Sickle Red Blood Cell-Derived Extracellular Vesicles Activate Endothelial Cells and Enhance Sickle Red Cell Adhesion Mediated by von Willebrand Factor

Endothelial activation and sickle red blood cell (RBC) adhesion are central to the pathogenesis of sickle cell disease (SCD). Quantitatively, RBC-derived extracellular vesicles (REVs) are more abundant from SS RBCs compared with healthy RBCs (AA RBCs). Sickle RBC-derived REVs (SS REVs) are known to promote endothelial cell (EC) activation through cell signalling and transcriptional regulation at longer terms. However, the SS REV-mediated short-term non-transcriptional response of EC is unclear. Here, we examined the impact of SS REVs on acute microvascular EC activation and RBC adhesion at 2 h. Compared with AA REVs, SS REVs promoted human pulmonary microvascular ECs (HPMEC) activation indicated by increased von Willebrand factor (VWF) expression. Under microfluidic conditions, we found abnormal SS RBC adhesion to HPMECs exposed to SS REVs. This enhanced SS RBC adhesion was reduced by haeme binding protein haemopexin or VWF cleaving protease ADAMTS13 to a level similar to HPMECs treated with AA REVs. Consistent with these observations, haemin- or SS REV-induced microvascular stasis in SS mice with implanted dorsal skin-fold chambers that was inhibited by ADAMTS13. The adhesion induced by SS REVs was variable and was higher with SS RBCs from patients with increased markers of haemolysis (lactate dehydrogenase and reticulocyte count) or a concomitant clinical diagnosis of deep vein thrombosis. Our results emphasise the critical contribution made by REVs to the pathophysiology of SCD by triggering acute microvascular EC activation and abnormal RBC adhesion. These findings may help to better understand acute pathophysiological mechanism of SCD and thereby the development of new treatment strategies using VWF as a potential target

Cancer-selective antiproliferative activity is a general property of some G-rich oligodeoxynucleotides

Oligodeoxynucleotide libraries containing randomly incorporated bases are used to generate DNA aptamers by systematic evolution of ligands by exponential enrichment (SELEX). We predicted that combinatorial libraries with alternative base compositions might have innate properties different from the standard library containing equimolar A + C + G + T bases. In particular, we hypothesized that G-rich libraries would contain a higher proportion of quadruplex-forming sequences, which may impart desirable qualities, such as increased nuclease resistance and enhanced cellular uptake. Here, we report on 11 synthetic oligodeoxynucleotide libraries of various base combinations and lengths, with regard to their circular dichroism, stability in serum-containing medium, cellular uptake, protein binding and antiproliferative activity. Unexpectedly, we found that some G-rich libraries (composed of G + T or G + C nucleotides) strongly inhibited cancer cell growth while sparing non-malignant cells. These libraries had spectral features consistent with G-quadruplex formation, were significantly more stable in serum than inactive libraries and showed enhanced cellular uptake. Active libraries generally had strong protein binding, while the pattern of protein binding suggested that G/T and G/C libraries have distinct mechanisms of action. In conclusion, cancer-selective antiproliferative activity may be a general feature of certain G-rich oligodeoxynucleotides and is associated with quadruplex formation, nuclease resistance, efficient cellular uptake and protein binding

Factor XII and Upar Upregulate Neutrophil Functions to Influence Wound Healing

Coagulation factor XII (FXII) deficiency is associated with decreased neutrophil migration, but the mechanisms remain uncharacterized. Here, we examine how FXII contributes to the inflammatory response. In 2 models of sterile inflammation, FXII-deficient mice (F12–/–) had fewer neutrophils recruited than WT mice. We discovered that neutrophils produced a pool of FXII that is functionally distinct from hepatic-derived FXII and contributes to neutrophil trafficking at sites of inflammation. FXII signals in neutrophils through urokinase plasminogen activator receptor–mediated (uPAR-mediated) Akt2 phosphorylation at S474 (pAktS474). Downstream of pAkt2S474, FXII stimulation of neutrophils upregulated surface expression of αMβ2 integrin, increased intracellular calcium, and promoted extracellular DNA release. The sum of these activities contributed to neutrophil cell adhesion, migration, and release of neutrophil extracellular traps in a process called NETosis. Decreased neutrophil signaling in F12–/– mice resulted in less inflammation and faster wound healing. Targeting hepatic F12 with siRNA did not affect neutrophil migration, whereas WT BM transplanted into F12–/– hosts was sufficient to correct the neutrophil migration defect in F12–/– mice and restore wound inflammation. Importantly, these activities were a zymogen FXII function and independent of FXIIa and contact activation, highlighting that FXII has a sophisticated role in vivo that has not been previously appreciated

A Platelet Acquired Storage Pool Disorder Associated with Tamoxifen Therapy

The antiestrogenic drug tamoxifen, used in patients with breast cancer, is associated with an increase in arterial and venous thrombotic events, the mechanism of which is not clearly understood. We report a case of a lady who presented with new bruising and prolonged bleeding following a tooth extraction 4–6 weeks after starting tamoxifen. Investigations were consistent with an acquired platelet storage pool disorder. Repeat platelet function analysis was normal, performed 3 months after discontinuation of tamoxifen. We present a previously clinically unreported effect of tamoxifen on platelet function

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Not AvailableFish roe is a nutritionally rich source of polyunsaturated fatty acids, essential amino acids and several vitamins. However, its utilization is currently limited to caviars from a few fsh species, as most of others form a jelly mass on cooking. In the present study, freeze dried carp roe mass was converted to caviar substitutes by reconstituting with sodium alginate. Further, oregano extract was added at different concentrations to the mixture as antioxidant and antimicrobial agent before casting. Scanning electron microscopic image revealed a honey-comb like structure for the freeze dried caviar samples, congenial for the retention of oregano extract for an extended period. DSC profle of caviar substitutes confrmed the stability and availability of caviar constituents at boiling temperature. Further, the biochemical, microbial and textural characteristics of caviar substitutes during storage at 4 degree celsius indicated lower bacterial count and minimum generation of lipid oxidation products in caviar substitutes containing 0.5 percentage oregano extractNot Availabl

Conversational AI Chatbot for HealthCare

Health is a state of total physical, mental, and social wellbeing. chatbots have been applied to this industry frequently and in a variety ofways in the past, there is still room for more inventive uses. Healthcareconversational AI use cases are flexible and may be tailored to the industry. Patients might use them to gain additional knowledge about their disease, the therapies that are available, or even their insurance coverage. Because research has shown that healthcare chatbots can improve patient satisfaction and significantly reduce wait times, many healthcare organisations are considering incorporating them into their operations. Chatbots for healthcare can be used for a number of purposes, such as monitoring, anonymity, personalization, in-person involvement, and more. In this case study, the user's input on the patient's symptoms will be used to determine the patient's likely ailment type. According on the type of sickness, precautions will be suggested, and the patient will be sent to a doctor who specialises in that field. A sequential model was utilised to extract the text's symptoms, and the KNN method was then applied to predict the patient's ailment type.