How do miRNAs mediate translational repression?

Micro(mi)RNAs regulate gene expression by what are believed to be related but separate mechanistic processes. The relative contribution that each process plays, their mechanistic overlap, and the degree by which they regulate complex genetic networks is still being unraveled. One process by which miRNAs inhibit gene expression occurs through translational repression. In recent years, there has been a plethora of studies published, which have resulted in various molecular models of how miRNAs impair translation. At first evaluation, it appears that these models are quite different and incompatible with one another. In this paper, we focus on possible explanations for the various interpretations of these data sets, and provide a model that we believe is consistent with many of the observations published to date

DevA, a GntR-like transcriptional regulator required for development in streptomyces coelicolor

The gram-positive filamentous bacterium Streptomyces coelicolor has a complex developmental cycle with three distinct phases: growth of the substrate mycelium, development of reproductive structures called aerial hyphae, and differentiation of these aerial filaments into long chains of exospores. During a transposon mutagenesis screen, we identified a novel gene (devA) required for proper development. The devA mutant produced only rare aerial hyphae, and those that were produced developed aberrant spore chains that were much shorter than wild-type chains and had misplaced septa. devA encodes a member of the GntR superfamily, a class of transcriptional regulators that typically respond to metabolite effector molecules. devA forms an operon with the downstream gene devB, which encodes a putative hydrolase that is also required for aerial mycelium formation on R5 medium. S1 nuclease protection analysis showed that transcription from the single devA promoter was temporally associated with vegetative growth, and enhanced green fluorescent protein transcriptional fusions showed that transcription was spatially confined to the substrate hyphae in the wild type. In contrast, devAB transcript levels were dramatically upregulated in a devA mutant and the devA promoter was also active in aerial hyphae and spores in this background, suggesting that DevA might negatively regulate its own production. This suggestion was confirmed by gel mobility shift assays that showed that DevA binds its own promoter region in vitro

Developing professionalism in new IT graduates? Who needs it?

A new graduate may require a period of ‘acclimatisation’ through a process of ‘developing their professionalism’ to fit into their work environment. The e-Skills UK Technology Counts Insights 2010 report suggests that 110,500 new entrants a year are required to fill IT & Telecoms professional job roles, with 20,800 coming from education (predominantly graduate level and higher). However, 43% of recruiters were reporting a lack of suitable candidates for IT & Telecoms posts where growing importance will be placed on relationship management, business process analysis and design, project and programme management. IT & Telecoms professionals are increasingly expected to be multi-skilled, with sophisticated business and interpersonal skills as well as technical competence. As the report also says: ‘UK growth will continue to be primarily in high-value roles with an increasing need for customer and business-oriented skills as well as sophisticated technical competencies.’ The diverse needs and requirements of the IT sector, as specified by various employer groups and professional bodies including BCS, IET, eSkills, the CBI and the SFIA Foundation, are discussed. According to the CBI, ‘62% of entrants to the IT sector need to draw on managerial and professional business skills almost immediately.’ For organisations to succeed, their IT graduate recruits must supplement their IT skills with managerial and professional business skills. Well considered CPD will ensure that recent graduates can enhance their ‘academic’ skills with the necessary work-based skills for the benefit of both themselves and their new employer. The focus of the improvement will balance the student-centred needs for development and the engaging employer’s commercial needs

SIDECACHE: Information access, management and dissemination framework for web services

<p>Abstract</p> <p>Background</p> <p>Many bioinformatics algorithms and data sets are deployed using web services so that the results can be explored via the Internet and easily integrated into other tools and services. These services often include data from other sites that is accessed either dynamically or through file downloads. Developers of these services face several problems because of the dynamic nature of the information from the upstream services. Many publicly available repositories of bioinformatics data frequently update their information. When such an update occurs, the developers of the downstream service may also need to update. For file downloads, this process is typically performed manually followed by web service restart. Requests for information obtained by dynamic access of upstream sources is sometimes subject to rate restrictions.</p> <p>Findings</p> <p>SideCache provides a framework for deploying web services that integrate information extracted from other databases and from web sources that are periodically updated. This situation occurs frequently in biotechnology where new information is being continuously generated and the latest information is important. SideCache provides several types of services including proxy access and rate control, local caching, and automatic web service updating.</p> <p>Conclusions</p> <p>We have used the SideCache framework to automate the deployment and updating of a number of bioinformatics web services and tools that extract information from remote primary sources such as NCBI, NCIBI, and Ensembl. The SideCache framework also has been used to share research results through the use of a SideCache derived web service.</p

Prevention of cisplatin-induced hearing loss in children: Informing the design of future clinical trials.

Cisplatin is an essential chemotherapeutic agent in the treatment of many pediatric cancers. Unfortunately, cisplatin-induced hearing loss (CIHL) is a common, clinically significant side effect with life-long ramifications, particularly for young children. ACCL05C1 and ACCL0431 are two recently completed Childrens Oncology Group studies focused on the measurement and prevention of CIHL. The purpose of this paper was to gain insights from ACCL05C1 and ACCL0431, the first published cooperative group studies dedicated solely to CIHL, to inform the design of future pediatric otoprotection trials. Use of otoprotective agents is an attractive strategy for preventing CIHL, but their successful development must overcome a unique constellation of methodological challenges related to translating preclinical research into clinical trials that are feasible, evaluate practical interventions, and limit risk. Issues particularly important for children include use of appropriate methods for hearing assessment and CIHL severity grading, and use of trial designs that are well-informed by preclinical models and suitable for relatively small sample sizes. Increasing interest has made available new funding opportunities for expanding this urgently needed research

Site-directed transposon integration in human cells

The Sleeping Beauty (SB) transposon is a promising gene transfer vector that integrates nonspecifically into host cell genomes. Herein, we attempt to direct transposon integration into predetermined DNA sites by coupling a site-specific DNA-binding domain (DBD) to the SB transposase. We engineered fusion proteins comprised of a hyperactive SB transposase (HSB5) joined via a variable-length linker to either end of the polydactyl zinc-finger protein E2C, which binds a unique sequence on human chromosome 17. Although DBD linkage to the C-terminus of SB abolished activity in a human cell transposition assay, the N-terminal addition of the E2C or Gal4 DBD did not. Molecular analyses indicated that these DBD-SB fusion proteins retained DNA-binding specificity for their respective substrate molecules and were capable of mediating bona fide transposition reactions. We also characterized transposon integrations in the presence of the E2C-SB fusion protein to determine its potential to target predefined DNA sites. Our results indicate that fusion protein-mediated tethering can effectively redirect transposon insertion site selection in human cells, but suggest that stable docking of integration complexes may also partially interfere with the cut-and-paste mechanism. These findings illustrate the feasibility of directed transposon integration and highlight potential means for future development

Fetal liver blood flow distribution: role in human developmental strategy to prioritize fat deposition versus brain development

Among primates, human neonates have the largest brains but also the highest proportion of body fat. If placental nutrient supply is limited, the fetus faces a dilemma: should resources be allocated to brain growth, or to fat deposition for use as a potential postnatal energy reserve? We hypothesised that resolving this dilemma operates at the level of umbilical blood distribution entering the fetal liver. In 381 uncomplicated pregnancies in third trimester, we measured blood flow perfusing the fetal liver, or bypassing it via the ductus venosus to supply the brain and heart using ultrasound techniques. Across the range of fetal growth and independent of the mother's adiposity and parity, greater liver blood flow was associated with greater offspring fat mass measured by dual-energy X-ray absorptiometry, both in the infant at birth (r = 0.43, P&lt;0.001) and at age 4 years (r = 0.16, P = 0.02). In contrast, smaller placentas less able to meet fetal demand for essential nutrients were associated with a brain-sparing flow pattern (r = 0.17, p = 0.02). This flow pattern was also associated with a higher degree of shunting through ductus venosus (P = 0.04). We propose that humans evolved a developmental strategy to prioritize nutrient allocation for prenatal fat deposition when the supply of conditionally essential nutrients requiring hepatic inter-conversion is limited, switching resource allocation to favour the brain if the supply of essential nutrients is limited. Facilitated placental transfer mechanisms for glucose and other nutrients evolved in environments less affluent than those now prevalent in developed populations, and we propose that in circumstances of maternal adiposity and nutrient excess these mechanisms now also lead to prenatal fat deposition. Prenatal developmental influences play important roles in the human propensity to deposit fa