240 research outputs found
Anisotropic Laminar Piezocomposite Actuator Incorporating Machined PMN-PT Single Crystal Fibers
The design, fabrication, and testing of a flexible, laminar, anisotropic piezoelectric composite actuator utilizing machined PMN-32%PT single crystal fibers is presented. The device consists of a layer of rectangular single crystal piezoelectric fibers in an epoxy matrix, packaged between interdigitated electrode polyimide films. Quasistatic free-strain measurements of the single crystal device are compared with measurements from geometrically identical specimens incorporating polycrystalline PZT-5A and PZT-5H piezoceramic fibers. Free-strain actuation of the single crystal actuator at low bipolar electric fields (+/- 250 V/mm) is approximately 400% greater than that of the baseline PZT-5A piezoceramic device, and 200% greater than that of the PZT-5H device. Free-strain actuation under high unipolar electric fields (0-4kV/mm) is approximately 200% of the PZT-5A baseline device, and 150% of the PZT-5H alternate piezoceramic device. Performance increases at low field are qualitatively consistent with predicted increases based on scaling the low-field d33 piezoelectric constants of the respective piezoelectric materials. High-field increases are much less than scaled d33 estimates, but appear consistent with high-field freestrain measurements reported for similar bulk single-crystal and piezoceramic compositions. Measurements of single crystal actuator capacitance and coupling coefficient are also provided. These properties were poorly predicted using scaled bulk material dielectric and coupling coefficient data. Rules-of-mixtures calculations of the effective elastic properties of the single crystal device and estimated actuation work energy densities are also presented. Results indicate longitudinal stiffnesses significantly lower (50% less) than either piezoceramic device. This suggests that single-crystal piezocomposite actuators will be best suited to low induced-stress, high strain and deflection applications
Strain-specificity in the hydrogen sulphide signalling network following dietary restriction in recombinant inbred mice
Modulation of the ageing process by dietary restriction (DR) across multiple taxa is well established. While the exact mechanism through which DR acts remains elusive, the gasotransmitter hydrogen sulphide (H2S) may play an important role. We employed a comparative-type approach using females from three ILSXISS recombinant inbred mouse strains previously reported to show differential lifespan responses following 40% DR. Following long-term (10 months) 40% DR, strain TejJ89âreported to show lifespan extension under DRâexhibited elevated hepatic H2S production relative to its strain-specific ad libitum (AL) control. Strain TejJ48 (no reported lifespan effect following 40% DR) exhibited significantly reduced hepatic H2S production, while H2S production was unaffected by DR in strain TejJ114 (shortened lifespan reported following 40% DR). These differences in H2S production were reflected in highly divergent gene and protein expression profiles of the major H2S production and disposal enzymes across strains. Increased hepatic H2S production in TejJ89 mice was associated with elevation of the mitochondrial H2S-producing enzyme 3-mercaptopyruvate sulfurtransferase (MPST). Our findings further support the potential role of H2S in DR-induced longevity and indicate the presence of genotypic-specificity in the production and disposal of hepatic H2S in response to 40% DR in mice
Total synthesis of dehaloperophoramidine using a highly diastereoselective Hosomi-Sakurai reaction
The authors would like to acknowledge EPSRC for PhD funding through the Doctoral Training Schemes.The synthesis of dehaloperophoramidine, a non-halogenated derivative of the marine natural product perophoramidine, is reported. The key steps included a [3,3]-Claisen rearrangement and an epoxide opening/allylsilylation (modified Hosomi-Sakurai) reaction to install the contiguous all-carbon quaternary stereocentres with the required relative stereochemistry. The first five steps were carried out on seventy gram scale without the need for chromatography. Resolution of the [3,3]-Claisen product gave samples of the highly enantiomerically-enriched ketones which are flexible starting points for the synthesis of a number of complex ring structures. A regio- and diastereo-selective iodocyclisation was then used to differentiate between two allyl groups enabling the synthesis of the target molecule by two different routes. A detailed comparison of the trifluoroacetic acid salt of the synthetic dehaloperophoramidine with authentic material was carried out including a key doping experiment. Biological testing showed that (±)-dehaloperophoramidine was cytotoxic to HCT116, HT29 and LoVo colorectal carcinoma cells with comparable activity to that reported for the halogenated perophoramidine. This demonstrated for the first time that the halogens are not essential for the biological activity of this alkaloid class.Publisher PDFPeer reviewe
Voltage Regulator Module Noise Analysis for High-Volume Server Applications
This paper presents a methodology to analyze voltage regulator module (VRM) noise coupling problems in high-volume server applications. The technique is applied on a real engineering design. The comprehensive model includes irregular power shapes, decoupling capacitors, and dielectric and conductive loss. Irregular shaped power plane modeling is cross-checked with four separate methods to demonstrate accuracy
A rapid in vivo screen for pancreatic ductal adenocarcinoma therapeutics
Pancreatic ductal adenocarcinoma (PDA) is the fourth leading cause of cancer-related deaths in the United States, and is projected to be second by 2025. It has the worst survival rate among all major cancers. Two pressing needs for extending life expectancy of affected individuals are the development of new approaches to identify improved therapeutics, addressed herein, and the identification of early markers. PDA advances through a complex series of intercellular and physiological interactions that drive cancer progression in response to organ stress, organ failure, malnutrition, and infiltrating immune and stromal cells. Candidate drugs identified in organ culture or cell-based screens must be validated in preclinical models such as KIC (p48Cre;LSL-KrasG12D;Cdkn2af/f) mice, a genetically engineered model of PDA in which large aggressive tumors develop by 4 weeks of age. We report a rapid, systematic and robust in vivo screen for effective drug combinations to treat Kras-dependent PDA. Kras mutations occur early in tumor progression in over 90% of human PDA cases. Protein kinase and G-protein coupled receptor (GPCR) signaling activates Kras. Regulators of G-protein signaling (RGS) proteins are coincidence detectors that can be induced by multiple inputs to feedback-regulate GPCR signaling. We crossed Rgs16::GFP bacterial artificial chromosome (BAC) transgenic mice withKIC mice and show that the Rgs16::GFP transgene is a KrasG12D-dependent marker of all stages of PDA, and increases proportionally to tumor burden in KIC mice. RNA sequencing (RNA-Seq) analysis of cultured primary PDA cells reveals characteristics of embryonic progenitors of pancreatic ducts and endocrine cells, and extraordinarily high expression of the receptor tyrosine kinase Axl, an emerging cancer drug target. In proof-of-principle drug screens, we find that weanling KIC mice with PDA treated for 2 weeks with gemcitabine (with or without Abraxane) plus inhibitors of Axl signaling (warfarin and BGB324) have fewer tumor initiation sites and reduced tumor size compared with the standard-of-care treatment. Rgs16::GFP is therefore an in vivo reporter of PDA progression and sensitivity to new chemotherapeutic drug regimens such as Axl-targeted agents. This screening strategy can potentially be applied to identify improved therapeutics for other cancers
Rationale and design for SHAREHD: a quality improvement collaborative to scale up Shared Haemodialysis Care for patients on centre based haemodialysis.
BACKGROUND: The study objective is to assess the effectiveness and economic impact of a structured programme to support patient involvement in centre-based haemodialysis and to understand what works for whom in what circumstances and why. It implements a program of Shared Haemodialysis Care (SHC) that aims to improve experience and outcomes for those who are treated with centre-based haemodialysis, and give more patients the confidence to dialyse independently both at centres and at home. METHODS/DESIGN: The 24 month mixed methods cohort evaluation of 600 prevalent centre based HD patients is nested within a 30 month quality improvement program that aims to scale up SHC at 12 dialysis centres across England. SHC describes an intervention where patients who receive centre-based haemodialysis are given the opportunity to learn, engage with and undertake tasks associated with their treatment. Following a 6-month set up period, a phased implementation programme is initiated across 12 dialysis units using a randomised stepped wedge design with 6 centres participating in each of 2 steps, each lasting 6 months. The intervention utilises quality improvement methodologies involving rapid tests of change to determine the most appropriate mechanisms for implementation in the context of a learning collaborative. Running parallel with the stepped wedge intervention is a mixed methods cohort evaluation that employs patient questionnaires and interviews, and will link with routinely collected data at the end of the study period. The primary outcome measure is the number of patients performing at least 5 dialysis-related tasks collected using 3 monthly questionnaires. Secondary outcomes measures include: the number of people choosing to perform home haemodialysis or dialyse independently in-centre by the end of the study period; end-user recommendation; home dialysis establishment delay; staff impact and confidence; hospitalisation; infection and health economics. DISCUSSION: The results from this study will provide evidence of impact of SHC, barriers to patient and centre level adoption and inform development of future interventions to support its implementation. TRIAL REGISTRATION: ISRCTN Number: 93999549 , (retrospectively registered 1st May 2017); NIHR Research Portfolio: 31566
Correlation between pseudotyped virus and authentic virus neutralisation assays, a systematic review and meta-analysis of the literature
Background: The virus neutralization assay is a principal method to assess the efficacy of antibodies in blocking viral entry. Due to biosafety handling requirements of viruses classified as hazard group 3 or 4, pseudotyped viruses can be used as a safer alternative. However, it is often queried how well the results derived from pseudotyped viruses correlate with authentic virus. This systematic review and meta-analysis was designed to comprehensively evaluate the correlation between the two assays.
Methods: Using PubMed and Google Scholar, reports that incorporated neutralisation assays with both pseudotyped virus, authentic virus, and the application of a mathematical formula to assess the relationship between the results, were selected for review. Our searches identified 67 reports, of which 22 underwent a three-level meta-analysis.
Results: The three-level meta-analysis revealed a high level of correlation between pseudotyped viruses and authentic viruses when used in an neutralisation assay. Reports that were not included in the meta-analysis also showed a high degree of correlation, with the exception of lentiviral-based pseudotyped Ebola viruses.
Conclusion: Pseudotyped viruses identified in this report can be used as a surrogate for authentic virus, though care must be taken in considering which pseudotype core to use when generating new uncharacterised pseudotyped viruses
Recommended from our members
COVID-19, systemic crisis, and possible implications for the wild meat trade in sub-Saharan Africa
Wild animals play an integral and complex role in the economies and ecologies of many
countries across the globe, including those of West and Central Africa, the focus of this
policy perspective. The trade in wild meat, and its role in diets, have been brought into
focus as a consequence of discussions over the origins of COVID-19. As a result, there
have been calls for the closure of Chinaâs âwet marketsâ; greater scrutiny of the wildlife
trade in general; and a spotlight has been placed on the potential risks posed by growing human populations and shrinking natural habitats for animal to human transmission of
zoonotic diseases. However, to date there has been little attention given to what the consequences of the COVID-19 economic shock may be for the wildlife trade; the people who
rely on it for their livelihoods; and the wildlife that is exploited. In this policy perspective,
we argue that the links between the COVID-19 pandemic, rural livelihoods and wildlife
are likely to be more complex, more nuanced, and more far-reaching, than is represented in
the literature to date. We develop a causal model that tracks the likely implications for the
wild meat trade of the systemic crisis triggered by COVID-19. We focus on the resulting
economic shockwave, as manifested in the collapse in global demand for commodities such
as oil, and international tourism services, and what this may mean for local African economies and livelihoods. We trace the shockwave through to the consequences for the use
of, and demand for, wild meats as households respond to these changes. We suggest that
understanding and predicting the complex dynamics of wild meat use requires increased
collaboration between environmental and resource economics and the ecological and conservation sciences
Suppression of costimulation by human cytomegalovirus promotes evasion of cellular immune defenses.
CD58 is an adhesion molecule that is known to play a critical role in costimulation of effector cells and is intrinsic to immune synapse structure. Herein, we describe a virally encoded gene that inhibits CD58 surface expression. Human cytomegalovirus (HCMV) UL148 was necessary and sufficient to promote intracellular retention of CD58 during HCMV infection. Blocking studies with antagonistic anti-CD58 mAb and an HCMV UL148 deletion mutant (HCMVâUL148) with restored CD58 expression demonstrated that the CD2/CD58 axis was essential for the recognition of HCMV-infected targets by CD8+ HCMV-specific cytotoxic T lymphocytes (CTLs). Further, challenge of peripheral blood mononuclear cells ex vivo with HCMVâUL148 increased both CTL and natural killer (NK) cell degranulation against HCMV-infected cells, including NK-driven antibody-dependent cellular cytotoxicity, showing that UL148 is a modulator of the function of multiple effector cell subsets. Our data stress the effect of HCMV immune evasion functions on shaping the immune response, highlighting the capacity for their potential use in modulating immunity during the development of anti-HCMV vaccines and HCMV-based vaccine vectors
- âŠ