Regulatory control and the costs and benefits of biochemical noise

Experiments in recent years have vividly demonstrated that gene expression can be highly stochastic. How protein concentration fluctuations affect the growth rate of a population of cells, is, however, a wide open question. We present a mathematical model that makes it possible to quantify the effect of protein concentration fluctuations on the growth rate of a population of genetically identical cells. The model predicts that the population's growth rate depends on how the growth rate of a single cell varies with protein concentration, the variance of the protein concentration fluctuations, and the correlation time of these fluctuations. The model also predicts that when the average concentration of a protein is close to the value that maximizes the growth rate, fluctuations in its concentration always reduce the growth rate. However, when the average protein concentration deviates sufficiently from the optimal level, fluctuations can enhance the growth rate of the population, even when the growth rate of a cell depends linearly on the protein concentration. The model also shows that the ensemble or population average of a quantity, such as the average protein expression level or its variance, is in general not equal to its time average as obtained from tracing a single cell and its descendants. We apply our model to perform a cost-benefit analysis of gene regulatory control. Our analysis predicts that the optimal expression level of a gene regulatory protein is determined by the trade-off between the cost of synthesizing the regulatory protein and the benefit of minimizing the fluctuations in the expression of its target gene. We discuss possible experiments that could test our predictions.Comment: Revised manuscript;35 pages, 4 figures, REVTeX4; to appear in PLoS Computational Biolog

Analysis of Motor Function in the Tg4-42 Mouse Model of Alzheimer’s Disease

Alzheimer’s disease (AD) is a neurodegenerative disorder and the most common form of dementia. Hallmarks of AD are memory impairments and cognitive deficits, but non-cognitive impairments, especially motor dysfunctions are also associated with the disease and may even precede classic clinical symptoms. With an aging society and increasing hospitalization of the elderly, motor deficits are of major interest to improve independent activities in daily living. Consistent with clinical findings, a variety of AD mouse models develop motor deficits as well. We investigated the motor function of 3- and 7-month-old Tg4-42 mice in comparison to wild-type controls and 5XFAD mice and discuss the results in context with several other AD mouse model. Our study shows impaired balance and motor coordination in aged Tg4-42 mice in the balance beam and rotarod test, while general locomotor activity and muscle strength is not impaired at 7 months. The cerebellum is a major player in the regulation and coordination of balance and locomotion through practice. Particularly, the rotarod test is able to detect cerebellar deficits. Furthermore, supposed cerebellar impairment was verified by 18F-FDG PET/MRI. Aged Tg4-42 mice showed reduced cerebellar glucose metabolism in the 18F-FDG PET. Suggesting that, deficits in coordination and balance are most likely due to cerebellar impairment. In conclusion, Tg4-42 mice develop motor deficits before memory deficits, without confounding memory test. Thus, making the Tg4-42 mouse model a good model to study the effects on cognitive decline of therapies targeting motor impairments

Standalone vertex finding in the ATLAS muon spectrometer

A dedicated reconstruction algorithm to find decay vertices in the ATLAS muon spectrometer is presented. The algorithm searches the region just upstream of or inside the muon spectrometer volume for multi-particle vertices that originate from the decay of particles with long decay paths. The performance of the algorithm is evaluated using both a sample of simulated Higgs boson events, in which the Higgs boson decays to long-lived neutral particles that in turn decay to bbar b final states, and pp collision data at √s = 7 TeV collected with the ATLAS detector at the LHC during 2011

Measurements of Higgs boson production and couplings in diboson final states with the ATLAS detector at the LHC

Measurements are presented of production properties and couplings of the recently discovered Higgs boson using the decays into boson pairs, H →γ γ, H → Z Z∗ →4l and H →W W∗ →lνlν. The results are based on the complete pp collision data sample recorded by the ATLAS experiment at the CERN Large Hadron Collider at centre-of-mass energies of √s = 7 TeV and √s = 8 TeV, corresponding to an integrated luminosity of about 25 fb−1. Evidence for Higgs boson production through vector-boson fusion is reported. Results of combined fits probing Higgs boson couplings to fermions and bosons, as well as anomalous contributions to loop-induced production and decay modes, are presented. All measurements are consistent with expectations for the Standard Model Higgs boson

Measurement of the top quark-pair production cross section with ATLAS in pp collisions at \sqrt{s}=7\TeV

A measurement of the production cross-section for top quark pairs(\ttbar) in $pp$ collisions at \sqrt{s}=7 \TeV is presented using data recorded with the ATLAS detector at the Large Hadron Collider. Events are selected in two different topologies: single lepton (electron $e$ or muon $\mu$) with large missing transverse energy and at least four jets, and dilepton ($ee$, $\mu\mu$ or $e\mu$) with large missing transverse energy and at least two jets. In a data sample of 2.9 pb-1, 37 candidate events are observed in the single-lepton topology and 9 events in the dilepton topology. The corresponding expected backgrounds from non-\ttbar Standard Model processes are estimated using data-driven methods and determined to be $12.2 \pm 3.9$ events and $2.5 \pm 0.6$ events, respectively. The kinematic properties of the selected events are consistent with SM \ttbar production. The inclusive top quark pair production cross-section is measured to be \sigmattbar=145 \pm 31 ^{+42}_{-27} pb where the first uncertainty is statistical and the second systematic. The measurement agrees with perturbative QCD calculations.Comment: 30 pages plus author list (50 pages total), 9 figures, 11 tables, CERN-PH number and final journal adde

Measurement of the top quark pair cross section with ATLAS in pp collisions at √s=7 TeV using final states with an electron or a muon and a hadronically decaying τ lepton

A measurement of the cross section of top quark pair production in proton-proton collisions recorded with the ATLAS detector at the Large Hadron Collider at a centre-of-mass energy of 7 TeV is reported. The data sample used corresponds to an integrated luminosity of 2.05 fb -1. Events with an isolated electron or muon and a τ lepton decaying hadronically are used. In addition, a large missing transverse momentum and two or more energetic jets are required. At least one of the jets must be identified as originating from a b quark. The measured cross section, σtt-=186±13(stat.)±20(syst.)±7(lumi.) pb, is in good agreement with the Standard Model prediction

Epigenetic Features of Human Mesenchymal Stem Cells Determine Their Permissiveness for Induction of Relevant Transcriptional Changes by SYT-SSX1

BACKGROUND: A characteristic SYT-SSX fusion gene resulting from the chromosomal translocation t(X;18)(p11;q11) is detectable in almost all synovial sarcomas, a malignant soft tissue tumor widely believed to originate from as yet unidentified pluripotent stem cells. The resulting fusion protein has no DNA binding motifs but possesses protein-protein interaction domains that are believed to mediate association with chromatin remodeling complexes. Despite recent advances in the identification of molecules that interact with SYT-SSX and with the corresponding wild type SYT and SSX proteins, the mechanisms whereby the SYT-SSX might contribute to neoplastic transformation remain unclear. Epigenetic deregulation has been suggested to be one possible mechanism. METHODOLOGY/PRINCIPAL FINDINGS: We addressed the effect of SYT/SSX expression on the transcriptome of four independent isolates of primary human bone marrow mesenchymal stem cells (hMSC). We observed transcriptional changes similar to the gene expression signature of synovial sarcoma, principally involving genes whose regulation is linked to epigenetic factors, including imprinted genes, genes with transcription start sites within a CpG island and chromatin related genes. Single population analysis revealed hMSC isolate-specific transcriptional changes involving genes that are important for biological functions of stem cells as well as genes that are considered to be molecular markers of synovial sarcoma including IGF2, EPHRINS, and BCL2. Methylation status analysis of sequences at the H19/IGF2 imprinted locus indicated that distinct epigenetic features characterize hMSC populations and condition the transcriptional effects of SYT-SSX expression. CONCLUSIONS/SIGNIFICANCE: Our observations suggest that epigenetic features may define the cellular microenvironment in which SYT-SSX displays its functional effects

Cognitive and memory training in adults at risk of dementia: A Systematic Review

<p>Abstract</p> <p>Background</p> <p>Effective non-pharmacological cognitive interventions to prevent Alzheimer's dementia or slow its progression are an urgent international priority. The aim of this review was to evaluate cognitive training trials in individuals with mild cognitive impairment (MCI), and evaluate the efficacy of training in memory strategies or cognitive exercises to determine if cognitive training could benefit individuals at risk of developing dementia.</p> <p>Methods</p> <p>A systematic review of eligible trials was undertaken, followed by effect size analysis. Cognitive training was differentiated from other cognitive interventions not meeting generally accepted definitions, and included both cognitive exercises and memory strategies.</p> <p>Results</p> <p>Ten studies enrolling a total of 305 subjects met criteria for cognitive training in MCI. Only five of the studies were randomized controlled trials. Meta-analysis was not considered appropriate due to the heterogeneity of interventions. Moderate effects on memory outcomes were identified in seven trials. Cognitive exercises (relative effect sizes ranged from .10 to 1.21) may lead to greater benefits than memory strategies (.88 to -1.18) on memory.</p> <p>Conclusions</p> <p>Previous conclusions of a lack of efficacy for cognitive training in MCI may have been influenced by not clearly defining the intervention. Our systematic review found that cognitive exercises can produce moderate-to-large beneficial effects on memory-related outcomes. However, the number of high quality RCTs remains low, and so further trials must be a priority. Several suggestions for the better design of cognitive training trials are provided.</p

Characterisation of the Physical Composition and Microbial Community Structure of Biofilms within a Model Full-Scale Drinking Water Distribution System

Within drinking water distribution systems (DWDS), microorganisms form multi-species biofilms on internal pipe surfaces. A matrix of extracellular polymeric substances (EPS) is produced by the attached community and provides structure and stability for the biofilm. If the EPS adhesive strength deteriorates or is overcome by external shear forces, biofilm ismobilised into the water potentially leading to degradation of water quality. However, little is known about the EPS within DWDS biofilms or how this is influenced by community composition or environmental parameters, because of the complications in obtaining biofilm samples and the difficulties in analysing EPS. Additionally, although biofilms may contain various microbial groups, research commonly focuses solely upon bacteria. This research applies an EPS analysis method based upon fluorescent confocal laser scanning microscopy (CLSM) in combination with digital image analysis (DIA), to concurrently characterize cells and EPS (carbohydrates and proteins) within drinking water biofilms from a full-scale DWDS experimental pipe loop facility with representative hydraulic conditions. Application of the EPS analysismethod, alongside DNA fingerprinting of bacterial, archaeal and fungal communities, was demonstrated for biofilms sampled from different positions around the pipeline, after 28 days growth within the DWDS experimental facility. The volume of EPS was 4.9 times greater than that of the cells within biofilms, with carbohydrates present as the dominant component. Additionally, the greatest proportion of EPS was located above that of the cells. Fungi and archaea were established as important components of the biofilm community, although bacteria were more diverse.Moreover, biofilms from different positions were similar with respect to community structure and the quantity, composition and three-dimensional distribution of cells and EPS, indicating that active colonisation of the pipe wall is an important driver inmaterial accumulation within the DWDS

Telephone based self-management support by 'lay health workers' and 'peer support workers' to prevent and manage vascular diseases: a systematic review and meta-analysis

Background: Improved prevention and management of vascular disease is a global priority. Non-health care professionals (such as, ‘lay health workers’ and ‘peer support workers’) are increasingly being used to offer telephone support alongside that offered by conventional services, to reach disadvantaged populations and to provide more efficient delivery of care. However, questions remain over the impact of such interventions, particularly on a wider range of vascular related conditions (such as, chronic kidney disease), and it is unclear how different types of telephone support impact on outcome. This study assessed the evidence on the effectiveness and cost-effectiveness of telephone self-management interventions led by ‘lay health workers’ and ‘peer support workers’ for patients with vascular disease and long-term conditions associated with vascular disease. Methods: Systematic review of randomised controlled trials. Three electronic databases were searched. Two authors independently extracted data according to the Cochrane risk of bias tool. Random effects meta-analysis was used to pool outcome measures. Results: Ten studies were included, primarily based in community settings in the United States; with participants who had diabetes; and used ‘peer support workers’ that shared characteristics with patients. The included studies were generally rated at risk of bias, as many methodological criteria were rated as ‘unclear’ because of a lack of information. Overall, peer telephone support was associated with small but significant improvements in self-management behaviour (SMD = 0.19, 95% CI 0.05 to 0.33, I2 = 20.4%) and significant reductions in HbA1c level (SMD = -0.26, 95% CI −0.41 to −0.11, I2 = 47.6%). There was no significant effect on mental health quality of life (SMD = 0.03, 95% CI −0.12 to 0.18, I2 = 0%). Data on health care utilisation were very limited and no studies reported cost effectiveness analyses. Conclusions: Positive effects were found for telephone self-management interventions via ‘lay workers’ and ‘peer support workers’ for patients on diabetes control and self-management outcomes, but the overall evidence base was limited in scope and quality. Well designed trials assessing non-healthcare professional delivered telephone support for the prevention and management of vascular disease are needed to identify the content of effective components on health outcomes, and to assess cost effectiveness, to determine if such interventions are potentially useful alternatives to professionally delivered care