Adaptations of Avian Flu Virus Are a Cause for Concern

We are in the midst of a revolutionary period in the life sciences. Technological capabilities have dramatically expanded, we have a much improved understanding of the complex biology of selected microorganisms, and we have a much improved ability to manipulate microbial genomes. With this has come unprecedented potential for better control of infectious diseases and significant societal benefit. However, there is also a growing risk that the same science will be deliberately misused and that the consequences could be catastrophic. Efforts to describe or define life-sciences research of particular concern have focused on the possibility that knowledge or products derived from such research, or new technologies, could be directly misapplied with a sufficiently broad scope to affect national or global security. Research that might greatly enhance the harm caused by microbial pathogens has been of special concern (1–3). Until now, these efforts have suffered from a lack of specificity and a paucity of concrete examples of “dual use research of concern” (3). Dual use is defined as research that could be used for good or bad purposes. We are now confronted by a potent, real-world example

Sequence Similarity Network Reveals Common Ancestry of Multidomain Proteins

We address the problem of homology identification in complex multidomain families with varied domain architectures. The challenge is to distinguish sequence pairs that share common ancestry from pairs that share an inserted domain but are otherwise unrelated. This distinction is essential for accuracy in gene annotation, function prediction, and comparative genomics. There are two major obstacles to multidomain homology identification: lack of a formal definition and lack of curated benchmarks for evaluating the performance of new methods. We offer preliminary solutions to both problems: 1) an extension of the traditional model of homology to include domain insertions; and 2) a manually curated benchmark of well-studied families in mouse and human. We further present Neighborhood Correlation, a novel method that exploits the local structure of the sequence similarity network to identify homologs with great accuracy based on the observation that gene duplication and domain shuffling leave distinct patterns in the sequence similarity network. In a rigorous, empirical comparison using our curated data, Neighborhood Correlation outperforms sequence similarity, alignment length, and domain architecture comparison. Neighborhood Correlation is well suited for automated, genome-scale analyses. It is easy to compute, does not require explicit knowledge of domain architecture, and classifies both single and multidomain homologs with high accuracy. Homolog predictions obtained with our method, as well as our manually curated benchmark and a web-based visualization tool for exploratory analysis of the network neighborhood structure, are available at http://www.neighborhoodcorrelation.org. Our work represents a departure from the prevailing view that the concept of homology cannot be applied to genes that have undergone domain shuffling. In contrast to current approaches that either focus on the homology of individual domains or consider only families with identical domain architectures, we show that homology can be rationally defined for multidomain families with diverse architectures by considering the genomic context of the genes that encode them. Our study demonstrates the utility of mining network structure for evolutionary information, suggesting this is a fertile approach for investigating evolutionary processes in the post-genomic era

The clinical effectiveness of a physiotherapy delivered physical and psychological group intervention for older adults with neurogenic claudication: the BOOST randomised controlled trial.

This is the final version. Available from Oxford University Press via the DOI in this record. BACKGROUND: Neurogenic claudication (NC) is a debilitating spinal condition affecting older adults' mobility and quality of life. METHODS: A randomised controlled trial of 438 participants evaluated the effectiveness of a physical and psychological group intervention (BOOST programme) compared to physiotherapy assessment and tailored advice (best practice advice [BPA]) for older adults with NC. Participants were identified from spinal clinics (community and secondary care) and general practice records and randomised 2:1 to the BOOST programme or BPA. The primary outcome was the Oswestry Disability Index (ODI) at 12 months. Data was also collected at 6 months. Other outcomes included ODI walking item, 6-minute walk test (6MWT) and falls. The primary analysis was intention-to-treat. RESULTS: The average age of participants was 74.9 years (SD 6.0) and 57% (246/435) were female. There was no significant difference in ODI scores between treatment groups at 12 months (adjusted mean difference (MD): -1.4 [95% Confidence Intervals (CI) -4.03, 1.17]), but, at 6 months, ODI scores favoured the BOOST programme (adjusted MD: -3.7 [95% CI -6.27, -1.06]). At 12 months, the BOOST programme resulted in greater improvements in walking capacity (6MWT MD 21.7m [95% CI 5.96, 37.38]) and ODI walking item (MD -0.2 [95% CI -0.45, -0.01]) and reduced falls risk (odds ratio 0.6 [95% CI 0.40, 0.98]) compared to BPA. No serious adverse events were related to either treatment. CONCLUSIONS: The BOOST programme substantially improved mobility for older adults with NC. Future iterations of the programme will consider ways to improve long-term pain related disability.National Institute for Health Research (NIHR

The Clinical Effectiveness of a Physiotherapy Delivered Physical and Psychological Group Intervention for Older Adults With Neurogenic Claudication: The BOOST Randomized Controlled Trial

Background Neurogenic claudication (NC) is a debilitating spinal condition affecting older adults’ mobility and quality of life. Methods A randomized controlled trial of 438 participants evaluated the effectiveness of a physical and psychological group intervention (BOOST program) compared to physiotherapy assessment and tailored advice (best practice advice [BPA]) for older adults with NC. Participants were identified from spinal clinics (community and secondary care) and general practice records and randomized 2:1 to the BOOST program or BPA. The primary outcome was the Oswestry Disability Index (ODI) at 12 months. Data were also collected at 6 months. Other outcomes included ODI walking item, 6-minute walk test (6MWT), and falls. The primary analysis was intention-to-treat. Results The average age of participants was 74.9 years (standard deviation [SD] 6.0) and 57% (246/435) were female. There was no significant difference in ODI scores between treatment groups at 12 months (adjusted mean difference [MD]: −1.4 [95% confidence intervals (CI) −4.03, 1.17]), but, at 6 months, ODI scores favored the BOOST program (adjusted MD: −3.7 [95% CI −6.27, −1.06]). At 12 months, the BOOST program resulted in greater improvements in walking capacity (6MWT MD: 21.7m [95% CI 5.96, 37.38]) and ODI walking item (MD: −0.2 [95% CI −0.45, −0.01]) and reduced falls risk (odds ratio: 0.6 [95% CI 0.40, 0.98]) compared to BPA. No serious adverse events were related to either treatment. Conclusions The BOOST program substantially improved mobility for older adults with NC. Future iterations of the program will consider ways to improve long-term pain-related disability. Clinical Trials Registration Number: ISRCTN1269867

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Multi-ancestry genome-wide association meta-analysis of Parkinson?s disease

Although over 90 independent risk variants have been identified for Parkinson’s disease using genome-wide association studies, most studies have been performed in just one population at a time. Here we performed a large-scale multi-ancestry meta-analysis of Parkinson’s disease with 49,049 cases, 18,785 proxy cases and 2,458,063 controls including individuals of European, East Asian, Latin American and African ancestry. In a meta-analysis, we identified 78 independent genome-wide significant loci, including 12 potentially novel loci (MTF2, PIK3CA, ADD1, SYBU, IRS2, USP8, PIGL, FASN, MYLK2, USP25, EP300 and PPP6R2) and fine-mapped 6 putative causal variants at 6 known PD loci. By combining our results with publicly available eQTL data, we identified 25 putative risk genes in these novel loci whose expression is associated with PD risk. This work lays the groundwork for future efforts aimed at identifying PD loci in non-European populations

Characterization of Insertion Sites in Rainbow Papaya, the First Commercialized Transgenic Fruit Crop

Inserts and insert sites in transgenic, papaya ringspot virus (PRSV)-resistant commercial papaya Rainbow and SunUp, were characterized as part of a petition to Japan to allow import of fresh fruit of these cultivars from the U.S. and to provide data for a larger study aimed at understanding the global impact of DNA transformation on whole genome structure. The number and types of inserts were determined by Southern analysis using probes spanning the entire transformation plasmid and their sequences determined from corresponding clones or sequence reads from the whole-genome shotgun (WGS) sequence of SunUp papaya. All the functional transgenes, coding for the PRSV coat protein (CP), neophosphotransferase (nptII) and β-glucuronidase (uidA) were found in a single 9,789 basepair (bp) insert. Only two other inserts, one consisting of a 290 bp nonfunctional fragment of the nptII gene and a 1,533 bp plasmid-derived fragment containing a nonfunctional 222 bp segment of the tetA gene were detected in Rainbow and SunUp. Detection of the same three inserts in samples representing transgenic generations five to eight (R5 to R8) suggests that the three inserts are stably inherited. Five out of the six genomic DNA segments flanking the three inserts were nuclear plastid sequences (nupts). From the biosafety standpoint, no changes to endogenous gene function based on sequence structure of the transformation plasmid DNA insertion sites could be determined and no allergenic or toxic proteins were predicted from analysis of the insertion site and flanking genomic DNA