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Selected AbstractsSmall molecule , -amyloid inhibitors that stabilize protofibrillar structures in vitro improve cognition and pathology in a mouse model of Alzheimer's diseaseEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 2 2010Cheryl A. Hawkes Abstract ,-Amyloid (A,) peptides are thought to play a major role in the pathogenesis of Alzheimer's disease. Compounds that disrupt the kinetic pathways of A, aggregation may be useful in elucidating the role of oligomeric, protofibrillar and fibrillar A, in the etiology of the disease. We have previously reported that scyllo -inositol inhibits A,42 fibril formation but the mechanism(s) by which this occurs has not been investigated in detail. Using a series of scyllo -inositol derivatives in which one or two hydroxyl groups were replaced with hydrogen, chlorine or methoxy substituents, we examined the role of hydrogen bonding and hydrophobicity in the structure,function relationship of scyllo -inositol,A, binding. We report here that all scyllo -inositol derivatives demonstrated reduced effectiveness in preventing A,42 fibrillization compared with scyllo -inositol, suggesting that scyllo -inositol interacts with A,42 via key hydrogen bonds that are formed by all hydroxyl groups. Increasing the hydrophobicity of scyllo -inositol by the addition of two methoxy groups (1,4-di- O -methyl- scyllo -inositol) produced a derivative that stabilized A,42 protofibrils in vitro. Prophylactic administration of 1,4-di- O -methyl- scyllo -inositol to TgCRND8 mice attenuated spatial memory impairments and significantly decreased cerebral amyloid pathology. These results suggest that A, aggregation can be targeted at multiple points along the kinetic pathway for the improvement of Alzheimer's disease-like pathology. [source] Individual job-choice decisions and the impact of job attributes and recruitment practices: A longitudinal field studyHUMAN RESOURCE MANAGEMENT, Issue 1 2003Wendy R. Boswell The present research is intended to contribute to the understanding of how job-choice decisions are made and the role of effective and ineffective recruiting practices in that process. The issues are examined by tracking job seekers through the job search and choice process. At multiple points in the process, structured interviews are used to elicit information from the job seekers pertaining to how they are making their decision and what factors play a role. Results provide theoretical and practical insights into the organizational and job attributes important to job choice, as well as how specific recruiting practices may exert a significant influence, positive or negative, on job-choice decisions. For example, our findings reinforced the importance of providing job seekers the opportunity to meet with multiple (and high-level) organizational constituents, impressive site-visit arrangements, and frequent and prompt follow-up. Also, imposing a deadline (i.e., "exploding offer") showed little effect on job-choice decisions. Recommendations for recruitment practice and continued research are provided. © 2003 Wiley Periodicals, Inc. [source] Granzyme B: a natural born killerIMMUNOLOGICAL REVIEWS, Issue 1 2003Sarah J. Lord Summary:, A main pathway used by cytotoxic T lymphocytes (CTLs) and natural killer cells to eliminate pathogenic cells is via exocytosis of granule components in the direction of the target cell, delivering a lethal hit of cytolytic molecules. Amongst these, granzyme B and perforin have been shown to induce CTL-mediated target cell DNA fragmentation and apoptosis. Once released from the CTL, granzyme B binds its receptor, the mannose-6-phosphate/insulin-like growth factor II receptor, and is endocytosed but remains arrested in endocytic vesicles until released by perforin. Once in the cytosol, granzyme B targets caspase-3 directly or indirectly through the mitochondria, initiating the caspase cascade to DNA fragmentation and apoptosis. Caspase activity is required for apoptosis to occur; however, in the absence of caspase activity, granzyme B can still initiate mitochondrial events via the cleavage of Bid. Recent work shows that granzyme B-mediated release of apoptotic factors from the mitochondria is essential for the full activation of caspase-3. Thus, granzyme B acts at multiple points to initiate the death of the offending cell. Studies of the granzyme B death receptor and internal signaling pathways may lead to critical advances in cell transplantation and cancer therapy. [source] Inflammatory bowel disease: Epidemiology, pathogenesis, and therapeutic opportunitiesINFLAMMATORY BOWEL DISEASES, Issue 5 2006Stephen B Hanauer MD Abstract Ulcerative colitis (UC) and Crohn's disease (CD), the primary constituents of inflammatory bowel disease (IBD), are precipitated by a complex interaction of environmental, genetic, and immunoregulatory factors. Higher rates of IBD are seen in northern, industrialized countries, with greater prevalence among Caucasians and Ashkenazic Jews. Racial gaps are closing, indicating that environmental factors may play a role. IBD is multigenic, with the most clearly established genetic link between certain NOD2 variants and CD. Regardless of the underlying genetic predisposition, a growing body of data implicates a dysfunctional mucosal immune response to commensal bacteria in the pathogenesis of IBD, especially CD. Possible triggers include a chronic inflammatory response precipitated by infection with a particular pathogen or virus or a defective mucosal barrier. The characteristic inflammatory response begins with an infiltration of neutrophils and macrophages, which then release chemokines and cytokines. These in turn exacerbate the dysfunctional immune response and activate either TH1 or TH2 cells in the gut mucosa, respectively associated with CD and, less conclusively, with UC. Elucidation of immunological and genetic factors indicate multiple points at which the inflammatory cascade may be interrupted, yielding the possibility of precise, targeted therapies for IBD. [source] How do adolescents with bulimia nervosa rate the acceptability and therapeutic relationship in family-based treatment?INTERNATIONAL JOURNAL OF EATING DISORDERS, Issue 5 2008Shannon L. Zaitsoff PhD Abstract Objective: To describe therapeutic alliance and treatment acceptability ratings of adolescents with bulimia nervosa (BN) participating in family-based treatment (FBT-BN) and to explore how participant characteristics relate to these constructs. Method: Adolescents with BN (n = 80) in a randomized controlled trial comparing FBT-BN and individual supportive psychotherapy (SPT), completed the Eating Disorder Examination, Rosenberg Self-esteem Scale, and Beck Depression Inventory prior to treatment. The Helping Relationship Questionnaire, patient expectancy for treatment, treatment suitability, and self-reported estimates of improvement ratings were obtained at multiple points throughout treatment. Results: Therapeutic alliance and treatment acceptability ratings were positive in both treatments and generally did not differ. Within FBT-BN, more severe eating disorder symptomatology pretreatment was related to lower alliance ratings mid-treatment (p < .05). However, reductions in binge and purge behaviors over the course of treatment were not related to alliance or acceptability for participants in FBT-BN (all p's > .10). Conclusion: Contrary to expectations of FBT-BN, adolescents receiving both treatments develop a strong alliance with the therapist. © 2008 by Wiley Periodicals, Inc. Int J Eat Disord 2008 [source] Life Course Transitions, the Generational Stake, and Grandparent-Grandchild RelationshipsJOURNAL OF MARRIAGE AND FAMILY, Issue 4 2002Robert Crosnoe Drawing on past research and prominent theoretical orientations, this research note suggests new approaches to intergenerational dynamics. For 316 grandparent-grandchild pairs, we found that the transition of grandchildren to higher education, controlling for other transitions, improves the quality of the grandparent-grandchild relationship. For grandparent mentoring, however, we see evidence of a generational stake, with grandparents overestimating their mentoring role, compared to grandchildren, during this transition. This generational stake reflects the importance of grandparent education, with increased mentoring for the college-going grandchildren of college-educated grandparents. These findings indicate that the intergenerational literature can be significantly advanced by taking a long-term perspective, incorporating multiple points of view, and examining contextual variation. Moreover, greater understanding of these intergenerational ties will benefit research on families and individual development. [source] Optical fiber sensor for localizing heating positions in multiple points using multichannel gratings with phase sampling and wavelength division multiplexing techniquesMICROWAVE AND OPTICAL TECHNOLOGY LETTERS, Issue 11 2008Li Xia Abstract An optical fiber sensor system with multichannel fiber Bragg gratings (FBGs) is proposed. The gratings are designed and fabricated by phase sampling technique within strongly chirped phase masks. The sensing application can be realized at multiple points through wavelength division multiplexing (WDM) technique. It means that the different point can be monitored by different gratings, which occupies different wavelength region, according to the central pitch and chirp coefficient of phase masks. The heating position with high resolution can be analyzed through three corresponding channel shifts in the multichannel profile. In our experiment, the two multichannel gratings with channel spacing of 0.8 and 1.6 nm, respectively, are fabricated and used for sensing in two points. At last, the 400 ,m accuracy of localizing the heating position is achieved. © 2008 Wiley Periodicals, Inc. Microwave Opt Technol Lett 50: 2951,2954, 2008; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/mop.23832 [source] PICKLE acts during germination to repress expression of embryonic traitsTHE PLANT JOURNAL, Issue 6 2005Hui-Chun Li Summary PICKLE (PKL) codes for a CHD3 chromatin remodeling factor that plays multiple roles in Arabidopsis growth and development. Previous analysis of the expression of genes that exhibit PKL -dependent regulation suggested that PKL acts during germination to repress expression of embryonic traits. In this study, we examined the expression of PKL protein to investigate when and where PKL acts to regulate development. A PKL:eGFP translational fusion is preferentially localized in the nucleus of cells, consistent with the proposed role for PKL as a chromatin remodeling factor. A steroid-inducible version of PKL [a fusion of PKL to the glucocorticoid receptor (PKL:GR)] was used to examine when PKL acts to repress expression of embryonic traits. We found that activation of PKL:GR during germination was sufficient to repress expression of embryonic traits in the primary roots of pkl seedlings, whereas activation of PKL:GR after germination had little effect. In contrast, we observed that PKL is required continuously after germination to repress expression of PHERES1, a type I MADS box gene that is normally expressed during early embryogenesis in wild-type plants. Thus, PKL acts at multiple points during development to regulate patterns of gene expression in Arabidopsis. [source] Electrocardiographic Body Surface Mapping: Potential Tool for the Detection of Transient Myocardial Ischemia in the 21st Century?ANNALS OF NONINVASIVE ELECTROCARDIOLOGY, Issue 2 2009Monique R. Robinson D.Phil Coronary artery disease (CAD) is one of the leading causes of cardiovascular mortality and morbidity worldwide. CAD presents as a wide spectrum of clinical disease from stable angina to ST segment elevation myocardial infarction. The 12-lead electrocardiogram (ECG) has been the main tool for the diagnosis of these events for almost a century but is limited in its diagnostic ability. For patients with suspected angina, the exercise tolerance test is often used to provoke and detect stress-induced ischemia but does not provide a definitive answer in a substantial proportion of patients. Body surface mapping (BSM) is a technique that samples multiple points around the thorax to provide a more comprehensive electrocardiographic data set than the conventional 12-lead ECG. Moreover, recent preliminary data demonstrate that BSM can detect and display transient regional myocardial ischemia in an intuitive fashion, employing subtraction color mapping, making it potentially valuable for diagnosing CAD causing transient regional ischemia. Research is ongoing to determine the full extent of its utility. [source] | |||||||||||||