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"Freedman, Jane"
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Circulating Extracellular Vesicles in Human Disease
Circulating extracellular vesicles, which are produced by normal and diseased tissues and released into body fluids, can be markers of disease processes and perhaps even tools to deliver new therapies.
Journal Article
MicroRNAs in platelet function and cardiovascular disease
Key Points
Platelet function has an important role in mediating particular common forms of cardiovascular disease, such as acute coronary syndromes and stroke
Although they lack nuclei, platelets contain RNAs, including small noncoding RNAs such as microRNAs, and the necessary machinery to perform translation
Data suggest that microRNAs can influence platelet functions, including thrombosis, atherosclerosis, and angiogenesis
Platelet RNA can also be transferred to other vascular cells, but further information about the role of microRNA transfer is needed
Despite being anucleate, platelets contain RNA transcripts, including microRNAs, which are involved in regulating platelet function and which can also be transferred to other vascular cells. In this Review, McManus and Freedman summarize the mechanistic roles of platelet-derived miRNAs in acute atherogenic and thrombotic diseases, such as acute coronary syndromes and stroke. These miRNAs might also be used as biomarkers of cardiovascular disease susceptibility, prognosis, and treatment.
Cardiovascular disease—a leading cause of morbidity and mortality among adults—is strongly influenced by platelet function through acute thrombotic and atherogenic mechanisms. Pathways that regulate platelet activity and lead to coronary occlusion are central to the pathogenesis of acute coronary syndromes. Platelet activation contributes to other thrombotic disorders and cardiovascular diseases, including stroke. Anucleate platelets are now understood to contain transcripts that might relate to other physiological or pathophysiological conditions, be released into the circulation, participate in protein formation, and engage in horizontal RNA transfer to other vascular cells. These platelet transcripts include microRNAs (miRNAs), which are small noncoding RNAs involved in many molecular processes, most notably regulation of gene expression. In platelets, these noncoding RNAs seem to participate in vascular homeostasis, inflammation, and platelet function. In addition, levels of platelet miRNAs in the circulation are associated with the presence or extent of cardiovascular diseases, such as atrial fibrillation and peripheral vascular disease. Accumulating data suggest mechanistic roles for platelet-derived miRNAs in haemostasis, thrombosis, and unstable coronary syndromes. In addition, evidence suggests that platelet-derived miRNAs might have important roles as biomarkers of cardiovascular disease susceptibility, prognosis, or treatment.
Journal Article
Gendering the international asylum and refugee debate
Refugees and asylum seekers are the subject of major debates both at national and international level. But the debates exclude a gendered perspective that considers the experiences and needs of men and women. This study provides a comprehensive account of the situation of women refugees globally and explains how they differ from men.
Book
The role of platelets in mediating a response to human influenza infection
Influenza infection increases the incidence of myocardial infarction but the reason is unknown. Platelets mediate vascular occlusion through thrombotic functions but are also recognized to have immunomodulatory activity. To determine if platelet processes are activated during influenza infection, we collected blood from 18 patients with acute influenza infection. Microscopy reveals activated platelets, many containing viral particles and extracellular-DNA associated with platelets. To understand the mechanism, we isolate human platelets and treat them with influenza A virus. Viral-engulfment leads to C3 release from platelets as a function of TLR7 and C3 leads to neutrophil-DNA release and aggregation. TLR7 specificity is confirmed in murine models lacking the receptor, and platelet depletion models support platelet-mediated C3 and neutrophil-DNA release post-influenza infection. These findings demonstrate that the initial intrinsic defense against influenza is mediated by platelet–neutrophil cross-communication that tightly regulates host immune and complement responses but can also lead to thrombotic vascular occlusion.
Influenza viremia is rare in human blood and not well studied. Here, the authors show that influenza can be found in human platelets and that platelet engulfment of influenza A results in TLR7-dependent C3 release, which in turn promotes neutrophil-DNA release and formation of platelet-DNA aggregates.
Journal Article
The Story of Fish & Snail
Every day, Snail waits for Fish to return and tell him a story but their friendship is tested when Fish asks Snail to take a leap out of their book to actually see a new pirate book in the library.
Book
Pattern recognition receptor-associated immuno-thrombotic transcript changes in platelets and leukocytes with COVID19
Respiratory infections are characterized by an increased risk of thrombosis, likely involving platelet-leukocyte crosstalk via pattern recognition receptors (PRRs). Here we characterized COVID19-mediated changes in PRR levels and their associations with thrombotic/coagulation-related transcriptional programs across platelets and leukocytes and assessed their correlation with COVID19 outcomes. Amplicon RNAseq of platelets and leukocytes from COVID19 patients (n = 10) and non-infected donors (n = 15) showed distinct patterns of PRR-expression levels based on cell type. Platelets from non-infected donors expressed TLR9 > RIG-I> CGAS at the highest level while leukocytes expressed TLR4 > TLR8 > RIG-I. COVID19 resulted in increased levels of TLR9, RIG-I, CGAS, and TLR1 in platelets and decreased levels of TLR6 and TLR8 in leukocytes, while the levels of the highest expressed PRRs remained almost unchanged. In platelets from COVID19 patients, MDA5, RIG-I, and LGP2 showed the highest associations with thrombotic-, coagulation-, and thrombolysis-associated transcripts, while in non-infected donors, TLR9 showed the highest associations with those transcripts. In leukocytes, RIG-I and MDA5 also correlated with coagulation-related transcripts when derived from the non-infected donors, but those associations were almost lost with COVID19. Platelet-leukocyte aggregates increased with COVID19 as did extracellular vesicles detected by imaging cytometry, immunofluorescence, or electron microscopy. Platelet-TLR3 and leukocyte-TLR5 positively correlated with severity and survival of the COVID19 patients, while leukocyte-TLR7 showed an inverse correlation. Coagulopathy, measured by INR, was associated with platelet-TLR4 and leukocyte-TLR10. Liver inflammation, assessed by ALT levels, correlated with platelet- and leukocyte-LGP2, in addition to leukocyte-TLR3, -TLR6, -TLR7, and -RIG-I. Analysis of publicly available whole-blood-RNAseq, showed that COVID19 and tuberculosis were more similar than COVID19 and influenza with respect to associations between PRRs and thrombotic/coagulation-related transcripts. Overall, platelets and leukocytes exhibit distinct patterns of PRR expression and correlations with thrombotic/coagulation-related transcripts that change with COVID19, and there are distinct PRRs in each cell population that associate with COVID19 severity, coagulopathy, and liver damage.
Journal Article
Blue chicken
An enterprising chicken attempts to help an artist paint the barnyard and accidentally turns the whole picture blue.
Book
Attomolar sensitivity microRNA detection using real-time digital microarrays
MicroRNAs (miRNAs) are a family of noncoding, functional RNAs. With recent developments in molecular biology, miRNA detection has attracted significant interest, as hundreds of miRNAs and their expression levels have shown to be linked to various diseases such as infections, cardiovascular disorders and cancers. A powerful and high throughput tool for nucleic acid detection is the DNA microarray technology. However, conventional methods do not meet the demands in sensitivity and specificity, presenting significant challenges for the adaptation of miRNA detection for diagnostic applications. In this study, we developed a highly sensitive and multiplexed digital microarray using plasmonic gold nanorods as labels. For proof of concept studies, we conducted experiments with two miRNAs, miRNA-451a (miR-451) and miRNA-223-3p (miR-223). We demonstrated improvements in sensitivity in comparison to traditional end-point assays that employ capture on solid phase support, by implementing real-time tracking of the target molecules on the sensor surface. Particle tracking overcomes the sensitivity limitations for detection of low-abundance biomarkers in the presence of low-affinity but high-abundance background molecules, where endpoint assays fall short. The absolute lowest measured concentration was 100 aM. The measured detection limit being well above the blank samples, we performed theoretical calculations for an extrapolated limit of detection (LOD). The dynamic tracking improved the extrapolated LODs from femtomolar range to
∼
10 attomolar (less than 1300 copies in 0.2 ml of sample) for both miRNAs and the total incubation time was decreased from 5 h to 35 min.
Journal Article