Heterogeneity in Bacillus subtilis : growth phase dependent activity and noise

PhD ThesisStochastic noise is a naturally occurring phenomena in all chemical reactions. The processes involved in gene expression are subject to the stochastic, random nature of chemical interactions. Single cell measurements of fluorescent activity have been used to deconstruct the sources of gene expression noise. These systems rely on the use of inducible gene expression from negatively regulated promoters. Gene expression noise is quantified by the fluorescent activity of the reporter. Single time-point assays have defined the contribution of transcription and translation as sources of gene expression noise. This thesis investigated gene expression noise in Bacillus subtilis. It extends the single time-point assays and places noise within the context of the bacterial growth curve. Two main findings were concluded from the data. Firstly, there is growth phase dependent fluorescent activity, due to the accumulation of a stable fluorescent protein. Secondly, high noise levels in gene expression are a transcription dependent feature of cells in stationary phase. Investigating the synthetic gene circuits responsible for these phenotypes highlight the importance of fully characterising the system. Differences in transcription, translation and fluorescent activity were observed in response to the architecture of the gene circuitsBiotechnology and Biological Sciences Research Council (BBSRC

Automated Function Implementation via Conditional Parameterized Quantum Circuits with Applications to Finance

Classical Monte Carlo algorithms can theoretically be sped up on a quantum computer by employing amplitude estimation (AE). To realize this, an efficient implementation of state-dependent functions is crucial. We develop a straightforward approach based on pre-training parameterized quantum circuits, and show how they can be transformed into their conditional variant, making them usable as a subroutine in an AE algorithm. To identify a suitable circuit, we propose a genetic optimization approach that combines variable ansatzes and data encoding. We apply our algorithm to the problem of pricing financial derivatives. At the expense of a costly pre-training process, this results in a quantum circuit implementing the derivatives' payoff function more efficiently than previously existing quantum algorithms. In particular, we compare the performance for European vanilla and basket options.Comment: 10 pages, 12 figures, 2 algorithm

AutoBayes Program Synthesis System Users Manual

Program synthesis is the systematic, automatic construction of efficient executable code from high-level declarative specifications. AutoBayes is a fully automatic program synthesis system for the statistical data analysis domain; in particular, it solves parameter estimation problems. It has seen many successful applications at NASA and is currently being used, for example, to analyze simulation results for Orion. The input to AutoBayes is a concise description of a data analysis problem composed of a parameterized statistical model and a goal that is a probability term involving parameters and input data. The output is optimized and fully documented C/C++ code computing the values for those parameters that maximize the probability term. AutoBayes can solve many subproblems symbolically rather than having to rely on numeric approximation algorithms, thus yielding effective, efficient, and compact code. Statistical analysis is faster and more reliable, because effort can be focused on model development and validation rather than manual development of solution algorithms and code

Assessment of available evidence in the management of gallbladder and bile duct stones:a systematic review of international guidelines

BACKGROUND: Gallstone disease is a frequent disorder in the Western world with a prevalence of 10-20%. Recommendations for the assessment and management of gallstones vary internationally. The aim of this systematic review was to assess quality of guideline recommendations for treatment of gallstones. METHODS: PubMed, EMBASE and websites of relevant associations were systematically searched. Guidelines without a critical appraisal of literature were excluded. Quality of guidelines was determined using the AGREE II instrument. Recommendations without consensus or with low level of evidence were considered to define problem areas and clinical research gaps. RESULTS: Fourteen guidelines were included. Overall quality of guidelines was low, with a mean score of 57/100 (standard deviation 19). Five of 14 guidelines were considered suitable for use in clinical practice without modifications. Ten recommendations from all included guidelines were based on low level of evidence and subject to controversy. These included major topics, such as definition of symptomatic gallstones, indications for cholecystectomy and intraoperative cholangiography. CONCLUSION: Only five guidelines on gallstones are evidence-based and of a high quality, but even in these controversy exists on important topics. High quality evidence is needed in specific areas before an international guideline can be developed and endorsed worldwide

Frequency of surgical treatment and related hospital procedures in the United Kingdom: A national ecological study using hospital episode statistics

T.E.F.A. is supported by a Medical Research Council and British Journal of Anaesthesia clinical research training fellowship (grant reference MR/M017974/1), and R.M.P. is supported by an NIHR research professorship. T.D.D. is funded by the Welsh Clinical Academic Training (WCAT) Fellowship. M.A.G. is a Chief Scientist Office (Scotland) NHS Research Scheme Clinicia

Time Marches on, and So Does the History of Public Relations

Editor's Introduction to History of Public Relations special issu

A Response to the Draft Climate Change Adaptation Sectoral Plan for Agriculture, Forest and Seafood Sector

Teagasc is pleased to have the opportunity to contribute to this Draft Climate Change Adaptation Sectoral Plan for Agriculture, Forest and Seafood Sectors, although our contribution will largely be limited to the agriculture and forestry sectors. We have also taken the liberty to contribute in the form of ‘submissions, observations and comments’ as indicated in the call for contributions rather than in the formal questionnaire which appears to be more appropriate for an individual submission rather than an organisational contribution

Transcriptomic evidence for modulation of host inflammatory responses during febrile Plasmodium falciparum malaria

Identifying molecular predictors and mechanisms of malaria disease is important for understanding how Plasmodium falciparum malaria is controlled. Transcriptomic studies in humans have so far been limited to retrospective analysis of blood samples from clinical cases. In this prospective, proof-of-principle study, we compared whole-blood RNA-seq profiles at pre-and post-infection time points from Malian adults who were either asymptomatic (n = 5) or febrile (n = 3) during their first seasonal PCR-positive P. falciparum infection with those from malaria-naïve Dutch adults after a single controlled human malaria infection (n = 5). Our data show a graded activation of pathways downstream of pro-inflammatory cytokines, with the highest activation in malaria-naïve Dutch individuals and significantly reduced activation in malaria-experienced Malians. Newly febrile and asymptomatic infections in Malians were statistically indistinguishable except for genes activated by pro-inflammatory cytokines. The combined data provide a molecular basis for the development of a pyrogenic threshold as individuals acquire immunity to clinical malaria

Inflammatory profiles across the spectrum of disease reveal a distinct role for GM-CSF in severe COVID-19

While it is now widely accepted that host inflammatory responses contribute to lung injury, the pathways that drive severity and distinguish coronavirus disease 2019 (COVID-19) from other viral lung diseases remain poorly characterized. We analyzed plasma samples from 471 hospitalized patients recruited through the prospective multicenter ISARIC4C study and 39 outpatients with mild disease, enabling extensive characterization of responses across a full spectrum of COVID-19 severity. Progressive elevation of levels of numerous inflammatory cytokines and chemokines (including IL-6, CXCL10, and GM-CSF) were associated with severity and accompanied by elevated markers of endothelial injury and thrombosis. Principal component and network analyses demonstrated central roles for IL-6 and GM-CSF in COVID-19 pathogenesis. Comparing these profiles to archived samples from patients with fatal influenza, IL-6 was equally elevated in both conditions whereas GM-CSF was prominent only in COVID-19. These findings further identify the key inflammatory, thrombotic, and vascular factors that characterize and distinguish severe and fatal COVID-19

Validation of Epidermal AMBRA1 and Loricrin (AMBLor) as a prognostic biomarker for non-ulcerated AJCC stage I/II cutaneous melanoma

Background: Combined expression of the autophagy-regulatory protein AMBRA1 (activating molecule in Beclin1-regulated autophagy) and the terminal differentiation marker loricrin in the peritumoral epidermis of stage I melanomas can identify tumour subsets at low risk of metastasis. Objectives: To validate the combined expression of peritumoral AMBRA1 and loricrin (AMBLor) as a prognostic biomarker able to identify both stage I and II melanomas at low risk of tumour recurrence. Methods: Automated immunohistochemistry was used to analyse peritumoral AMBRA1 and loricrin expression in geographically distinct discovery (n = 540) and validation (n = 300) cohorts of nonulcerated American Joint Committee on Cancer (AJCC) stage I and II melanomas. AMBLor status was correlated with clinical outcomes in the discovery and validation cohorts separately and combined. Results: Analysis of AMBLor in the discovery cohort revealed a recurrence-free survival (RFS) rate of 95.5% in the AMBLor low-risk group vs. 81.7% in the AMBLor at-risk group (multivariate log-rank, P < 0.001) and a negative predictive value (NPV) of 96.0%. In the validation cohort, AMBLor analysis revealed a RFS rate of 97.6% in the AMBLor low-risk group vs. 78.3% in the at-risk group (multivariate log-rank, P < 0.001) and a NPV of 97.6%. In a multivariate model considering AMBLor, Breslow thickness, age and sex, analysis of the combined discovery and validation cohorts showed that the estimated effect of AMBLor was statistically significant ,with a hazard ratio of 3.469 (95% confidence interval 1.403–8.580, P = 0.007) and an overall NPV of 96.5%. Conclusions These data provide further evidence validating AMBLor as a prognostic biomarker to identify nonulcerated AJCC stage I and II melanoma tumours at low risk of disease recurrence