Novel diagnostic approaches and management of coronary microvascular dysfunction

\ua9 2024 The Authors. The mechanism underlying ischaemic heart disease (IHD) has been primarily attributed to obstructive coronary artery disease (CAD). However, non-obstructive coronary arteries are identified in >50% of patients undergoing elective coronary angiography, recently leading to growing interest in the investigation and management of angina/ischaemia with non-obstructive coronary arteries (ANOCA/INOCA). INOCA is an umbrella term encompassing a multiple spectrum of possible pathogenetic entities, including coronary vasomotor disorders which consist of two major endotypes: coronary microvascular dysfunction (CMD) and vasospastic angina. Both conditions can coexist and be associated with concomitant obstructive CAD. Particularly, CMD refers to myocardial ischaemia due to reduced vasodilatory capacity of coronary microcirculation secondary to structural remodelling or impaired resting microvascular tone (functional) or a combination of both. CMD is not a benign condition and is more prevalent in women presenting with chronic coronary syndrome compared to men. In this setting, an impaired coronary flow reserve has been associated with increased risk of major adverse cardiovascular events. ANOCA/INOCA patients also experience impaired quality of life and associated increased healthcare costs. Therefore, research in this scenario has led to better definition, classification, and prognostic stratification based on the underlying pathophysiological mechanisms. The development and validation of non-invasive imaging modalities, invasive coronary vasomotor function testing and angiography-derived indices provide a comprehensive characterisation of CMD. The present narrative review aims to summarise current data relating to the diagnostic approach to CMD and provides details on the sequence that therapeutic management should follow

Flexible Electronics Applications of Ge-rich andSelenium Substituted Phase-change Materials in Non-volatile Memories

This is the author accepted manuscript.The crystallization properties of Ge-rich GeSbTe (GST) and selenium substituted GeSbSeTe (GSST) alloys are investigated and the materials’ applicability for use in flexible memory devices is assessed. The electrical and structural properties of Ge-rich GST and GSST are measured as a function of temperature, where the high temperature stability of the amorphous phase is demonstrated. Finally the electrical switching of a Ge-rich flexible memory device is shown and simulations of GSST undergoing phase switching in a memory architecture suitable for integration into flexible electronics is demonstrated.PragmatI

Flexible Electronics Applications of Ge-Rich and Se-Substituted Phase-Change Materials in Nonvolatile Memories

This is the author accepted manuscript. The final version is available from Wiley via the DOI in this recordData Availability Statement: The data that support the findings of this study are available from the corresponding author upon reasonable request.Flexible electronics which are easy to manufacture and integrate into everyday items require suitable memory technology that can function on flexible surfaces. Herein, the properties of Ge-rich GeSbTe (GST) and Se-substituted GeSbSeTe (GSST) phase-change alloys are investigated for application as nonvolatile write-once and rewritable memories in flexible electronics. These materials have a higher crystallization temperature than the archetypal composition of Ge2Sb2Te5 and hence better data retention properties. Moreover, their high crystallization temperature provides for a particularly straightforward implementation of a write-once memory configuration. Material properties of Ge-rich GST and GSST are measured as a function of temperature using four-point probe electrical testing, Raman spectroscopy, and X-ray diffraction. Following this, the switching of flexible memory devices is investigated through both simulation and experiment. More specifically, crossbar memory devices fabricated using Ge-rich GST are experimentally fabricated and tested, while the operation of GSST pore cell structures suitable for flexible memory applications is demonstrated through simulation.Engineering and Physical Sciences Research Council (EPSRC)PragmatIC Semiconductor Lt

Real time Raman imaging to understand dissolution performance of amorphous solid dispersions

We have employed for the first time Raman spectroscopic imaging along with multi-variate curve resolution (MCR) analysis to investigate in real time and in-situ the dissolution mechanisms that underpin amorphous solid dispersions, with data being collected directly from the dosage form itself. We have also employed a novel rotating disk dissolution rate (RDDR) methodology to track, through the use of high-performance liquid chromatography (HPLC), the dissolution trends of both drug and polymer simultaneously in multi-component systems. Two formulations of poorly water-soluble felodipine in a polymeric matrix of copovidone VA64 which have different drug loadings of 5% and 50% w/w were used as models with the aim of studying the effects of increasing the amount of active ingredient on the dissolution performance. It was found that felodipine and copovidone in the 5% dispersion dissolve with the same dissolution rate and that no Raman spectral changes accompanied the dissolution, indicating that the two components dissolve as single entity, whose behaviour is dominated by water-soluble copovidone. For the 50% drug-loaded dispersion, partial RDDR values of both felodipine and copovidone were found to be extremely low. MCR Raman maps along with classical Raman/X-ray powder diffraction (XRPD) characterisation revealed that after an initial loss of copovidone from the extrudate the drug re-crystallises, pointing to a release dynamics dependent on the low water solubility and high hydrophobicity of felodipine. Raman imaging revealed different rates of transition from amorphous to crystalline felodipine at different locations within the dosage form

Apicoplast isoprenoid precursor synthesis and the molecular basis of fosmidomycin resistance in Toxoplasma gondii

Expression of a bacterial transporter protein in Toxoplasma gondii results in parasite susceptibility to Formidomycin, a drug targeting isoprenoid precursor synthesis

An exploration of the determinants for decision to migrate existing resources to cloud computing using an integrated TOE-DOI model

Migrating existing resources to cloud computing is a strategic organisational decision that can be difficult. It requires the consideration and evaluation of a wide range of technical and organisational aspects. Although a significant amount of attention has been paid by many industrialists and academics to aid migration decisions, the procedure remains difficult. This is mainly due to underestimation of the range of factors and characteristics affecting the decision for cloud migration. Further research is needed to investigate the level of effect these factors have on migration decisions and the overall complexity. This paper aims to explore the level of complexity of the decision to migrate the cloud. A research model based on the diffusion of innovation (DOI) theory and the technology-organization-environment (TOE) framework was developed. The model was tested using exploratory and confirmatory factor analysis. The quantitative analysis shows the level of impact of the identified variables on the decision to migrate. Seven determinants that contribute to the complexity of the decisions are identified. They need to be taken into account to ensure successful migration. This result has expanded the collective knowledge about the complexity of the issues that have to be considered when making decisions to migrate to the cloud. It contributes to the literature that addresses the complex and multidimensional nature of migrating to the cloud

The Nucleosome (Histone-DNA Complex) Is the TLR9-Specific Immunostimulatory Component of Plasmodium falciparum That Activates DCs

The systemic clinical symptoms of Plasmodium falciparum infection such as fever and chills correspond to the proinflammatory cytokines produced in response to the parasite components released during the synchronized rupture of schizonts. We recently demonstrated that, among the schizont-released products, merozoites are the predominant components that activate dendritic cells (DCs) by TLR9-specific recognition to induce the maturation of cells and to produce proinflammatory cytokines. We also demonstrated that DNA is the active constituent and that formation of a DNA-protein complex is essential for the entry of parasite DNA into cells for recognition by TLR9. However, the nature of endogenous protein-DNA complex in the parasite is not known. In this study, we show that parasite nucleosome constitute the major protein-DNA complex involved in the activation of DCs by parasite nuclear material. The parasite components were fractionated into the nuclear and non-nuclear materials. The nuclear material was further fractionated into chromatin and the proteins loosely bound to chromatin. Polynucleosomes and oligonucleosomes were prepared from the chromatin. These were tested for their ability to activate DCs obtained by the FLT3 ligand differentiation of bone marrow cells from the wild type, and TLR2−/−, TLR9−/− and MyD88−/− mice. DCs stimulated with the nuclear material and polynucleosomes as well as mono- and oligonucleosomes efficiently induced the production of proinflammatory cytokines in a TLR9-dependent manner, demonstrating that nucleosomes (histone-DNA complex) represent the major TLR9-specific DC-immunostimulatory component of the malaria parasite nuclear material. Thus, our data provide a significant insight into the activation of DCs by malaria parasites and have important implications for malaria vaccine development

Stunned Silence: Gene Expression Programs in Human Cells Infected with Monkeypox or Vaccinia Virus

Poxviruses use an arsenal of molecular weapons to evade detection and disarm host immune responses. We used DNA microarrays to investigate the gene expression responses to infection by monkeypox virus (MPV), an emerging human pathogen, and Vaccinia virus (VAC), a widely used model and vaccine organism, in primary human macrophages, primary human fibroblasts and HeLa cells. Even as the overwhelmingly infected cells approached their demise, with extensive cytopathic changes, their gene expression programs appeared almost oblivious to poxvirus infection. Although killed (gamma-irradiated) MPV potently induced a transcriptional program characteristic of the interferon response, no such response was observed during infection with either live MPV or VAC. Moreover, while the gene expression response of infected cells to stimulation with ionomycin plus phorbol 12-myristate 13-acetate (PMA), or poly (I-C) was largely unimpaired by infection with MPV, a cluster of pro-inflammatory genes were a notable exception. Poly(I-C) induction of genes involved in alerting the innate immune system to the infectious threat, including TNF-alpha, IL-1 alpha and beta, CCL5 and IL-6, were suppressed by infection with live MPV. Thus, MPV selectively inhibits expression of genes with critical roles in cell-signaling pathways that activate innate immune responses, as part of its strategy for stealthy infection

Fosmidomycin Uptake into Plasmodium and Babesia-Infected Erythrocytes Is Facilitated by Parasite-Induced New Permeability Pathways

., a mouse malaria parasite. and related parasites. Our data provide further evidence that parasite-induced new permeability pathways may be exploited as routes for drug delivery