Autophagy and Spinal Muscular Atrophy: Towards a Pathway-Centric Therapy for a Fatal Childhood Disorder

Spinal muscular atrophy (SMA) is a devastating neuromuscular and the primary cause of infant death. SMA is characterised by the loss of motor neurons in the spinal resulting in progressive muscle atrophy, paralysis and respiratory defects leading to early childhood death. SMA is caused by a depletion of the ubiquitously expressed survival motor neuron (SMN) protein that performs a key regulatory function in the assembly of the eukaryotic mRNA splicing machinery and is thus required for the survival of all tissues. The genetic elements responsible for SMA are very well characterised but, after decades of research, it is still unknown why depletion of this ubiquitous specifically affects motor neurons. Numerous studies are now emerging that implicate disruption of autophagy, a highly conserved lysosomal degradative pathway responsible for the bulk removal of cytosolic cargo too large for the proteasome, in the disease pathology of SMA. In the present study, we utilise the powerful genetic tools of a Caenorhabditis elegans SMA model to delineate how disruptions in the autophagic pathway may contribute to SMA pathogenesis. Using an RNA interference genetic screen, we identified three putative modifiers of SMN loss of function neuromuscular defects in the C. elegans SMA model – epg-8, sqst-1 and atg-16.1. In line with pre-existing studies, our results indicate that autophagy is disrupted in SMA, and that this disruption is likely occur during the initial regulatory stages of the pathway. Although further study will be required to identify the precise mechanisms through which this autophagic disruption occurs, these findings show that autophagy has promising potential for novel therapeutic targets

An economic analysis of trading on private information by external administrators: international comparisons

This paper examines the regulation of trades in listed securities by external administrators (EAs), such as trustees in bankruptcy, liquidators, receivers, and administrators on the basis of private information. We consider the economic policy issues associated with such trades. The principal considerations counsel in favour of taking a permissive approach. These are: the difficulties of associating trades with insider information, given the EA's necessarily short expected holding period, the asymmetric application of the insider trading prohibition to sales (rather than decisions not to sell), the market incentives not to misuse private information that apply to EAs, and the unlikelihood that the EA has monopolistic access to the information in question. We consider these considerations by reference to a number of hypothetical scenarios. The paper argues that the law should regulate the subject by coupling a broad exemption for EAs with a "goiod faith" proviso, a continuous disclosure obligation, and a requirement to sell "all or nothing" of a holding of listed securities

Power reserve following ramp-incremental cycling to exhaustion: Implications for muscle fatigue and function

In ramp-incremental cycling exercise, some individuals are capable of producing power output (PO) in excess of that produced at their limit of tolerance (LoT) while others cannot. This study sought to describe the: 1) prevalence of a “power reserve” within a group of young men (n=21; mean ± SD: age 25±4 years; V̇O2max45±8 ml•kg-1•min-1); and 2) muscle fatigue characteristics of those with and without a power reserve. Power reserve was determined as the difference between peak PO achieved during a ramp-incremental test to exhaustion and maximal, single-leg isokinetic dynamometer power. Pre- versus post-exercise changes in voluntary and electrically-stimulated single-leg muscle force production measures (maximal voluntary contraction, voluntary activation, maximal isotonic velocity and isokinetic power; 1-, 10-, 50-Hz torque and 10/50-Hz ratio), V̇O2max and constant-PO cycling time-to-exhaustionalso were assessed. A dichotomy in power reserve was prevalent within the sample resulting in two groups: 1) “No Reserve” (NRES: \u3c5% reserve; n=10) and 2) “Reserve” (RES: \u3e15% reserve; n=11). At the LoT, all participants had achieved V̇O2max. Muscle fatigue was evident in both groups, although the NRES group had greater reductions (p\u3c0.05) in 10-Hz peak torque (PT), 10/50 Hz ratio, and maximal velocity. Time-to-exhaustion during the constant-PO test was 22±16% greater (p\u3c0.05) in RES (116±19 s; PO = 317±52 W) than in NRES (90±23 s; PO = 337±71 W), despite similar ramp-incremental exercise durations and V̇O2max between groups. The differences in muscle fatigue and function between groups suggest that the mechanisms contributing to the LoT are not uniform

The Problem Of Human Subjectivity In Hegel's Thought, With Particular Regard To The Relationship Between Hegel's <i>Early Theological Writings</i> And His Mature Philosophy Of Religion

I seek, in this thesis, by means of a critical exposition and comparison of Hegel’s Early Theological Writings and his mature Lectures on the Philosophy of Religion, to elucidate the relationship between human subjectivity, the self-conscious experience of humanity and the absolute truth which is absolute spirit, God. The apparent divorce of positive biblical narrative from its reflective interpretation is not, it is to be argued, the result of the importing of critical philosophy into the domain of Christian experience. Rather, it is intrinsic to that very experience. The tension between positivity and inwardness, so central a problem to the concerns of the earlier philosophy has, by the time of the mature philosophy of religion, become an opportunity, rather than just a problem, for Christianity. Understanding the continuity between Hegel’s Early Theological Writings and the ostensibly very different speculative system, also enables one to understand the relevance of both to contemporary (and especially religious) experience

Draft Genome Sequences of Strains of Pasteurella multocida Isolated from the United Kingdom and the United States

Pasteurella multocida is a major pathogen of farm animals and has worldwide distribution. Here we report the draft genome sequences of four strains that were isolated from animals in the United Kingdom and the United States and represent pathogenic and commensal presentation of the bacterium

Natural Hazards in Puerto Rico

Puerto Rico faces natural hazards including hurricanes, earthquakes, tsunamis, landslides, subsidence, and flooding. Although Puerto Ricans perceive themselves as highly vulnerable to these hazards, few have adopted mitigation measures except for mandatory insurance

Earthquake Insurance: Mandated Disclosure and Homeowner Response in California

Earthquake insurance can reduce potentially disastrous economic losses to house• holds and is therefore a prime method of mitigating against the worst economic effects of damaging earthquakes. The decision to purchase such insurance is a special case in the general study of individual response to uncertainty in the environment. An understanding of this decision process elucidates the ways in which environmental information becomes translated into behavior change. Although California legislation has mandated the disclosure of the availability of earthquake insurance to all residential property owners since 1984, less than half of California homeowners have earthquake insurance. This paper reports on the results of a survey of 3,500 owner-occupiers in Contra Costa, Santa Clara, Los Angeles, and San Bernardino Counties conducted in the summer of 1989. The survey was undertaken to discover the locational concentrations of insurance policy-holders and the socioeconomic, demographic, and attitudinal characteristics that distinguish insured from noninsured homeowners. The results show that insurance purchase is not spatially related to geophysical risk and that the purchase of insurance is not systematically related to income, equity in the home, age of the head of household, or other socioeconomic characteristics. Instead, perceived risk is the primary factor associated with insurance purchase