Transcriptional Interference Regulates the Evolutionary Development of Speech

The human capacity to speak is fundamental to our advanced intellectual, technological and social development. Yet so very little is known regarding the evolutionary genetics of speech or its relationship with the broader aspects of evolutionary development in primates. In this study, we describe a large family with evolutionary retrograde development of the larynx and wrist. The family presented with severe speech impairment and incremental retrograde elongations of the pisiform in the wrist that limited wrist rotation from 180◦ to 90◦ as in primitive primates. To our surprise, we found that a previously unknown primate-specific gene TOSPEAK had been disrupted in the family. TOSPEAK emerged de novo in an ancestor of extant primates across a 540 kb region of the genome with a pre-existing highly conserved long-range laryngeal enhancer for a neighbouring bone morphogenetic protein gene GDF6. We used transgenic mouse modelling to identify two additional GDF6 long-range enhancers within TOSPEAK that regulate GDF6 expression in the wrist. Disruption of TOSPEAK in the affected family blocked the transcription of TOSPEAK across the 3 GDF6 enhancers in association with a reduction in GDF6 expression and retrograde development of the larynx and wrist. Furthermore, we describe how TOSPEAK developed a human-specific promoter through the expansion of a penta-nucleotide direct repeat that first emerged de novo in the promoter of TOSPEAK in gibbon. This repeat subsequently expanded incrementally in higher hominids to form an overlapping series of Sp1/KLF transcription factor consensus binding sites in human that correlated with incremental increases in the promoter strength of TOSPEAK with human having the strongest promoter. Our research indicates a dual evolutionary role for the incremental increases in TOSPEAK transcriptional interference of GDF6 enhancers in the incremental evolutionary development of the wrist and larynx in hominids and the human capacity to speak and their retrogression with the reduction of TOSPEAK transcription in the affected family

A high frequency boundary element method for scattering by a class of nonconvex obstacles

This is a post-peer-review, pre-copyedit version of an article published in Numerische Mathematik. The final authenticated version is available online at: https://doi.org/10.1007/s00211-014-0648-7EPSR

Mutation of Rubie, a Novel Long Non-Coding RNA Located Upstream of Bmp4, Causes Vestibular Malformation in Mice

Background: The vestibular apparatus of the vertebrate inner ear uses three fluid-filled semicircular canals to sense angular acceleration of the head. Malformation of these canals disrupts the sense of balance and frequently causes circling behavior in mice. The Epistatic circler (Ecl) is a complex mutant derived from wildtype SWR/J and C57L/J mice. Ecl circling has been shown to result from the epistatic interaction of an SWR-derived locus on chromosome 14 and a C57L-derived locus on chromosome 4, but the causative genes have not been previously identified. Methodology/Principal Findings: We developed a mouse chromosome substitution strain (CSS-14) that carries an SWR/J chromosome 14 on a C57BL/10J genetic background and, like Ecl, exhibits circling behavior due to lateral semicircular canal malformation. We utilized CSS-14 to identify the chromosome 14 Ecl gene by positional cloning. Our candidate interval is located upstream of bone morphogenetic protein 4 (Bmp4) and contains an inner ear-specific, long non-coding RNA that we have designated Rubie (RNA upstream of Bmp4 expressed in inner ear). Rubie is spliced and polyadenylated, and is expressed in developing semicircular canals. However, we discovered that the SWR/J allele of Rubie is disrupted by an intronic endogenous retrovirus that causes aberrant splicing and premature polyadenylation of the transcript. Rubie lies in the conserved gene desert upstream of Bmp4, within a region previously shown to be important for inner ear expression of Bmp4. We found that the expression patterns of Bmp4 and Rubie are nearly identical in developing inner ears

Converting between estimates of moderate-to-vigorous physical activity derived from raw accelerations measured at the wrist and from ActiGraph counts measured at the hip: The Rosetta Stone

The ability to compare published group-level estimates of objectively measured moderate-to-vigorous physical activity (MVPA) across studies continues to increase in difficulty. The objective of this study was to develop conversion equations and demonstrate their utility to compare estimates of MVPA derived from the wrist and hip. Data from three studies of youth (N = 232, 9-12yrs, 50% boys) who concurrently wore a hip-worn ActiGraph and a wrist-worn GENEActiv for 7-days. ActiGraph hip count data were reduced using four established cutpoints: Evenson, Pate, Puyau, and Freedson 3MET. Wrist accelerations were reduced using the Hildebrand MVPA 200 mg threshold. Conversion equations were developed on a randomly selected subsample of 132 youth. Equations were cross-validated and absolute error, absolute percent error, and modified Bland-Altman plots were evaluated for conversion accuracy. Across equations R2adj was 0.51-0.56 with individual-level absolute error in minutes ranging from 7 (wrist-to-hip Puyau) to 14.5 minutes (wrist-to-hip Freedson 3MET) and absolute percent differences ranging from 13.9%-24.5%. Group-level cross-validation to convert hip-to-wrist MVPA resulted in average absolute percent errors ranging from 3.1%-4.9%. Conversion of wrist- to-hip MVPA resulted in average absolute percent errors ranging from 3.0%-10.0%. We recommend the use of these equations to compare published estimates of MVPA between the wear-site cut-point combinations presented

Improving local health through community health workers in Cambodia: challenges and solutions

Volunteer community health workers (CHWs) are an important link between the public health system and the community. The ‘Community Participation Policy for Health’ in Cambodia identifies CHWs as key to local health promotion and as a critical link between district health centres and the community. However, research on the challenges CHWs face and identifying what is required to optimise their performance is limited in the Cambodian context. This research explores the views of CHWs in rural Cambodia, on the challenges they face when implementing health initiatives

On the projection of future fire danger conditions with various instantaneous/mean-daily data sources

Fire danger indices are descriptors of fire potential in a large area, and combine a few variables that affect the initiation, spread and control of forest fires. The Canadian Fire Weather Index (FWI) is one of the most widely used fire danger indices in the world, and it is built upon instantaneous values of temperature, relative humidity and wind velocity at noon, together with 24 hourly accumulated precipitation. However, the scarcity of appropriate data has motivated the use of daily mean values as surrogates of the instantaneous ones in several studies that aimed to assess the impact of global warming on fire. In this paper we test the sensitivity of FWI values to both instantaneous and daily mean values, analyzing their effect on mean seasonal fire danger (seasonal severity rating, SSR) and extreme fire danger conditions (90th percentile, FWI90, and FWI>30, FOT30), with a special focus on its influence in climate change impact studies. To this aim, we analyzed reanalysis and regional climate model (RCM) simulations, and compared the resulting instantaneous and daily mean versions both in the present climate and in a future scenario. In particular, we were interested in determining the effect of these datasets on the projected changes obtained for the mean and extreme seasonal fire danger conditions in future climate scenarios, as given by a RCM. Overall, our results warn against the use of daily mean data for the computation of present and future fire danger conditions. Daily mean data lead to systematic negative biases of fire danger calculations. Although the mean seasonal fire danger indices might be corrected to compensate for this bias, fire danger extremes (FWI90 and specially FOT30) cannot be reliably transformed to accommodate the spatial pattern and magnitude of their respective instantaneous versions, leading to inconsistent results when projected into the future. As a result, we advocate caution when using daily mean data and strongly recommend the application of the standard definition for its calculation as closely as possible. Threshold-dependent indices derived from FWI are not reliably represented by the daily mean version and thus can neither be applied for the estimation of future fire danger season length and severity, nor for the estimation of future extreme events.The research leading to these results has received funding from the European Union's Seventh Framework Programme (FP7/2007-2013) under grant agreement 243888 (FUME Project). J.F. acknowledges nancial support from the Spanish R&D&I programme through grant CGL2010-22158-C02 (CORWES project). The ESCENA project (200800050084265) of the Spanish \Strategic action on energy and climate change" provided the WRF RCM simulation used in this study. We acknowledge three anonymous referees for their useful comments that helped to improve the original manuscript

Addressing fluorogenic real-time qPCR inhibition using the novel custom Excel file system 'FocusField2-6GallupqPCRSet-upTool-001' to attain consistently high fidelity qPCR reactions

The purpose of this manuscript is to discuss fluorogenic real-time quantitative polymerase chain reaction (qPCR) inhibition and to introduce/define a novel Microsoft Excel-based file system which provides a way to detect and avoid inhibition, and enables investigators to consistently design dynamically-sound, truly LOG-linear qPCR reactions very quickly. The qPCR problems this invention solves are universal to all qPCR reactions, and it performs all necessary qPCR set-up calculations in about 52 seconds (using a pentium 4 processor) for up to seven qPCR targets and seventy-two samples at a time – calculations that commonly take capable investigators days to finish. We have named this custom Excel-based file system "FocusField2-6GallupqPCRSet-upTool-001" (FF2-6-001 qPCR set-up tool), and are in the process of transforming it into professional qPCR set-up software to be made available in 2007. The current prototype is already fully functional

Towards a conceptual framework demonstrating the effectiveness of audiovisual patient descriptions (patient video cases): a review of the current literature

Background: Technological advances have enabled the widespread use of video cases via web-streaming and online download as an educational medium. The use of real subjects to demonstrate acute pathology should aid the education of health care professionals. However, the methodology by which this effect may be tested is not clear. Methods: We undertook a literature review of major databases, found relevant articles relevant to using patient video cases as educational interventions, extracted the methodologies used and assessed these methods for internal and construct validity. Results: A review of 2532 abstracts revealed 23 studies meeting the inclusion criteria and a final review of 18 of relevance. Medical students were the most commonly studied group (10 articles) with a spread of learner satisfaction, knowledge and behaviour tested. Only two of the studies fulfilled defined criteria on achieving internal and construct validity. The heterogeneity of articles meant it was not possible to perform any meta-analysis. Conclusions: Previous studies have not well classified which facet of training or educational outcome the study is aiming to explore and had poor internal and construct validity. Future research should aim to validate a particular outcome measure, preferably by reproducing previous work rather than adopting new methods. In particular cognitive processing enhancement, demonstrated in a number of the medical student studies, should be tested at a postgraduate level