Comparative analysis of multiple genomes in a phylogenetic framework dramatically improves the precision and sensitivity of evolutionary inference, producing more robust results than single-genome analyses can provide. The genomes of 12 Drosophila species, ten of which are presented here for the first time (sechellia, simulans, yakuba, erecta, ananassae, persimilis, willistoni, mojavensis, virilis and grimshawi), illustrate how rates and patterns of sequence divergence across taxa can illuminate evolutionary processes on a genomic scale. These genome sequences augment the formidable genetic tools that have made Drosophila melanogaster a pre-eminent model for animal genetics, and will further catalyse fundamental research on mechanisms of development, cell biology, genetics, disease, neurobiology, behaviour, physiology and evolution. Despite remarkable similarities among these Drosophila species, we identified many putatively non-neutral changes in protein-coding genes, non-coding RNA genes, and cis-regulatory regions. These may prove to underlie differences in the ecology and behaviour of these diverse species.

Genomes of eusocial insects code for dramatic examples of phenotypic plasticity and social organization. We compared the genomes of seven ants, the honeybee, and various solitary insects to examine whether eusocial lineages share distinct features of genomic organization. Each ant lineage contains ∼4000 novel genes, but only 64 of these genes are conserved among all seven ants. Many gene families have been expanded in ants, notably those involved in chemical communication (e.g., desaturases and odorant receptors). Alignment of the ant genomes revealed reduced purifying selection compared with Drosophila without significantly reduced synteny. Correspondingly, ant genomes exhibit dramatic divergence of noncoding regulatory elements; however, extant conserved regions are enriched for novel noncoding RNAs and transcription factor-binding sites. Comparison of orthologous gene promoters between eusocial and solitary species revealed significant regulatory evolution in both cis (e.g., Creb) and trans (e.g., fork head) for nearly 2000 genes, many of which exhibit phenotypic plasticity. Our results emphasize that genomic changes can occur remarkably fast in ants, because two recently diverged leaf-cutter ant species exhibit faster accumulation of species-specific genes and greater divergence in regulatory elements compared with other ants or Drosophila. Thus, while the "socio-genomes" of ants and the honeybee are broadly characterized by a pervasive pattern of divergence in gene composition and regulation, they preserve lineage-specific regulatory features linked to eusociality. We propose that changes in gene regulation played a key role in the origins of insect eusociality, whereas changes in gene composition were more relevant for lineage-specific eusocial adaptations

Carvedilol is one of the most effective beta-blockers for preventing ventricular tachyarrhythmias (VTs) in heart failure (HF), but the mechanisms underlying its favorable anti-arrhythmic benefits remain unclear. Spontaneous Ca2+ waves, also termed store-overload-induced Ca2+ release (SOICR), are known to evoke VTs in patients with HF. Here we show that carvedilol is the only beta-blocker that effectively suppresses SOICR by directly reducing the open duration of the cardiac ryanodine receptor (RyR2). This unique anti-SOICR activity of carvedilol combined with its beta-blocking activity likely contributes to its favorable anti-arrhythmic effect. To allow individual and optimal titration of these beneficial activities, we developed a novel SOICR-inhibiting, minimally-beta-blocking carvedilol analogue VK-II-86. We found that VK-II-86 alone prevented stress-induced VTs in RyR2 mutant mice, and was more effective when combined with a selective beta-blocker metoprolol or bisoprolol. Thus, SOICR inhibition combined with optimal beta-blockade presents a new, promising and potentially patient-tailorable anti-arrhythmic approach.

The Genomics Education Partnership offers an inclusive model for undergraduate research experiences incorporated into the academic year science curriculum, with students pooling their work to contribute to international data bases.

Many children who speak English as an additional language (EAL) underachieve in areas of English literacy, especially in the primary years. These difficulties are often attributed to low levels of English language fluency as they enter the education system. In an effort to provide a greater understanding of this underachievement, the cognitive-linguistic factors underlying literacy development in monolingual children and children learning EAL were examined in a three-year longitudinal project. The project, conducted in schools in the north of England, followed the developmental progression of forty-three children learning EAL and forty-three monolingual children from school years Two to Four. Children were assessed on measures of reading accuracy, reading and listening comprehension, receptive and expressive vocabulary, and reception of grammar. Analysis revealed similarities between the two groups of children on reading accuracy, but children learning EAL had lower levels of vocabulary and comprehension at each point in time. Data are discussed in terms of the development of underlying language skills and the impact of these skills on both reading and listening comprehension. The implications of the findings for classroom practice are considered.At the present time in England 9.8% of the primary school population and 8% of the secondary school population speak English as an additional language (Department for Education and Employment statistical volume, 2001). A recent concern has been the educational underachievement of minority ethnic children (Gillborn and Gipps, 1996;Pathak, 2000) especially in relation to English literacy skills (OFSTED, 1999). Local Education Authority Key Stage results reveal lower levels of attainment for both Pakistani and Bangladeshi pupils than their monolingual peers (OFSTED, 1999). This underachievement continues at GCSE level with the attainment of fewer high grade GCSEs than their monolingual peers (Pathak, 2000). Educational achievement is linked to a variety of factors but research reveals that the size of the lexicon plays a major role in school success (Vermeer, 1992) and is a common factor for many children learning EAL who underachieve (McWilliam, 1998).As children learning EAL start school they often have little or no experience of the English language, with monolingual children having a four or five-year advantage in English oral language experience. It has been estimated that children learning EAL

We investigated the incidence of and risk factors for venous thromboembolism (VTE) following surgery of the shoulder and elbow and assessed the role of thromboprophylaxis in upper limb surgery. All papers describing VTE after shoulder and elbow surgery published in the English language literature before 31 March 2012 were reviewed. A total of 14 papers were available for analysis, most of which were retrospective studies and case series. The incidence of VTE was 0.038% from 92 440 shoulder arthroscopic procedures, 0.52% from 42 261 shoulder replacements, and 0.64% from 4833 procedures for fractures of the proximal humerus (open reduction and internal fixation or hemiarthroplasty). The incidence following replacement of the elbow was 0.26% from 2701 procedures. Diabetes mellitus, rheumatoid arthritis and ischaemic heart disease were identified as the major risk factors.The evidence that exists on thromboprophylaxis is based on level III and IV studies, and we therefore cannot make any recommendations on prophylaxis based on the current evidence. It seems reasonable to adopt a multimodal approach that involves all patients receiving mechanical prophylaxis, with chemical prophylaxis reserved for those who are at high risk for VTE.

The outcome of an anatomical shoulder replacement depends on an intact rotator cuff. In 1981 Grammont designed a novel large-head reverse shoulder replacement for patients with cuff deficiency. Such has been the success of this replacement that it has led to a rapid expansion of the indications. We performed a systematic review of the literature to evaluate the functional outcome of each indication for the reverse shoulder replacement. Secondary outcome measures of range of movement, pain scores and complication rates are also presented.The modern reverse shoulder replacement (RSR) can offer a surgical option for the management of arthritis of the shoulder that would be precluded by a conventional design. 1,2The success of the prosthesis has led to expansion of the indications from cuff tear arthropathy to any disease about the shoulder where cuff function is deficient. 3-5The prosthesis has also been a financial success, leading many companies to introduce their own version with small changes to the original design, such as the Aequalis Reversed Shoulder (Tornier, SaintIsmier, France) and the SMR Shoulder (Lima, Udine, Italy). As a result of the expansion of the indications for RSR, the procedure now accounts for over a large proportion of all shoulder replacements performed in mainland Europe.This article will look at the benefits and risks of RSR for each indication. The original indication for RSR was cuff tear arthropathy. The results obtained for new indications were compared with those for cuff tear arthropathy, with a primary outcome measure as a functional score. Secondary outcome measures were range of movement, rate of complications and pain scores. In order to allow for comparison between groups, the outcome scores, complication rates and pain scores have been converted to percentages.A systematic review of the English-language literature was undertaken; the keywords used were shoulder and reverse; arthroplasty; inverse or delta. Medline, were all searched. Inclusion criteria included studies presenting new data from more than one case and where functional outcome scores were reported. Exclusion criteria included studies that had a mixture of surgical techniques presented as a single group. Further exclusion criteria for the cuff tear arthropathy group were studies published more than five years ago; studies with less than 50 patients and those from more than one centre.We identified 22 papers, which were reviewed in full. The complications of RSR for any indication were discussed and specific issues for each pathology highlighted.All the abstracts were reviewed independently by two of the authors (CDS, PG) to identify studies for full review and the bibliographies of these articles were also reviewed for additional studies. Any disagreements with regards to inclusion and exclusion were resolved by discussion with the senior author (TDB). Cuff tear arthropathyThe modern concept of cuff tear arthropathy is the combination of arthritis and a massive cuff tear where the shoulder joint may remain concent...

We have used the annotations of six animal genomes (Homo sapiens, Mus musculus, Ciona intestinalis, Drosophila melanogaster, Anopheles gambiae, and Caenorhabditis elegans) together with the sequences of five unannotated Drosophila genomes to survey changes in protein sequence and gene structure over a variety of timescales—from the less than 5 million years since the divergence of D. simulans and D. melanogaster to the more than 500 million years that have elapsed since the Cambrian explosion. To do so, we have developed a new open-source software library called CGL (for “Comparative Genomics Library”). Our results demonstrate that change in intron–exon structure is gradual, clock-like, and largely independent of coding-sequence evolution. This means that genome annotations can be used in new ways to inform, corroborate, and test conclusions drawn from comparative genomics analyses that are based upon protein and nucleotide sequence similarities.