Vascular malformations of the brain (VMB) comprise abnormal development of blood vessels. A small fraction of VMBs causes hemorrhages with neurological morbidity and risk of mortality in patients. Most often, they are symptomatically silent and are detected at advanced stages of disease progression. The most common forms of VMBs are arteriovenous and cavernous malformations in the brain. Radiopathological features of these diseases are complex with high phenotypic variability. Early detection of these malformations followed by preclusion of severe neurological deficits such as hemorrhage and stroke is crucial in the clinical management of patients with VMBs. The technological advances in high-throughput omics platforms have currently infused a zest in translational research in VMBs. Besides finding novel biomarkers and therapeutic targets, these studies have withal contributed significantly to the understanding of the etiopathogenesis of VMBs. Here we discuss the recent advances in predictive and prognostic biomarker research in sporadic and familial arteriovenous malformations as well as cerebral cavernous malformations. Furthermore, we analyze the clinical applicability of protein and noncoding RNA-based molecular-targeted therapies which may have a potentially key role in disease management.

Background Cerebral arteriovenous malformations (cAVM) are a significant cause of intracranial hemorrhagic stroke and brain damage. The arteriovenous junctions in AVM nidus are known to have hemodynamic disturbances such as altered shear stress, which could lead to endothelial dysfunction. The molecular mechanisms coupling shear stress and endothelial dysfunction in cAVMs are poorly understood. We speculated that disturbed blood flow in artery–vein junctions activates Notch receptors and promotes endothelial mesenchymal plasticity during cAVM formation. Methods We investigated the expression profile of endothelial mesenchymal transition (EndMT) and cell adhesion markers, as well as activated Notch receptors, in 18 human cAVM samples and 15 control brain tissues, by quantitative real-time PCR (qRT-PCR) and immunohistochemical evaluation. Employing a combination of a microfluidic system, qRT-PCR, immunofluorescence, as well as invasion and inhibitor assays, the effects of various shear stress conditions on Notch-induced EndMT and invasive potential of human cerebral microvascular endothelial cells (hCMEC/d3) were analyzed. Results We found evidence for EndMT and enhanced expression of activated Notch intracellular domain (NICD3 and NICD4) in human AVM nidus samples. The expression of transmembrane adhesion receptor integrin α9/β1 is significantly reduced in cAVM nidal vessels. Cell–cell adhesion proteins such as VE-cadherin and N-cadherin were differentially expressed in AVM nidus compared with control brain tissues. Using well-characterized hCMECs, we show that altered fluid shear stress steers Notch3 nuclear translocation and promotes SNAI1/2 expression and nuclear localization. Oscillatory flow downregulates integrin α9/β1 and VE-cadherin expression, while N-cadherin expression and endothelial cell invasiveness are augmented. Gamma-secretase inhibitor RO4929097, and to a lesser level DAPT, prevent the mesenchymal transition and invasiveness of cerebral microvascular endothelial cells exposed to oscillatory fluid flow. Conclusions Our study provides, for the first time, evidence for the role of oscillatory shear stress in mediating the EndMT process and dysregulated expression of cell adhesion molecules, especially multifunctional integrin α9/β1 in human cAVM nidus. Concomitantly, our findings indicate the potential use of small-molecular inhibitors such as RO4929097 in the less-invasive therapeutic management of cAVMs. Graphical Abstract

In this study, electrospun polyurethane nanofibre composite incorporated with drug loaded halloysite nanotubes is presented. Chlorhexidine acetate (CA) drug was loaded into the halloysite nanotubes (HNT) to facilitate its controlled release for prolonged efficacy. The drug loading percentage in HNT was determined using thermo-gravimetric (TG) analysis. Uniform fibrous webs were obtained by electrospinning technique with optimised process parameters (i.e., 10 KV, flow rate of 5 μl min−1 and needle to collector distance of 10 cm) which was evident from SEM images. Antimicrobial efficiency of the nanowebs was determined using disk diffusion method (AATCC 90) against both the Gram-positive (S. aureus) and Gram-negative (E. coli) bacteria. The polyurethane/HNT-CA nanowebs showed very good activity against these strains. The drug release analysis of the nanowebs was carried by UV–vis spectrophotometry using total immersion method. The nanocomposite with drug loaded in HNT showed higher controlled release characteristics as evident from the drug release assay.

The novel Single phase Z source half bridge inverter is presented as applying Z network in the half bridge inverter.The inverter can convert dc to ac.The proposed converter can solve limited voltage and shoot through problem.By using the Z network voltage source converter in the main circuit can be used as current source and vice versa.The proposed converter can solve the midpoint balance of the input capacitors.By using the Z source half bridge inverter it can improve the voltage as compared to the conventional half bridge inverter.The z network can overcome the disadvantage of voltage source inverter and the current source inverter.The Z network can be applied to dc-dc,dc-ac,ac-ac and ac-dc.The Z source half bridge inverter is working in the duty ratio of 1.2.It is a special case and it can act as buck boost converter by interchanging the duties of the switches. The proposed inverter is increases the efficiency. Total harmonics distortion in conventional half bridge inverter and the single phase z source half bridge inverter is 7.03% and 0.88% respectively.The proposed converter is simulated using MATLAB/Simulink. Keywords-Half Bridge Inverter,MATLAB/Simulink,THD,Z networkI.