Accessing the dynamics of large many-particle systems using Stochastic Series Expansion

The Stochastic Series Expansion method (SSE) is a Quantum Monte Carlo (QMC) technique working directly in the imaginary time continuum and thus avoiding "Trotter discretization" errors. Using a non-local "operator-loop update" it allows treating large quantum mechanical systems of many thousand sites. In this paper we first give a comprehensive review on SSE and present benchmark calculations of SSE's scaling behavior with system size and inverse temperature, and compare it to the loop algorithm, whose scaling is known to be one of the best of all QMC methods. Finally we introduce a new and efficient algorithm to measure Green's functions and thus dynamical properties within SSE.Comment: 11 RevTeX pages including 7 figures and 5 table

Dynamin impacts homology-directed repair and breast cancer response to chemotherapy

After the initial responsiveness of triple-negative breast cancers (TNBCs) to chemotherapy, they often recur as chemotherapy-resistant tumors, and this has been associated with upregulated homology-directed repair (HDR). Thus, inhibitors of HDR could be a useful adjunct to chemotherapy treatment of these cancers. We performed a high-throughput chemical screen for inhibitors of HDR from which we obtained a number of hits that disrupted microtubule dynamics. We postulated that high levels of the target molecules of our screen in tumors would correlate with poor chemotherapy response. We found that inhibition or knockdown of dynamin 2 (DNM2), known for its role in endocytic cell trafficking and microtubule dynamics, impaired HDR and improved response to chemotherapy of cells and of tumors in mice. In a retrospective analysis, levels of DNM2 at the time of treatment strongly predicted chemotherapy outcome for estrogen receptor-negative and especially for TNBC patients. We propose that DNM2-associated DNA repair enzyme trafficking is important for HDR efficiency and is a powerful predictor of sensitivity to breast cancer chemotherapy and an important target for therapy

Prototype ATLAS IBL Modules using the FE-I4A Front-End Readout Chip

The ATLAS Collaboration will upgrade its semiconductor pixel tracking detector with a new Insertable B-layer (IBL) between the existing pixel detector and the vacuum pipe of the Large Hadron Collider. The extreme operating conditions at this location have necessitated the development of new radiation hard pixel sensor technologies and a new front-end readout chip, called the FE-I4. Planar pixel sensors and 3D pixel sensors have been investigated to equip this new pixel layer, and prototype modules using the FE-I4A have been fabricated and characterized using 120 GeV pions at the CERN SPS and 4 GeV positrons at DESY, before and after module irradiation. Beam test results are presented, including charge collection efficiency, tracking efficiency and charge sharing.Comment: 45 pages, 30 figures, submitted to JINS

Hyperacute Directional Hearing and Phonotactic Steering in the Cricket (Gryllus bimaculatus deGeer)

Background: Auditory mate or prey localisation is central to the lifestyle of many animals and requires precise directional hearing. However, when the incident angle of sound approaches 0u azimuth, interaural time and intensity differences gradually vanish. This poses a demanding challenge to animals especially when interaural distances are small. To cope with these limitations imposed by the laws of acoustics, crickets employ a frequency tuned peripheral hearing system. Although this enhances auditory directionality the actual precision of directional hearing and phonotactic steering has never been studied in the behaviourally important frontal range. Principal Findings: Here we analysed the directionality of phonotaxis in female crickets (Gryllus bimaculatus) walking on an open-loop trackball system by measuring their steering accuracy towards male calling song presented at frontal angles of incidence. Within the range of 630u, females reliably discriminated the side of acoustic stimulation, even when the sound source deviated by only 1u from the animal’s length axis. Moreover, for angles of sound incidence between 1u and 6u the females precisely walked towards the sound source. Measuring the tympanic membrane oscillations of the front leg ears with a laser vibrometer revealed between 0u and 30u a linear increasing function of interaural amplitude differences with a slope of 0.4 dB/u. Auditory nerve recordings closely reflected these bilateral differences in afferent response latency and intensity that provide the physiological basis for precise auditory steering

AB-QTL analysis in winter wheat: II. Genetic analysis of seedling and field resistance against leaf rust in a wheat advanced backcross population

The present study aimed to localize exotic quantitative trait locus (QTL) alleles for the improvement of leaf rust (P.triticina) resistance in an advanced backcross (AB) population, B22, which is derived from a cross between the winter wheat cultivar Batis (Triticumaestivum) and the synthetic wheat accession Syn022L. The latter was developed from hybridization of T.turgidum ssp. dicoccoides and T.tauschii. Altogether, 250 BC2F3 lines of B22 were assessed for seedling resistance against the leaf rust isolate 77WxR under controlled conditions. In addition, field resistance against leaf rust was evaluated by assessing symptom severity under natural infestation across multiple environments. Simultaneously, population B22 was genotyped with a total of 97 SSR markers, distributed over the wheat A, B and D genomes. The phenotype and genotype data were subjected to QTL analysis by applying a 3-factorial mixed model analysis of variance including the marker genotype as a fixed effect and the environments, the lines and the marker by environment interactions as random effects. The QTL analysis revealed six putative QTLs for seedling resistance and seven for field resistance. For seedling resistance, the effects of exotic QTL alleles improved resistance at all detected loci. The maximum decrease of disease symptoms (−46.3%) was associated with marker locus Xbarc149 on chromosome 1D. For field resistance, two loci had stable main effects across environments and five loci exhibited marker by environment interaction effects. The strongest effects were detected at marker locus Xbarc149 on chromosome 1D, at which the exotic allele decreased seedling symptoms by 46.3% and field symptoms by 43.6%, respectively. Some of the detected QTLs co-localized with known resistance genes, while others appear to be as novel resistance loci. Our findings indicate, that the exotic wheat accession Syn022L may be useful for the improvement of leaf rust resistance in cultivated wheat

The German MultiCare-study: Patterns of multimorbidity in primary health care – protocol of a prospective cohort study

Background Multimorbidity is a highly frequent condition in older people, but well designed longitudinal studies on the impact of multimorbidity on patients and the health care system have been remarkably scarce in numbers until today. Little is known about the long term impact of multimorbidity on the patients' life expectancy, functional status and quality of life as well as health care utilization over time. As a consequence, there is little help for GPs in adjusting care for these patients, even though studies suggest that adhering to present clinical practice guidelines in the care of patients with multimorbidity may have adverse effects. Methods The study is designed as a multicentre prospective, observational cohort study of 3.050 patients aged 65 to 85 at baseline with at least three different diagnoses out of a list of 29 illnesses and syndromes. The patients will be recruited in approx. 120 to 150 GP surgeries in 8 study centres distributed across Germany. Information about the patients' morbidity will be collected mainly in GP interviews and from chart reviews. Functional status, resources/risk factors, health care utilization and additional morbidity data will be assessed in patient interviews, in which a multitude of well established standardized questionnaires and tests will be performed. Discussion The main aim of the cohort study is to monitor the course of the illness process and to analyse for which reasons medical conditions are stable, deteriorating or only temporarily present. First, clusters of combinations of diseases/disorders (multimorbidity patterns) with a comparable impact (e.g. on quality of life and/or functional status) will be identified. Then the development of these clusters over time will be analysed, especially with regard to prognostic variables and the somatic, psychological and social consequences as well as the utilization of health care resources. The results will allow the development of an instrument for prediction of the deterioration of the illness process and point at possibilities of prevention. The practical consequences of the study results for primary care will be analysed in expert focus groups in order to develop strategies for the inclusion of the aspects of multimorbidity in primary care guidelines

Intracellular Trafficking and Synaptic Function of APL-1 in Caenorhabditis elegans

Background: Alzheimer’s disease (AD) is a neurodegenerative disorder primarily characterized by the deposition of b-amyloid plaques in the brain. Plaques are composed of the amyloid-b peptide derived from cleavage of the amyloid precursor protein (APP). Mutations in APP lead to the development of Familial Alzheimer’s Disease (FAD), however, the normal function of this protein has proven elusive. The organism Caenorhabditis elegans is an attractive model as the amyloid precursor-like protein (APL-1) is the single ortholog of APP, and loss of apl-1 leads to a severe molting defect and early larval lethality. Methodology/Principal Findings: We report here that lethality and molting can be rescued by full length APL-1, C-terminal mutations as well as a C-terminal truncation, suggesting that the extracellular region of the protein is essential for viability. RNAi knock-down of apl-1 followed by drug testing on the acetylcholinesterase inhibitor aldicarb showed that loss of apl-1 leads to aldicarb hypersensitivity, indicating a defect in synaptic function. The aldicarb hypersensitivity can be rescued by full length APL-1 in a dose dependent fashion. At the cellular level, kinesins UNC-104/KIF-1A and UNC-116/kinesin-1 are positive regulators of APL-1 expression in the neurons. Knock-down of the small GTPase rab-5 also leads to a dramatic decrease in the amount of apl-1 expression in neurons, suggesting that trafficking from the plasma membrane to the early endosome is important for apl-1 function. Loss of function of a different small GTPase, UNC-108, on the contrary, leads t

The influence of age, gender and socio-economic status on multimorbidity patterns in primary care. first results from the multicare cohort study

Background: Multimorbidity is a phenomenon with high burden and high prevalence in the elderly. Our previous research has shown that multimorbidity can be divided into the multimorbidity patterns of 1) anxiety, depression, somatoform disorders (ADS) and pain, and 2) cardiovascular and metabolic disorders. However, it is not yet known, how these patterns are influenced by patient characteristics. The objective of this paper is to analyze the association of socio-demographic variables, and especially socio-economic status with multimorbidity in general and with each multimorbidity pattern. Methods: The MultiCare Cohort Study is a multicentre, prospective, observational cohort study of 3.189 multimorbid patients aged 65+ randomly selected from 158 GP practices. Data were collected in GP interviews and comprehensive patient interviews. Missing values have been imputed by hot deck imputation based on Gower distance in morbidity and other variables. The association of patient characteristics with the number of chronic conditions is analysed by multilevel mixed-effects linear regression analyses. Results: Multimorbidity in general is associated with age (+0.07 chronic conditions per year), gender (-0.27 conditions for female), education (-0.26 conditions for medium and -0.29 conditions for high level vs. low level) and income (-0.27 conditions per logarithmic unit). The pattern of cardiovascular and metabolic disorders shows comparable associations with a higher coefficient for gender (-1.29 conditions for female), while multimorbidity within the pattern of ADS and pain correlates with gender (+0.79 conditions for female), but not with age or socioeconomic status. Conclusions: Our study confirms that the morbidity load of multimorbid patients is associated with age, gender and the socioeconomic status of the patients, but there were no effects of living arrangements and marital status. We could also show that the influence of patient characteristics is dependent on the multimorbidity pattern concerned, i.e. there seem to be at least two types of elderly multimorbid patients. First, there are patients with mainly cardiovascular and metabolic disorders, who are more often male, have an older age and a lower socio-economic status. Second, there are patients mainly with ADS and pain-related morbidity, who are more often female and equally distributed across age and socio-economic groups

Gene Expression Profiling of Two Distinct Neuronal Populations in the Rodent Spinal Cord

BACKGROUND: In the field of neuroscience microarray gene expression profiles on anatomically defined brain structures are being used increasingly to study both normal brain functions as well as pathological states. Fluorescent tracing techniques in brain tissue that identifies distinct neuronal populations can in combination with global gene expression profiling potentially increase the resolution and specificity of such studies to shed new light on neuronal functions at the cellular level. METHODOLOGY/PRINCIPAL FINDINGS: We examine the microarray gene expression profiles of two distinct neuronal populations in the spinal cord of the neonatal rat, the principal motor neurons and specific interneurons involved in motor control. The gene expression profiles of the respective cell populations were obtained from amplified mRNA originating from 50-250 fluorescently identified and laser microdissected cells. In the data analysis we combine a new microarray normalization procedure with a conglomerate measure of significant differential gene expression. Using our methodology we find 32 genes to be more expressed in the interneurons compared to the motor neurons that all except one have not previously been associated with this neuronal population. As a validation of our method we find 17 genes to be more expressed in the motor neurons than in the interneurons and of these only one had not previously been described in this population. CONCLUSIONS/SIGNIFICANCE: We provide an optimized experimental protocol that allows isolation of gene transcripts from fluorescent retrogradely labeled cell populations in fresh tissue, which can be used to generate amplified aRNA for microarray hybridization from as few as 50 laser microdissected cells. Using this optimized experimental protocol in combination with our microarray analysis methodology we find 49 differentially expressed genes between the motor neurons and the interneurons that reflect the functional differences between these two cell populations in generating and transmitting the motor output in the rodent spinal cord