The Authorship of St. John\u27s Gospel

Some New Testament books contain clear statements as to who wrote them. Oftentimes the author\u27s name is mentioned at the beginning of the book. This is natural when it is an Epistle, for it is usual to specify in a letter both by whom it is written, and to whom it is sent. Most New Testament Epistles begin with the name of the sender and also mention the name or names of those to whom the Letter is addressed. The Epistle to the Galatians, for instance, opens with the author\u27s name: Paul, an Apostle ... to the churches of Galatia. The writer not only gives his name, but also adds a personal attribute which proves his identity

Infection or Contamination with Rothia, Kocuria, Arthrobacter and Pseudoglutamicibacter — a Retrospective Observational Study of Non-Micrococcus Micrococcaceae in the Clinic

Rothia, Kocuria, Arthrobacter, and Pseudoglutamicibacter are bacterial species within the family Micrococcaeae. Knowledge of human infections due to these bacteria is limited. This study aimed to examine features of infections caused by non-Micrococcus Micrococcaeae (NMM). Findings of NMM from blood cultures and other sterile cultures from 2012 to 2021 were identified from the records of the Department of Clinical Microbiology in Region Skåne, Lund, Sweden. Medical records were retrospectively reviewed. True infection was defined as having signs of infection, no other more likely pathogen, and no other focal infection, together with two positive blood cultures or one positive blood culture and an intravascular device. A total of 197 patients with findings of NMM in blood cultures were included. Among adult patients with bacteremia, 29 patients (22%) were considered to have a true infection. Adults with true infection were significantly more likely to have malignancy (69%), leukopenia (62%), and treatment with chemotherapeutics (66%) compared to patients with contaminated samples (24%, 3%, and 8%, respectively) (

Proteomics in thrombosis research

A State of the Art lecture titled “Proteomics in Thrombosis Research” was presented at the ISTH Congress in 2021. In clinical practice, there is a need for improved plasma biomarker-based tools for diagnosis and risk prediction of venous thromboembolism (VTE). Analysis of blood, to identify plasma proteins with potential utility for such tools, could enable an individualized approach to treatment and prevention. Technological advances to study the plasma proteome on a large scale allows broad screening for the identification of novel plasma biomarkers, both by targeted and nontargeted proteomics methods. However, assay limitations need to be considered when interpreting results, with orthogonal validation required before conclusions are drawn. Here, we review and provide perspectives on the application of affinityand mass spectrometry-based methods for the identification and analysis of plasma protein biomarkers, with potential application in the field of VTE. We also provide a future perspective on discovery strategies and emerging technologies for targeted proteomics in thrombosis research. Finally, we summarize relevant new data on this topic, presented during the 2021 ISTH Congress

Alternative promoter usage of the membrane glycoprotein CD36

BACKGROUND: CD36 is a membrane glycoprotein involved in a variety of cellular processes such as lipid transport, immune regulation, hemostasis, adhesion, angiogenesis and atherosclerosis. It is expressed in many tissues and cell types, with a tissue specific expression pattern that is a result of a complex regulation for which the molecular mechanisms are not yet fully understood. There are several alternative mRNA isoforms described for the gene. We have investigated the expression patterns of five alternative first exons of the CD36 gene in several human tissues and cell types, to better understand the molecular details behind its regulation. RESULTS: We have identified one novel alternative first exon of the CD36 gene, and confirmed the expression of four previously known alternative first exons of the gene. The alternative transcripts are all expressed in more than one human tissue and their expression patterns vary highly in skeletal muscle, heart, liver, adipose tissue, placenta, spinal cord, cerebrum and monocytes. All alternative first exons are upregulated in THP-1 macrophages in response to oxidized low density lipoproteins. The alternative promoters lack TATA-boxes and CpG islands. The upstream region of exon 1b contains several features common for house keeping gene and monocyte specific gene promoters. CONCLUSION: Tissue-specific expression patterns of the alternative first exons of CD36 suggest that the alternative first exons of the gene are regulated individually and tissue specifically. At the same time, the fact that all first exons are upregulated in THP-1 macrophages in response to oxidized low density lipoproteins may suggest that the alternative first exons are coregulated in this cell type and environmental condition. The molecular mechanisms regulating CD36 thus appear to be unusually complex, which might reflect the multifunctional role of the gene in different tissues and cellular conditions

Markers of neutrophil activation and neutrophil extracellular traps in diagnosing patients with acute venous thromboembolism: A feasibility study based on two VTE cohorts

Background Venous thromboembolism (VTE) diagnosis would greatly benefit from the identification of novel biomarkers to complement D-dimer, a marker limited by low specificity. Neutrophil extracellular traps (NETs) have been shown to promote thrombosis and could hypothetically be used for diagnosis of acute VTE. Objectives To assess the levels of specific markers of neutrophil activation and NETs and compare their diagnostic accuracy to D-dimer. Methods We measured plasma levels of neutrophil activation marker neutrophil elastase (NE), the NET marker nucleosomal citrullinated histone H3 (H3Cit-DNA) and cell-free DNA in patients (n = 294) with suspected VTE (pulmonary embolism and deep vein thrombosis) as well as healthy controls (n = 30). A total of 112 VTE positive and 182 VTE negative patients from two prospective cohort studies were included. Results Higher levels of H3Cit-DNA and NE, but not cell-free DNA, were associated with VTE. Area under receiver operating curves (AUC) were 0.90 and 0.93 for D-dimer, 0.65 and 0.68 for NE and 0.60 and 0.67 for H3Cit-DNA in the respective cohorts. Adding NE and H3Cit-DNA to a D-dimer based risk model did not improve AUC. Conclusions Our study demonstrates the presence of neutrophil activation and NET formation in VTE using specific markers. However, the addition of NE or H3Cit-DNA to D-dimer did not improve the discrimination compared to D-dimer alone. This study provides information on the feasibility of using markers of NETs as diagnostic tools in acute VTE. Based on our findings, we believe the potential of these markers are limited in this setting

In Silico Detection of Sequence Variations Modifying Transcriptional Regulation

Identification of functional genetic variation associated with increased susceptibility to complex diseases can elucidate genes and underlying biochemical mechanisms linked to disease onset and progression. For genes linked to genetic diseases, most identified causal mutations alter an encoded protein sequence. Technological advances for measuring RNA abundance suggest that a significant number of undiscovered causal mutations may alter the regulation of gene transcription. However, it remains a challenge to separate causal genetic variations from linked neutral variations. Here we present an in silico driven approach to identify possible genetic variation in regulatory sequences. The approach combines phylogenetic footprinting and transcription factor binding site prediction to identify variation in candidate cis-regulatory elements. The bioinformatics approach has been tested on a set of SNPs that are reported to have a regulatory function, as well as background SNPs. In the absence of additional information about an analyzed gene, the poor specificity of binding site prediction is prohibitive to its application. However, when additional data is available that can give guidance on which transcription factor is involved in the regulation of the gene, the in silico binding site prediction improves the selection of candidate regulatory polymorphisms for further analyses. The bioinformatics software generated for the analysis has been implemented as a Web-based application system entitled RAVEN (regulatory analysis of variation in enhancers). The RAVEN system is available at http://www.cisreg.ca for all researchers interested in the detection and characterization of regulatory sequence variation

Assessing the Effect of Firearms Regulations Using Partial Identification Methods: A Case Study of the Impact of Stand Your Ground Laws on Violent Crime

To understand renal functions and disease, it is important to define the molecular constituents of the various compartments of the kidney. Here, we used comparative transcriptomic analysis of all major organs and tissues in the human body, in combination with kidney tissue micro array based immunohistochemistry, to generate a comprehensive description of the kidney-specific transcriptome and proteome. A special emphasis was placed on the identification of genes and proteins that were elevated in specific kidney subcompartments. Our analysis identified close to 400 genes that had elevated expression in the kidney, as compared to the other analysed tissues, and these were further subdivided, depending on expression levels, into tissue enriched, group enriched or tissue enhanced. Immunohistochemistry allowed us to identify proteins with distinct localisation to the glomeruli (n=11), proximal tubules (n=120), distal tubules (n=9) or collecting ducts (n=8). Among the identified kidney elevated transcripts, we found several proteins not previously characterised or identified as elevated in kidney. This description of the kidney specific transcriptome and proteome provides a resource for basic and clinical research to facilitate studies to understand kidney biology and disease

Correlation of computed tomography with carotid plaque transcriptomes associates calcification with lesion-stabilization

Background and aims: Unstable carotid atherosclerosis causes stroke, but methods to identify patients and lesions at risk are lacking. We recently found enrichment of genes associated with calcification in carotid plaques from asymptomatic patients. Here, we hypothesized that calcification represents a stabilising feature of plaques and investigated how macro-calcification, as estimated by computed tomography (CT), correlates with gene expression profiles in lesions. Methods: Plaque calcification was measured in pre-operative CT angiographies. Plaques were sorted into high- and lowcalcified, profiled with microarrays, followed by bioinformatic analyses. Immunohistochemistry and qPCR were performed to evaluate the findings in plaques and arteries with medial calcification from chronic kidney disease patients. Results: Smooth muscle cell (SMC) markers were upregulated in high-calcified plaques and calcified plaques from symptomatic patients, whereas macrophage markers were downregulated. The most enriched processes in high-calcified plaques were related to SMCs and extracellular matrix (ECM) organization, while inflammation, lipid transport and chemokine signaling were repressed. These findings were confirmed in arteries with high medial calcification. Proteoglycan 4 (PRG4) was identified as the most upregulated gene in association with plaque calcification and found in the ECM, SMA+ and CD68+/TRAP + cells. Conclusions: Macro-calcification in carotid lesions correlated with a transcriptional profile typical for stable plaques, with altered SMC phenotype and ECM composition and repressed inflammation. PRG4, previously not described in atherosclerosis, was enriched in the calcified ECM and localized to activated macrophages and smooth muscle-like cells. This study strengthens the notion that assessment of calcification may aid evaluation of plaque phenotype and stroke risk.The European Union’s Horizon 2020/Marie Sklodowska-Curie grant agreement No 722609 (INTRICARE);Swedish Heart and Lung FoundationSwedish Research Council (K2009-65X-2233-01-3, K2013- 65X-06816-30-4, 349-2007-8703)Uppdrag Besegra Stroke (P581/ 2011-123)Stockholm County Council (ALF2011-0260, ALF-2011- 0279)Swedish Society for Medical ResearchTore Nilsson’s FoundationMagnus Bergvall’s FoundationKarolinska Institutet FoundationEuropean Commission (722609)Publishe

Markers of neutrophil activation and neutrophil extracellular traps in diagnosing patients with acute venous thromboembolism: A feasibility study based on two VTE cohorts

Background: Venous thromboembolism (VTE) diagnosis would greatly benefit from the identification of novel biomarkers to complement D-dimer, a marker limited by low specificity. Neutrophil extracellular traps (NETs) have been shown to promote thrombosis and could hypothetically be used for diagnosis of acute VTE. Objectives: To assess the levels of specific markers of neutrophil activation and NETs and compare their diagnostic accuracy to D-dimer. Methods: We measured plasma levels of neutrophil activation marker neutrophil elastase (NE), the NET marker nucleosomal citrullinated histone H3 (H3Cit-DNA) and cell-free DNA in patients (n = 294) with suspected VTE (pulmonary embolism and deep vein thrombosis) as well as healthy controls (n = 30). A total of 112 VTE positive and 182 VTE negative patients from two prospective cohort studies were included. Results: Higher levels of H3Cit-DNA and NE, but not cell-free DNA, were associated with VTE. Area under receiver operating curves (AUC) were 0.90 and 0.93 for D-dimer, 0.65 and 0.68 for NE and 0.60 and 0.67 for H3Cit-DNA in the respective cohorts. Adding NE and H3Cit-DNA to a D-dimer based risk model did not improve AUC. Conclusions: Our study demonstrates the presence of neutrophil activation and NET formation in VTE using specific markers. However, the addition of NE or H3Cit-DNA to D-dimer did not improve the discrimination compared to D-dimer alone. This study provides information on the feasibility of using markers of NETs as diagnostic tools in acute VTE. Based on our findings, we believe the potential of these markers are limited in this setting