Calpain inhibition mediates autophagy-dependent protection against polyglutamine toxicity.

Over recent years, accumulated evidence suggests that autophagy induction is protective in animal models of a number of neurodegenerative diseases. Intense research in the field has elucidated different pathways through which autophagy can be upregulated and it is important to establish how modulation of these pathways impacts upon disease progression in vivo and therefore which, if any, may have further therapeutic relevance. In addition, it is important to understand how alterations in these target pathways may affect normal physiology when constitutively modulated over a long time period, as would be required for treatment of neurodegenerative diseases. Here we evaluate the potential protective effect of downregulation of calpains. We demonstrate, in Drosophila, that calpain knockdown protects against the aggregation and toxicity of proteins, like mutant huntingtin, in an autophagy-dependent fashion. Furthermore, we demonstrate that, overexpression of the calpain inhibitor, calpastatin, increases autophagosome levels and is protective in a mouse model of Huntington's disease, improving motor signs and delaying the onset of tremors. Importantly, long-term inhibition of calpains did not result in any overt deleterious phenotypes in mice. Thus, calpain inhibition, or activation of autophagy pathways downstream of calpains, may be suitable therapeutic targets for diseases like Huntington's disease.This is the published version of the manuscript. It is available online from NPG in Cell Death and Differentiaiton here: http://www.nature.com/cdd/journal/vaop/ncurrent/full/cdd2014151a.html

Modeling emergency department visit patterns for infectious disease complaints: results and application to disease surveillance

BACKGROUND: Concern over bio-terrorism has led to recognition that traditional public health surveillance for specific conditions is unlikely to provide timely indication of some disease outbreaks, either naturally occurring or induced by a bioweapon. In non-traditional surveillance, the use of health care resources are monitored in "near real" time for the first signs of an outbreak, such as increases in emergency department (ED) visits for respiratory, gastrointestinal or neurological chief complaints (CC). METHODS: We collected ED CCs from 2/1/94 – 5/31/02 as a training set. A first-order model was developed for each of seven CC categories by accounting for long-term, day-of-week, and seasonal effects. We assessed predictive performance on subsequent data from 6/1/02 – 5/31/03, compared CC counts to predictions and confidence limits, and identified anomalies (simulated and real). RESULTS: Each CC category exhibited significant day-of-week differences. For most categories, counts peaked on Monday. There were seasonal cycles in both respiratory and undifferentiated infection complaints and the season-to-season variability in peak date was summarized using a hierarchical model. For example, the average peak date for respiratory complaints was January 22, with a season-to-season standard deviation of 12 days. This season-to-season variation makes it challenging to predict respiratory CCs so we focused our effort and discussion on prediction performance for this difficult category. Total ED visits increased over the study period by 4%, but respiratory complaints decreased by roughly 20%, illustrating that long-term averages in the data set need not reflect future behavior in data subsets. CONCLUSION: We found that ED CCs provided timely indicators for outbreaks. Our approach led to successful identification of a respiratory outbreak one-to-two weeks in advance of reports from the state-wide sentinel flu surveillance and of a reported increase in positive laboratory test results

Imageability ratings across languages

Imageability is a psycholinguistic variable that indicates how well a word gives rise to a mental image or sensory experience. Imageability ratings are used extensively in psycholinguistic, neuropsychological, and aphasiological studies. However, little formal knowledge exists about whether and how these ratings are associated between and within languages. Fifteen imageability databases were cross-correlated using nonparametric statistics. Some of these corresponded to unpublished data collected within a European research network-the Collaboration of Aphasia Trialists (COST IS1208). All but four of the correlations were significant. The average strength of the correlations (rho = .68) and the variance explained (R (2) = 46%) were moderate. This implies that factors other than imageability may explain 54% of the results. Imageability ratings often correlate across languages. Different possibly interacting factors may explain the moderate strength and variance explained in the correlations: (1) linguistic and cultural factors; (2) intrinsic differences between the databases; (3) range effects; (4) small numbers of words in each database, equivalent words, and participants; and (5) mean age of the participants. The results suggest that imageability ratings may be used cross-linguistically. However, further understanding of the factors explaining the variance in the correlations will be needed before research and practical recommendations can be made

Multivariate statistical analysis of net diatom species distributions in the Southwestern Atlantic and Indian Ocean

Vertical net haul diatom assemblages from near South Georgia, and from between Africa and Antarctica, were examined and compared. Variation among South Georgia stations was examined by principal component, cluster and canonical discriminant analyses. Diatom distributions provide evidence for at least two distinct water masses. The region north of the island is characterized by neritic, temperate diatoms and by an assemblage with low species diversity. The region south of the island is characterized by oceanic, antarctic species and relatively high species diversity. The regions are most distinct to the west of the island, intergrading east of the island. Within the north-south division, five station groupings were detected on the basis of distribution of dominant net diatoms. By comparing classical species ecological categorizations to results of principal component analysis, a “neritic-oceanic” factor was identified from net diatom distributions. This factor was common to both areas in spite of the fact that Biscoe and Agulhas collections were from different seasons.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/46982/1/300_2004_Article_BF00446041.pd

The Greek-Orthodox version of the Brief Religious Coping (B-RCOPE) instrument: psychometric properties in three samples and associations with mental disorders, suicidality, illness perceptions, and quality of life

Background: The B-RCOPE is a brief measure assessing religious coping. We aimed to assess the psychometric properties of its Greek version in people with and without long-term conditions (LTCs). Associations between religious coping and mental illness, suicidality, illness perceptions, and quality of life were also investigated. Methods: The B-RCOPE was administered to 351 patients with diabetes, chronic pulmonary obstructive disease (COPD), and rheumatic diseases attending either the emergency department (N = 74) or specialty clinics (N = 302) and 127 people without LTCs. Diagnosis of mental disorders was established by the MINI. Associations with depressive symptom severity (PHQ-9), suicidal risk (RASS), illness perceptions (B-IPQ), and health-related quality of life (WHOQOL-BREF) were also investigated. Results: The Greek version of B-RCOPE showed a coherent two-dimensional factor structure with remarkable stability across the three samples corresponding to the positive (PRC) and negative (NRC) religious coping dimensions. Cronbach’s alphas were 0.91–0.96 and 0.77–0.92 for the PRC and NRC dimensions, respectively. Furthermore, NRC was associated with poorer mental health, greater depressive symptom severity and suicidality, and impaired HRQoL. In patients with LTCs, PRC correlated with lower perceived illness timeline, while NRC was associated with greater perceived illness consequences, lower perceived treatment control, greater illness concern, and lower illness comprehensibility. Conclusions: These findings indicate that the Greek-Orthodox B-RCOPE version may reliably assess religious coping. In addition, negative religious coping (i.e., religious struggle) is associated with adverse illness perceptions, and thus may detrimentally impact adaptation to medical illness. These findings deserve replication in prospective studies

Can environmental or occupational hazards alter the sex ratio at birth? A systematic review

More than 100 studies have examined whether environmental or occupational exposures of parents affect the sex ratio of their offspring at birth. For this review, we searched Medline and Web of Science using the terms ‘sex ratio at birth’ and ‘sex ratio and exposure’ for all dates, and reviewed bibliographies of relevant studies to find additional articles. This review focuses on exposures that have been the subject of at least four studies including polychlorinated biphenyls (PCBs), dioxins, pesticides, lead and other metals, radiation, boron, and g-forces. For paternal exposures, only dioxins and PCBs were consistently associated with sex ratios higher or lower than the expected 1.06. Dioxins were associated with a decreased proportion of male births, whereas PCBs were associated with an increased proportion of male births. There was limited evidence for a decrease in the proportion of male births after paternal exposure to DBCP, lead, methylmercury, non-ionizing radiation, ionizing radiation treatment for childhood cancer, boron, or g-forces. Few studies have found higher or lower sex ratios associated with maternal exposures. Studies in humans and animals have found a reduction in the number of male births associated with lower male fertility, but the mechanism by which environmental hazards might change the sex ratio has not yet been established

The acquisition of past tense morphology in Icelandic and Norwegian children: an experimental study.

Icelandic and Norwegian past tense morphology contain strong patterns of inflection and two weak patterns of inflection. We report the results of an elicitation task that tests Icelandic and Norwegian children's knowledge of the past tense forms of a representative sample of verbs. This cross-sectional study of four-, six- and eight-year-old Icelandic (n = 92) and Norwegian (n = 96) children systematically manipulates verb characteristics such as type frequency, token frequency and phonological coherence--factors that are generally considered to have an important impact on the acquisition of inflectional morphology in other languages. Our findings confirm that these factors play an important role in the acquisition of Icelandic and Norwegian. In addition, the results indicate that the predominant source of errors in children shifts during the later stages of development from one weak verb class to the other. We conclude that these findings are consistent with the view that exemplar-based learning, whereby patterns of categorization and generalization are driven by similarity to known forms, appropriately characterizes the acquisition of inflectional systems by Icelandic and Norwegian children

Cross-linguistic variation in word-initial cluster production in adult and child language: evidence from English and Norwegian

Young children simplify word initial consonant clusters by omitting or substituting one (or both) of the elements. Vocalic insertion, coalescence and metathesis are said to be used more seldom (McLeod, van Doorn & Reed, 2001). Data from Norwegian children, however, have shown vocalic insertion to be more frequently used (Simonsen, 1990; Simonsen, Garmann & Kristoffersen, 2019). To investigate the extent to which children use this strategy to differing degrees depending on the ambient language, we analysed word initial cluster production acoustically in nine Norwegian and nine English speaking children aged 2;6-6 years, and eight adults, four from each language. The results showed that Norwegian-speaking children produce significantly more instances of vocalic insertions than English-speaking children do. The same pattern is found in Norwegian- versus English-speaking adults. We argue that this cross-linguistic difference is an example of the influence of prosodic-phonetic biases in language-specific developmental paths in the acquisition of speech