The genetic organisation of prokaryotic two-component system signalling pathways

<p>Abstract</p> <p>Background</p> <p>Two-component systems (TCSs) are modular and diverse signalling pathways, involving a stimulus-responsive transfer of phosphoryl groups from transmitter to partner receiver domains. TCS gene and domain organisation are both potentially informative regarding biological function, interaction partnerships and molecular mechanisms. However, there is currently little understanding of the relationships between domain architecture, gene organisation and TCS pathway structure.</p> <p>Results</p> <p>Here we classify the gene and domain organisation of TCS gene loci from 1405 prokaryotic replicons (>40,000 TCS proteins). We find that 200 bp is the most appropriate distance cut-off for defining whether two TCS genes are functionally linked. More than 90% of all TCS gene loci encode just one or two transmitter and/or receiver domains, however numerous other geometries exist, often with large numbers of encoded TCS domains. Such information provides insights into the distribution of TCS domains between genes, and within genes. As expected, the organisation of TCS genes and domains is affected by phylogeny, and plasmid-encoded TCS exhibit differences in organisation from their chromosomally-encoded counterparts.</p> <p>Conclusions</p> <p>We provide here an overview of the genomic and genetic organisation of TCS domains, as a resource for further research. We also propose novel metrics that build upon TCS gene/domain organisation data and allow comparisons between genomic complements of TCSs. In particular, '<it>percentage orphaned TCS genes</it>' (or 'Dissemination') and '<it>percentage of complex loci</it>' (or 'Sophistication') appear to be useful discriminators, and to reflect mechanistic aspects of TCS organisation not captured by existing metrics.</p

Uptake of home-based voluntary HIV testing in sub-Saharan Africa: a systematic review and meta-analysis

Improving access to HIV testing is a key priority in scaling up HIV treatment and prevention services. Home-based voluntary counselling and testing (HBT) as an approach to delivering wide-scale HIV testing is explored here

Current knowledge, challenges and innovations in developmental pharmacology: A combined conect4children Expert Group and European Society for Developmental, Perinatal and Paediatric Pharmacology White Paper

Developmental pharmacology describes the impact of maturation on drug disposition (pharmacokinetics, PK) and drug effects (pharmacodynamics, PD) throughout the paediatric age range. This paper, written by a multidisciplinary group of experts, summarizes current knowledge, and provides suggestions to pharmaceutical companies, regulatory agencies and academicians on how to incorporate the latest knowledge regarding developmental pharmacology and innovative techniques into neonatal and paediatric drug development. Biological aspects of drug absorption, distribution, metabolism and excretion (ADME) throughout development are summarized. Although this area made enormous progress during the last two decades, remaining knowledge gaps were identified. Minimal risk and burden designs allow for optimally informative but minimally invasive PK sampling, while concomitant profiling of drug metabolites may provide additional insight in the unique PK behavior in children. Furthermore, developmental PD needs to be considered during drug development, which is illustrated by disease- and/or target organ-specific examples. Identifying and testing PD targets and effects in special populations, and application of age- and/or population-specific assessment tools are discussed. Drug development plans also need to incorporate innovative techniques like preclinical models to study therapeutic strategies, and shift from sequential enrollment of subgroups, to more rational designs. To stimulate appropriate research plans, illustrations of specific PK/PD-related as well as drug safety-related challenges during drug development are provided. The suggestions made in this joint paper of the Innovative Medicines Initiative conect4children Expert group on Developmental Pharmacology and the European Society for Developmental, Perinatal and Paediatric Pharmacology, should facilitate all those involved in drug development

A molecular insight into algal-oomycete warfare : cDNA analysis of Ectocarpus siliculosus infected with the basal oomycete Eurychasma dicksonii

Peer reviewedPublisher PD

The association of patient weight and dose of fosphenytoin, levetiracetam, and valproic acid with treatment success in status epilepticus

The Established Status Epilepticus Treatment Trial was a blinded, comparative‐effectiveness study of fosphenytoin, levetiracetam, and valproic acid in benzodiazepine‐refractory status epilepticus. The primary outcome was clinical seizure cessation and increased responsiveness without additional anticonvulsant medications. Weight‐based dosing was capped at 75 kg. Hence, patients weighing >75 kg received a lower mg/kg dose. Logistic regression models were developed in 235 adults to determine the association of weight (≤ or >75 kg, ≤ or >90 kg), sex, treatment, and weight‐normalized dose with the primary outcome and solely seizure cessation. The primary outcome was achieved in 45.1% and 42.5% of those ≤75 kg and >75 kg, respectively. Using univariate analyses, the likelihood of success for those >75 kg (odds ratio [OR] = 0.9, 95% confidence interval [CI] = 0.54‐1.51) or >90 kg (OR = 0.85, 95% CI = 0.42‐1.66) was not statistically different compared with those ≤75 kg or ≤90 kg, respectively. Similarly, other predictors were not significantly associated with primary outcome or clinical seizure cessation. Our findings suggest that doses, capped at 75 kg, likely resulted in concentrations greater than those needed for outcome. Studies that include drug concentrations and heavier individuals are needed to confirm these findings

Phaeoviruses discovered in kelp (Laminariales)

Phaeoviruses are latent double-stranded DNA viruses that insert their genomes into those of their brown algal (Phaeophyceae) hosts. So far these viruses are known only from members of the Ectocarpales, which are small and short-lived macroalgae. Here we report molecular and morphological evidence for a new Phaeovirus cluster, referred to as sub-group C, infecting kelps (Laminariales) of the genera Laminaria and Saccharina, which are ecologically and commercially important seaweeds. Epifluorescence and TEM observations indicate that the Laminaria digitata Virus (LdigV), the type species of sub-group C, targets the host nucleus for its genome replication, followed by gradual degradation of the chloroplast and assembly of virions in the cytoplasm of both vegetative and reproductive cells. This study is the first to describe phaeoviruses in kelp. In the field, these viruses infected two thirds of their host populations; however, their biological impact remains unknown

Emission of volatile halogenated compounds, speciation and localization of bromine and iodine in the brown algal genome model Ectocarpus siliculosus

This study explores key features of bromine and iodine metabolism in the filamentous brown alga and genomics model Ectocarpus siliculosus. Both elements are accumulated in Ectocarpus, albeit at much lower concentration factors (2-3 orders of magnitude for iodine, and < 1 order of magnitude for bromine) than e.g. in the kelp Laminaria digitata. Iodide competitively reduces the accumulation of bromide. Both iodide and bromide are accumulated in the cell wall (apoplast) of Ectocarpus, with minor amounts of bromine also detectable in the cytosol. Ectocarpus emits a range of volatile halogenated compounds, the most prominent of which by far is methyl iodide. Interestingly, biosynthesis of this compound cannot be accounted for by vanadium haloperoxidase since the latter have not been found to catalyze direct halogenation of an unactivated methyl group or hydrocarbon so a methyl halide transferase-type production mechanism is proposed

Genetic educational needs and the role of genetics in primary care: a focus group study with multiple perspectives

Contains fulltext : 96953.pdf (publisher's version ) (Open Access)BACKGROUND: Available evidence suggests that improvements in genetics education are needed to prepare primary care providers for the impact of ongoing rapid advances in genomics. Postgraduate (physician training) and master (midwifery training) programmes in primary care and public health are failing to meet these perceived educational needs. The aim of this study was to explore the role of genetics in primary care (i.e. family medicine and midwifery care) and the need for education in this area as perceived by primary care providers, patient advocacy groups and clinical genetics professionals. METHODS: Forty-four participants took part in three types of focus groups: mono-disciplinary groups of general practitioners and midwives, respectively and multidisciplinary groups composed of a diverse set of experts. The focus group sessions were audio-taped, transcribed verbatim and analysed using content analysis. Recurrent themes were identified. RESULTS: Four themes emerged regarding the educational needs and the role of genetics in primary care: (1) genetics knowledge, (2) family history, (3) ethical dilemmas and psychosocial effects in relation to genetics and (4) insight into the organisation and role of clinical genetics services. These themes reflect a shift in the role of genetics in primary care with implications for education. Although all focus group participants acknowledged the importance of genetics education, general practitioners felt this need more urgently than midwives and more strongly emphasized their perceived knowledge deficiencies. CONCLUSION: The responsibilities of primary care providers with regard to genetics require further study. The results of this study will help to develop effective genetics education strategies to improve primary care providers' competencies in this area. More research into the educational priorities in genetics is needed to design courses that are suitable for postgraduate and master programmes for general practitioners and midwives

A novel evolutionary strategy revealed in the Phaeoviruses

Phaeoviruses infect the brown algae, which are major contributors to primary production of coastal waters and estuaries. They exploit a Persistent evolutionary strategy akin to a K- selected life strategy via genome integration and are the only known representatives to do so within the giant algal viruses that are typified by r- selected Acute lytic viruses. In screening the genomes of five species within the filamentous brown algal lineage, here we show an unprecedented diversity of viral gene sequence variants especially amongst the smaller phaeoviral genomes. Moreover, one variant shares features from both the two major sub-groups within the phaeoviruses. These phaeoviruses have exploited the reduction of their giant dsDNA genomes and accompanying loss of DNA proofreading capability, typical of an Acute life strategist, but uniquely retain a Persistent life strategy

Extrapulmonary tuberculosis, human immunodeficiency virus, and foreign birth in North Carolina, 1993 – 2006

<p>Abstract</p> <p>Background</p> <p>The proportion of extrapulmonary tuberculosis (EPTB) reported in the United States has been gradually increasing. HIV infection and foreign birth are increasingly associated with tuberculosis and understanding their effect on the clinical presentation of tuberculosis is important.</p> <p>Methods</p> <p>Case-control study of 6,124 persons with tuberculosis reported to the North Carolina Division of Public health from January 1, 1993 to December 31, 2006. Multivariate logistic regression was used to obtain adjusted odds ratios measuring the associations of foreign birth region and US born race/ethnicity, by HIV status, with EPTB.</p> <p>Results</p> <p>Among all patients with tuberculosis, 1,366 (22.3%) had EPTB, 563 (9.2%) were HIV co-infected, and 1,299 (21.2%) were foreign born. Among HIV negative patients, EPTB was associated with being foreign born (adjusted ORs 1.36 to 5.09, depending on region of birth) and with being US born, Black/African American (OR 1.84; 95% CI 1.42, 2.39). Among HIV infected patients, EPTB was associated with being US born, Black/African American (OR 2.60; 95% CI 1.83, 3.71) and with foreign birth in the Americas (OR 5.12; 95% CI 2.84, 9.23).</p> <p>Conclusion</p> <p>Foreign born tuberculosis cases were more likely to have EPTB than US born tuberculosis cases, even in the absence of HIV infection. Increasing proportions of foreign born and HIV-attributable tuberculosis cases in the United States will likely result in a sustained burden of EPTB. Further research is needed to explore why the occurrence and type of EPTB differs by region of birth and whether host genetic and/or bacterial variation can explain these differences in EPTB.</p