Proteomic analyses reveal misregulation of LIN28 expression and delayed timing of glial differentiation in human iPS cells with MECP2 loss-of-function.

Rett syndrome (RTT) is a pervasive developmental disorder caused by mutations in MECP2. Complete loss of MECP2 function in males causes congenital encephalopathy, neurodevelopmental arrest, and early lethality. Induced pluripotent stem cell (iPSC) lines from male patients harboring mutations in MECP2, along with control lines from their unaffected fathers, give us an opportunity to identify some of the earliest cellular and molecular changes associated with MECP2 loss-of-function (LOF). We differentiated iPSC-derived neural progenitor cells (NPCs) using retinoic acid (RA) and found that astrocyte differentiation is perturbed in iPSC lines derived from two different patients. Using highly stringent quantitative proteomic analyses, we found that LIN28, a gene important for cell fate regulation and developmental timing, is upregulated in mutant NPCs compared to WT controls. Overexpression of LIN28 protein in control NPCs suppressed astrocyte differentiation and reduced neuronal synapse density, whereas downregulation of LIN28 expression in mutant NPCs partially rescued this synaptic deficiency. These results indicate that the pathophysiology of RTT may be caused in part by misregulation of developmental timing in neural progenitors, and the subsequent consequences of this disruption on neuronal and glial differentiation

Phenomenology, Astrophysics and Cosmology of Theories with Sub-Millimeter Dimensions and TeV Scale Quantum Gravity

We recently proposed a solution to the hierarchy problem not relying on low-energy supersymmetry or technicolor. Instead, the problem is nullified by bringing quantum gravity down to the TeV scale. This is accomplished by the presence of $n \geq 2$ new dimensions of sub-millimeter size, with the SM fields localised on a 3-brane in the higher dimensional space. In this paper we systematically study the experimental viability of this scenario. Constraints arise both from strong quantum gravitational effects at the TeV scale, and more importantly from the production of massless higher dimensional gravitons with TeV suppressed couplings. Theories with $n>2$ are safe due mainly to the infrared softness of higher dimensional gravity. For $n=2$, the six dimensional Planck scale must be pushed above $\sim 30$ TeV to avoid cooling SN1987A and distortions of the diffuse photon background. Nevertheless, the particular implementation of our framework within type I string theory can evade all constraints, for any $n \geq 2$, with string scale $m_s \sim 1$ TeV. We also explore novel phenomena resulting from the existence of new states propagating in the higher dimensional space. The Peccei-Quinn solution to the strong CP problem is revived with a weak scale axion in the bulk. Gauge fields in the bulk can mediate repulsive forces $\sim 10^6 - 10^8$ times stronger than gravity at sub-mm distances, and may help stabilize the proton. Higher-dimensional gravitons produced on our brane and captured on a different "fat" brane can provide a natural dark matter candidate.Comment: 51 pages, late

Small Numbers from Tunneling Between Brane Throats

Generic classes of string compactifications include ``brane throats'' emanating from the compact dimensions and separated by effective potential barriers raised by the background gravitational fields. The interaction of observers inside different throats occurs via tunnelling and is consequently weak. This provides a new mechanism for generating small numbers in Nature. We apply it to the hierarchy problem, where supersymmetry breaking near the unification scale causes TeV sparticle masses inside the standard model throat. We also design naturally long-lived cold dark matter which decays within a Hubble time to the approximate conformal matter of a long throat. This may soften structure formation at galactic scales and raises the possibility that much of the dark matter of the universe is conformal matter. Finally, the tunnelling rate shows that the coupling between throats, mediated by bulk modes, is stronger than a naive application of holography suggests.Comment: 11 pages, 2 figures. Small corrections to match the published versio

Supersymmetric Unification Without Low Energy Supersymmetry And Signatures for Fine-Tuning at the LHC

The cosmological constant problem is a failure of naturalness and suggests that a fine-tuning mechanism is at work, which may also address the hierarchy problem. An example -- supported by Weinberg's successful prediction of the cosmological constant -- is the potentially vast landscape of vacua in string theory, where the existence of galaxies and atoms is promoted to a vacuum selection criterion. Then, low energy SUSY becomes unnecessary, and supersymmetry -- if present in the fundamental theory -- can be broken near the unification scale. All the scalars of the supersymmetric standard model become ultraheavy, except for a single finely tuned Higgs. Yet, the fermions of the supersymmetric standard model can remain light, protected by chiral symmetry, and account for the successful unification of gauge couplings. This framework removes all the difficulties of the SSM: the absence of a light Higgs and sparticles, dimension five proton decay, SUSY flavor and CP problems, and the cosmological gravitino and moduli problems. High-scale SUSY breaking raises the mass of the light Higgs to about 120-150 GeV. The gluino is strikingly long lived, and a measurement of its lifetime can determine the ultraheavy scalar mass scale. Measuring the four Yukawa couplings of the Higgs to the gauginos and higgsinos precisely tests for high-scale SUSY. These ideas, if confirmed, will demonstrate that supersymmetry is present but irrelevant for the hierarchy problem -- just as it has been irrelevant for the cosmological constant problem -- strongly suggesting the existence of a fine-tuning mechanism in nature.Comment: Typos and equations fixed, references adde

Knowledge, attitudes and anxiety towards influenza A/H1N1 vaccination of healthcare workers in Turkey

<p>Abstract</p> <p>Background</p> <p>This study aimed to analyze the factors associated with knowledge and attitudes about influenza A (H1N1) and vaccination, and possible relations of these factors with anxiety among healthcare workers (HCW).</p> <p>Methods</p> <p>The study used a cross-sectional descriptive design, and it was carried out between 23 November and 4 December 2009. A total of 300 HCW from two hospitals completed a questionnaire. Data collection tools comprised a questionnaire and the State-Trait Anxiety Inventory (STAI).</p> <p>Results</p> <p>Vaccination rate for 2009 pandemic influenza A(H1N1) among HCW was low (12.7%). Most of the respondents believed the vaccine was not safe and protective. Vaccination refusal was mostly related to the vaccine's side effects, disbelief to vaccine's protectiveness, negative news about the vaccine and the perceived negative attitude of the Prime Minister to the vaccine. State anxiety was found to be high in respondents who felt the vaccine was unsafe.</p> <p>Conclusions</p> <p>HCW considered the seriousness of the outbreak, their vaccination rate was low. In vaccination campaigns, governments have to aim at providing trust, and media campaigns should be used to reinforce this trust as well. Accurate reporting by the media of the safety and efficacy of influenza vaccines and the importance of vaccines for the public health would likely have a positive influence on vaccine uptake. Uncertain or negative reporting about the vaccine is detrimental to vaccination efforts.</p

Quantitative isotope-dilution high-resolution-mass-apectrometry analysis of multiple intracellular metabolites in Clostridium autoethanogenum with uniformly 13C-labeled standards derived from Spirulina

We have investigated the applicability of commercially available lyophilized spirulina (Arthrospira platensis), a microorganism uniformly labeled with 13C, as a readily accessible source of multiple 13C-labeled metabolites suitable as internal standards for the quantitative determination of intracellular bacterial metabolites. Metabolites of interest were analyzed by hydrophilic-interaction liquid chromatography coupled with high-resolution mass spectrometry. Multiple internal standards obtained from uniformly (U)-13C-labeled extracts from spirulina were used to enable isotope-dilution mass spectrometry (IDMS) in the identification and quantification of intracellular metabolites. Extraction of the intracellular metabolites of Clostridium autoethanogenum using 2:1:1 chloroform/methanol/water was found to be the optimal method in comparison with freeze–thaw, homogenization, and sonication methods. The limits of quantification were ≤1 μM with excellent linearity for all of the calibration curves (R2 ≥ 0.99) for 74 metabolites. The precision and accuracy were found to be within relative standard deviations (RSDs) of 15% for 49 of the metabolites and within RSDs of 20% for all of the metabolites. The method was applied to study the effects of feeding different levels of carbon monoxide (as a carbon source) on the central metabolism and Wood–Ljungdahl pathway of C. autoethanogenum grown in continuous culture over 35 days. Using LC-IDMS with U-13C spirulina allowed the successful quantification of 52 metabolites in the samples, including amino acids, carboxylic acids, sugar phosphates, purines, and pyrimidines. The method provided absolute quantitative data on intracellular metabolites that was suitable for computational modeling to understand and optimize the C. autoethanogenum metabolic pathways active in gas fermentation

New origin for approximate symmetries from distant breaking in extra dimensions

The recently proposed theories with TeV-scale quantum gravity remove the usual ultraviolet desert between $\sim 10^{3} - 10^{19}$ GeV where effective field theory ideas apply. Consequently, the success of the desert in explaining approximate symmetries is lost, and theories of flavor, neutrino masses, proton longevity or supersymmetry breaking, lose their usual habitat. In this paper we show that these ideas can find a new home in an infrared desert: the large space in the extra dimensions. The main idea is that symmetries are primordially exact on our brane, but are broken at O(1) on distant branes. This breaking is communicated to us in a distance-suppressed way by bulk messengers. We illustrate these ideas in a number of settings: 1) We construct theories for the fermion mass hierarchy which avoid large FCNC's. 2) We re-iterate that proton stability can arise if baryon number is gauged in the bulk. 3) We study experimental constraints on light gauge fields and scalars in the bulk. 4) We remark that the same ideas can be used to explain small neutrino masses, and hierarchical supersymmetry breaking. 5) We construct a theory with bulk technicolor, avoiding the difficulties with extended technicolor. There are also interesting experimental signals of these ideas: 1) Attractive or repulsive, isotope dependent sub-millimeter forces $\sim 10^6$ times gravitational strength, from the exchange of light bulk particles. 2) Novel Higgs decays to light generation fermions plus bulk scalars. 3) Collider production of bulk vector and scalar fields, leading to large $\gamma$ or jet+ missing energy signals.Comment: 29 pages, late

Evidence that the rat osteopetrotic mutation toothless (tl) is not in the TNFSF11 (TRANCE, RANKL, ODF, OPGL) gene

The toothless (tl) osteopetrotic mutation in the rat affects an osteoblast-derived factor that is required for normal osteoclast differentiation. Although the genetic locus remains unknown, the phenotypic impact of the tl mutation on multiple systems has been well characterized. Some of its actions are similar to tumornecrosis factor superfamily member 11(TNFSF11; also called TRANCE, RANKL, ODF and OPGL) null mice. TNFSF11 is a recently described member of the tumor necrosis factor superfamily which, when expressed by activated T cells, enhances the survival of antigen-presenting dendritic cells, and when expressed by osteoblasts, promotes the differentiation and activation of osteoclasts. The skeletal similarities between tl rats and TNFSF11(-/-) mice include 1) profound osteoclastopenia (TNFSF11-null mice, 0% and tl rats 0-1% of normal); 2) persistent, non-resolving osteopetrosis that results from 3) a defect not in the osteoclast lineage itself, but in an osteoblast-derived, osteoclastogenic signal; and 4) a severe chondrodysplasia of the growth plates of long bones not seen in other osteopetrotic mutations. The latter includes thickening of the growth plate with age, disorganization of chondrocyte columns, and disturbances of chondrocyte maturation. These striking similarities prompted us to undertake studies to rule in or out a TNFSF11 mutation in the tl rat. We looked for expression of TNFSF11 mRNA in tl long bones and found it to be over-expressed and of the correct size. We also tested TNFSF11 protein function in the tl rat. This was shown to be normal by flow cytometry experiments in which activated, spleen-derived T-cells from tl rats exhibited normal receptor binding competence, as measured by a recombinant receptor assay. We also found that tl rats develop histologically normal mesenteric and peripheral lymph nodes, which are absent from TNFSF11-null mice. Next, we found that injections of recombinant TNFSF11, which restores bone resorption in null mice, had no therapeutic effect in tl rats. Finally, gene mapping studies using co-segregation of polymorphic markers excluded the chromosomal region containing the TNFSF11 gene as harboring the mutation responsible for the tl phenotype. We conclude that, despite substantial phenotypic similarities to TNFSF11(-/-) mice, the tl rat mutation is not in the TNFSF11 locus, and that its identification must await the results of further studies

Serial CT analysis in idiopathic pulmonary fibrosis: comparison of visual features that determine patient outcome

Aims: Patients with idiopathic pulmonary fibrosis (IPF) receiving antifibrotic medication and patients with non-IPF fibrosing lung disease often demonstrate rates of annualised forced vital capacity (FVC) decline within the range of measurement variation (5.0%–9.9%). We examined whether change in visual CT variables could help confirm whether marginal FVC declines represented genuine clinical deterioration rather than measurement noise. Methods: In two IPF cohorts (cohort 1: n=103, cohort 2: n=108), separate pairs of radiologists scored paired volumetric CTs (acquired between 6 and 24 months from baseline). Change in interstitial lung disease, honeycombing, reticulation, ground-glass opacity extents and traction bronchiectasis severity was evaluated using a 5-point scale, with mortality prediction analysed using univariable and multivariable Cox regression analyses. Both IPF populations were then combined to determine whether change in CT variables could predict mortality in patients with marginal FVC declines. Results: On univariate analysis, change in all CT variables except ground-glass opacity predicted mortality in both cohorts. On multivariate analysis adjusted for patient age, gender, antifibrotic use and baseline disease severity (diffusing capacity for carbon monoxide), change in traction bronchiectasis severity predicted mortality independent of FVC decline. Change in traction bronchiectasis severity demonstrated good interobserver agreement among both scorer pairs. Across all study patients with marginal FVC declines, change in traction bronchiectasis severity independently predicted mortality and identified more patients with deterioration than change in honeycombing extent. Conclusions: Change in traction bronchiectasis severity is a measure of disease progression that could be used to help resolve the clinical importance of marginal FVC declines

Toward full-stack in silico synthetic biology: integrating model specification, simulation, verification, and biological compilation

YesWe present the Infobiotics Workbench (IBW), a user-friendly, scalable, and integrated computational environment for the computer-aided design of synthetic biological systems. It supports an iterative workflow that begins with specification of the desired synthetic system, followed by simulation and verification of the system in high- performance environments and ending with the eventual compilation of the system specification into suitable genetic constructs. IBW integrates modelling, simulation, verification and bicompilation features into a single software suite. This integration is achieved through a new domain-specific biological programming language, the Infobiotics Language (IBL), which tightly combines these different aspects of in silico synthetic biology into a full-stack integrated development environment. Unlike existing synthetic biology modelling or specification languages, IBL uniquely blends modelling, verification and biocompilation statements into a single file. This allows biologists to incorporate design constraints within the specification file rather than using decoupled and independent formalisms for different in silico analyses. This novel approach offers seamless interoperability across different tools as well as compatibility with SBOL and SBML frameworks and removes the burden of doing manual translations for standalone applications. We demonstrate the features, usability, and effectiveness of IBW and IBL using well-established synthetic biological circuits.The work of S.K. is supported by EPSRC (EP/R043787/1). N.K., A.W., and B.B. acknowledge a Royal Academy of Engineering Chair in Emerging Technologies award and an EPSRC programme grant (EP/N031962/1)