Could Proteomic Research Deliver the Next Generation of Treatments for Pneumococcal Meningitis?

Streptococcus pneumoniae is the most common bacterial cause of community-acquired meningitis worldwide. Despite optimal antibiotic therapy and supportive care, the mortality of this condition remains very high at 20–30% in the developed world and over 60% in under-resourced hospitals. In developed countries, approximately half of the survivors suffer intellectual impairment, hearing loss, or other neurological damage. There is an urgent need for more information about the mechanisms of brain damage and death in pneumococcal meningitis so that new treatments can be designed. Using proteomic techniques and bioinformatics, the protein content of cerebrospinal fluid can be examined in great detail. Animal models have added greatly to our knowledge of possible mechanisms and shown that hippocampal apoptosis and cortical necrosis are distinct mechanisms of neuronal death. The contribution of these pathways to human disease is unknown. Using proteomic techniques, neuronal death pathways could be described in CSF samples. This information could lead to the design of novel therapies to minimize brain damage and lower mortality. This minireview will summarize the known pathogenesis of meningitis, and current gaps in knowledge, that could be filled by proteomic analysis

Death is associated with complement C3 depletion in cerebrospinal fluid of patients with pneumococcal meningitis.

Pneumococcal meningitis can lead to death or serious neurological sequelae as a result of the host inflammatory response. We investigated the association between host response protein expression and outcome in patients with pneumococcal meningitis. Cerebrospinal fluid (CSF) was obtained from 80 patients with pneumococcal meningitis (40 nonsurvivors and 40 survivors) and 10 normal controls. Candidate proteins were analyzed for an association with survival. Complement C3 levels were 5-fold lower in nonsurvivors than in survivors (P < 0.05). This C3 reduction was not associated with lower levels in serum, indicating a compartmentalized CSF response. Transferrin levels were significantly higher in CSF (but not serum) from nonsurvivors than in CSF from survivors, suggestive of blood-brain barrier damage. Classical apoptosis proteins caspase 3 and apoptosis-inducing factor were not present in CSF. Expression of creatine kinase BB in clinically infected CSF suggested neuronal necrosis, but there was no clear association between level of expression and clinical outcome. Increased blood-brain barrier permeability and complement C3 depletion may have a role in determining outcome from bacterial meningitis. Therapeutic use of citicoline or caspase inhibitors is unlikely to have beneficial effects in patients with meningitis. IMPORTANCE: We previously identified proteins associated with clinical outcome in patients diagnosed with pneumococcal meningitis in a pilot proteomics study of cerebrospinal fluid (CSF). In this article, we have quantitatively assayed specific proteins identified from this previous proteomics analysis along with proteins associated with cell death by using Western blotting

Exploration of the high temperature phase evolution of electrochemically modified Sc2(WO4)3via potassium discharge

The activation of Sc2(WO4)3via electrochemical discharge against potassium metal is investigated, as well as the subsequent thermal evolution of Sc2(WO4)3. On subsequent heating from 100 to 623 K the discharged electrode exhibits essentially the same thermal expansion as that of the pure powder. Between 673 and 973 K a trigonal K2WO4-type phase (P[3 with combining macron]m1) is formed. Variable-temperature X-ray diffraction data indicates that upon heating from 923 K–1023 K, this phase has a thermal expansion coefficient of −1.90(10) × 10−4 K−1

Why do Process Improvement Projects Fail in Organizations? A Review and Future Research Agenda

Purpose: The purpose of this article is to examine the Critical Failure Factors (CFFs) linked to various types of Process improvement (PI) projects such as Kaizen, Lean, Six Sigma, Lean Six Sigma and Agile. Proposing a mitigation framework accordingly is also an aim of this study. Design/ Methodology/ Approach: This research undertakes a systematic literature review of 49 articles that were relevant to the scope of our study and that were published in four prominent databases including Google Scholar, Scopus, Web of Science and EBSCO. Findings: Further analysis identifies 39 factors that contribute to the failure of PI projects. Among these factors, significant emphasis is placed on issues such as "resistance to cultural change," "insufficient support from top management," "inadequate training and education," "poor communication," and "lack of resources", as primary causes of PI project failures. To address and overcome the PI project failures, we propose a framework for failure mitigation based on change management models. We present future research directions that aim to enhance both the theoretical understanding and practical aspects of PI project failures. Practical Implications: Through this study researchers and project managers can benefit from well structured guidelines and invaluable insights that will help them identify and address potential failures, leading to successful implementation and sustainable improvements within organizations. Originality: This paper is the first study of its kind that examine the CFFs of five PI methodologies and introduces a novel approach derived from change management theory as a solution to minimize the risk associated with PI failure

Blocking formation of the stable HIV reservoir: A new perspective for HIV-1 cure

Recent studies demonstrate that the stable HIV-1 reservoir in resting CD4+ T cells is mostly formed from viruses circulating when combination antiretroviral therapy (ART) is initiated. Here we explore the immunological basis for these observations. Untreated HIV-1 infection is characterized by a progressive depletion of memory CD4+ T cells which mostly express CD127, the α chain of the IL-7 receptor (IL-7R). Depletion results from both direct infection and bystander loss of memory CD4+ T cells in part attributed to dysregulated IL-7/IL-7R signaling. While IL-7/IL7R signaling is not essential for the generation of effector CD4+ T cells from naïve cells, it is essential for the further transition of effectors to memory CD4+ T cells and their subsequent homeostatic maintenance. HIV-1 infection therefore limits the transition of CD4+ T cells from an effector to long-lived memory state. With the onset of ART, virus load (VL) levels rapidly decrease and the frequency of CD127+ CD4+ memory T cells increases, indicating restoration of effector to memory transition in CD4+ T cells. Collectively these data suggest that following ART initiation, HIV-1 infected effector CD4+ T cells transition to long-lived, CD127+ CD4+ T cells forming the majority of the stable HIV-1 reservoir. We propose that combining ART initiation with inhibition of IL-7/IL-7R signaling to block CD4+ T cell memory formation will limit the generation of long-lived HIV-infected CD4+ T cells and reduce the overall size of the stable HIV-1 reservoir. © 2019 Goonetilleke, Clutton, Swanstrom and Joseph

De novo mutations in EIF2B1 affecting eIF2 signaling cause neonatal/early onset diabetes and transient hepatic dysfunction

This is the author accepted manuscript. The final version is available from the American Diabetes Association via the DOI in this recordData and resource availability. EIF2B1 mutation details have been deposited in the Decipher database (https://decipher.sanger.ac.uk/). All other data sets generated and/or analysed for this study are available from the corresponding author upon reasonable request.Permanent neonatal diabetes is caused by reduced β-cell number or impaired β-cell function. Understanding the genetic basis of this disorder highlights fundamental β-cell mechanisms. We performed trio genome sequencing for 44 permanent neonatal diabetes patients and their unaffected parents to identify causative de novo variants. Replication studies were performed in 188 patients diagnosed with diabetes before 2 years of age without a genetic diagnosis. EIF2B1 (encoding the eIF2B complex α subunit) was the only gene with novel de novo variants (all missense) in at least three patients. Replication studies identified 2 further patients with de novo EIF2B1 variants. In addition to diabetes, 4/5 patients had hepatitis-like episodes in childhood. The EIF2B1 de novo mutations were found to map to the same protein surface. We propose that these variants render the eIF2B complex insensitive to eIF2 phosphorylation which occurs under stress conditions and triggers expression of stress-response genes. Failure of eIF2B to sense eIF2 phosphorylation likely leads to unregulated unfolded protein response and cell death. Our results establish de novo EIF2B1 mutations as a novel cause of permanent diabetes and liver dysfunction. These findings confirm the importance of cell stress regulation for β-cells and highlight EIF2B1’s fundamental role within this pathway.European Foundation for the Study of DiabetesDiabetes UKDiabetes Research and Wellness FoundationWellcome TrustNational Institute for Health Research (NIHR)Royal Societ

Genotyping by Sequencing in Almond: SNP Discovery, Linkage Mapping, and Marker Design

In crop plant genetics, linkage maps provide the basis for the mapping of loci that affect important traits and for the selection of markers to be applied in crop improvement. In outcrossing species such as almond (Prunus dulcis Mill. D. A. Webb), application of a double pseudotestcross mapping approach to the F1 progeny of a biparental cross leads to the construction of a linkage map for each parent. Here, we report on the application of genotyping by sequencing to discover and map single nucleotide polymorphisms in the almond cultivars "Nonpareil" and "Lauranne." Allele-specific marker assays were developed for 309 tag pairs. Application of these assays to 231 Nonpareil × Lauranne F1 progeny provided robust linkage maps for each parent. Analysis of phenotypic data for shell hardness demonstrated the utility of these maps for quantitative trait locus mapping. Comparison of these maps to the peach genome assembly confirmed high synteny and collinearity between the peach and almond genomes. The marker assays were applied to progeny from several other Nonpareil crosses, providing the basis for a composite linkage map of Nonpareil. Applications of the assays to a panel of almond clones and a panel of rootstocks used for almond production demonstrated the broad applicability of the markers and provide subsets of markers that could be used to discriminate among accessions. The sequence-based linkage maps and single nucleotide polymorphism assays presented here could be useful resources for the genetic analysis and genetic improvement of almond.info:eu-repo/semantics/publishedVersio