Gap junctions and connexin hemichannels in the regulation of haemostasis and thrombosis

Platelets are involved in the maintenance of haemostasis but their inappropriate activation leads to thrombosis, a principal trigger for heart attack and ischemic stroke. Although platelets circulate in isolation, upon activation they accumulate or aggregate together to form a thrombus, where they function in a coordinated manner to prevent loss of blood and control wound repair. Recent reports indicate that the stability and functions of a thrombus are maintained through sustained, contact dependent signalling between platelets. Given the role of gap junctions in the coordination of tissue responses, it was hypothesized that gap junctions may be present within a thrombus and mediate intercellular communication between platelets. Therefore studies were performed to explore the presence and functions of connexins in platelets. In this brief review, the roles of hemichannels and gap junctions in the control of thrombosis and haemostasis and the future directions for this research will be discussed

Fragile X Syndrome

Recent data from a national survey highlighted a significant difference in obesity rates in young fragile X males (31%) compared to age matched controls (18%). Fragile X syndrome (FXS) is the most common cause of intellectual disability in males and the most common single gene cause of autism. This X-linked disorder is caused by an expansion of a trinucleotide CGG repeat (>200) on the promotor region of the fragile X mental retardation 1 gene (FMR1). As a result, the promotor region often becomes methylated which leads to a deficiency or absence of the FMR1 protein (FMRP). Common characteristics of FXS include mild to severe cognitive impairments in males but less severe cognitive impairment in females. Physical features of FXS include an elongated face, prominent ears, and post-pubertal macroorchidism. Severe obesity in full mutation males is often associated with the Prader-Willi phenotype (PWP) which includes hyperphagia, lack of satiation after meals, and hypogonadism or delayed puberty; however, there is no deletion at 15q11-q13 nor uniparental maternal disomy. Herein, we discuss the molecular mechanisms leading to FXS and the Prader-Willi phenotype with an emphasis on mouse FMR1 knockout studies that have shown the reversal of weight increase through mGluR antagonists. Finally, we review the current medications used in treatment of FXS including the atypical antipsychotics that can lead to weight gain and the research regarding the use of targeted treatments in FXS that will hopefully have a significantly beneficial effect on cognition and behavior without weight gain

M12L8 metallo-supramolecular cube with cyclotriguaiacylene-type ligand: spontaneous resolution of cube and its constituent host ligand.

Data to support study of Ag12L8 metallo-cube and clathrate complexes of tris-(4-methylthiazolyl)cyclotriguaiacylene, where both Ag12L8 cube and clathrate complexes show spontaneous chiral resolution on crystallisation

Salting our Freshwater Lakes

The highest densities of lakes on Earth are in north temperate ecosystems, where increasing urbanization and associated chloride runoff can salinize freshwaters and threaten lake water quality and the many ecosystem services lakes provide. However, the extent to which lake salinity may be changing at broad spatial scales remains unknown, leading us to first identify spatial patterns and then investigate the drivers of these patterns. Significant decadal trends in lake salinization were identified using a dataset of long-term chloride concentrations from 371 North American lakes. Landscape and climate metrics calculated for each site demonstrated that impervious land cover was a strong predictor of chloride trends in Northeast and Midwest North American lakes. As little as 1% impervious land cover surrounding a lake increased the likelihood of long-term salinization. Considering that 27% of large lakes in the United States have \u3e1% impervious land cover around their perimeters, the potential for steady and long-term salinization of these aquatic systems is high. This study predicts that many lakes will exceed the aquatic life threshold criterion for chronic chloride exposure (230 mg L−1), stipulated by the US Environmental Protection Agency (EPA), in the next 50 y if current trends continue

RXR ligands negatively regulate thrombosis and hemostasis

OBJECTIVE: Platelets have been found to express intracellular nuclear receptors including the Retinoid X receptors (RXRα and RXRβ). Treatment of platelets with ligands of RXR has been shown to inhibit platelet responses to ADP and thromboxane A2, however the effects on responses to other platelet agonists as well as the underlying mechanism has not been fully characterised. APPROACH AND RESULTS: The effect of 9-cis-retinoic acid (9-cis-RA), docosahexaenoic acid and synthetic ligand for RXR, methoprene acid on collagen receptor (GPVI) agonists and Thrombin stimulated platelet function; including aggregation, granule secretion, integrin activation, calcium mobilisation, integrin αIIbβ3 outside-in signalling and thrombus formation in vitro and in vivo were determined. Treatment of platelets with RXR ligands resulted in attenuation of platelet functional responses following stimulation by GPVI agonists and thrombin and inhibition of integrin αIIbβ3 outside-in signalling. Treatment with 9-cis-RA caused inhibition of thrombus formation in vitro and an impairment of thrombosis and haemostasis in vivo. Both RXR ligands stimulated protein kinase A activation, measured by VASP S157 phosphorylation, that was found to be dependent on both cAMP and NFκB activity. CONCLUSIONS: This study identifies a widespread, negative regulatory role for RXR in the regulation of platelet functional responses and thrombus formation and describes novel events that lead to the upregulation of PKA, a known negative regulator of many aspects of platelet function. This mechanism may offer a possible explanation for the cardioprotective effects described in vivo following treatment with RXR ligands

Microenvironmental regulation of telomerase isoforms in human embryonic stem cells

Recent evidence points to extra-telomeric, noncanonical roles for telomerase in regulating stem cell function. In this study, human embryonic stem cells (hESCs) were cultured in 20% or 2% O2 microenvironments for up to 5 days and evaluated for telomerase reverse transcriptase (TERT) expression and telomerase activity. Results showed increased cell survival and maintenance of the undifferentiated state with elevated levels of nuclear TERT in 2% O 2-cultured hESCs despite no significant difference in telomerase activity compared with their high-O2-cultured counterparts. Pharmacological inhibition of telomerase activity using a synthetic tea catechin resulted in spontaneous hESC differentiation, while telomerase inhibition with a phosphorothioate oligonucleotide telomere mimic did not. Reverse transcription polymerase chain reaction (RT-PCR) analysis revealed variations in transcript levels of full-length and alternate splice variants of TERT in hESCs cultured under varying O2 atmospheres. Steric-blocking of Δα and Δβ hTERT splicing using morpholino oligonucleotides altered the hTERT splicing pattern and rapidly induced spontaneous hESC differentiation that appeared biased toward endomesodermal and neuroectodermal cell fates, respectively. Together, these results suggest that post-transcriptional regulation of TERT under varying O2 microenvironments may help regulate hESC survival, self-renewal, and differentiation capabilities through expression of extra-telomeric telomerase isoforms. © 2014, Mary Ann Liebert, Inc

Autojammin' - Designing progression in traffic and music

Since the early days of automotive entertainment, music has played a crucial role in establishing pleasurable driving experiences. Future autonomous driving technologies will relieve the driver from the responsibility of driving and will allow for more interactive types of non-driving activities. However, there is a lack of research on how the liberation from the driving task will impact in-car music experiences. In this paper we present AutoJam, an interactive music application designed to explore the potential of (semi-) autonomous driving. We describe how the AutoJam prototype capitalizes on the context of the driving situation as structural features of the interactive music system. We report on a simulator pilot study and discuss participants’ driving experience with AutoJam in traffic. By proposing design implications that help to re- connect music entertainment with the driving experience of the future, we contribute to the design space for autonomous driving experiences

Educating and Debating Social and Political Issues in the Naperville Lyceum

This historical research responds to a call from other scholars to allow thetopics discussed in the lyceum of the nineteenth century to shed light onthe social consciousness of the frontier settlements of the era. The recentdiscovery of the “Proceedings of the Naperville Lyceum” (1836-1843)provided the means to do this. Since political topics were clearly central tothe Naperville Lyceum members, this research focused on those items. Itis revealing that lyceum topics in this location were not self-absorbed. Thedebated topics included several global issues and did not simplychampion the American status quo. It suggests that the frontier settlers ofNaperville were concerned with concerns of justice as citizens of acosmopolitan world, one in which they valued self-governance. The studyfurther reveals how some topics have continued to be politically relevantfor more than 180 years since the Naperville Lyceum began. Many of thesame topics are prominent in modern political discussion and debate

Metallo-cryptophane cages from cis-linked and trans-linked strategies.

Data supporting study of Pd(II) metallo-cage species from cyclotriguaiacylene derived ligands