Mutations in human immunodeficiency virus type 1 reverse transcriptase that make it sensitive to degradation by the viral protease in virions are selected against in patients

AbstractMutations in the thumb subdomain of reverse transcriptase (RT) of HIV-1 can cause this enzyme to be degraded in virions by the viral protease (PR). Many of these mutations confer a temperature-sensitive phenotype on RT and viral replication. The degradation of RT by PR appears to take place after Gag-Pol has been processed. We show here that mutations in other parts of RT, including the RNase H domain, can make RT PR-sensitive and temperature-sensitive. These data explain why some mutations in the RNase H domain, which had little or no effect on the polymerase activity of purified recombinant RT, had a profound effect on viral titer. Because the PR-sensitive phenotype significantly reduced viral titer, we previously suggested that these mutations would be selected against in patients. We also show that RT mutations that are known to confer a temperature sensitive phenotype are rarely found in the Stanford database

Antepartal Bed rest: Conflicts, Costs, Controversies and Ethical Considerations

Currently, more than 90% of obstetricians prescribe bed rest for antepartal women who are experiencing complications in pregnancy. Even though researchers have found that bed rest is not effective in reducing preterm births, 20 percent of pregnant women will spend at least one week during pregnancy on bed rest. Preterm premature rupture of membranes (PPROM) accounts for 33% of all preterm births and is significantly associated with maternal, fetal, and neonatal morbidity and mortality risks. Antenatal bed rest creates physical, emotional and financial costs for the patient, families, and third-party payers. National health care dollars spent in 2001 for short gestation was $1,887, 716,535. Treatment decisions are often made on an emotional basis or medical litigation issues rather than ethical outcomes surrounding the threshold of fetal/neonatal viability

A Descriptive Profile of Physical Education Teachers and Related Program Characteristics in Alberta

A survey of teachers and principals in Alberta was conducted to gain a descriptive profile of who is leaching physical education (PE) and to assess the relationship between PE specialists and variables associated with program delivery. A probability-sampling procedure was used to obtain a representative sample of schools. In these schools nonprobability procedures were used to recruit teachers. A total of'480 teachers' and 162 principals' questionnaires were returned. Although 50% (n=236) of PE teachers in the sample were classified as PE specialists (i.e., had either a degree, major or minor, in PE or a closely related area), there was a significant gap in the number of PE classes being taught by division. Of the 1,219 PE classes surveyed in this study, PE specialists taught 49% and 55% of classes at the elementary levels (Divisions I & 11) compared with 91% of junior high (Division III) and 90% of secondary (Division TV) PE classes. Significant differences were found between PE specialists and non-PE specialists on a number of items including perceptions of preparedness, teaching enjoyment and competence to teach PE, the number of PE specialists across grade levels, and the percentage of time devoted to PE in the timetable. Implications with respect to implementing PE specialists across all grades and the need for future pedagogical research to investigate the effect of PE specialists are also discussed.Une enquête a été entreprise auprès d'enseignants et de directeurs d'école en Alberta dans le but d'établir un profil descriptif des enseignants d'éducation physique (EP) et d'évaluer le rapport entre les spécialistes en EP et les variables associées à l'exécution de programmes. On a eu recours aune méthode d'échantillonnage au hasard pour obtenir un échantillon représentatif des écoles. Par la suite, on y a employé des procédures non probabilistes pour recruter des enseignants. En tout, 642 questionnaires (480 provenant d'enseignants et 162 de directeurs) nous ont été renvoyés. Alors que 50% (n=236) des enseignants de EP de l'échantillon se classaient comme spécialistes en EP (c'est-à-dire qu'ils avaient soit un diplôme, une majeure ou une mineure en EP ou dans un domaine connexe), un écart notable existait dans le nombre de cours de EP enseignés par division. Des 1 219 cours de EP inclus dans l'enquête, à l'élémentaire, 49% (Division I) et 55% (Division II) d'entre eux étaient enseignés par des spécialistes en EP. Au secondaire premier cycle (Division III), 91% des cours étaient enseignés par des spécialistes en EP; au secondaire (Division IV), 90% des cours l'étaient. Des différences importantes distinguaient les spécialistes en EP des non spécialistes, y compris leurs perceptions quant à leur état de préparation, le plaisir qu'il retirait de l'enseignement de l'EP, leur compétence à le faire, le nombre de spécialistes en EP à tous les niveaux scolaires et le nombre d'heures consacrées aux cours de EP. Une discussion portant sur les implications de la mise en place de spécialistes en EP à tous les niveaux scolaires et sur la nécessité d'étudier l'effet qu'exercent ceux-ci, termine l'article

Local and global processing in savant artists with autism

Abstract. We explored the hypothesis that an enhanced local processing style is characteristic of both art and autism spectrum disorder (ASD) by examining local and global processing in savant artists with ASD. Specifically, savant artists were compared against non-talented individuals with ASD or mild/moderate learning difficulties (MLD), as well as artistically talented or non- talented students, on the block-design task and meaningful and abstract versions of the embedded figures test (EFT). Results demonstrated that there were no significant differences between the meaningful and abstract versions of the EFT, in any of the groups. This suggests that the primary process governing performance on this task was perceptual (local), rather than conceptual (global). More interestingly, the savant artists performed above the level of the ASD and MLD groups on the block-design test, but not the EFT. Despite both the block-design task and the EFT measuring local processing abilities, we suggest that this result is due to the block-design task being an active construction task (requiring the conversion of a visual input into a motor output), whereas the EFT is a passive recognition task. Therefore, although an enhanced local processing style is an important aspect of savant artistic talent, motor control also appears to be a necessary skill

Perturbation with Intrabodies Reveals That Calpain Cleavage Is Required for Degradation of Huntingtin Exon 1

Background: Proteolytic processing of mutant huntingtin (mHtt), the protein that causes Huntington's disease (HD), is critical for mHtt toxicity and disease progression. mHtt contains several caspase and calpain cleavage sites that generate N-terminal fragments that are more toxic than full-length mHtt. Further processing is then required for the degradation of these fragments, which in turn, reduces toxicity. This unknown, secondary degradative process represents a promising therapeutic target for HD. Methodology/Principal Findings: We have used intrabodies, intracellularly expressed antibody fragments, to gain insight into the mechanism of mutant huntingtin exon 1 (mHDx-1) clearance. Happ1, an intrabody recognizing the proline-rich region of mHDx-1, reduces the level of soluble mHDx-1 by increasing clearance. While proteasome and macroautophagy inhibitors reduce turnover of mHDx-1, Happ1 is still able to reduce mHDx-1 under these conditions, indicating Happ1-accelerated mHDx-1 clearance does not rely on these processes. In contrast, a calpain inhibitor or an inhibitor of lysosomal pH block Happ1-mediated acceleration of mHDx-1 clearance. These results suggest that mHDx-1 is cleaved by calpain, likely followed by lysosomal degradation and this process regulates the turnover rate of mHDx-1. Sequence analysis identifies amino acid (AA) 15 as a potential calpain cleavage site. Calpain cleavage of recombinant mHDx-1 in vitro yields fragments of sizes corresponding to this prediction. Moreover, when the site is blocked by binding of another intrabody, V_L12.3, turnover of soluble mHDx-1 in living cells is blocked. Conclusions/Significance: These results indicate that calpain-mediated removal of the 15 N-terminal AAs is required for the degradation of mHDx-1, a finding that may have therapeutic implications

Angiomatous meningiomas have a distinct genetic profile with multiple chromosomal polysomies including polysomy of chromosome 5

Meningiomas are a diverse group of tumors with a broad spectrum of histologic features. There are over 12 variants of meningioma, whose genetic features are just beginning to be described. Angiomatous meningioma is a World Health Organization (WHO) meningioma variant with a predominance of blood vessels. They are uncommon and confirming the histopathologic classification can be challenging. Given a lack of biomarkers that define the angiomatous subtype and limited understanding of the genetic changes underlying its tumorigenesis, we compared the genomic characteristics of angiomatous meningioma to more common meningioma subtypes. While typical grade I meningiomas demonstrate monosomy of chromosome 22 or lack copy number aberrations, 13 of 14 cases of angiomatous meningioma demonstrated a distinct copy number profile – polysomies of at least one chromosome, but often of many, especially in chromosomes 5, 13, and 20. WHO grade II atypical meningiomas with angiomatous features have both polysomies and genetic aberrations characteristic of other atypical meningiomas. Sequencing of over 560 cancer-relevant genes in 16 cases of angiomatous meningioma showed that these tumors lack common mutations found in other variants of meningioma. Our study demonstrates that angiomatous meningiomas have distinct genomic features that may be clinically useful for their diagnosis

Clinical multiplexed exome sequencing distinguishes adult oligodendroglial neoplasms from astrocytic and mixed lineage gliomas

Classifying adult gliomas remains largely a histologic diagnosis based on morphology; however astrocytic, oligodendroglial and mixed lineage tumors can display overlapping histologic features. We used multiplexed exome sequencing (OncoPanel) on 108 primary or recurrent adult gliomas, comprising 65 oligodendrogliomas, 28 astrocytomas and 15 mixed oligoastrocytomas to identify lesions that could enhance lineage classification. Mutations in TP53 (20/28, 71%) and ATRX (15/28, 54%) were enriched in astrocytic tumors compared to oligodendroglial tumors of which 4/65 (6%) had mutations in TP53 and 2/65 (3%) had ATRX mutations. We found that oligoastrocytomas harbored mutations in TP53 (80%, 12/15) and ATRX (60%, 9/15) at frequencies similar to pure astrocytic tumors, suggesting that oligoastrocytomas and astrocytomas may represent a single genetic or biological entity. p53 protein expression correlated with mutation status and showed significant increases in astrocytomas and oligoastrocytomas compared to oligodendrogliomas, a finding that also may facilitate accurate classification. Furthermore our OncoPanel analysis revealed that 15% of IDH1/2 mutant gliomas would not be detected by traditional IDH1 (p.R132H) antibody testing, supporting the use of genomic technologies in providing clinically relevant data. In all, our results demonstrate that multiplexed exome sequencing can support evaluation and classification of adult low-grade gliomas with a single clinical test