Platelet endothelial cell adhesion molecule 1 (PECAM-1) and its interactions with glycosaminoglycans: 1. Molecular modeling studies

Platelet endothelial cell adhesion molecule 1 (PECAM-1) has many functions, including its roles in leukocyte extravasation as part of the inflammatory response and in the maintenance of vascular integrity through its contribution to endothelial cell−cell adhesion. PECAM-1 has been shown to mediate cell−cell adhesion through homophilic binding events that involve interactions between domain 1 of PECAM-1 molecules on adjacent cells. However, various heterophilic ligands of PECAM-1 have also been proposed. The possible interaction of PECAM-1 with glycosaminoglycans (GAGs) is the focus of this study. The three-dimensional structure of the extracellular immunoglobulin (Ig) domains of PECAM-1 were constructed using homology modeling and threading methods. Potential heparin/heparan sulfate-binding sites were predicted on the basis of their amino acid consensus sequences and a comparison with known structures of sulfate-binding proteins. Heparin and other GAG fragments have been docked to investigate the structural determinants of their protein-binding specificity and selectivity. The modeling has predicted two regions in PECAM-1 that appear to bind heparin oligosaccharides. A high-affinity binding site was located in Ig domains 2 and 3, and evidence for a low-affinity site in Ig domains 5 and 6 was obtained. These GAG-binding regions were distinct from regions involved in PECAM-1 homophilic interactions.

Diaryl dihydropyrazole-3-carboxamides with significant in vivo antiobesity activity related to CB1 receptor antagonism: Synthesis, biological evaluation, and molecular modeling in the homology model

A number of analogues of diaryl dihydropyrazole-3-carboxamides have been synthesized. Their activities were evaluated for appetite suppression and body weight reduction in animal models. Depending on the chemical modification of the selected dihydropyrazole scaffold, the lead compoundsthe bisulfate salt of (±)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4,5-dihydro-1H-pyrazole-3-carboxylic acid morpholin-4-ylamide 26 and the bisulfate salt of (−)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4,5-dihydro-1H-pyrazole-3-carboxylic acid morpholin-4-ylamide 30showed significant body weight reduction in vivo, which is attributed to their CB1 antagonistic activity and exhibited a favorable pharmacokinetic profile. The molecular modeling studies also showed interactions of two isomers of (±)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4,5-dihydro-1H-pyrazole-3-carboxylic acid morpholin-4-ylamide 9 with CB1 receptor in the homology model similar to those of N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-3-pyrazole-carboxamide (rimonabant) 1 and 4S-(−)-3-(4-chlorophenyl)-N-methyl-N‘-[(4-chlorophenyl)-sulfonyl]-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine (SLV-319) 2.

Molecular modeling of Bt Cry1Ac (DI–DII)–ASAL (Allium sativum lectin)–fusion protein and its interaction with aminopeptidase N (APN) receptor of Manduca sexta

Genetic engineering of Bacillus thuringiensis (Bt) Cry proteins has resulted in the synthesis of various novel toxin proteins with enhanced insecticidal activity and specificity towards different insect pests. In this study, a fusion protein consisting of the DI–DII domains of Cry1Ac and garlic lectin (ASAL) has been designed in silico by replacing the DIII domain of Cry1Ac with ASAL. The binding interface between the DI–DII domains of Cry1Ac and lectin has been identified using protein–protein docking studies. Free energy of binding calculations and interaction profiles between the Cry1Ac and lectin domains confirmed the stability of fusion protein. A total of 18 hydrogen bonds was observed in the DI–DII–lectin fusion protein compared to 11 hydrogen bonds in the Cry1Ac (DI–DII–DIII) protein. Molecular mechanics/Poisson–Boltzmann (generalized-Born) surface area [MM/PB (GB) SA] methods were used for predicting free energy of interactions of the fusion proteins. Protein–protein docking studies based on the number of hydrogen bonds, hydrophobic interactions, aromatic–aromatic, aromatic–sulphur, cation–pi interactions and binding energy of Cry1Ac/fusion proteins with the aminopeptidase N (APN) of Manduca sexta rationalised the higher binding affinity of the fusion protein with the APN receptor compared to that of the Cry1Ac–APN complex, as predicted by ZDOCK, Rosetta and ClusPro analysis. The molecular binding interface between the fusion protein and the APN receptor is well packed, analogously to that of the Cry1Ac–APN complex. These findings offer scope for the design and development of customized fusion molecules for improved pest management in crop plants.

A hybrid agent architecture for modeling autonomous agents in SAGE

This paper highlights the Hybrid agent construction model being developed that allows the description and development of autonomous agents in SAGE (Scalable, fault Tolerant Agent Grooming Environment) - a second generation FIPA-Compliant Multi-Agent system. We aim to provide the programmer with a generic and well defined agent architecture enabling the development of sophisticated agents on SAGE, possessing the desired properties of autonomous agents - reactivity, pro-activity, social ability and knowledge based reasoning. © Springer-Verlag Berlin Heidelberg 2005.

The tired foot. The effects of physical activity, energy expenditure and sleep on the diabetic foot population

Background The most common pathway to development of diabetes foot ulcers is repetitive daily activity stress on the plantar surface of the neuropathic foot. Studies suggest an association between different diabetic foot complications and physical activity. However, to the best of the authors knowledge the steps/day and sleep patterns of people with diabetic foot ulcers has yet to be investigated. This observational study aims to investigate the physical activity and sleep patterns of three groups of adults with type 2 diabetes and different foot complications Methods Participants with type 2 diabetes were recruited into three groups: 1. those with no reported foot complications (DNIL), 2. those with diagnosis of neuropathy (DPN) and 3. those with a neuropathic ulcer (DFU). Exclusion criteria included peripheral arterial disease and mobility aid use. Participants wore a SenseWear Pro 3 Armband continuously for 7 days and completed an Epworth Sleepiness Scale. The Armband is a validated automated measure of activity (walking steps, average Metabolic Equivalent Task (MET), physical activity (>3 METs) duration), energy expenditure(kJ) (total and physical activity (>3 METs)) and sleep (duration). Data on age, sex, BMI, diabetes duration and HbA1c were also collected. Results Sixty-Six (14 DNIL, 22 DPN and 30 DFU's participants were recruited; 71% males, mean age 61(±12) years, diabetes duration 13(±9) years, HbA1c 8.3(±2.8), BMI 32.6(±5.9), average METs 1.2(0.2). Significant differences were reported in mean(SD) steps/day (5,859(±2,381) in DNIL; 5,007(±3,349) in DPN and 3,271(±2,417) in DFU's and daily energy expenditure (10,868(±1,307)kJ in DNIL; 11,060(±1,916)kJ in DPN and 13,006(± 3,559) in DFU's(p <0.05). No significant differences were reported for average METs, physical activity duration or energy expenditure, sleep time or Epworth score (p>0.1). Conclusions Preliminary findings suggest people with diabetes are sedentary. Results indicate that patients with a diabetic foot ulcer work significantly less than those with neuropathy or nil complications and use significantly more energy to do so. Sleep Parameters showed no differences. Recruitment is still on going.

Ratios of T-cell immune-effectors with tumour associated macrophages and PD-1/PD-L1 axis immune-checkpoint molecules, as prognosticators in diffuse large B cell lymphoma: A population-based study

Background Risk-stratification of diffuse large B-cell lymphoma (DLBCL) requires identification of patients with disease that is not cured despite initial R-CHOP. Although the prognostic importance of the tumour microenvironment (TME) is established, the optimal strategy to quantify it is unknown. Methods The relationship between immune-effector and inhibitory (checkpoint) genes was assessed by NanoString™ in 252 paraffin-embedded DLBCL tissues. A model to quantify net anti-tumoural immunity as an outcome predictor was tested in 158 R-CHOP treated patients, and validated in tissue/blood from two independent R-CHOP treated cohorts of 233 and 140 patients respectively. Findings T and NK-cell immune-effector molecule expression correlated with tumour associated macrophage and PD-1/PD-L1 axis markers consistent with malignant B-cells triggering a dynamic checkpoint response to adapt to and evade immune-surveillance. A tree-based survival model was performed to test if immune-effector to checkpoint ratios were prognostic. The CD4*CD8:(CD163/CD68)*PD-L1 ratio was better able to stratify overall survival than any single or combination of immune markers, distinguishing groups with disparate 4-year survivals (92% versus 47%). The immune ratio was independent of and added to the revised international prognostic index (R-IPI) and cell-of-origin (COO). Tissue findings were validated in 233 DLBCL R-CHOP treated patients. Furthermore, within the blood of 140 R-CHOP treated patients immune-effector:checkpoint ratios were associated with differential interim-PET/CT+ve/-ve expression.

A rare P2X7 variant Arg307Gln with absent pore formation function protects against neuroinflammation in multiple sclerosis

Multiple sclerosis (MS) is a chronic relapsing-remitting inflammatory disease of the central nervous system characterized by oligodendrocyte damage, demyelination and neuronal death. Genetic association studies have shown a 2-fold or greater prevalence of the HLA-DRB1*1501 allele in the MS population compared with normal Caucasians. In discovery cohorts of Australasian patients with MS (total 2941 patients and 3008 controls), we examined the associations of 12 functional polymorphisms of P2X7, a microglial/macrophage receptor with proinflammatory effects when activated by extracellular adenosine triphosphate (ATP). In discovery cohorts, rs28360457, coding for Arg307Gln was associated with MS and combined analysis showed a 2-fold lower minor allele frequency compared with controls (1.11% for MS and 2.15% for controls, P = 0.0000071). Replication analysis of four independent European MS case–control cohorts (total 2140 cases and 2634 controls) confirmed this association [odds ratio (OR) = 0.69, P = 0.026]. A meta-analysis of all Australasian and European cohorts indicated that Arg307Gln confers a 1.8-fold protective effect on MS risk (OR = 0.57, P = 0.0000024). Fresh human monocytes heterozygous for Arg307Gln have >85% loss of ‘pore’ function of the P2X7 receptor measured by ATP-induced ethidium uptake. Analysis shows Arg307Gln always occurred with 270His suggesting a single 307Gln–270His haplotype that confers dominant negative effects on P2X7 function and protection against MS. Modeling based on the homologous zP2X4 receptor showed Arg307 is located in a region rich in basic residues located only 12 Å from the ligand binding site. Our data show the protective effect against MS of a rare genetic variant of P2RX7 with heterozygotes showing near absent proinflammatory ‘pore’ function.

Elucidating the neuropsychological profile of apathetic syndrome and disinhibition syndrome in a brain-injured population in Oman

The purpose of this study was to compare the neuropsychological performance of two frontal dysexecutive phenotypes - disinhibited&' syndrome (DS) and &'apathetic&' syndrome (AS) following a traumatic brain injury in a non-western population, Oman. Methods: The study compared the performance of DS and AS in neuropsychological measures including those tapping into verbal reasoning ability/working memory/attention planning/goal-directed behavior and affective ranges. Results: The present analysis showed that DS and AS participants did not differ on indices measuring working memory/attention and affective ranges. However, the two cohorts differed significantly in measures of planning/goal-directed behaviour. Conclusion: This study lays the groundwork for further scrutiny in delineating the different characteristics of what has been previously labelled as frontal dysexecutive phenotype. This study indicates that DS and AS are marked with specific neuropsychological deficits.

Reflections from East Asia's ageing population: An interaction designers' challenge

As Asia experiences the demographic imbalance between working and ageing populations, the need for attention in this area is highlighted. The shift of a country's age structure that results from people having small families and living long lives, where previously they had large families and lived short lives, results in more workers and fewer dependents creating economic growth, known as the demographic dividend. However for a generation after this bulge and dividend, a disproportionate number of older people must be supported by a smaller working population, a current concern in Asia with its rapidly growing number of older adults. This extended abstract draws practical and unique insights from three of the oldest and richest nations in Asia - Japan, South Korea and China, on the perspective of interactive technology design for older adults. ICT has powerful potential to ameliorate the imbalance in the population demographic through its potential to leverage various kinds of support. As HCI researchers, this is a challenge we embrace; a challenge for the ageing society of unique individuals to exploit the technologies that they have helped to create. The paper draws lessons from key sample studies, one from each country, which aimed to understand their ageing population. The insights for interaction designers are presented in the form of a practical set of reflections to guide the authors, who are in the early stages of research on technology design for older adults.

The psychometric properties of the Kessler Psychological Distress Scale (K6) in a general population sample of adolescents

The 6-item Kessler Psychological Distress Scale (K6; Kessler et al., 2002) is a screener for psychological distress that has robust psychometric properties among adults. Given that a significant proportion of adolescents experience mental illness, there is a need for measures that accurately and reliably screen for mental disorders in this age group. This study examined the psychometric properties of the K6 in a large general population sample of adolescents (N = 4,434; mean age = 13.5 years; 44.6% male). Factor analyses were conducted to examine the dimensionality of the K6 in adolescents and to investigate sex-based measurement invariance. This study also evaluated the K6 as a predictor of scores on the Strengths and Difficulties Questionnaire (SDQ; Goodman, 1997). The K6 demonstrated high levels of internal consistency, with the 6 items loading primarily on 1 factor. Consistent with previous research, females reported higher mean levels of psychological distress when compared with males. The identification of sex-based measurement noninvariance in the item thresholds indicated that these mean differences most likely represented reporting bias in the K6 items rather than true differences in the underlying psychological distress construct. The K6 was a fair to good predictor of abnormal scores on the SDQ, but predictive utility was relatively low among males. Future research needs to focus on refining and augmenting the K6 scale to maximize its utility in adolescents. (PsycINFO Database Record (c) 2015 APA, all rights reserved)