Disease-specific, neurosphere-derived cells as models for brain disorders

There is a pressing need for patient-derived cell models of brain diseases that are relevant and robust enough to produce the large quantities of cells required for molecular and functional analyses. We describe here a new cell model based on patient-derived cells from the human olfactory mucosa, the organ of smell, which regenerates throughout life from neural stem cells. Olfactory mucosa biopsies were obtained from healthy controls and patients with either schizophrenia, a neurodevelopmental psychiatric disorder, or Parkinson's disease, a neurodegenerative disease. Biopsies were dissociated and grown as neurospheres in defined medium. Neurosphere-derived cell lines were grown in serum-containing medium as adherent monolayers and stored frozen. By comparing 42 patient and control cell lines we demonstrated significant disease-specific alterations in gene expression, protein expression and cell function, including dysregulated neurodevelopmental pathways in schizophrenia and dysregulated mitochondrial function, oxidative stress and xenobiotic metabolism in Parkinson's disease. The study has identified new candidate genes and cell pathways for future investigation. Fibroblasts from schizophrenia patients did not show these differences. Olfactory neurosphere-derived cells have many advantages over embryonic stem cells and induced pluripotent stem cells as models for brain diseases. They do not require genetic reprogramming and they can be obtained from adults with complex genetic diseases. They will be useful for understanding disease aetiology, for diagnostics and for drug discovery

Modeling of Photoionized Plasmas

In this paper I review the motivation and current status of modeling of plasmas exposed to strong radiation fields, as it applies to the study of cosmic X-ray sources. This includes some of the astrophysical issues which can be addressed, the ingredients for the models, the current computational tools, the limitations imposed by currently available atomic data, and the validity of some of the standard assumptions. I will also discuss ideas for the future: challenges associated with future missions, opportunities presented by improved computers, and goals for atomic data collection.Comment: 17 pages, 8 figures, to appear in the proceedings of Xray2010, Utrecht, the Netherlands, March 15-17 201

Reversible Band Gap Engineering in Carbon Nanotubes by Radial Deformation

We present a systematic analysis of the effect of radial deformation on the atomic and electronic structure of zigzag and armchair single wall carbon nanotubes using the first principle plane wave method. The nanotubes were deformed by applying a radial strain, which distorts the circular cross section to an elliptical one. The atomic structure of the nanotubes under this strain are fully optimized, and the electronic structure is calculated self-consistently to determine the response of individual bands to the radial deformation. The band gap of the insulating tube is closed and eventually an insulator-metal transition sets in by the radial strain which is in the elastic range. Using this property a multiple quantum well structure with tunable and reversible electronic structure is formed on an individual nanotube and its band-lineup is determined from first-principles. The elastic energy due to the radial deformation and elastic constants are calculated and compared with classical theories.Comment: To be appear in Phys. Rev. B, Apr 15, 200

Time-averaged wavefront analysis demonstrates preferential pathways of atrial fibrillation, predicting pulmonary vein isolation acute response

Electrical activation during atrial fibrillation (AF) appears chaotic and disorganised, which impedes characterisation of the underlying substrate and treatment planning. While globally chaotic, there may be local preferential activation pathways that represent potential ablation targets. This study aimed to identify preferential activation pathways during AF and predict the acute ablation response when these are targeted by pulmonary vein isolation (PVI). In patients with persistent AF (n = 14), simultaneous biatrial contact mapping with basket catheters was performed pre-ablation and following each ablation strategy (PVI, roof, and mitral lines). Unipolar wavefront activation directions were averaged over 10 s to identify preferential activation pathways. Clinical cases were classified as responders or non-responders to PVI during the procedure. Clinical data were augmented with a virtual cohort of 100 models. In AF pre-ablation, pathways originated from the pulmonary vein (PV) antra in PVI responders (7/7) but not in PVI non-responders (6/6). We proposed a novel index that measured activation waves from the PV antra into the atrial body. This index was significantly higher in PVI responders than non-responders (clinical: 16.3 vs. 3.7%, p = 0.04; simulated: 21.1 vs. 14.1%, p = 0.02). Overall, this novel technique and proof of concept study demonstrated that preferential activation pathways exist during AF. Targeting patient-specific activation pathways that flowed from the PV antra to the left atrial body using PVI resulted in AF termination during the procedure. These PV activation flow pathways may correspond to the presence of drivers in the PV regions

Search for the standard model Higgs boson decaying into two photons in pp collisions at sqrt(s)=7 TeV

A search for a Higgs boson decaying into two photons is described. The analysis is performed using a dataset recorded by the CMS experiment at the LHC from pp collisions at a centre-of-mass energy of 7 TeV, which corresponds to an integrated luminosity of 4.8 inverse femtobarns. Limits are set on the cross section of the standard model Higgs boson decaying to two photons. The expected exclusion limit at 95% confidence level is between 1.4 and 2.4 times the standard model cross section in the mass range between 110 and 150 GeV. The analysis of the data excludes, at 95% confidence level, the standard model Higgs boson decaying into two photons in the mass range 128 to 132 GeV. The largest excess of events above the expected standard model background is observed for a Higgs boson mass hypothesis of 124 GeV with a local significance of 3.1 sigma. The global significance of observing an excess with a local significance greater than 3.1 sigma anywhere in the search range 110-150 GeV is estimated to be 1.8 sigma. More data are required to ascertain the origin of this excess.Comment: Submitted to Physics Letters

Models for Type Ia supernovae and related astrophysical transients

We give an overview of recent efforts to model Type Ia supernovae and related astrophysical transients resulting from thermonuclear explosions in white dwarfs. In particular we point out the challenges resulting from the multi-physics multi-scale nature of the problem and discuss possible numerical approaches to meet them in hydrodynamical explosion simulations and radiative transfer modeling. We give examples of how these methods are applied to several explosion scenarios that have been proposed to explain distinct subsets or, in some cases, the majority of the observed events. In case we comment on some of the successes and shortcoming of these scenarios and highlight important outstanding issues.Comment: 20 pages, 2 figures, review published in Space Science Reviews as part of the topical collection on supernovae, replacement corrects typos in the conclusions sectio

Measurement of isolated photon production in pp and PbPb collisions at sqrt(sNN) = 2.76 TeV

Isolated photon production is measured in proton-proton and lead-lead collisions at nucleon-nucleon centre-of-mass energies of 2.76 TeV in the pseudorapidity range |eta|<1.44 and transverse energies ET between 20 and 80 GeV with the CMS detector at the LHC. The measured ET spectra are found to be in good agreement with next-to-leading-order perturbative QCD predictions. The ratio of PbPb to pp isolated photon ET-differential yields, scaled by the number of incoherent nucleon-nucleon collisions, is consistent with unity for all PbPb reaction centralities.Comment: Submitted to Physics Letters

Management and outcomes of gastrointestinal congenital anomalies in low, middle and high income countries: Protocol for a multicentre, international, prospective cohort study

Introduction Congenital anomalies are the fifth leading cause of death in children <5 years of age globally, contributing an estimated half a million deaths per year. Very limited literature exists from low and middle income countries (LMICs) where most of these deaths occur. The Global PaedSurg Research Collaboration aims to undertake the first multicentre, international, prospective cohort study of a selection of common congenital anomalies comparing management and outcomes between low, middle and high income countries (HICs) globally. Methods and analysis The Global PaedSurg Research Collaboration consists of surgeons, paediatricians, anaesthetists and allied healthcare professionals involved in the surgical care of children globally. Collaborators will prospectively collect observational data on consecutive patients presenting for the first time, with one of seven common congenital anomalies (oesophageal atresia, congenital diaphragmatic hernia, intestinal atresia, gastroschisis, exomphalos, anorectal malformation and Hirschsprung''s disease). Patient recruitment will be for a minimum of 1 month from October 2018 to April 2019 with a 30-day post-primary intervention follow-up period. Anonymous data will be collected on patient demographics, clinical status, interventions and outcomes using REDCap. Collaborators will complete a survey regarding the resources and facilities for neonatal and paediatric surgery at their centre. The primary outcome is all-cause in-hospital mortality. Secondary outcomes include the occurrence of postoperative complications. Chi-squared analysis will be used to compare mortality between LMICs and HICs. Multilevel, multivariate logistic regression analysis will be undertaken to identify patient-level and hospital-level factors affecting outcomes with adjustment for confounding factors. Ethics and dissemination At the host centre, this study is classified as an audit not requiring ethical approval. All participating collaborators have gained local approval in accordance with their institutional ethical regulations. Collaborators will be encouraged to present the results locally, nationally and internationally. The results will be submitted for open access publication in a peer reviewed journal

Amiloride-sensitive channels in type I fungiform taste cells in mouse

<p>Abstract</p> <p>Background</p> <p>Taste buds are the sensory organs of taste perception. Three types of taste cells have been described. Type I cells have voltage-gated outward currents, but lack voltage-gated inward currents. These cells have been presumed to play only a support role in the taste bud. Type II cells have voltage-gated Na⁺and K⁺current, and the receptors and transduction machinery for bitter, sweet, and umami taste stimuli. Type III cells have voltage-gated Na⁺, K⁺, and Ca²⁺currents, and make prominent synapses with afferent nerve fibers. Na⁺salt transduction in part involves amiloride-sensitive epithelial sodium channels (ENaCs). In rodents, these channels are located in taste cells of fungiform papillae on the anterior part of the tongue innervated by the chorda tympani nerve. However, the taste cell type that expresses ENaCs is not known. This study used whole cell recordings of single fungiform taste cells of transgenic mice expressing GFP in Type II taste cells to identify the taste cells responding to amiloride. We also used immunocytochemistry to further define and compare cell types in fungiform and circumvallate taste buds of these mice.</p> <p>Results</p> <p>Taste cell types were identified by their response to depolarizing voltage steps and their presence or absence of GFP fluorescence. TRPM5-GFP taste cells expressed large voltage-gated Na⁺and K⁺currents, but lacked voltage-gated Ca²⁺currents, as expected from previous studies. Approximately half of the unlabeled cells had similar membrane properties, suggesting they comprise a separate population of Type II cells. The other half expressed voltage-gated outward currents only, typical of Type I cells. A single taste cell had voltage-gated Ca²⁺current characteristic of Type III cells. Responses to amiloride occurred only in cells that lacked voltage-gated inward currents. Immunocytochemistry showed that fungiform taste buds have significantly fewer Type II cells expressing PLC signalling components, and significantly fewer Type III cells than circumvallate taste buds.</p> <p>Conclusion</p> <p>The principal finding is that amiloride-sensitive Na⁺channels appear to be expressed in cells that lack voltage-gated inward currents, likely the Type I taste cells. These cells were previously assumed to provide only a support function in the taste bud.</p