Tracking protein function with sodium multi quantum spectroscopy in a 3D-tissue culture based on microcavity arrays

The aim of this study was to observe the effects of strophanthin induced inhibition of the Na-/KATPase in liver cells using a magnetic resonance (MR) compatible bioreactor. A microcavity array with a high density three-dimensional cell culture served as a functional magnetic resonance imaging (MRI) phantom for sodium multi quantum (MQ) spectroscopy. Direct contrast enhanced (DCE) MRI revealed the homogenous distribution of biochemical substances inside the bioreactor. NMR experiments using advanced bioreactors have advantages with respect to having full control over a variety of physiological parameters such as temperature, gas composition and fluid flow. Simultaneous detection of single quantum (SQ) and triple quantum (TQ) MR signals improves accuracy and was achieved by application of a pulse sequence with a time proportional phase increment (TQTPPI). The time course of the Na-/KATPase inhibition in the cell culture was demonstrated by the corresponding alterations of sodium TQ/ SQ MR signals

Some open questions in TDDFT: Clues from Lattice Models and Kadanoff-Baym Dynamics

Two aspects of TDDFT, the linear response approach and the adiabatic local density approximation, are examined from the perspective of lattice models. To this end, we review the DFT formulations on the lattice and give a concise presentation of the time-dependent Kadanoff-Baym equations, used to asses the limitations of the adiabatic approximation in TDDFT. We present results for the density response function of the 3D homogeneous Hubbard model, and point out a drawback of the linear response scheme based on the linearized Sham-Schl\"uter equation. We then suggest a prescription on how to amend it. Finally, we analyze the time evolution of the density in a small cubic cluster, and compare exact, adiabatic-TDDFT and Kadanoff-Baym-Equations densities. Our results show that non-perturbative (in the interaction) adiabatic potentials can perform quite well for slow perturbations but that, for faster external fields, memory effects, as already present in simple many-body approximations, are clearly required.Comment: 15 pages, submitted to Chemical Physic

Non-manifesting AHI1 truncations indicate localized loss-of-function tolerance in a severe Mendelian disease gene

Determination of variant pathogenicity represents a major challenge in the era of high-throughput sequencing. Erroneous categorization may result if variants affect genes that are in fact dispensable. We demonstrate that this also applies to rare, apparently unambiguous truncating mutations of an established disease gene. By whole-exome sequencing (WES) in a consanguineous family with congenital non-syndromic deafness, we unexpectedly identified a homozygous nonsense variant, p.Arg1066*, in AHI1, a gene associated with Joubert syndrome (JBTS), a severe recessive ciliopathy. None of four homozygotes expressed any signs of JBTS, and one of them had normal hearing, which also ruled out p.Arg1066* as the cause of deafness. Homozygosity mapping and WES in the only other reported JBTS family with a homozygous C-terminal truncation (p.Trp1088Leufs*16) confirmed AHI1 as disease gene, but based on a more N-terminal missense mutation impairing WD40-repeat formation. Morpholinos against N-terminal zebrafish Ahi1, orthologous to where human mutations cluster, produced a ciliopathy, but targeting near human p.Arg1066 and p.Trp1088 did not. Most AHI1 mutations in JBTS patients result in truncated protein lacking WD40-repeats and the SH3 domain; disease was hitherto attributed to loss of these protein interaction modules. Our findings indicate that normal development does not require the C-terminal SH3 domain. This has far-reaching implications, considering that variants like p.Glu984* identified by preconception screening (‘Kingsmore panel') do not necessarily indicate JBTS carriership. Genomes of individuals with consanguineous background are enriched for homozygous variants that may unmask dispensable regions of disease genes and unrecognized false positives in diagnostic large-scale sequencing and preconception carrier screenin

Finite element-based micromechanical modeling of the influence of phase properties on the elastic response of cementitious mortars

This study reports the influence of inclusion stiffness and its distribution on the stress distributions in the microstructural phases of different cementitious mortars using microstructure-guided finite element simulations. Randomly generated periodic microstructures with single/multiple inclusion sizes and random spatial distribution, subjected to periodic boundary conditions and a strain-controlled virtual testing regime are chosen for final analysis. Numerical simulations reveal: (i) the differences in locations/magnitudes of stress concentrations as a function of inclusion stiffness and size distribution, and (ii) the sometimes detrimental influence of matrix and interface stiffening/strengthening on the overall composite response, leading to material design strategies when non-conventional inclusions are used in cementitious systems for special properties. The constitutive behavior in the linear elastic regime is extracted based on the predicted dominant principal stresses and strains in the representative area element. Thus, in addition to the microstructural phase stresses, this methodology also provides predictions of the composite elastic modulus, which are observed to be more reliable than those obtained from analytical prediction models

Role of students' context in predicting academic performance at a medical school: a retrospective cohort study

OBJECTIVES: This study examines associations between medical students’ background characteristics (postcode-based measures of disadvantage, high school attended, sociodemographic characteristics), and academic achievement at a Russell Group University. DESIGN: Retrospective cohort analysis. SETTING: Applicants accepted at the University of Liverpool medical school between 2004 and 2006, finalising their studies between 2010 and 2011. PARTICIPANTS: 571 students (with an English home postcode) registered on the full-time Medicine and Surgery programme, who successfully completed their medical degree. MAIN OUTCOME MEASURES: Final average at year 4 of the medical programme (represented as a percentage). RESULTS: Entry grades were positively associated with final attainment (p<0.001). Students from high-performing schools entered university with higher qualifications than students from low-performing schools (p<0.001), though these differences did not persist at university. Comprehensive school students entered university with higher grades than independent school students (p<0.01), and attained higher averages at university, though differences were not significant after controlling for multiple effects. Associations between school type and achievement differed between sexes. Females attained higher averages than males at university. Significant academic differences were observed between ethnic groups at entry level and university. Neither of the postcode-based measures of disadvantage predicted significant differences in attainment at school or university. CONCLUSIONS: The findings of this study suggest that educational attainment at school is a good, albeit imperfect, predictor of academic attainment at medical school. Most attainment differences observed between students either decreased or disappeared during university. Unlike previous studies, independent school students did not enter university with the highest grades, but achieved the lowest attainment at university. Such variations depict how patterns may differ between subjects and higher-education institutions. Findings advocate for further evidence to help guide the implementation of changes in admissions processes and widen participation at medical schools fairly

Search for new phenomena in final states with an energetic jet and large missing transverse momentum in pp collisions at √ s = 8 TeV with the ATLAS detector

Results of a search for new phenomena in final states with an energetic jet and large missing transverse momentum are reported. The search uses 20.3 fb−1 of √ s = 8 TeV data collected in 2012 with the ATLAS detector at the LHC. Events are required to have at least one jet with pT > 120 GeV and no leptons. Nine signal regions are considered with increasing missing transverse momentum requirements between Emiss T > 150 GeV and Emiss T > 700 GeV. Good agreement is observed between the number of events in data and Standard Model expectations. The results are translated into exclusion limits on models with either large extra spatial dimensions, pair production of weakly interacting dark matter candidates, or production of very light gravitinos in a gauge-mediated supersymmetric model. In addition, limits on the production of an invisibly decaying Higgs-like boson leading to similar topologies in the final state are presente