Inherited PTEN mutations and the prediction of phenotype

AbstractPTEN has been heavily studied due to its role as a tumour suppressor and as a core inhibitory component of the phosphoinositide 3-kinase (PI3K) signalling network. It is a broadly expressed phosphatase which displays complexity and diversity in both its functions and regulation and accordingly, in the laboratory numerous classes of functionally distinct mutations have been generated. Inherited loss of function mutations in the PTEN gene were originally identified in sufferers of Cowden disease, but later shown to associate with more diverse human pathologies, mostly relating to cell and tissue overgrowth, leading to the use of the broader term, PTEN Hamartoma Tumour Syndrome. Recent phenotypic analysis of clinical cohorts of PTEN mutation carriers, combined with laboratory studies of the consequences of these mutations implies that stable catalytically inactive PTEN mutants may lead to the most severe phenotypes, and conversely, that mutants retaining partial function associate more frequently with a milder phenotype, with autism spectrum disorder often being diagnosed. Future work will be needed to confirm and to refine these genotype–phenotype relationships and convert this developing knowledge into improved patient management and potentially treatment with emerging drugs which target the PI3K pathway

Use of co-grinding as a solvent-free solid state method to synthesize dibenzophenazines

International audienceMany synthetic methods exist for dibenzoquinoxalines but only a few for dibenzophenazines and their aza derivatives and even less are `green'. Some dibenzophenazines and dibenzopyridoquinoxaline have been efficiently obtained with good to excellent yield by a very simple method which does not require use of solvent or catalyst. Solid phase synthesis using co-grinding presents thus many advantages in developing greener synthetic organic pathways. (C) 2011 Elsevier Ltd. All rights reserved

Bacteriophages pass through candle-shaped porous ceramic filters: Application for the collection of viruses in soil water

Despite the ubiquity of viruses in soils, their diversity in soil water has not been explored, mainly due to the difficulty of collecting them. In hydrology, soil water is usually collected using porous candles. This study proposes using these porous candles as a new tool for sampling viruses in soil water to analyze their passage through the ceramic part of the candles. The recovery of the viruses was determined after filtration under laboratory conditions using three model bacteriophages (MS2, ΦX174, and Φ6) and Escherichia coli, at neutral and acidic pH. Then, a field experiment was carried out where soil water filtration and viral identification by metagenomic shotgun were performed. At neutral pH, all bacteriophages tested successfully passed through the porous candles during the filtration process, with reductions of 0.02 log, 0.16 log, and 0.55 log for MS2 ΦX174 and Φ6, respectively. At pH 4.4, the passage of MS2 was not affected while ΦX174 underwent a slight reduction in recovery, probably caused by adsorption onto the filter material. Regarding the application of the porous candles in the field, the results obtained allowed the successful recovery of viruses, exposing porous candles as a new method suitable for the collection of viruses from soil water in the context of the study of viral communities

Jumping on the Blockchain Bandwagon: Lessons of the Past and Outlook to the Future

The panel focuses on blockchain, the technology behind Bitcoin and Ethereum. The topic has drawn much attention recently in both business and academic circles. The blockchain is a distributed, immutable digital record system that is shared among many independent parties and can be updated only by their consensus. If unbiased and incorruptible blockchain-based information systems become prevalent repositories of our records, trusting other humans with constructing and maintaining key records to define the resources at our disposal could become unnecessary. In principle, blockchain could provide a decentralized information infrastructure that no one fully controls, thereby no one has absolute power and no one can distort past or current records. The full potential let alone implications of blockchain is still unknown. The panel explores blockchain challenges and opportunities from the IS research perspective

A female signal reflects MHC genotype in a social primate.

BACKGROUND: Males from many species are believed to advertise their genetic quality through striking ornaments that attract mates. Yet the connections between signal expression, body condition and the genes associated with individual quality are rarely elucidated. This is particularly problematic for the signals of females in species with conventional sex roles, whose evolutionary significance has received little attention and is poorly understood. Here we explore these questions in the sexual swellings of female primates, which are among the most conspicuous of mammalian sexual signals and highly variable in size, shape and colour. We investigated the relationships between two components of sexual swellings (size and shape), body condition, and genes of the Major Histocompatibility Complex (MHC) in a wild baboon population (Papio ursinus) where males prefer large swellings. RESULTS: Although there was no effect of MHC diversity on the sexual swelling components, one specific MHC supertype (S1) was associated with poor body condition together with swellings of small size and a particular shape. The variation in swelling characteristics linked with the possession of supertype S1 appeared to be partially mediated by body condition and remained detectable when taking into account the possession of other supertypes. CONCLUSIONS: These findings suggest a pathway from immunity genes to sexual signals via physical condition for the first time in females. They further indicate that mechanisms of sexual selection traditionally assigned to males can also operate in females.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are

T-cell dependent immunogenicity of protein therapeutics: Preclinical assessment and mitigation

Protein therapeutics hold a prominent and rapidly expanding place among medicinal products. Purified blood products, recombinant cytokines, growth factors, enzyme replacement factors, monoclonal antibodies, fusion proteins, and chimeric fusion proteins are all examples of therapeutic proteins that have been developed in the past few decades and approved for use in the treatment of human disease. Despite early belief that the fully human nature of these proteins would represent a significant advantage, adverse effects associated with immune responses to some biologic therapies have become a topic of some concern. As a result, drug developers are devising strategies to assess immune responses to protein therapeutics during both the preclinical and the clinical phases of development. While there are many factors that contribute to protein immunogenicity, T cell- (thymus-) dependent (Td) responses appear to play a critical role in the development of antibody responses to biologic therapeutics. A range of methodologies to predict and measure Td immune responses to protein drugs has been developed. This review will focus on the Td contribution to immunogenicity, summarizing current approaches for the prediction and measurement of T cell-dependent immune responses to protein biologics, discussing the advantages and limitations of these technologies, and suggesting a practical approach for assessing and mitigating Td immunogenicity

Non-detection of Helium in the Upper Atmospheres of Three Sub-Neptune Exoplanets

We present a search for helium in the upper atmospheres of three sub-Neptune size planets to investigate the origins of these ubiquitous objects. The detection of helium for a low density planet would be strong evidence for the presence of a primary atmosphere accreted from the protoplanetary nebula because large amounts of helium are not expected in the secondary atmospheres of rocky planets. We used Keck+NIRSPEC to obtain high-resolution transit spectroscopy of the planets GJ1214b, GJ9827d, and HD97658b around the 10,833 Ang He triplet feature. We did not detect helium absorption for any of the planets despite achieving a high level of sensitivity. We used the non-detections to set limits on the planets' thermosphere temperatures and atmospheric loss rates by comparing grids of 1D models to the data. We also performed coupled interior structure and atmospheric loss calculations, which suggest that the bulk atmospheres (winds) of the planets would be at most modestly enhanced (depleted) in helium relative to their primordial composition. Our lack of detections of the helium triplet for GJ1214b and GJ9827d are highly inconsistent with the predictions of models for the present day mass loss on these planets. Higher signal-to-noise data would be needed to detect the helium feature predicted for HD97658b. We identify uncertainties in the EUV fluxes of the host stars and the lack of detailed mass loss models specifically for cool and metal-enhanced atmospheres as the main limitations to the interpretation of our results. Ultimately, our results suggest that the upper atmospheres of sub-Neptune planets are fundamentally different than those of gas giant planets.Comment: AJ in pres

Rapid Publication Widespread Long-term Gene Transfer to Mouse Skeletal Muscles and Heart

Abstract Method

Dual Orientation of the Outer Membrane Lipoprotein P6 of Nontypeable Haemophilus influenzae

The majority of outer membrane (OM) lipoproteins in Gram-negative bacteria are tethered to the membrane via an attached lipid moiety and oriented facing in toward the periplasmic space; a few lipoproteins have been shown to be surface exposed. The outer membrane lipoprotein P6 from the Gram-negative pathogenic bacterium nontypeable Haemophilus influenzae (NTHi) is surface exposed and a leading vaccine candidate for prevention of NTHi infections. However, we recently found that P6 is not a transmembrane protein as previously thought (L. V. Michel, B. Kalmeta, M. McCreary, J. Snyder, P. Craig, M. E. Pichichero, Vaccine 29:1624–1627, 2011). Here we pursued studies to show that P6 has a dual orientation, existing infrequently as surface exposed and predominantly as internally oriented toward the periplasmic space. Flow cytometry using three monoclonal antibodies with specificity for P6 showed surface staining of whole NTHi cells. Confocal microscopy imaging confirmed that antibodies targeted surface-exposed P6 of intact NTHi cells and not internal P6 in membrane-compromised or dead cells. Western blots of two wild-type NTHi strains and a mutant NTHi strain that does not express P6 showed that P6 antibodies do not detect a promiscuous epitope on NTHi. Depletion of targets to nonlipidated P6 significantly decreased bactericidal activity of human serum. Protease digestion of surface-exposed P6 demonstrated that P6 is predominantly internally localized in a manner similar to its homologue Pal in Escherichia coli. We conclude that P6 of NTHi is likely inserted into the OM in two distinct orientations, with the predominant orientation facing in toward the periplasm