Broad clinical phenotypes associated with TAR-DNA binding protein (TARDBP) mutations in amyotrophic lateral sclerosis

The finding of TDP-43 as a major component of ubiquitinated protein inclusions in amyotrophic lateral sclerosis (ALS) has led to the identification of 30 mutations in the transactive response-DNA binding protein (TARDBP) gene, encoding TDP-43. All but one are in exon 6, which encodes the glycine-rich domain. The aim of this study was to determine the frequency of TARDBP mutations in a large cohort of motor neurone disease patients from Northern England (42 non-superoxide dismutase 1 (SOD1) familial ALS (FALS), nine ALS-frontotemporal dementia, 474 sporadic ALS (SALS), 45 progressive muscular atrophy cases). We identified four mutations, two of which were novel, in two familial (FALS) and two sporadic (SALS) cases, giving a frequency of TARDBP mutations in non-SOD1 FALS of 5% and SALS of 0.4%. Analysis of clinical data identified that patients had typical ALS, with limb or bulbar onset, and showed considerable variation in age of onset and rapidity of disease course. However, all cases had an absence of clinically overt cognitive dysfunction

Analysis of pmpD Expression and PmpD Post-Translational Processing during the Life Cycle of Chlamydia trachomatis Serovars A, D, and L2

BACKGROUND: The polymorphic membrane protein D (PmpD) in Chlamydia is structurally similar to autotransporter proteins described in other bacteria and may be involved in cellular and humoral protective immunity against Chlamydia. The mechanism of PmpD post-translational processing and the role of its protein products in the pathogenesis of chlamydial infection have not been very well elucidated to date. METHODOLOGY/PRINCIPAL FINDINGS: Here we examined the expression and post-translational processing of the protein product of the pmpD gene during the life cycle of C. trachomatis serovars A, D, and L2. Each of these three serovars targets different human organs and tissues and encodes a different pmpD gene nucleotide sequence. Our quantitative real-time reverse transcription polymerase chain reaction results demonstrate that the pmpD gene is up-regulated at 12-24 hours after infection regardless of the Chlamydia serovar. This up-regulation is coincidental with the period of exponential growth and replication of reticulate bodies (RB) of Chlamydia and indicates a probable similarity in function of pmpD in serovars A, D, and L2 of Chlamydia. Using mass spectrometry analysis, we identified the protein products of post-translational processing of PmpD of C. trachomatis serovar L2 and propose a double pathway model for PmpD processing, with one cleavage site between the passenger and autotransporter domains and the other site in the middle of the passenger domain. Notably, when Chlamydia infected culture cells were subjected to low (28 degrees C) temperature, PmpD post-translational processing and secretion was found to be uninhibited in the resulting persistent infection. In addition, confocal microscopy of cells infected with Chlamydia confirms our earlier hypothesis that PmpD is secreted outside Chlamydia and its secretion increases with growth of the chlamydial inclusion. CONCLUSION/SIGNIFICANCE: The results of this current study involving multiple Chlamydia serovars support the general consensus that the pmpD gene is maximally expressed at mid infection and provide new information about PmpD as an autotransporter protein which is post-translationally processed and secreted outside Chlamydia during normal and low temperature induced persistent chlamydial infection

Barriers to following dietary recommendations in Type 2 diabetes

Aims  To evaluate barriers to following dietary recommendations in patients with Type 2 diabetes. Methods  We conducted focus groups and surveys in urban and suburban VA and academic medical centres. For the written survey, a self-administered questionnaire was mailed to a random sample of 446 patients with diabetes. For the focus groups, six groups of patients with diabetes (three urban, three suburban) were conducted, with 6–12 participants in each group. The focus groups explored barriers across various types of diabetes self-management; we extracted all comments relevant to barriers that limited patients’ ability to follow a recommended diet. Results  The written survey measured the burden of diabetes therapies (on a seven-point rating scale). Moderate diet was seen as a greater burden than oral agents (median 1 vs. 0, P  = 0.001), but less of a burden than insulin (median 1 vs. 4, P  < 0.001). A strict diet aimed at weight loss was rated as being similarly burdensome to insulin (median 4 vs. 4, P  = NS). Despite this, self-reported adherence was much higher for both pills and insulin than it was for a moderate diet. In the focus groups, the most commonly identified barrier was the cost (14/14 reviews), followed by small portion sizes (13/14 reviews), support and family issues (13/14 reviews), and quality of life and lifestyle issues (12/14 reviews). Patients in the urban site, who were predominantly African-American, noted greater difficulties communicating with their provider about diet and social circumstances, and also that the rigid schedule of a diabetes diet was problematic. Conclusions  Barriers to adherence to dietary therapies are numerous, but some, such as cost, and in the urban setting, communication with providers, are potentially remediable. Interventions aimed at improving patients’ ability to modify their diet need to specifically address these areas. Furthermore, treatment guidelines need to consider patients’ preferences and barriers when setting goals for treatment. Diabet. Med. (2004)Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/73213/1/j.1464-5491.2004.01342.x.pd

The biogeography of South African terrestrial plant invasions

Thousands of plant species have been introduced, intentionally and accidentally, to South Africa from many parts of the world. Alien plants are now conspicuous features of many South African landscapes and hundreds of species have naturalised (i.e. reproduce regularly without human intervention), many of which are also invasive (i.e. have spread over long distances). There is no comprehensive inventory of alien, naturalised, and invasive plants for South Africa, but 327 plant taxa, most of which are invasive, are listed in national legislation. We collated records of 759 plant taxa in 126 families and 418 genera that have naturalised in natural and semi-natural ecosystems. Over half of these naturalised taxa are trees or shrubs, just under a tenth are in the families Fabaceae (73 taxa) and Asteraceae (64); genera with the most species are Eucalyptus,Acacia, and Opuntia. The southern African Plant Invaders Atlas (SAPIA) provides the best data for assessing the extent of invasions at the national scale. SAPIA data show that naturalised plants occur in 83% of quarter-degree grid cells in the country. While SAPIA data highlight general distribution patterns (high alien plant species richness in areas with high native plant species richness and around the main human settlements), an accurate, repeatable method for estimating the area invaded by plants is lacking. Introductions and dissemination of alien plants over more than three centuries, and invasions over at least 120 years (and especially in the last 50 years) have shaped the distribution of alien plants in South Africa. Distribution patterns of naturalised and invasive plants define four ecologically-meaningful clusters or “alien plant species assemblage zones”, each with signature alien plant taxa for which trait-environment interactions can be postulated as strong determinants of success. Some widespread invasive taxa occur in high frequencies across multiple zones; these taxa occur mainly in riparian zones and other azonal habitats,or depend on human-mediated disturbance, which weakens or overcomes the factors that determine specificity to any biogeographical region

Noncentral bimatrix variate generalised beta distributions

In this paper, we determine the density functions of nonsymmetrised doubly noncentral matrix variate beta type I and II distributions. The nonsymetrised density functions of doubly noncentral and noncentral bimatrix variate generalised beta type I and II distributions are also obtained.Comment: 14 page

An Inducer of VGF Protects Cells against ER Stress-Induced Cell Death and Prolongs Survival in the Mutant SOD1 Animal Models of Familial ALS

Amyotrophic lateral sclerosis (ALS) is the most frequent adult-onset motor neuron disease, and recent evidence has suggested that endoplasmic reticulum (ER) stress signaling is involved in the pathogenesis of ALS. Here we identified a small molecule, SUN N8075, which has a marked protective effect on ER stress-induced cell death, in an in vitro cell-based screening, and its protective mechanism was mediated by an induction of VGF nerve growth factor inducible (VGF): VGF knockdown with siRNA completely abolished the protective effect of SUN N8075 against ER-induced cell death, and overexpression of VGF inhibited ER-stress-induced cell death. VGF level was lower in the spinal cords of sporadic ALS patients than in the control patients. Furthermore, SUN N8075 slowed disease progression and prolonged survival in mutant SOD1 transgenic mouse and rat models of ALS, preventing the decrease of VGF expression in the spinal cords of ALS mice. These data suggest that VGF plays a critical role in motor neuron survival and may be a potential new therapeutic target for ALS, and SUN N8075 may become a potential therapeutic candidate for treatment of ALS

Stranger to Familiar: Wild Strepsirhines Manage Xenophobia by Playing

The power of play in limiting xenophobia is a well-known phenomenon in humans. Yet, the evidence in social animals remains meager. Here, we aim to determine whether play promotes social tolerance toward strangers in one of the most basal group of primates, the strepsirhines. We observed two groups of wild lemurs (Propithecus verreauxi, Verreaux's sifaka) during the mating season. Data were also collected on nine visiting, outgroup males. We compared the distribution of play, grooming, and aggressive interactions across three conditions: OUT (resident/outgroup interactions), IN (resident/resident interactions in presence of outgroups) and BL-IN (baseline of resident/resident interactions in absence of outgroups). Play frequency between males was higher in OUT than in IN and BL-IN conditions; whereas, grooming was more frequent in IN than in OUT and BL-IN conditions. Aggression rates between resident and outgroup males were significantly higher than those between residents. However, aggressions between resident and outgroup males significantly decreased after the first play session and became comparable with resident-resident aggression levels. The presence of strangers in a well-established group implies the onset of novel social circumstances, which sifaka males cope with by two different tactics: grooming with ingroup males and playing with outgroup ones. The grooming peak, concurrently with the visit of outgroups, probably represents a social shield adopted by resident males to make their pre-existing affiliation more evident to the stranger “audience”. Being mostly restricted to unfamiliar males, adult play in sifaka appears to have a role in managing new social situations more than in maintaining old relationships. In particular, our results indicate not only that play is the interface between strangers but also that it has a specific function in reducing xenophobia. In conclusion, play appears to be an ice-breaker mechanism in the critical process that “upgrades” an individual from stranger to familiar