BMP signaling modulation attenuates cerebral arteriovenous malformation formation in a vertebrate model

Cerebral arteriovenous malformations (AVMs) are vascular anomalies that carry a high risk of stroke and death. To test potential AVM therapies, a reverse genetics approach was used to model AVMs in zebrafish. Antisense morpholino oligonucleotides were used to knockdown activin receptor-like kinase I (alk1), which encodes a transforming growth factor (TGF)-beta family type I receptor implicated in a subset of human AVMs. Knockdown of alk1 caused a spectrum of morphologic, functional, and molecular defects that resemble those seen in humans with AVMs. It was found that losartan, an angiotensin II receptor antagonist, attenuated abnormal blood vessel morphology and systemic manifestations of high-output arteriovenous shunting in vivo. SMAD1 phosphorylation was significantly decreased in alk1 morphants compared with uninjected organisms (0.189±0.0201, 0.429±0.0164, P=0.0002). After treatment, morphant SMAD1 levels approached uninjected levels (0.326±0.0360, P=0.0355) and were significantly higher than those seen in the morphant-control group (P=0.0294). These data suggest that modulating the BMP signaling pathway with losartan, a drug in widespread clinical use in humans as an antihypertensive, may have the potential to be further evaluated as a therapeutic strategy for patients with AVMs

Zebrafish models of cerebrovascular disease

Perturbations in cerebral blood flow and abnormalities in blood vessel structure are the hallmarks of cerebrovascular disease. While there are many genetic and environmental factors that affect these entities through a heterogeneous group of disease processes, the ultimate final pathologic insult in humans is defined as a stroke, or damage to brain parenchyma. In the case of ischemic stroke, blood fails to reach its target destination whereas in hemorrhagic stroke, extravasation of blood occurs outside of the blood vessel lumen, resulting in direct damage to brain parenchyma. As these acute events can be neurologically devastating, if not fatal, development of novel therapeutics are urgently needed. The zebrafish (Danio rerio) is an attractive model for the study of cerebrovascular disease because of its morphological and physiological similarity to human cerebral vasculature, its ability to be genetically manipulated, and its fecundity allowing for large-scale, phenotype-based screens

“Not walled facts, their essence”: Derek Walcott’s Tiepolo’s Hound and Camille Pissarro

Life-writing — a genre which goes beyond traditional biography, includes both fact and fiction, and is concerned with either entire lives or days-in-the-lives of individuals, communities, objects, or institutions — has always played an important role in Derek Walcott’s work, from Another Life (1973),Walcott’s autobiography in verse, to his last play O Starry Starry Night (2014), where he re-imagines Paul Gauguin and Vincent Van Gogh’s (often tempestuous) cohabitation in the so-called “Yellow House” in 1888 Arles. In Tiepolo’s Hound (2000), Walcott’s life rhymes with that of the Impressionist painter Jacob Camille Pissarro, who was born in the Caribbean island of St Thomas in 1830. In this work, biographical and autobiographical impulses, fact and fiction, are productively combined, as “creation” (what “might have happened”) shapes Walcott’s life-writing as much as “recreation” (what “actually” happened). Walcott’s Pissarro is an individual immersed in a set of historical networks but also a figure at the centre of a web of imagined relations which illuminate the predicament of present and past artists in the Caribbean region and the ways in which they articulate their vision vis-à-vis the metropolitan centre, their relationship with their social and natural environment, and their individual and collective identity. Tiepolo’s Hound is enriched by the inclusion of twenty-six of Walcott’s own paintings which engage in conversation with the poet’s words and add complexity to his meditation on the nature and purpose of (re)writing and (re)creating lives. Extending the catholicity of life-writing to animals, in this case dogs and, in particular, mongrels, Tiepolo’s Hound also entails a careful, if counterintuitive, evaluation of anonymity

Direct Observation of Phosphate Inhibiting the Force-Generating Capacity of a Miniensemble of Myosin Molecules

AbstractElevated levels of phosphate (Pi) reduce isometric force, providing support for the notion that the release of Pi from myosin is closely associated with the generation of muscular force. Pi is thought to rebind to actomyosin in an ADP-bound state and reverse the force-generating steps, including the rotation of the lever arm (i.e., the powerstroke). Despite extensive study, this mechanism remains controversial, in part because it fails to explain the effects of Pi on isometric ATPase and unloaded shortening velocity. To gain new insight into this process, we determined the effect of Pi on the force-generating capacity of a small ensemble of myosin (∼12 myosin heads) using a three-bead laser trap assay. In the absence of Pi, myosin pulled the actin filament out of the laser trap an average distance of 54 ± 4 nm, translating into an average peak force of 1.2 pN. By contrast, in the presence of 30 mM Pi, myosin generated only enough force to displace the actin filament by 13 ± 1 nm, generating just 0.2 pN of force. The elevated Pi also caused a >65% reduction in binding-event lifetime, suggesting that Pi induces premature detachment from a strongly bound state. Definitive evidence of a Pi-induced powerstroke reversal was not observed, therefore we determined if a branched kinetic model in which Pi induces detachment from a strongly bound, postpowerstroke state could explain these observations. The model was able to accurately reproduce not only the data presented here, but also the effects of Pi on both isometric ATPase in muscle fibers and actin filament velocity in a motility assay. The ability of the model to capture the findings presented here as well as previous findings suggests that Pi-induced inhibition of force may proceed along a kinetic pathway different from that of force generation

Colour object search

The visual search process is required when locating an object in some region of space. To perform this search two capabilities must be available: the ability to recognise the object when it comes into view; and a way of selecting these views. Visual search is often complicated by object occlusion and low spatial resolutions of the object. Although the human visual system performs this task effortlessly, the mechanisms of it are not properly understood. Object colour and geometry, however do play an important role. This thesis develops an object search methodology which assumes that a computer vision system captures both wide-angle and zoomed images of the scene containing the object. Since most of the research has focused on object recognition using geometry, this system is purely colour-based. It is not expected that object colour will always give a definitive solution, however database pruning will often occur leading to reduced search times. The thesis argues that because colour is salient and more resilient than geometry to decreases in spatial resolution, it is more appropriate for visual search when the object occupies a small spatial resolution in an image with a large field of view. It also demonstrates that colour can be used to recognise objects when they occupy most of the field of view; as well as discriminate between database models with similar colour proportions but different region topologies. These conclusions are supported by the results produced by three algorithms, two of which perform colour object search and one that performs colour object recognition. The first object search algorithm uses image locations containing salient object colours as a method of selecting views. Each of these views are ranked indicating which view most likely contains the object. The second object search algorithm identifies image regions with similar colour and topology as the object. These results are produced in a best-first order. The object recognition algorithm uses an invariant based on region area to identify three corresponding model and image regions. A transformation is calculated to bring the model and object into the same viewpoint where region matches are based on position and colour. Each of these methods produced good results in complex indoor scenes with fluorescence and/or tungsten filament lighting; also the search speeds were impressive

Automated Decision-Support System for Prediction of Treatment Responders in Acute Ischemic Stroke

MRI is widely used in the assessment of acute ischemic stroke. In particular, it identifies the mismatch between hypoperfused and the permanently damaged tissue, the PWI-DWI mismatch volume. It is used to help triage patients into active or supportive treatment pathways. COMBAT Stroke is an automated software tool for estimating the mismatch volume and ratio based on MRI. Herein, we validate the decision made by the software with actual clinical decision rendered. Furthermore, we evaluate the association between treatment decisions (both automated and actual) and outcomes. COMBAT Stroke was used to determine PWI-DWI mismatch volume and ratio in 228 patients from two European multi-center stroke databases. We performed confusion matrix analysis to summarize the agreement between the automated selection and the clinical decision. Finally, we evaluated the clinical and imaging outcomes of the patients in the four entries of the confusion matrix (true positive, true negative, false negative, and false positive). About 186 of 228 patients with acute stroke underwent thrombolytic treatment, with the remaining 42 receiving supportive treatment only. Selection based on radiographic criteria using COMBAT Stroke classified 142 patients as potential candidates for thrombolytic treatment and 86 for supportive treatment; 60% sensitivity and 29% specificity. The patients deemed eligible for thrombolytic treatment by COMBAT Stroke demonstrated significantly higher rates of compromised tissue salvage, less neurological deficit, and were more likely to experience thrombus dissolving and reestablishment of normal blood flow at 24 h follow-up compared to those who were treated without substantial PWI-DWI mismatch. These results provide evidence that COMBAT Stroke, in addition to clinical assessment, may offer an optimal framework for a fast, efficient, and standardized clinical support tool to select patients for thrombolysis in acute ischemic stroke

Radiation Treatment for WHO Grade II and III Meningiomas

The treatment of meningiomas is tailored to their histological grade. While World Health Organization (WHO) grade I lesions can be treated with either surgery or external beam radiation, WHO Grade II and III lesions often require a combination of the two modalities. For these high-grade lesions, conventional external beam radiation is delivered to either the residual tumor or the surgical resection margin. The optimal timing of radiation, either immediately following surgical resection or at the time of recurrence, is yet to be determined. Additionally, another method of radiation delivery, brachytherapy, can be administered locally at the time of surgery for recurrent lesions. Altogether, the complex nature of WHO grade II and III meningiomas requires careful treatment planning and delivery by a multidisciplinary team