Proline residues within spacer peptide p1 are important for human immunodeficiency virus type 1 infectivity, protein processing, and genomic RNA dimer stability

The full-length human immunodeficiency virus type 1 (HIV-1) mRNA encodes two precursor polyproteins, Gag and GagProPol. An infrequent ribosomal frameshifting event allows these proteins to be synthesized from the same mRNA in a predetermined ratio of 20 Gag proteins for each GagProPol. The RNA frameshift signal consists of a slippery sequence and a hairpin stem-loop whose thermodynamic stability has been shown in in vitro translation systems to be critical to frameshifting efficiency. In this study we examined the frameshift region of HIV-1, investigating the effects of altering stem-loop stability in the context of the complete viral genome and assessing the role of the Gag spacer peptide p1 and the GagProPol transframe (TF) protein that are encoded in this region. By creating a series of frameshift region mutants that systematically altered the stability of the frameshift stem-loop and the protein sequences of the p1 spacer peptide and TF protein, we have demonstrated the importance of stem-loop thermodynamic stability in frameshifting efficiency and viral infectivity. Multiple changes to the amino acid sequence of p1 resulted in altered protein processing, reduced genomic RNA dimer stability, and abolished viral infectivity. The role of the two highly conserved proline residues in p1 (position 7 and 13) was also investigated. Replacement of the two proline residues by leucines resulted in mutants with altered protein processing and reduced genomic RNA dimer stability that were also noninfectious. The unique ability of proline to confer conformational constraints on a peptide suggests that the correct folding of p1 may be important for viral function.<br /

Inferencing Abilities of Deaf College Students: Foundations and Implications for Metaphor Comprehension and Theory of Mind

Understanding nonliteral language requires inferencing ability and is an important but complex aspect of social interaction, involving cognitive (e.g., theory of mind, executive function) as well as language skill, areas in which many deaf individuals struggle. This study examined comprehension of metaphor and sarcasm, assessing the contributions of hearing status, inferencing ability, executive function (verbal short-term/working memory capacity), and deaf individuals’ communication skills (spoken versus signed language, cochlear implant use). Deaf and hearing college students completed a multiple-choice metaphor comprehension task and inferencing tasks that included both social-emotional (i.e., theory of mind) and neutral inferences, as well as short-term memory span and working memory tasks. Results indicated the hearing students to have better comprehension of nonliteral language and the ability to make social-emotional inferences, as well as greater memory capacity. Deaf students evidenced strong relationships among inferential comprehension, communication skills, and memory capacity, with substantial proportions of the variance in understanding of metaphor and sarcasm accounted for by these variables. The results of this study enhance understanding of the language and cognitive skills underlying figurative language comprehension and theory of mind and have implications for the social functioning of deaf individuals

Clinicopathological characteristics of histiocytic sarcoma affecting the central nervous system in dogs.

BackgroundHistiocytic sarcoma affecting the central nervous system (CNS HS) in dogs may present as primary or disseminated disease, often characterized by inflammation. Prognosis is poor, and imaging differentiation from other CNS tumors can be problematic.ObjectiveTo characterize the clinicopathological inflammatory features, breed predisposition, and survival in dogs with CNS HS.AnimalsOne hundred two dogs with HS, 62 dogs with meningioma.MethodsRetrospective case series. Records were reviewed for results of cerebrospinal fluid (CSF) analysis, CBC, treatment, and outcome data.ResultsPredisposition for CNS HS was seen in Bernese Mountain Dogs, Golden Retrievers, Rottweilers, Corgis, and Shetland Sheepdogs (P ≤ .001). Corgis and Shetland Sheepdogs had predominantly primary tumors; Rottweilers had exclusively disseminated tumors. Marked CSF inflammation was characteristic of primary rather than disseminated HS, and neoplastic cells were detected in CSF of 52% of affected dogs. Increased neutrophil to lymphocyte ratios were seen in all groups relative to controls (P &lt;.008) but not among tumor subtypes. Definitive versus palliative treatment resulted in improved survival times (P &lt; .001), but overall prognosis was poor.Conclusions and clinical importanceClinicopathological differences between primary and disseminated HS suggest that tumor biological behavior and origin may be different. Corgis and Shetland Sheepdogs are predisposed to primary CNS HS, characterized by inflammatory CSF. High total nucleated cell count and the presence of neoplastic cells support the use of CSF analysis as a valuable diagnostic test. Prognosis for CNS HS is poor, but further evaluation of inflammatory mechanisms may provide novel therapeutic opportunities

Maternal Perceptions of Mealtimes: Comparison of Children with Autism Spectrum Disorder and Children with Typical Development

Background: This study examined mealtime techniques reported by mothers of preschool children with Autism Spectrum Disorder (ASD) and mothers of children with typical development (TD). The mothers’ perceived levels of success and sources of information for mealtime techniques were also reported. Method: The participants were 24 mothers of children with ASD (ASD group) and 24 mothers of children with typical development (TD group) between 3 and 6 years of age. The Background Information Survey and the Mealtime Techniques Interview were administered. Results: The ASD group used significantly more techniques in categories of food appearances, restrictive diets, and vitamin/supplement therapy. The TD group used significantly more techniques in the categories of etiquette and negative consequences. Both groups rated techniques similarly with no significant difference between the perceived rate of success for each category. Finally, 91% of mealtime techniques for both groups were parent generated with few from professionals. Conclusion: The results showed that many of the mothers in both groups used similar mealtime techniques and most implemented techniques that were self-generated with generally moderate perception of success. Occupational therapists should collaboratively work with families to increase mealtime success by recommending interventions that are individualized and family centered

Reduction of low- and high-grade cervical abnormalities associated with high uptake of the HPV bivalent vaccine in Scotland

In Scotland, a national HPV immunisation programme began in 2008 for 12-13 year olds, with a catch-up campaign from 2008-2011 for those under the age of 18. To monitor the impact of HPV immunisation on cervical disease at the population level, a programme of national surveillance was established.  We analysed colposcopy data from a cohort of women born between 1988-1992 who entered the Scottish Cervical Screening Programme (SCSP) and were aged 20-21 in 2008-2012.  By linking datasets from the SCSP and colposcopy services, we observed a significant reduction in diagnoses of cervical intraepithelial neoplasia 1 (CIN 1) (RR 0.71, 95% CI 0.58 to 0.87, p=0.0008), CIN 2 (RR 0.5, 95% CI 0.4, 0.63, p<0.0001) and CIN 3 (RR 0.45, 95% CI 0.35 to 0.58, p< 0.0001) for women who received 3 doses of vaccine compared with unvaccinated women.  To our knowledge, this is one of the first studies to show a reduction of low and high grade cervical intraepithelial neoplasia associated with high uptake of the HPV bivalent vaccine at the population level. These data are very encouraging for countries that have achieved high HPV vaccine uptake

Transition phenomena in unstably stratified turbulent flows

We study experimentally and theoretically transition phenomena caused by the external forcing from Rayleigh-Benard convection with the large-scale circulation (LSC) to the limiting regime of unstably stratified turbulent flow without LSC whereby the temperature field behaves like a passive scalar. In the experiments we use the Rayleigh-B\'enard apparatus with an additional source of turbulence produced by two oscillating grids located nearby the side walls of the chamber. When the frequency of the grid oscillations is larger than 2 Hz, the large-scale circulation (LSC) in turbulent convection is destroyed, and the destruction of the LSC is accompanied by a strong change of the mean temperature distribution. However, in all regimes of the unstably stratified turbulent flow the ratio $\big[(\ell_x \nabla_x T)^2 + (\ell_y \nabla_y T)^2 + (\ell_z \nabla_z T)^2\big] /$ varies slightly (even in the range of parameters whereby the behaviour of the temperature field is different from that of the passive scalar). Here $\ell_i$ are the integral scales of turbulence along x, y, z directions, T and \theta are the mean and fluctuating parts of the fluid temperature. At all frequencies of the grid oscillations we have detected the long-term nonlinear oscillations of the mean temperature. The theoretical predictions based on the budget equations for turbulent kinetic energy, turbulent temperature fluctuations and turbulent heat flux, are in agreement with the experimental results.Comment: 14 pages, 14 figures, REVTEX4-1, revised versio

Combining qualitative and quantitative operational research methods to inform quality improvement in pathways that span multiple settings

BACKGROUND: Improving integration and continuity of care across sectors within resource constraints is a priority in many health systems. Qualitative operational research methods of problem structuring have been used to address quality improvement in services involving multiple sectors but not in combination with quantitative operational research methods that enable targeting of interventions according to patient risk. We aimed to combine these methods to augment and inform an improvement initiative concerning infants with congenital heart disease (CHD) whose complex care pathway spans multiple sectors. METHODS: Soft systems methodology was used to consider systematically changes to services from the perspectives of community, primary, secondary and tertiary care professionals and a patient group, incorporating relevant evidence. Classification and regression tree (CART) analysis of national audit datasets was conducted along with data visualisation designed to inform service improvement within the context of limited resources. RESULTS: A 'Rich Picture' was developed capturing the main features of services for infants with CHD pertinent to service improvement. This was used, along with a graphical summary of the CART analysis, to guide discussions about targeting interventions at specific patient risk groups. Agreement was reached across representatives of relevant health professions and patients on a coherent set of targeted recommendations for quality improvement. These fed into national decisions about service provision and commissioning. CONCLUSIONS: When tackling complex problems in service provision across multiple settings, it is important to acknowledge and work with multiple perspectives systematically and to consider targeting service improvements in response to confined resources. Our research demonstrates that applying a combination of qualitative and quantitative operational research methods is one approach to doing so that warrants further consideration

Decreased NK Cell FcRγ in HIV-1 Infected Individuals Receiving Combination Antiretroviral Therapy: a Cross Sectional Study

Background: FcRc is an immunoreceptor tyrosine-based activation motif (ITAM)-signalling protein essential for immunoreceptor signaling and monocyte, macrophage and NK cell function. Previous study from our laboratory showed that FcRc is down-regulated in HIV-infected macrophages in vitro. FcRc expression in immune cells present in HIV-infected individuals is unknown. Methodology/Principal Findings: We compared FcRc expression in peripheral blood mononuclear cells isolated from HIV-1-infected individuals receiving combination antiretroviral therapy and healthy, HIV-1-uninfected individuals. FcRc mRNA and protein levels were measured using quantitative real-time PCR and immunoblotting, respectively. CD56 + CD94 + lymphocytes isolated from blood of HIV-1 infected individuals had reduced FcRc protein expression compared to HIVuninfected individuals (decrease = 76.8%, n = 18 and n = 12 respectively, p = 0.0036). In a second group of patients, highly purified NK cells had reduced FcRc protein expression compared to uninfected controls (decrease = 50.2%, n = 9 and n = 8 respectively, p = 0.021). Decreased FcRc expression in CD56+CD94+ lymphocytes was associated with reduced mRNA (51.7%, p = 0.021) but this was not observed for the smaller group of patients analysed for NK cell expression (p = 0.36). Conclusion/Significance: These data suggest biochemical defects in ITAM-dependent signalling within NK cells in HIVinfecte