Lysosomal enzyme cathepsin D protects against alpha-synuclein aggregation and toxicity

α-synuclein (α-syn) is a main component of Lewy bodies (LB) that occur in many neurodegenerative diseases, including Parkinson's disease (PD), dementia with LB (DLB) and multi-system atrophy. α-syn mutations or amplifications are responsible for a subset of autosomal dominant familial PD cases, and overexpression causes neurodegeneration and motor disturbances in animals. To investigate mechanisms for α-syn accumulation and toxicity, we studied a mouse model of lysosomal enzyme cathepsin D (CD) deficiency, and found extensive accumulation of endogenous α-syn in neurons without overabundance of α-syn mRNA. In addition to impaired macroautophagy, CD deficiency reduced proteasome activity, suggesting an essential role for lysosomal CD function in regulating multiple proteolytic pathways that are important for α-syn metabolism. Conversely, CD overexpression reduces α-syn aggregation and is neuroprotective against α-syn overexpression-induced cell death in vitro. In a C. elegans model, CD deficiency exacerbates α-syn accumulation while its overexpression is protective against α-syn-induced dopaminergic neurodegeneration. Mutated CD with diminished enzymatic activity or overexpression of cathepsins B (CB) or L (CL) is not protective in the worm model, indicating a unique requirement for enzymatically active CD. Our data identify a conserved CD function in α-syn degradation and identify CD as a novel target for LB disease therapeutics

An exploration of the current knowledge on young people who kill: a systematic review

This exploratory systematic review assessed the quality of primary studies on young people who kill and synthesised the findings regarding the characteristics of these offenders. An electronic search yielded 12,717 hits of papers published between 1989 and 2012. Of these, 8,395 duplicates, 3,787 irrelevant hits, and 527 publications not meeting the inclusion criteria of the review were excluded (15 publications were added after searching the grey literature), leaving 23 good quality studies. From these, a further seven were removed due to their small sample size (i.e., n < 30), leaving a total of 16 studies reviewed in detail. A search update was carried out on 2 February 2014 and no further studies meeting the inclusion criteria were found. The results indicate that juvenile homicide offenders are a heterogeneous group and the risk factors for juvenile homicide are cumulative and evolve through life. The findings are mixed, but ten risk factors are identified which appear to be consistent for offenders across the studies reviewed. The limitations of the current review are highlighted and recommendations for future research are outlined, with particular consideration given to improving the quality of the literature in this field

Ethical and Economic Perspectives on Global Health Interventions

Interventions that improve childhood health directly improve the quality of life and, in addition, have multiplier effects, producing sustained population and economic gains in poor countries. We suggest how contemporary global institutions shaping the development, pricing and distribution of vaccines and drugs may be modified to deliver large improvements in health. To support a justice argument for such modification, we show how the current global economic order may contribute to perpetuating poverty and poor health in less-developed countries

Clean Electricity from the Detroit River: A Novel Hydro-Generator

ME450 Capstone Design and Manufacturing Experience: Winter 2008The VIVACE (Vortex Induced Vibration Aquatic Clean Energy) hydroelectric converter is a device that can be implemented anywhere that there is fluid flow. It works by converting the energy produced by Vortex Induced Vibrations (VIV) into linear oscillation motion. This motion is then converted into electrical energy through a Power Take Off (PTO) system. Our goal was to come up with a design that is robust, cost-effective, scalable, efficient, and environmentally friendly. Our design is a linear induction generator that works by passing a magnet over a non-corrosive tube containing coiled wire. This produces an electrical current through electromagnetic induction which will then be used to produce power.Prof. Michael Bernitsashttp://deepblue.lib.umich.edu/bitstream/2027.42/58692/1/me450w08project10_report.pd

Pulse Rate Variability Analysis During Hemorrhage in an Experimental Porcine Model

During the acute phase of hemorrhage, heart rate and peripheral resistance increases to maintain proper oxygen delivery to vital organs. This response is mediated by the autonomic nervous system. Heart rate variability (HRV) has become a widely utilized measure to determine the autonomic nervous system control over the heart. Recently, pulse rate variability (PRV) has been suggested to serve as a surrogate for HRV. This study evaluates the ability of PRV obtained from peripheral arterial pressure waveforms as a method for detecting hemorrhage. Time domain and frequency domain metrics were evaluated for 5-minute and 15-minute arterial pressure waveform signals prior to hemorrhage, during acute hemorrhage, and after the commencement of hemorrhage in four porcine subjects. PRV analysis demonstrates an increase in time domain and frequency domain metrics at the onset of hemorrhage, followed by an opposing decrease at the commencement of hemorrhage. The frequency domain metrics associated with sympathetic input increased at the onset of hemorrhage and decreased once hemorrhage ended. These results suggest that PRV metrics obtained from arterial pressure waveforms have the potential to serve as a diagnostic method for acute hemorrhage

Concurrent course of transient neonatal diabetes with cholestasis and paucity of interlobular bile ducts: a case report

We report for the first time a patient with both transient neonatal diabetes mellitus (TNDM) and idiopathic neonatal cholestasis, with both features resolving over a similar time course. Cholestasis was due to paucity of interlobular bile ducts (PILBD). Genetic analysis was consistent with a uniparental disomy of chromosome 6. Paucity of interlobular bile ducts is common in Alagille syndrome but also occurs by unknown mechanisms in a wide spectrum of other diseases. We propose a shared explanation for this patient's TNDM and PILBD mediated by the noted chromosomal abnormality. We suggest that hepatobiliary function be evaluated in patients with TNDM to determine the prevalence and course of cholestasis of the diseas

The spatial distribution and potential sources of polycyclic aromatic hydrocarbons (PAHs) over the Asian marginal seas and the Indian and Atlantic Oceans

Gaseous and particle-bound polycyclic aromatic hydrocarbons (PAHs) were analyzed in air samples taken on a voyage of the Scholar Ship from January 16th to March 14th, 2008. Samples were taken from the Asian marginal seas and the Indian and Atlantic Oceans, providing an opportunity to assess spatial trends and potential sources of atmospheric PAHs over those oceans. The results show that continental sources were still responsible for some high concentrations of PAHs measured over the oceans. The Σ15PAHs in the gaseous phase were elevated on the approach to China and India, while the highest Σ15PAHs in the particulate phase were found at Chennai Harbor and close to Guinea. The high proportion of fluorene in the gas phase over the East and South China Sea could be a marker of coal and coke related combustion emission from Mainland China. The elevated high-molecular-weight PAHs in particles close to Guinea might be related to biomass burning in Africa. These results are consistent with previous PAH emission inventories and highlight the potential impact of continental PAH sources in China, India and Africa on the adjacent marine atmosphere