild clinical hypoglycaemic episode occurred observed despite tight blood glucose control. In conclusion, intensive blood glucose control is safe and effective in diabetic cats using home monitoring and treatment with glargine