Alzheimer’s disease: Amyloid oligomers, therapeutic agents, their target and mode of action

Das umfassende Ziel dieser Arbeit ist es die Effekte von natürlich vorkommenden Autoantikörpern (Nabs) und CNI-1493 (immunmodulatorische Substanz) auf Amyloid-beta (Aβ) Oligomere zu beschreiben. Die extrazelluläre Anreicherung von Aβ im Gehirn steht im Verdacht Ursache und Auslöser der Alzheimer’schen Demenz (AD) zu sein. Die genaue physiologische Rolle von Aβ ist jedoch unklar. Jüngere Ergebnisse zeigen dass monomeres Aβ an der normalern synaptischen Aktivität beteiligt sein könnte. Im Gegensatz dazu behindert oligomeres Aβ die synaptische Aktivität. Daher ist ein immuntherapeutischer Ansatz, der Aβ zum Ziel hat, eine vielversprechende Behandlungsstrategie für AD. Eine der Herausforderungen eines immuntherapeutischen Ansatzes ist es spezifisch die toxischen, fehl-gefalteten Formen von Aβ zu bekämpfen ohne die physiologisch relevanten Aβ Monomere zu stören. Die Menge an natürlich vorkommenden Autoantikörpern gegen Aβ ist in AD Patienten erniedrigt. Im ersten Kapitel habe ich die Aß-Epitop-Region von natürlich vorkommenden Aβ-Autonatikörpern (Nabs-Aβ) mit Bindungsstudien ermittelt. Ich verglich die Bindung von Nabs-Aβ gegenüber einer Reihe von mutierten und verkürzten Aβ-Peptiden. Die Nabs–Aβ zeigten eine stärkere Bindung zum C-terminalen Ende von Aβ, das membrangebunden vorliegt. Das C-terminale Ende von Aβ ist entscheidend für die Oligomerisation. Deshalb könnten C-terminal-spezifische Nabs-Aβ helfen die Oligomerisierung zu minimieren. Zusätzlich könnte diese Spezifität eine Interaktion von nabs-Aβ mit membrangebundenen Amyloid-Vorläufer-Protein (APP), Aβ-Monomeren, und Aβ-Fibrillen ausschließen. Weitere Studien zur Epitop-Charakterisierung wurden mit ortsgerichteter Mutagenese durchgeführt. Die Ergebnisse zeigten dass Lysin an Position 28 und Isoleuzin an Position 32 von Aβ entscheidend für die Bindung von Nabs-Aß sind. Das Fehlen oder Ersetzen einer dieser beiden Aminosäuren führte zum Bindungsverlust. Zusätzliche Bindunsgstudien mit konformatorisch fixierten sogenannte Aβ-click-Peptiden zeigten dass nabs-Aβ spezifisch für niedermolekulare anti-parallele Aβ Dimere sind. Interessanterweise zeigten Nabs-Aβ eine exzellente Bindung mit Aβ mit 2 Muationen am C-terminalen Ende (Aβ1-40; G29,33 Ile). Die Charaktersisierung von Aβ1-40; G29,33 Ile zeigte, dass das Molekül einen unterschiedlichen Oligomerisierungsprozess durchläuft und SDS-stabile Trimere bildet. Zytotoxizitäts-Studien zeigten dass Aβ-Wildtyp unter bestimmten Inkubationsbedingungen toxische Oligomere bildet, während Aβ1-40; G29,33 Ile unter diesen Bedingungen nicht toxisch ist. Entsprechend meines derzeitigen Kenntnisstands ist Aβ1-40; G29,33 Ile die erste Aβ-Oligomer-Spezies die stabil ist und eine hohe Affinität zu Nabs-Aβ besitzt. Nicht-steroidale ani-inflammatorische Heilmittel haben Berichten zufolge einen positiven Behandlungs-Effekt bei AD. Ich untersuchte in dieser Arbeit die Rolle von CNI-1493, einer anti-inflammatorischen Verbindung. Die in vitro Experimente zeigten dass CNI-1493 Aß-Oligomere bindet und den Komplex in Richtung Monomere verschiebt. In dieser Arbeit habe ich im Detail die Effekte von zwei AD-Heilmittel-Kandidaten untersucht, die mit dem Immunsystem assoziiert sind; Nabs-Aβ und CNI-1493. Die Ergebnisse helfen unserem Verständnis über Nabs-Aβ und unterstützen ihre mögliche Rolle als sicheren und effektiven AD-Immuntherapie-Kandidaten. Der immunmodulatorische Wirkung von CNI-1493, sowie seine Effekte auf Aβ-Oligomerbildung machen dieses Molekül zu einem interessanten Arzeinmittel Kandidaten für AD Therapie-Studien. Zusätzlich könnte die neue Aβ-Mutante, nach weiterer Charakterisierung, als mögliche Vakzine oder diagnostisches Verfahren entwickelt werden

Cangrelor - rising from the ashes: a phoenix story

Cangrelor is a novel intravenous antiplatelet agent that has been approved for usage in the setting of percutaneous coronary revascularization in patients with acute coronary syndrome. The drug was evaluated in three major trials namely Champion-Platform, Champion-PCI and Champion Phoenix with a total of 25,107 patients. Although there was a reduction in the incidence of ischemia driven revascularization, Q wave MI and stent thromboses in the first 48 hours among cangrelor users as compared to clopidogrel, there was no difference in the incidence of all-cause mortality or myocardial infarction. In terms of safety, cangrelor does not appear to have a higher bleeding risk. A distinct appeal with cangrelor is its unique pharmacokinetic property of having a rapid onset and offset of action. The drug would also have a niche role among patients with challenges to oral drug administration as in mechanically ventilated patients and those with severe vomiting. Although the drug managed to rise against odds in getting regulatory approval from the FDA, it remains to be seen if this could become a frontline agent among the current array of anti-platelet molecules

Detection, Isolation and Characterization of Principal Synthetic Route Indicative Impurities in Verapamil Hydrochloride

Two unknown impurities were detected in verapamil hydrochloride bulk drug using isocratic reversed-phase high performance liquid chromatography (HPLC). These impurities were isolated by preparative HPLC. Spectral data for the isolated impurities were collected. Based on the spectral data derived from two-dimensional nuclear magnetic resonance (2D-NMR) spectroscopy and mass spectrometry (MS), impurity-1 and impurity-2 were characterized as 2-(3,4-dimethoxyphenyl)-3-methylbut-2-enenitrile and 2-(3,4-dimethoxyphenyl)-2-isopropyl-3-methylbutanenitrile, respectively

MAINTENANCE STRATEGY EVALUATION BASED ON AHP – TOPSIS

This paper presents an application of Analytical Hierarchy Process (AHP) is combined with Technique for Order Preference by Similarly to Ideal Solution (TOPSIS) model for selection of the best maintenance strategy for pump in paper industry. AHP is used to compute the criteria weights whereas TOPSIS is used to ranking the maintenance strategy alternatives. This study focuses on four maintenance strategies such as Corrective Maintenance (CM), Predictive maintenance (PM), Time based preventive Maintenance (TM) & Condition Based Maintenance (CBM) and four main criteria such as safety, cost, added value and feasibility are used to evaluate the optimum maintenance strategy

Studies on the Effect of Pomegranate Rind Powder Extract as Natural Antioxidant in Chicken Meat Balls During Refrigerated Storage

Trials were conducted to study the effect of pomegranate rind powder extract as natural antioxidant in chicken meat balls during refrigerated storage. Significantly (p<0.05) lower values for cooking loss, pH and 2-thiobarbituric acid (2-TBARS) values and higher values for emulsion stability were obtained due to the incorporation of pomegranate rind powder extract at 5 percent level followed by 2.5 percent level than the other treatments. There was a significant (p<0.05) increase in cooking loss, pH, 2-TBARS values and free fatty acid content as the storage period progressed from 0 to 8 days, however emulsion stability of chicken meat balls decreased significantly (p<0.05) during the course of refrigeration. Microbial quality evaluation revealed that chicken meat balls incorporated with pomegranate rind powder extract at 5 percent level had significantly (p<0.05) lower standard plate count during refrigerated storage and a significant (p<0.05) increase in microbial load was observed. Organoleptic evaluation indicated that addition of pomegranate rind powder extract at 5 and 2.5 percent levels to chicken meat balls registered significantly (p<0.05) higher sensory scores for various eating quality attributes than the other treatments. However there was a significant (p<0.05) in all the organoleptic attributes of the product as the storage period increased

Studies on the Effect of Essential Oils of Spices on Physico-Chemical, Microbial and Organoleptic Properties OF Chicken Meat Patties during Refrigerated Storage

At the storage temperature of 5+10C samples treated with essential oil of garlic with 1:250 concentration, up to day 8 and 1:500 and 1:1000 concentrations resulted in lower pH values up to day 6 of storage. Clove with 1:250 and 1:500 concentrations resulted in lower pH values up to day 12 of storage and 1:1000 concentration decreased the pH values up to day 10 of storage, cinnamon with 1:250, 1:500 and 1:1000 concentrations resulted in lower pH values up to day 8 of storage compared to the control. A significant (p<0.05) reduction in 2–thiobarbituric acid values on day 6 of storage compared to the control in the samples treated with essential oils of garlic, clove and cinnamon at 1:250 and 1:500 concentrations, whereas in samples with 1:1000 concentration showed a significant (p<0.05) reduction on day 4 of storage. Total plate count of chicken meat patties with essential oil of garlic at 1:250 and 1:500 concentrations resulted in decreased counts on day 2 of storage, then there was a gradual increase, and the counts were well within the prescribed standards up to day 10, day 6 and day 4 in patties with garlic at 1:250, 1:500 and 1:1000 concentrations respectively, with clove at 1:250 and 1:500 concentrations the counts were significantly (P<0.05) reduced up to day 6 and day 4 respectively, afterwards gradual increase was observed and they were well within the prescribed standards up to day 12 of storage for all the three concentrations, cinnamon at 1:250 and 1:500 concentrations the counts were significantly (P<0.05) reduced up to day 4 of storage, then gradual increase was observed and they were well within the prescribed standards up to day 14, day 12 and day 8 for 1:250, 1:500 and 1:1000 concentrations respectively. Yeast and mold count of patties with essential oil of garlic, at 1:250, 1:500 and 1:1000 concentrations significantly (P<0.05) reduced up to day 12, 10 and day 4 of storage respectively, with clove the counts were significantly (P<0.05) reduced up to day 14 of storage at 1:250 concentration whereas at 1:500 and 1:1000 concentrations the counts were significantly (P<0.05) reduced up to day 10 and day 4 respectively. Essential oil of cinnamon at 1:250, 1:500 and 1:1000 concentration significantly (P<0.05) reduced the counts up to day 12, day 10 and day 4 of storage respectively. With regard to the colour and flavour scores of samples with the mixture of essential oils of garlic, clove and cinnamon at 1:250, 1:500 and 1:1000 concentrations were found to have higher colour and flavour scores compared to the control through out the storage period but the samples with the mixture of essential oils of spices at 1:500 concentration had higher flavour scores when compared to the rest of the treatments. Hence clove at 1:250 concentration is considered to be the best one to increase the shelf life of chicken meat patties

Artificial Intelligence in Human Resource Management: Advancements, Implications and Future Prospects

The present condition, challenges, and potential applications of artificial intelligence (AI) in human resource management (HRM) are all explored in this survey article. As an innovation, artificial intelligence (AI) has the potential to completely revolutionize several facets of human resource management (HRM). Examining the usage of AI-powered tools and systems in different HR processes, the present situation with AI in HRM is examined. These encompass learning and development, performance management, employee engagement, and recruiting. The use of AI algorithms and machine learning approaches to automate regular HR operations, analyze vast amounts of employee data, and provide insightful data to aid decision-making is addressed in this article. However, integrating AI into HRM also poses a number of difficulties that must be resolved. Bias, privacy issues, and transparency are just a few of the ethical and legal ramifications of using AI in decision-making processes that are discussed in this survey. The study emphasizes how accountability and fairness must be maintained in AI systems by responsible design, oversight, and periodic evaluation. With an emphasis on job displacement and workforce reorganization, the possible influence of AI on the human workforce is also explored. To effectively traverse this change, strategies including work role redefinition, employee up skilling, and establishing a collaborative atmosphere between humans and AI are suggested. The possible advantages and breakthroughs that AI might bring to HRM practices are highlighted as the future perspectives of AI in HRM are examined. As new applications for AI in HRM, sentiment analysis, predictive analytics, intelligent decision support, and personalized employee experiences are all highlighted. In order to fully realize the promise of AI in HRM, the study underlines the significance of data infrastructure, data governance frameworks, and a data-driven culture. Overall, this survey study offers an in-depth review of the existing situation, difficulties, and prospects for AI in HRM. It aggregates current information, identifies research gaps, and gives practitioners and scholars new perspectives on how AI will fundamentally alter the way HRM activities are carried out in the future