Phase equilibria and glass transition in colloidal systems with short-ranged attractive interactions. Application to protein crystallization

We have studied a model of a complex fluid consisting of particles interacting through a hard core and a short range attractive potential of both Yukawa and square-well form. Using a hybrid method, including a self-consistent and quite accurate approximation for the liquid integral equation in the case of the Yukawa fluid, perturbation theory to evaluate the crystal free energies, and mode-coupling theory of the glass transition, we determine both the equilibrium phase diagram of the system and the lines of equilibrium between the supercooled fluid and the glass phases. For these potentials, we study the phase diagrams for different values of the potential range, the ratio of the range of the interaction to the diameter of the repulsive core being the main control parameter. Our arguments are relevant to a variety of systems, from dense colloidal systems with depletion forces, through particle gels, nano-particle aggregation, and globular protein crystallization.Comment: 20 pages, 10 figure

Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia.

The occurrence of non-epileptic hyperkinetic movements in the context of developmental epileptic encephalopathies is an increasingly recognized phenomenon. Identification of causative mutations provides an important insight into common pathogenic mechanisms that cause both seizures and abnormal motor control. We report bi-allelic loss-of-function CACNA1B variants in six children from three unrelated families whose affected members present with a complex and progressive neurological syndrome. All affected individuals presented with epileptic encephalopathy, severe neurodevelopmental delay (often with regression), and a hyperkinetic movement disorder. Additional neurological features included postnatal microcephaly and hypotonia. Five children died in childhood or adolescence (mean age of death: 9 years), mainly as a result of secondary respiratory complications. CACNA1B encodes the pore-forming subunit of the pre-synaptic neuronal voltage-gated calcium channel Cav2.2/N-type, crucial for SNARE-mediated neurotransmission, particularly in the early postnatal period. Bi-allelic loss-of-function variants in CACNA1B are predicted to cause disruption of Ca2+ influx, leading to impaired synaptic neurotransmission. The resultant effect on neuronal function is likely to be important in the development of involuntary movements and epilepsy. Overall, our findings provide further evidence for the key role of Cav2.2 in normal human neurodevelopment.MAK is funded by an NIHR Research Professorship and receives funding from the Wellcome Trust, Great Ormond Street Children's Hospital Charity, and Rosetrees Trust. E.M. received funding from the Rosetrees Trust (CD-A53) and Great Ormond Street Hospital Children's Charity. K.G. received funding from Temple Street Foundation. A.M. is funded by Great Ormond Street Hospital, the National Institute for Health Research (NIHR), and Biomedical Research Centre. F.L.R. and D.G. are funded by Cambridge Biomedical Research Centre. K.C. and A.S.J. are funded by NIHR Bioresource for Rare Diseases. The DDD Study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute (grant number WT098051). We acknowledge support from the UK Department of Health via the NIHR comprehensive Biomedical Research Centre award to Guy's and St. Thomas' National Health Service (NHS) Foundation Trust in partnership with King's College London. This research was also supported by the NIHR Great Ormond Street Hospital Biomedical Research Centre. J.H.C. is in receipt of an NIHR Senior Investigator Award. The research team acknowledges the support of the NIHR through the Comprehensive Clinical Research Network. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, Department of Health, or Wellcome Trust. E.R.M. acknowledges support from NIHR Cambridge Biomedical Research Centre, an NIHR Senior Investigator Award, and the University of Cambridge has received salary support in respect of E.R.M. from the NHS in the East of England through the Clinical Academic Reserve. I.E.S. is supported by the National Health and Medical Research Council of Australia (Program Grant and Practitioner Fellowship)

Exploring delay-based tcp congestion control

The thesis begins with a short review of TCP and new congestion control schemes in Chapter 2. Following this, chapter 3 explores the question of whether correlation between congestion and the delay signal of each flow on a link is really necessary for delay-based congestion control to function. It also explores the behaviour of the delay-based AIMD (DB-AIMD) algorithm in various network environments. Chapter 4 presents an experimental study into the effectiveness of a particular delay-based methodology for emptying network queues where congestion is detected. Finally, chapter 5 discussed some practical issues involved in how one measures RTT in practice for the purposes of congestion control

Finite-energy extension of a lattice glass model

We extend a previously studied lattice model of particles with infinite repulsions to the case of finite-energy interactions. The phase diagram is studied using grand canonical Monte Carlo simulation. Simulations of dynamical phenomena are made using the canonical ensemble. We find interesting order-disorder transitions in the equilibrium phase diagram and identify several anomalous regimes of diffusivity. These phenomena may be relevant to the case of strong orientational bonding near freezing

Competition between short-ranged attraction and short-ranged repulsion in crowded configurational space: A lattice model description

We describe a simple nearest-neighbor Ising model that is capable of supporting a gas, liquid, and crystal, in characteristic relationship to each other. As the parameters of the model are varied, one obtains characteristic patterns of phase behavior reminiscent of continuum systems where the range of the interaction is varied. The model also possesses dynamical arrest, and although we have not studied it in detail, these “transitions” appear to have a reasonable relationship to the phases and their transitions

Role of immunosuppression in an antibiotic stewardship intervention and its association with clinical outcomes and antibiotic use : protocol for an observational study (RISC-sepsis)

Introduction Sepsis is characterised by a dysregulated immune response to infection, with exaggerated pro-inflammatory and anti-inflammatory responses. A predominant immunosuppressive profile affecting both innate and adaptive immune responses is associated with increased hospital-acquired infection and reduced infection-free survival. While hospital-acquired infection leads to additional antibiotic use, the role of the immunosuppressive phenotype in guiding complex decisions, such as those affecting antibiotic stewardship, is uncertain. This study is a mechanistic substudy embedded within a multicentre clinical and cost-effectiveness trial of biomarker-guided antibiotic stewardship. This mechanistic study aims to determine the effect of sepsis-associated immunosuppression on the trial outcome measures. Methods and analysis RISC-sepsis is a prospective, multicentre, exploratory, observational study embedded within the ADAPT-sepsis trial. A subgroup of 180 participants with antibiotics commenced for suspected sepsis, enrolled in the ADAPT-sepsis trial, will be recruited. Blood samples will be collected on alternate days until day 7. At each time point, blood will be collected for flow cytometric analysis into cell preservation tubes. Immunophenotyping will be performed at a central testing hub by flow cytometry. The primary outcome measures are monocyte human leucocyte antigen-DR; neutrophil CD88; programmed cell death-1 on monocytes, neutrophils and T lymphocytes and the percentage of regulatory T cells. Secondary outcome measures will link to trial outcomes from the ADAPT-sepsis trial including antibiotic days; occurrence of hospital-acquired infection and length of ICU-stay and hospital-stay

Incorporating High-Dimensional Exposure Modelling into Studies of Air Pollution and Health

Performing studies on the risks of environmental hazards on human health requires accurate estimates of exposures that might be experienced by the populations at risk. Often there will be missing data and in many epidemiological studies, the locations and times of exposure measurements and health data do not match. To a large extent this will be due to the health and exposure data having arisen from completely different data sources and not as the result of a carefully designed study, leading to problems of both ‘change of support’ and ‘misaligned data’. In such cases, a direct comparison of the exposure and health outcome is often not possible without an underlying model to align the two in the spatial and temporal domains. The Bayesian approach provides the natural framework for such models; however, the large amounts of data that can arise from environmental networks means that inference using Markov Chain Monte Carlo might not be computationally feasible in this setting. Here we adapt the integrated nested Laplace approximation to implement spatio–temporal exposure models. We also propose methods for the integration of large-scale exposure models and health analyses. It is important that any model structure allows the correct propagation of uncertainty from the predictions of the exposure model through to the estimates of risk and associated confidence intervals. The methods are demonstrated using a case study of the levels of black smoke in the UK, measured over several decades, and respiratory mortality