The role of inclusions in ALS pathogenesis

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease that primarily afflicts motor neurons, leading to paralysis and death within 3 to 5 years after diagnosis. Genetic studies have uncovered multiple genetic defects causing familial forms of ALS and mutations occurring in proteins with a variety of functions, including RNA metabolism (TDP43, FUS) and oxygen free radical homeostasis (SOD1). A commonality among all ALS forms is the presence of intracellular inclusions that primarily consist of insoluble protein aggregates. These inclusions indicate that protein aggregation is a central pathogenic event shared by multiple ALS forms. The research of the present thesis focuses on the role of protein aggregation and inclusion formation in two types of ALS: 1) ALS caused by mutations in the superoxide dismutase 1 (SOD1) gene (ALS1); and 2) ALS caused by mutations in the vesicle-associated membrane protein (VAMP)-associated protein B (VAPB) gene (ALS8)

Анализ влияния теории информационных каскадов и стадного поведения агентов на формирование финансовых пузырей

Розглянуто питання формування фінансових бульбашок на основі ірраціональної поведінки економічних агентів та теорії інформаційних каскадів. Наведено базову модель інформаційних каскадів, характеристику та етапи утворення фінансових бульбашок. Ключові слова: прийняття рішень, стадна поведінка, фінансові ринки, інформаційний каскад, фінансові бульбашки.Рассмотрены вопросы формирования финансовых пузырей на основе иррациональных подходов стадного поведения экономических агентов и теории информационных каскадов. Приведена базовая модель информационных каскадов, характеристика и этапы образования финансовых пузырей. Ключевые слова: принятие решений, стадное поведение, финансовые рынки, информационный каскад, финансовые пузыри.The paper deals with formation of bubbles on the basis of irrational approaches of herd behaviour of the economic agents and the theory of information cascades. A basic model of information cascades is presented, as well as characteristics and stages in formation of financial bubbles. Keywords: decision making, herd bahaviour, financial markets, information cascade, financial bubbles

Airway dimensions and pathologies of trumpet players vs. non-trumpet players.

Objective: The objective of this retrospective, 3-dimensional cone beam computed tomography study was to determine if there is a significant difference between the most constricted area of the airway, the prevertebral soft tissue thickness and airway dimensions (length and volume) of the nasal cavity, nasopharynx, oropharynx, and maxillary sinuses of university trumpet players versus non-trumpet playing controls. The second objective was to determine significant differences in the prevalence of airway pathologies between university trumpet players and controls. Method: Following IRB approval and consent and reliability studies, measurements of airway parameters and pathology were compared between 66 Caucasian trumpeters and 22 ethnicmatched controls. An analysis of covariance, with age and sex included as covariates, was used to compare the airway measures. Since there was a significant difference in gender and age, comparisons between groups for the presence of any airway pathologies was made using logistic regression including age and sex as covariates. A 5% significance level was used for all comparisons. Result: The trumpet players had significantly smaller nasal cavity volume (18028 + 595 mm3 vs. 25266 + 1116 mm3; p<0.0001) and significantly greater soft tissue thickness at CV2ia (3.29 + 0.10 mm vs 2.70 + 0.10 mm; p=0.03) and CV3sa (4.55 + 0.13 mm vs 3.74 + 0.14 mm; p=0.005) than the controls. No other airway measure demonstrated a significant difference between the two groups. Trumpeters had significantly (p=0.002) more airway pathology (n=33; 50%) than the controls (n=4; 18%). Antral pseudocysts or polyps composed 52% of trumpeter pathologies as compared with 0% controls. Conclusion: The only significant differences in airway dimensions between trumpet players and controls were decreased nasal cavity volume and some areas of prevertebral soft tissue thickness. Trumpeters were almost three times as likely to exhibit airway pathology when compared with controls. Funding: IUPUI Signature Center Initiative – 3D Imaging of the Craniofacial Complex Center and the Joseph and Aida Jarabak Endowed Professorship

Cardiovascular risk prediction in the Netherlands

Background: In clinical practice, Systematic COronary Risk Evaluation (SCORE) risk prediction functions and charts are used to identify persons at high risk for cardiovascular diseases (CVD), who are considered eligible for drug treatment of elevated blood pressure and serum cholesterol. These functions use classical risk factors (age, gender, smoking, blood pressure and the ratio of total-to-HDL-cholesterol) to predict absolute 10-year risk of CVD mortality rather than total (fatal plus nonfatal) CVD. The aim of this thesis was to improve cardiovascular risk prediction in the Netherlands and to correctly classify high-risk persons. Methods: We primarily used data from the Monitoring Project on Chronic Disease Risk Factors (MORGEN project) of the National Institute for Public Health and the Environment (RIVM). Risk factor data of more than 20,000 men and women aged 20-65 years were collected between 1993 and 1997. Ten-year follow up data on CVD mortality and morbidity were obtained from Statistics Netherlands and the National Hospital Discharge Register, respectively. Risk functions were developed using multivariable Cox proportional hazard models. Results: The SCORE risk function for low-risk countries was the best predictor of CVD mortality in the Netherlands. Total CVD was approximately four times higher than CVD mortality. Obesity (BMI ≥30 kg/m2) and parental history of myocardial infarction before age 70 were independent predictors of total CVD. Risk functions predicting risk of CVD mortality and total CVD, and their ability to discriminate between future cases and non-cases, did not differ. Of the high-risk persons with a CVD mortality risk of at least 5%, approximately 20% developed a nonfatal or fatal CVD event during 10 years of follow-up. When a cut-off point of 2% CVD mortality was used, approximately 10% of the high-risk persons developed a CVD event. When obesity and parental history of MI were added to the classical risk factor function, correct risk classification improved by 5%. This improvement in risk prediction was mainly due to obesity. Conclusions: Discrimination between future cases and non-cases did not improve by expanding the endpoint of risk prediction from fatal CVD to total CVD. Adding obesity and parental history to the classical risk factor functions slightly increased the number of correctly classified persons. </p

Amyotrophic lateral sclerosis (ALS)-associated VAPB-P56S inclusions represent an ER quality control compartment

BACKGROUND: Protein aggregation and the formation of intracellular inclusions are a central feature of many neurodegenerative disorders, but precise knowledge about their pathogenic role is lacking in most instances. Here we have characterized inclusions formed in transgenic mice carrying the P56S mutant form of VAPB that causes various motor neuron syndromes including ALS8.RESULTS: Inclusions in motor neurons of VAPB-P56S transgenic mice are characterized by the presence of smooth ER-like tubular profiles, and are immunoreactive for factors that operate in the ER associated degradation (ERAD) pathway, including p97/VCP, Derlin-1, and the ER membrane chaperone BAP31. The presence of these inclusions does not correlate with signs of axonal and neuronal degeneration, and axotomy leads to their gradual disappearance, indicating that they represent reversible structures. Inhibition of the proteasome and knockdown of the ER membrane chaperone BAP31 increased the size of mutant VAPB inclusions in primary neuron cultures, while knockdown of TEB4, an ERAD ubiquitin-protein ligase, reduced their size. Mutant VAPB did not codistribute with mutant forms of seipin that are associated with an autosomal dominant motor neuron disease, and accumulate in a protective ER derived compartment termed ERPO (ER protective organelle) in neurons.CONCLUSIONS: The data indicate that the VAPB-P56S inclusions represent a novel reversible ER quality control compartment that is formed when the amount of mutant VAPB exceeds the capacity of the ERAD pathway and that isolates misfolded and aggregated VAPB from the rest of the ER. The presence of this quality control compartment reveals an additional level of flexibility of neurons to cope with misfolded protein stress in the ER

The impact of private equity on IPO underpricing in the DACH region

This research provides a study to the difference in underpricing between private equity backed initial public offerings and non-private equity backed initial public offerings in the DACH region between 2003 and 2017. The results show that PE-backed IPO underpricing does not differ from non-PE backed IPO underpricing. Common aspects such as the size of the company, the age of the company or the rank of the underwriter could not explain various influences on underpricing. The aftermarket shows no discrepancy as well up to the first twelve months after the IPO. This implies that it is possible to gain from investing in PE-backed IPOs from one year after the IPO