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"Murray, Kevin"
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Communicate to inspire
\" Communicate to Inspire answers some of the key practical questions for becoming a better leader, such as: \"How do you learn to be yourself, better?\" and \"What should you examine and how should you articulate your own purpose and values?\" Kevin Murray presents a model that charts the leadership process and draws stories from his experience coaching leaders. This book offers principles of leadership communication that address: how to become more audience-centric; how to emphasize values; how to focus on the people leaders need to inspire; what methods and tools to use to try to see the world through their eyes and address their needs; and mastering the art of public speaking. Communicate to Inspire uses charts and information gathered from dozens of successful training programs to determine how to turn a department, division or company into a better listening, faster responding, more innovative entity, just by holding more and better structured conversations\"-- Provided by publisher.
Book
Cryo-EM of full-length α-synuclein reveals fibril polymorphs with a common structural kernel
α-Synuclein (aSyn) fibrillar polymorphs have distinct in vitro and in vivo seeding activities, contributing differently to synucleinopathies. Despite numerous prior attempts, how polymorphic aSyn fibrils differ in atomic structure remains elusive. Here, we present fibril polymorphs from the full-length recombinant human aSyn and their seeding capacity and cytotoxicity in vitro. By cryo-electron microscopy helical reconstruction, we determine the structures of the two predominant species, a rod and a twister, both at 3.7 Å resolution. Our atomic models reveal that both polymorphs share a kernel structure of a bent β-arch, but differ in their inter-protofilament interfaces. Thus, different packing of the same kernel structure gives rise to distinct fibril polymorphs. Analyses of disease-related familial mutations suggest their potential contribution to the pathogenesis of synucleinopathies by altering population distribution of the fibril polymorphs. Drug design targeting amyloid fibrils in neurodegenerative diseases should consider the formation and distribution of concurrent fibril polymorphs.
The intrinsically disordered protein alpha-synuclein (aSyn) forms polymorphic fibrils. Here the authors provide molecular insights into aSyn fibril polymorphism and present the cryo-EM structures of the two predominant species, a rod and a twister both determined at 3.7 Å resolution.
Journal Article
Structure-based discovery of small molecules that disaggregate Alzheimer’s disease tissue derived tau fibrils in vitro
Alzheimer’s disease (AD) is the consequence of neuronal death and brain atrophy associated with the aggregation of protein tau into fibrils. Thus disaggregation of tau fibrils could be a therapeutic approach to AD. The small molecule EGCG, abundant in green tea, has long been known to disaggregate tau and other amyloid fibrils, but EGCG has poor drug-like properties, failing to fully penetrate the brain. Here we have cryogenically trapped an intermediate of brain-extracted tau fibrils on the kinetic pathway to EGCG-induced disaggregation and have determined its cryoEM structure. The structure reveals that EGCG molecules stack in polar clefts between the paired helical protofilaments that pathologically define AD. Treating the EGCG binding position as a pharmacophore, we computationally screened thousands of drug-like compounds for compatibility for the pharmacophore, discovering several that experimentally disaggregate brain-derived tau fibrils in vitro. This work suggests the potential of structure-based, small-molecule drug discovery for amyloid diseases.
Evidence suggests that fibrous aggregates of protein tau may be the proximal cause of Alzheimer’s disease. Here, using atomic structures of tau fibrils from brains of people with Alzheimer’s disease, the authors have found small-molecule drug leads that disaggregate tau fibrils in vitro.
Journal Article
Flavonoid intake is associated with lower mortality in the Danish Diet Cancer and Health Cohort
Flavonoids, plant-derived polyphenolic compounds, have been linked with health benefits. However, evidence from observational studies is incomplete; studies on cancer mortality are scarce and moderating effects of lifestyle risk factors for early mortality are unknown. In this prospective cohort study including 56,048 participants of the Danish Diet, Cancer, and Health cohort crosslinked with Danish nationwide registries and followed for 23 years, there are 14,083 deaths. A moderate habitual intake of flavonoids is inversely associated with all-cause, cardiovascular- and cancer-related mortality. This strong association plateaus at intakes of approximately 500 mg/day. Furthermore, the inverse associations between total flavonoid intake and mortality outcomes are stronger and more linear in smokers than in non-smokers, as well as in heavy (>20 g/d) vs. low-moderate (<20 g/d) alcohol consumers. These findings highlight the potential to reduce mortality through recommendations to increase intakes of flavonoid-rich foods, particularly in smokers and high alcohol consumers.
The studies showing health benefits of flavonoids and their impact on cancer mortality are incomplete. Here, the authors perform a prospective cohort study in Danish participants and demonstrate an inverse association between regular flavonoid intake and both cardiovascular and cancer related mortality.
Journal Article
جنرالات صدام : وجهات نظر عن الحرب العراقية-الإيرانية
يتناول كتاب (جنرالات صدام : وجهات نظر عن الحرب العراقية-الإيرانية) والذي قام بتأليفه (كيفن م. وودز، وليامسن موراي، إليزابيث أ. ناثان، ليلى صبارا، آنا م. فينيغاس) في حوالي (408) صفحة من القطع المتوسط موضوع (الحرب الإيرانية العراقية) مستعرضا المحتويات التالية : الخليفة، أصول الحرب والتخطيط لشنها، تعليم صدام في الحرب، تأقلم القوات المسلحة العراقية مع واقع الحرب، السياق التاريخي ولائحة الأحداث بحسب تسلسلها الزمني، حوار مع الفريق الركن مجيد رشيد الحمداني، القيادة العامة للقوات المسلحة المساعدة الأجنبية.
BOOK
De novo designed protein inhibitors of amyloid aggregation and seeding
Neurodegenerative diseases are characterized by the pathologic accumulation of aggregated proteins. Known as amyloid, these fibrillar aggregates include proteins such as tau and amyloid-β (Aβ) in Alzheimer’s disease (AD) and alpha-synuclein (αSyn) in Parkinson’s disease (PD). The development and spread of amyloid fibrils within the brain correlates with disease onset and progression, and inhibiting amyloid formation is a possible route toward therapeutic development. Recent advances have enabled the determination of amyloid fibril structures to atomic-level resolution, improving the possibility of structure-based inhibitor design. In this work, we use these amyloid structures to design inhibitors that bind to the ends of fibrils, “capping” them so as to prevent further growth. Using de novo protein design, we develop a library of miniprotein inhibitors of 35 to 48 residues that target the amyloid structures of tau, Aβ, and αSyn. Biophysical characterization of top in silico designed inhibitors shows they form stable folds, have no sequence similarity to naturally occurring proteins, and specifically prevent the aggregation of their targeted amyloid-prone proteins in vitro. The inhibitors also prevent the seeded aggregation and toxicity of fibrils in cells. In vivo evaluation reveals their ability to reduce aggregation and rescue motor deficits in Caenorhabditis elegans models of PD and AD.
Journal Article