Neuronal activity triggers uptake of hematopoietic extracellular vesicles in vivo

Communication with the hematopoietic system is a vital component of regulating brain function in health and disease. Traditionally, the major routes considered for this neuroimmune communication are by individual molecules such as cytokines carried by blood, by neural transmission, or, in more severe pathologies, by the entry of peripheral immune cells into the brain. In addition, functional mRNA from peripheral blood can be directly transferred to neurons via extracellular vesicles (EVs), but the parameters that determine their uptake are unknown. Using varied animal models that stimulate neuronal activity by peripheral inflammation, optogenetics, and selective proteasome inhibition of dopaminergic (DA) neurons, we show that the transfer of EVs from blood is triggered by neuronal activity in vivo. Importantly, this transfer occurs not only in pathological stimulation but also by neuronal activation caused by the physiological stimulus of novel object placement. This discovery suggests a continuous role of EVs under pathological conditions as well as during routine cognitive tasks in the healthy brain

Neuronal activity triggers uptake of hematopoietic extracellular vesicles in vivo

Communication with the hematopoietic system is a vital component of regulating brain function in health and disease. Traditionally, the major routes considered for this neuroimmune communication are by individual molecules such as cytokines carried by blood, by neural transmission, or, in more severe pathologies, by the entry of peripheral immune cells into the brain. In addition, functional mRNA from peripheral blood can be directly transferred to neurons via extracellular vesicles (EVs), but the parameters that determine their uptake are unknown. Using varied animal models that stimulate neuronal activity by peripheral inflammation, optogenetics, and selective proteasome inhibition of dopaminergic (DA) neurons, we show that the transfer of EVs from blood is triggered by neuronal activity in vivo. Importantly, this transfer occurs not only in pathological stimulation but also by neuronal activation caused by the physiological stimulus of novel object placement. This discovery suggests a continuous role of EVs under pathological conditions as well as during routine cognitive tasks in the healthy brain

Non-statin interventions in the prevention of cardiovascular events: Sex-based meta-analysis

Objective: To explore the sex-specific association of non-statin classes of drugs in reducing cardiovascular outcomes. Methods: Published data search up to November 2019 reporting primary outcomes that approximate with major vascular events (MVEs) after treatment with non-statin group of drugs was performed. The primary outcome was the sex-specific association with MVEs. Random-effects meta-analysis was performed to estimate relative risk (RR) of the individual classes of therapies. Results: Seven Randomized Clinical Trials (RCTs) including 122,164 patients were included in our analysis. Four studies compared the Triglyceride (TG)-lowering group of drugs with placebo and 3 studies compared low-density lipoprotein cholesterol (LDL-c) lowering drugs with placebo. Overall, with non-statin drugs, there was no difference in the risk reduction of cardiovascular (CV) events between men (RR 0.86; 95% CI 0.79–0.94, p-valu

Appendices and supplementary material

Appendices and Supplementary Material

Data from: Neuropathy with vascular endothelial growth factor receptor tyrosine kinase inhibitors

Objective: To explore the association of peripheral neuropathy with vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs) use in cancer patients. Methods: Published data search up to November 2018 reporting peripheral neuropathy in cancer patients treated with VEGFR-TKIs was performed. The primary outcome was presence of peripheral neuropathy at the end of the trial. Random-effects meta-analysis was performed to estimate Relative Risk (RR) of individual treatment. Results: Thirty Randomized Clinical Trials (RCTs) including 12,490 cancer patients were included in this analysis. Eight studies compared VEGFR-TKIs with placebo and the remaining studies compared VEGFR-TKIs with the standard chemotherapeutic regimen. When compared against placebo VEGFR-TKIs were associated with a higher risk of peripheral neuropathy (RR=1.76, 95% CI 1.13-2.75, p-value 0.01). Similarly, a stronger association was noted for sensory neuropathy with VEGFR-TKIs monotherapy (RR = 1.61; 95% CI 1.09-2.37, p = 0.02). Risk of peripheral neuropathy with VEGFR-TKIs was higher even when they were compared against control (either placebo or standard chemotherapeutic agents); RR=1.08, 95% CI 1.01-1.15, p-value 0.03. High-grade neuropathy (RR 1.28, 95% CI 1.06-1.54, p-value <0.01) and high-grade sensory neuropathy (RR 1.38, 95% CI 1.09-1.74, p-value <0.01) were noted more frequently with VEGFR-TKIs treatment compared against control. Conclusions: VEGFR-TKIs therapy appeared to be associated with an increased risk of neuropathy

Red blood cell-derived extracellular vesicles mediate intercellular communication in ischemic heart failure

Summary Extracellular vesicles (EV) mediate intercellular signaling by transferring their cargo to recipient cells. Red blood cell (RBC)-derived EVs constitute a significant proportion of circulating EVs and have been implicated in regulating immune responses. Here, we describe a transgenic mouse model for fluorescent-based mapping of RBC-EV target cells based on the functional transfer of EV-contained Cre-recombinase to target cells. In a murine model of ischemic heart failure, we detect an increase in RBC-EV-targeted cardiomyocytes in the hearts and microglial cells in the brains. Cells targeted by RBC-EVs present an enrichment of genes implicated in cell proliferation and metabolism pathways compared to non-recombined (non-targeted) cells. Cardiomyocytes targeted by RBC-EVs are more likely to demonstrate cellular markers of DNA synthesis and proliferation, suggesting functional significance of EV-mediated signaling. In conclusion, we leverage our mouse model for mapping of RBC-EV targets in murine ischemic heart failure to demonstrate quantitative and qualitative changes in RBC-EV recipients

COVID-19 Pandemic: Cardiovascular Complications and Future Implications

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is now a global pandemic with the highest number of affected individuals in the modern era. Not only is the infection inflicting significant morbidity and mortality, but there has also been\ua0a significant strain to the health care system and the economy. COVID-19 typically presents as viral pneumonia, occasionally leading to acute respiratory distress syndrome (ARDS) and death. However, emerging evidence suggests that it has a significant impact on the cardiovascular (CV) system by direct myocardial damage, severe systemic inflammatory response, hypoxia, right heart strain secondary to ARDS and lung injury, and plaque rupture secondary to inflammation. Primary cardiac manifestations include acute myocarditis, myocardial infarction, arrhythmia, and abnormal clotting. Several consensus documents have been released to help manage CV disease during this pandemic. In this review, we summarize key cardiac manifestations, their management, and future implications

Additional file 1: of Evaluation of commercially available small RNASeq library preparation kits using low input RNA

Table S1. Percentage of input reads aligned to the human transcriptome, human rRNA, UniVec contaminant sequences and discarded because they are too short (< 15 nts) and unmapped to the human transcriptome. Table S2. Median (Inter-quartile range) of percentage of input reads aligned to the human transcriptome, human rRNA, UniVec contaminant sequences. Table S3. Percentage of reads aligned to the human transcriptome to each RNA biotype for all samples. Table S4. Median (Inter-quartile range) of percentage of input reads aligned to different RNA biotypes between the three sequencing kits. Table S5. Median (IQR) of percentage of input reads aligned and comparison of input amount of RNA. Table S6. Median (IQR) of percentage of input reads aligned and comparison between the two sites for the two input amounts of RNA. Table S7. Median (IQR) of number of miRNAs greater than 10 counts detected in at least 25% of the samples between the two sites for the two input amounts of RNA. Table S8. Pearson’s and Spearman’s correlation coefficient by tissue, kit and input amount. Table S9. Kit specific miRNAs found in each tissue for each kit. The top 5 miRNAs for each tissue that have expression greater than 10 RPM in one kit, but less than 5 RPM in the other two are presented for each tissue and kit. Table S10. miRNAs included on the custom made FirePlex Panel. The columns denote the number of samples that had above detection-limit expression in each tissue. Table S11. Database of RNA biotypes used. (XLSX 89 kb