Stroke is the second leading cause of death and a major contributor to disability worldwide. The prevalence of stroke is highest in developing countries, with ischemic stroke being the most common type. Considerable progress has been made in our understanding of the pathophysiology of stroke and the underlying mechanisms leading to ischemic insult. Stroke therapy primarily focuses on restoring blood flow to the brain and treating stroke-induced neurological damage. Lack of success in recent clinical trials has led to significant refinement of animal models, focus-driven study design and use of new technologies in stroke research. Simultaneously, despite progress in stroke management, post-stroke care exerts a substantial impact on families, the healthcare system and the economy. Improvements in pre-clinical and clinical care are likely to underpin successful stroke treatment, recovery, rehabilitation and prevention. In this review, we focus on the pathophysiology of stroke, major advances in the identification of therapeutic targets and recent trends in stroke research.

Tropomyosin 1 (TPM1) is an essential sarcomeric component, stabilising the thin filament and facilitating actin's interaction with myosin. A number of sarcomeric proteins, such as alpha myosin heavy chain, play crucial roles in cardiac development. Mutations in these genes have been linked to congenital heart defects (CHDs), occurring in approximately 1 in 145 live births. To date, TPM1 has not been associated with isolated CHDs. Analysis of 380 CHD cases revealed three novel mutations in the TPM1 gene; IVS1 + 2T > C, I130V, S229F and a polyadenylation signal site variant GATAAA/AATAAA. Analysis of IVS1 + 2T > C revealed aberrant pre-mRNA splicing. In addition, abnormal structural properties were found in hearts transfected with TPM1 carrying I130V and S229F mutations. Phenotypic analysis of TPM1 morpholino-treated embryos revealed roles for TPM1 in cardiac looping, atrial septation and ventricular trabeculae formation and increased apoptosis was seen within the heart. In addition, sarcomere assembly was affected and altered action potentials were exhibited. This study demonstrated that sarcomeric TPM1 plays vital roles in cardiogenesis and is a suitable candidate gene for screening individuals with isolated CHDs.

No abstract

No abstract

MicroRNAs (miRs) are critical for many cellular processes, including neurogenesis. Little is known about the components of upstream regulation of miR. We studied regulation of miR-9, which is highly expressed in the brain. Using Collaborative Cross mice, significant quantitative trait loci (QTL) were mapped to regions containing 131 candidate genes. These were characterized by RNAi interference, qPCR and neuronal differentiation assays to derive a short list of candidates. Three of these encoded proteins (Panx2, Polr1c and Mgea5) were shown by ChIP-seq and Co-IP to associate mutually with each other and bind to the miR-9 locus. We named this DNA-protein interaction complex that acts upstream of miR-9, which serves as the site for regulating miRs' expression, “miRSome”. A 3C/ChIP-loop assay confirmed the chromatin organisation of the miRSome on the miR-9 locus. These results describe the components of upstream regulatory mechanism of miR-9 expression during neurogenesis.