3,017 research outputs found
Ohmic and step noise from a single trapping center hybridized with a Fermi sea
We show that single electron tunneling devices such as the Cooper-pair box or
double quantum dot can be sensitive to the zero-point fluctuation of a single
trapping center hybridized with a Fermi sea. If the trap energy level is close
to the Fermi sea and has line-width \gamma > k_B T, its noise spectrum has an
Ohmic Johnson-Nyquist form, whereas for \gamma < k_B T the noise has a
Lorentzian form expected from the semiclassical limit. Trap levels above the
Fermi level are shown to lead to steps in the noise spectrum that can be used
to probe their energetics, allowing the identification of individual trapping
centers coupled to the device.Comment: Revised version to appear in Phys. Rev. Let
Maladaptation and the paradox of robustness in evolution
Background. Organisms use a variety of mechanisms to protect themselves
against perturbations. For example, repair mechanisms fix damage, feedback
loops keep homeostatic systems at their setpoints, and biochemical filters
distinguish signal from noise. Such buffering mechanisms are often discussed in
terms of robustness, which may be measured by reduced sensitivity of
performance to perturbations. Methodology/Principal Findings. I use a
mathematical model to analyze the evolutionary dynamics of robustness in order
to understand aspects of organismal design by natural selection. I focus on two
characters: one character performs an adaptive task; the other character
buffers the performance of the first character against perturbations. Increased
perturbations favor enhanced buffering and robustness, which in turn decreases
sensitivity and reduces the intensity of natural selection on the adaptive
character. Reduced selective pressure on the adaptive character often leads to
a less costly, lower performance trait. Conclusions/Significance. The paradox
of robustness arises from evolutionary dynamics: enhanced robustness causes an
evolutionary reduction in the adaptive performance of the target character,
leading to a degree of maladaptation compared to what could be achieved by
natural selection in the absence of robustness mechanisms. Over evolutionary
time, buffering traits may become layered on top of each other, while the
underlying adaptive traits become replaced by cheaper, lower performance
components. The paradox of robustness has widespread implications for
understanding organismal design
Inhibition of phage infection in capsule-producing Streptococcus thermophilus using concanavalin A, lysozyme and saccharides
Lactic cultures that produce capsular polysaccharides are widely used in the dairy industry. However, little information is available on their phage-cell interactions. Concanavalin A (Con A), lysozyme, andsaccharides were investigated for their ability to modify phage-cell interactions in such a manner as to inhibit phage infection. The ability of phage to infect cells was determined by measuring acidproduction in Elliker broth. Acid production by capsule-producing Streptococcus thermophilus was inhibited less by bacteriophage when cells were pretreated with Con. A than was acid production by acapsule-free variant. The presence of 0.5 mg/ml lysozyme in Elliker broth significantly reduced phage infection. However, there was no increased effect when lysozyme and Con A were combined in thegrowth medium. The addition of 5 g/L of glucosamine to Elliker broth also inhibited phage infection. The results of this study indicate that it is possible to reduce phage infection of capsule-forming S.thermophilus by blocking or modifying phage adsorption sites
Self-amplified Cherenkov radiation from a relativistic electron in a waveguide partially filled with a laminated material
The radiation from a relativistic electron uniformly moving along the axis of
cylindrical waveguide filled with laminated material of finite length is
investigated. Expressions for the spectral distribution of radiation passing
throw the transverse section of waveguide at large distances from the laminated
material are derived with no limitations on the amplitude and variation profile
of the layered medium permittivity and permeability. Numerical results for
layered material consisting of dielectric plates alternated with vacuum gaps
are given. It is shown that at a special choice of problem parameters,
Cherenkov radiation generated by the relativistic electron inside the plates is
self-amplified. The visual explanation of this effect is given and a possible
application is discussed.Comment: 8 pages, 4 figures,1 table, the paper is accepted for publication in
the Journal of Physics: Conference Serie
Microscopic model of critical current noise in Josephson-junction qubits: Subgap resonances and Andreev bound states
We propose a microscopic model of critical current noise in
Josephson-junctions based on individual trapping-centers in the tunnel barrier
hybridized with electrons in the superconducting leads. We calculate the noise
exactly in the limit of no on-site Coulomb repulsion. Our result reveals a
noise spectrum that is dramatically different from the usual Lorentzian assumed
in simple models. We show that the noise is dominated by sharp subgap
resonances associated to the formation of pairs of Andreev bound states, thus
providing a possible explanation for the spurious two-level systems
(microresonators) observed in Josephson junction qubits [R.W. Simmonds et al.,
Phys. Rev. Lett. 93, 077003 (2004)]. Another implication of our model is that
each trapping-center will contribute a sharp dielectric resonance only in the
superconducting phase, providing an effective way to validate our results
experimentally. We derive an effective Hamiltonian for a qubit interacting with
Andreev bound states, establishing a direct connection between phenomenological
models and the microscopic parameters of a Fermionic bath.Comment: 11 pages, 8 figure
Kinetics of cancer: a method to test hypotheses of genetic causation
BACKGROUND: Mouse studies have recently compared the age-onset patterns of cancer between different genotypes. Genes associated with earlier onset are tentatively assigned a causal role in carcinogenesis. These standard analyses ignore the great amount of information about kinetics contained in age-onset curves. We present a method for analyzing kinetics that measures quantitatively the causal role of candidate genes in cancer progression. We use our method to demonstrate a clear association between somatic mutation rates of different DNA mismatch repair (MMR) genotypes and the kinetics of cancer progression. METHODS: Most experimental studies report age-onset curves as the fraction diagnosed with tumors at each age for each group. We use such data to estimate smoothed survival curves, then measure incidence rates at each age by the slope of the fitted curve divided by the fraction of mice that remain undiagnosed for tumors at that age. With the estimated incidence curves, we compare between different genotypes the median age of cancer onset and the acceleration of cancer, which is the rate of increase in incidence with age. RESULTS: The direction of change in somatic mutation rate between MMR genotypes predicts the direction of change in the acceleration of cancer onset in all 7 cases (p Ë 0.008), with the same result for the association between mutation rate and the median age of onset. CONCLUSION: Many animal experiments compare qualitatively the onset curves for different genotypes. If such experiments were designed to analyze kinetics, the research could move to the next stage in which the mechanistic consequences of particular genetic pathways are related to the dynamics of carcinogenesis. The data we analyzed here were not collected to test mechanistic and quantitative hypotheses about kinetics. Even so, a simple reanalysis revealed significant insights about how DNA repair genotypes affect separately the age of onset and the acceleration of cancer. Our method of comparing genotypes provides good statistical tests even with small samples for each genotype
Associations between SNPs and immune-related circulating proteins in schizophrenia
Genome-wide association studies (GWAS) and proteomic studies have provided convincing evidence implicating alterations in immune/inflammatory processes in schizophrenia. However, despite the convergence of evidence, direct links between the genetic and proteomic findings are still lacking for schizophrenia. We investigated associations between single nucleotide polymorphisms (SNPs) from the custom-made PsychArray and the expression levels of 190 multiplex immunoassay profiled serum proteins in 149 schizophrenia patients and 198 matched controls. We identified associations between 81 SNPs and 29 proteins, primarily involved in immune/inflammation responses. Significant SNPxDiagnosis interactions were identified for eight serum proteins including Factor-VII[rs555212], Alpha-1-Antitrypsin[rs11846959], Interferon-Gamma Induced Protein 10[rs4256246] and von-Willebrand-Factor[rs12829220] in the control group; Chromogranin-A[rs9658644], Cystatin-C[rs2424577] and Vitamin K-Dependent Protein S[rs6123] in the schizophrenia group; Interleukin-6 receptor[rs7553796] in both the control and schizophrenia groups. These results suggested that the effect of these SNPs on expression of the respective proteins varies with diagnosis. The combination of patient-specific genetic information with blood biomarker data opens a novel approach to investigate disease mechanisms in schizophrenia and other psychiatric disorders. Our findings not only suggest that blood protein expression is influenced by polymorphisms in the corresponding gene, but also that the effect of certain SNPs on expression of proteins can vary with diagnosis
Transcriptomic profiling of pancreatic alpha, beta and delta cell populations identifies delta cells as a principal target for ghrelin in mouse islets.
AIMS/HYPOTHESIS: Intra-islet and gut-islet crosstalk are critical in orchestrating basal and postprandial metabolism. The aim of this study was to identify regulatory proteins and receptors underlying somatostatin secretion though the use of transcriptomic comparison of purified murine alpha, beta and delta cells. METHODS: Sst-Cre mice crossed with fluorescent reporters were used to identify delta cells, while Glu-Venus (with Venus reported under the control of the Glu [also known as Gcg] promoter) mice were used to identify alpha and beta cells. Alpha, beta and delta cells were purified using flow cytometry and analysed by RNA sequencing. The role of the ghrelin receptor was validated by imaging delta cell calcium concentrations using islets with delta cell restricted expression of the calcium reporter GCaMP3, and in perfused mouse pancreases. RESULTS: A database was constructed of all genes expressed in alpha, beta and delta cells. The gene encoding the ghrelin receptor, Ghsr, was highlighted as being highly expressed and enriched in delta cells. Activation of the ghrelin receptor raised cytosolic calcium levels in primary pancreatic delta cells and enhanced somatostatin secretion in perfused pancreases, correlating with a decrease in insulin and glucagon release. The inhibition of insulin secretion by ghrelin was prevented by somatostatin receptor antagonism. CONCLUSIONS/INTERPRETATION: Our transcriptomic database of genes expressed in the principal islet cell populations will facilitate rational drug design to target specific islet cell types. The present study indicates that ghrelin acts specifically on delta cells within pancreatic islets to elicit somatostatin secretion, which in turn inhibits insulin and glucagon release. This highlights a potential role for ghrelin in the control of glucose metabolism.This work was supported by the European Foundation for the
Study of Diabetes and Boehringer Ingelheim Basic Research Programme;
the Wellcome Trust (grants 106262/Z/14/Z, 106263/Z/14/Z and 100574/
Z/12/Z); the Medical Research Council Metabolic Diseases Unit (grants
MRC_MC_UU_12012/3 and MRC_MC_UU_12012/5); and the Novo
Nordisk Foundation
Social sciences research in neglected tropical diseases 3: Investment in social science research in neglected diseases of poverty: a case study of Bill and Melinda Gates Foundation
This article has been made available through the Brunel Open Access Publishing Fund.BACKGROUND: The level of funding provides a good proxy for the level of commitment or prioritisation given to a particular issue. While the need for research relevant to social, economic, cultural and behavioural aspects of neglected tropical diseases (NTD) control has been acknowledged, there is limited data on the level of funding that supports NTD social science research.
METHOD: A case study was carried out in which the spending of a major independent funder, the Bill and Melinda Gates Foundation (BMGF) - was analysed. A total of 67 projects funded between October 1998 and November 2008 were identified from the BMGF database. With the help of keywords within the titles of 67 grantees, they were categorised as social science or non-social science research based on available definition of social science. A descriptive analysis was conducted.
RESULTS: Of 67 projects analysed, 26 projects (39%) were social science related while 41 projects (61%) were basic science or other translational research including drug development. A total of US 241 million) went to social science research. Although the level of funding for social science research has generally been lower than that for non-social science research over 10 year period, social science research attracted more funding in 2004 and 2008.
CONCLUSION: The evidence presented in this case study indicates that funding on NTD social science research compared to basic and translational research is not as low as it is perceived to be. However, as there is the acute need for improved delivery and utilisation of current NTD drugs/technologies, informed by research from social science approaches, funding priorities need to reflect the need to invest significantly more in NTD social science research
Are genetic risk factors for psychosis also associated with dimension-specific psychotic experiences in adolescence?
Psychosis has been hypothesised to be a continuously distributed quantitative phenotype and disorders such as schizophrenia and bipolar disorder represent its extreme manifestations. Evidence suggests that common genetic variants play an important role in liability to both schizophrenia and bipolar disorder. Here we tested the hypothesis that these common variants would also influence psychotic experiences measured dimensionally in adolescents in the general population. Our aim was to test whether schizophrenia and bipolar disorder polygenic risk scores (PRS), as well as specific single nucleotide polymorphisms (SNPs) previously identified as risk variants for schizophrenia, were associated with adolescent dimension-specific psychotic experiences. Self-reported Paranoia, Hallucinations, Cognitive Disorganisation, Grandiosity, Anhedonia, and Parent-rated Negative Symptoms, as measured by the Specific Psychotic Experiences Questionnaire (SPEQ), were assessed in a community sample of 2,152 16-year-olds. Polygenic risk scores were calculated using estimates of the log of odds ratios from the Psychiatric Genomics Consortium GWAS stage-1 mega-analysis of schizophrenia and bipolar disorder. The polygenic risk analyses yielded no significant associations between schizophrenia and bipolar disorder PRS and the SPEQ measures. The analyses on the 28 individual SNPs previously associated with schizophrenia found that two SNPs in TCF4 returned a significant association with the SPEQ Paranoia dimension, rs17512836 (p-value=2.57x10-4) and rs9960767 (p-value=6.23x10-4). Replication in an independent sample of 16-year-olds (N=3,427) assessed using the Psychotic-Like Symptoms Questionnaire (PLIKS-Q), a composite measure of multiple positive psychotic experiences, failed to yield significant results. Future research with PRS derived from larger samples, as well as larger adolescent validation samples, would improve the predictive power to test these hypotheses further. The challenges of relating adult clinical diagnostic constructs such as schizophrenia to adolescent psychotic experiences at a genetic level are discussed
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