James Davies - Academia.edu (original) (raw)

Papers by James Davies

Journal of General Virology

Molluscum contagiosum virus (MCV) is a common cause of benign skin lesions in young children and ... more Molluscum contagiosum virus (MCV) is a common cause of benign skin lesions in young children and currently the only endemic human poxvirus. Following the infection of primary keratinocytes in the epidermis, MCV induces the proliferation of infected cells and this results in the production of wart-like growths. Full productive infection is observed only after the infected cells differentiate. During this prolonged replication cycle the virus must avoid elimination by the host immune system. We therefore sought to investigate the function of the two major histocompatibility complex class-I-related genes encoded by the MCV genes mc033 and mc080. Following insertion into a replication-deficient adenovirus vector, codon-optimized versions of mc033 and mc080 were expressed as endoglycosidase-sensitive glycoproteins that localized primarily in the endoplasmic reticulum. MC080, but not MC033, downregulated cell-surface expression of endogenous classical human leucocyte antigen (HLA) class I...

Journal of Investigative Surgery

The Lancet Psychiatry

Association between attention deficit hyperactivity disorder and asthma: a systematic review and ... more Association between attention deficit hyperactivity disorder and asthma: a systematic review and meta-analysis and a Swedish population-based study.

Analytical chemistry, Jan 21, 2017

Recent studies suggest that reactions in aqueous microcompartments can occur at significantly dif... more Recent studies suggest that reactions in aqueous microcompartments can occur at significantly different rates than those in the bulk. Most studies have used electrospray to generate a polydisperse source of highly charged microdroplets, leading to multiple confounding factors potentially influencing reaction rates (e.g., evaporation, charge, and size). Thus, the underlying mechanism for the observed enhancement remains unclear. We present a new type of electrodynamic balance-the branched quadrupole trap (BQT)-which can be used to study reactions in microdroplets in a controlled environment. The BQT allows for condensed phase chemical reactions to be initiated by colliding droplets with different reactants and levitating the merged droplet indefinitely. The performance of the BQT is characterized in several ways. Sub-millisecond mixing times as fast as ∼400 μs are measured for low velocity (∼0.1 m/s) collisions of droplets with <40 μm diameters. The reaction of o-phthalaldehyde (O...

Cancer Discovery

Protein-coding mutations in clear cell renal cell carcinoma (ccRCC) have been extensively charact... more Protein-coding mutations in clear cell renal cell carcinoma (ccRCC) have been extensively characterized, frequently involving inactivation of the von Hippel-Lindau (VHL) tumor suppressor. Roles for noncoding cis-regulatory aberrations in ccRCC tumorigenesis, however, remain unclear. Analyzing 10 primary tumor/normal pairs and 9 cell lines across 79 chromatin profiles, we observed pervasive enhancer malfunction in ccRCC, with cognate enhancer-target genes associated with tissue-specific aspects of malignancy. Superenhancer profiling identified ZNF395 as a ccRCCspecific and VHL-regulated master regulator whose depletion causes near-complete tumor elimination in vitro and in vivo. VHL loss predominantly drives enhancer/superenhancer deregulation more so than promoters, with acquisition of active enhancer marks (H3K27ac, H3K4me1) near ccRCC hallmark genes. Mechanistically, VHL loss stabilizes HIF2α-HIF1β heterodimer binding at enhancers, subsequently recruiting histone acetyltransferase p300 without overtly affecting preexisting promoter-enhancer interactions. Subtype-specific driver mutations such as VHL may thus propagate unique pathogenic dependencies in ccRCC by modulating epigenomic landscapes and cancer gene expression. SIGNIFICANCE: Comprehensive epigenomic profiling of ccRCC establishes a compendium of somatically altered cis-regulatory elements, uncovering new potential targets including ZNF395, a ccRCC master regulator. Loss of VHL, a ccRCC signature event, causes pervasive enhancer malfunction, with binding of enhancer-centric HIF2α and recruitment of histone acetyltransferase p300 at preexisting lineage-specific promoter-enhancer complexes. Cancer Discov; 7(11); 1-22. ©2017 AACR.

BMJ open, Nov 28, 2016

Cancer-associated thrombosis (CAT) complex condition, which may present to any healthcare profess... more Cancer-associated thrombosis (CAT) complex condition, which may present to any healthcare professional and at any point during the cancer journey. As such, patients may be managed by a number of specialties, resulting in inconsistent practice and suboptimal care. We describe the development of a dedicated CAT service and its evaluation. Specialist cancer centre, district general hospital and primary care. Patients with CAT and their referring clinicians. A cross specialty team developed a dedicated CAT service , including clear referral pathways, consistent access to medicines, patient's information and a specialist clinic. The service was evaluated using a mixed-methods evaluation , including audits of clinical practice, clinical outcomes, staff surveys and qualitative interviewing of patients and healthcare professionals. Data from 457 consecutive referrals over an 18-month period were evaluated. The CAT service has led to an 88% increase in safe and consistent community presc...

International Review of Scottish Studies, 2007

EMBO reports, Oct 8, 2016

Hypoxia-inducible factor (HIF) directs an extensive transcriptional cascade that transduces numer... more Hypoxia-inducible factor (HIF) directs an extensive transcriptional cascade that transduces numerous adaptive responses to hypoxia. Pan-genomic analyses, using chromatin immunoprecipitation and transcript profiling, have revealed large numbers of HIF-binding sites that are generally associated with hypoxia-inducible transcripts, even over long chromosomal distances. However, these studies do not define the specific targets of HIF-binding sites and do not reveal how induction of HIF affects chromatin conformation over distantly connected functional elements. To address these questions, we deployed a recently developed chromosome conformation assay that enables simultaneous high-resolution analyses from multiple viewpoints. These assays defined specific long-range interactions between intergenic HIF-binding regions and one or more promoters of hypoxia-inducible genes, revealing the existence of multiple enhancer-promoter, promoter-enhancer, and enhancer-enhancer interactions. However,...

Analytical chemistry, Jan 11, 2016

The formation of ultra-viscous, glassy and amorphous gel states in aqueous aerosol following the ... more The formation of ultra-viscous, glassy and amorphous gel states in aqueous aerosol following the loss of water results in non-equilibrium dynamics due to the extended timescales for diffusive mixing. Existing techniques for measuring water diffusion using isotopic exchange are limited by contact of samples with the substrate, and methods applied to infer diffusion coefficients from mass transport in levitated droplets requires analysis using complex coupled differential equations to derive diffusion coefficients. We present a new technique that combines contactless levitation using aerosol optical tweezers with isotopic exchange (D2O/H2O) to measure the water diffusion coefficient over a broad range (Dw ~10-12 - 10-17 m2 s-1) in viscous organic liquids (citric acid, sucrose and shikimic acid) and inorganic gels (magnesium sulfate, MgSO4). For the organic liquids in binary and ternary mixtures, Dw depends on relative humidity and follows a simple compositional Vignes relationship. In...

The Annals of thoracic surgery, Jan 22, 2015

Acute myocardial infarction complicated by cardiogenic shock (AMI-CS) is associated with substant... more Acute myocardial infarction complicated by cardiogenic shock (AMI-CS) is associated with substantial mortality. We evaluated outcomes of patients in The Society of Thoracic Surgeons Adult Cardiac Surgery Database who underwent coronary artery bypass graft surgery (CABG) in the setting of AMI-CS. All patients with AMI-CS who underwent nonelective CABG or CABG with ventricular assist device implantation within 7 days after myocardial infarction were enrolled. The primary analysis sample consisted of patients who underwent surgery between June 2011 and December 2013. Baseline characteristics, operative findings, outcomes, and the utilization of mechanical circulatory support (MCS) were assessed in detail in this population. We also evaluated trends in unadjusted mortality for all patients undergoing CABG or CABG with ventricular assist device for AMI-CS from January 2005 to December 2013. A total of 5,496 patients met study criteria, comprising 1.5% of all patients undergoing CABG duri...

We estimate the level and distribution of global household wealth. The levels of assets and debts... more We estimate the level and distribution of global household wealth. The levels of assets and debts for 39 countries are measured using household balance sheet and survey data centred on the year 2000. The determinants of mean financial assets, non-financial assets, and liabilities are studied empirically, and the results used to estimate average wealth holdings for countries lacking direct evidence. Data on the pattern of household distribution of wealth are assembled for 20 countries, which together account for 59 per cent of the global population and 75 per cent of global wealth. The observed relation between wealth and income distribution in these 20 countries allows estimates of wealth inequality to be produced for many other nations. Combining the figures for individual countries reveals that net worth averaged US$44,024 per adult in PPP terms across the globe. Wealth of US$8,635 was needed to be in the top half of the global distribution, and US$518,364 to be in the top one per cent. The top 10 per cent owned 71 per cent of world wealth, and the Gini coefficient for the global distribution of wealth is estimated to be 0.802, indicating greater inequality than that observed in the global distribution of consumption or income.

The Journal of Physical Chemistry A, 2012

The influence of solute species on mass transfer to and from aqueous aerosol droplets is investig... more The influence of solute species on mass transfer to and from aqueous aerosol droplets is investigated using an electrodynamic balance coupled with light scattering techniques. In particular, we explore the limitations imposed on water evaporation by slow bulk phase diffusion and by the formation of surface organic films. Measurements of evaporation from ionic salt solutions, specifically sodium chloride and ammonium sulfate, are compared with predictions from an analytical model framework, highlighting the uncertainties associated with quantifying gas diffusional transport. The influence of low solubility organic acids on mass transfer is reported and compared to both model predictions and previous work. The limiting value of the evaporation coefficient that can be resolved by this approach, when uncertainties in key thermophysical quantities are accounted for, is estimated. The limitation of slow bulk phase diffusion on the evaporation rate is investigated for gel and glass states formed during the evaporation of magnesium sulfate and sucrose droplets, respectively. Finally, the effect of surfactants on evaporation has been probed, with soluble surfactants (such as sodium dodecyl sulfate) leading to little or no retardation of evaporation through slowing of surface layer kinetics.

European Journal of Immunology, 2011

TLR and complement activation ensures efficient clearance of infection. Previous studies document... more TLR and complement activation ensures efficient clearance of infection. Previous studies documented synergism between TLRs and the receptor for the pro-inflammatory complement peptide C5a (C5aR/CD88), and regulation of TLR-induced pro-inflammatory responses by C5aR, suggesting crosstalk between TLRs and C5aR. However, it is unclear whether and how TLRs modulate C5a-induced pro-inflammatory responses. We demonstrate a marked positive modulatory effect of TLR activation on cell sensitivity to C5a in vitro and ex vivo and identify an underlying mechanistic target. Pre-exposure of PBMCs and whole blood to diverse TLR ligands or bacteria enhanced C5a-induced pro-inflammatory responses. This effect was not observed in TLR4 signalling-deficient mice. TLR-induced hypersensitivity to C5a did not result from C5aR upregulation or modulation of C5a-induced Ca 21 mobilization. Rather, TLRs targeted another C5a receptor, C5L2 (acting as a negative modulator of C5aR), by reducing C5L2 activity. TLR-induced hypersensitivity to C5a was mimicked by blocking C5L2 and was not observed in C5L2KO mice. Furthermore, TLR activation inhibited C5L2 expression upon C5a stimulation. These findings identify a novel pathway of crosstalk within the innate immune system that amplifies innate host defense at the TLR-complement interface. Unravelling the mutually regulated activities of TLRs and complement may reveal new therapeutic avenues to control inflammation.

Critical Care Medicine, 1999

The adhesion molecule L-selectin plays an important role in leukocyte-endothelium interactions, t... more The adhesion molecule L-selectin plays an important role in leukocyte-endothelium interactions, thereby contributing to inflammatory reactions. We tested the hypothesis that humanized anti-L-selectin antibodies reduce trauma-associated organ damage and mortality. Prospective, randomized experimental study. Independent nonprofit research laboratory in a trauma hospital (Ludwig Boltzmann Institute) and a contract research institute (Biocon). Twenty-eight male baboons (Papio ursinus), 18 to 29 kg. Hemorrhagic-traumatic shock was created by complement activation with cobra venom factor, followed by withdrawal of blood to a mean arterial pressure of 35 to 45 mm Hg. Blood and lactated Ringer&amp;amp;amp;#39;s solution were reinfused. Animals were randomized to receive either 2 mg/kg humanized anti-L-selectin antibody (HuDREG-55 [Ab]) or placebo (lactated Ringer&amp;amp;amp;#39;s solution [LRS]). Treatment with humanized anti-L-selectin antibody decreased mortality (Ab 21% vs. LRS 71%; p = .011) and improved survival time (p = .016). A trend toward reduced organ damage, especially in the adrenal glands (score 1.2 +/- 0.2 placebo vs. 1.0 +/- 0.1 antibody; p = .059) was seen, and at 24 hrs was accompanied by significantly increased mean arterial pressure (Ab 99 +/- 6 mm Hg vs. LRS 79 +/- 8 mm Hg; p = .023), cardiac output (Ab 3.4 +/- 0.2 L/min vs. LRS 2.4 +/- 0.3 L/min; p = .007), core temperature (p = .048), and improved perfusion, with less negative base excess (Ab 2.9 +/- 1.1 vs. LRS 2.1 +/- 1.7; p = .019) and a trend toward less lactate (p = .065). These improvements were accompanied by significantly (p = .006) decreased fluid requirements in the treatment group (Ab 11.7 +/- 2.5 mL/kg/hr vs. LRS 23.0 +/- 2.3 mL/kg/hr). There were also fewer circulating leukocytes (p = .042) in the treatment group at 24 hrs. Humanized anti-L-selectin antibody has beneficial effects on survival in a long-term in vivo model of hemorrhagic. traumatic shock.

Clinical Toxicology, 2008

Introduction. Acute self-poisoning with the organophosphorus (OP) pesticide dimethoate has a huma... more Introduction. Acute self-poisoning with the organophosphorus (OP) pesticide dimethoate has a human case fatality threefold higher than poisoning with chlorpyrifos despite similar animal toxicity. The typical clinical presentation of severe dimethoate poisoning is quite distinct from that of chlorpyrifos and other OP pesticides: many patients present with hypotension that progresses to shock and death within 12-48 h post-ingestion. The pathophysiology of this syndrome is not clear. Case reports. We present here three patients with proven severe dimethoate poisoning. Clinically, all had inappropriate peripheral vasodilatation and profound hypotension on presentation, which progressed despite treatment with atropine, i.v. fluids, pralidoxime chloride, and inotropes. All died 2.5-32 h post-admission. Continuous cardiac monitoring and quantification of troponin T provided little evidence for a primary cardiotoxic effect of dimethoate. Conclusion. Severe dimethoate self-poisoning causes a syndrome characterized by marked hypotension with progression to distributive shock and death despite standard treatments. A lack of cardiotoxicity until just before death suggests that the mechanism is of OP-induced low systemic vascular resistance (SVR). Further invasive studies of cardiac function and SVR, and post-mortem histology, are required to better describe this syndrome and to establish the role of vasopressors and high-dose atropine in therapy.