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London, United Kingdom

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London, United Kingdom

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Hartl M.,Hammersmith Hospital Campus | Hartl M.,Max Planck Institute of Neurobiology | Grunwald Kadow I.C.,Max Planck Institute of Neurobiology
Frontiers in Molecular Neuroscience | Year: 2013

Since their discovery, microRNAs became prominent candidates providing missing links on how to explain the developmental and phenotypical variation within one species or among different species. In addition, microRNAs were implicated in diseases such as neurodegeneration and cancer. More recently, the regulation of animal behavior was shown to beinfluenced bymicroRNAs. Inspiteof their numerous functions, onlyafew microRNAs were discovered by using classic genetic approaches. Due to the very mild or redundant phenotypes of most microRNAs or their genomic location within introns of other genes many regulatory microRNAs were missed. In this review, we focus on three microRNAs first identified in a forward genetic screen in invertebrates for their essential function in animal development, namely bantam, let-7, and miR-279. All three are essential for survival, are not located in introns of other genes, and are highly conserved among species. We highlight their important functions in the nervous system and discuss their emerging roles, especially during nervous system disease and behavior. © 2013 Hartl andGrunwaldKadow.


Nowak A.A.,Hammersmith Hospital Campus | Canis K.,Imperial College London | Riddell A.,University College London | Laffan M.A.,Hammersmith Hospital Campus | McKinnon T.A.J.,Hammersmith Hospital Campus
Blood | Year: 2012

We have examined the effect of the O-linked glycan (OLG) structures of VWF on its interaction with the platelet receptor glycoprotein Ibα. The 10 OLGs were mutated individually and as clusters (Clus) on either and both sides of the A1 domain: Clus1 (N-terminal side), Clus2 (C-terminal side), and double cluster (DC), in both full-length-VWF and in a VWF construct spanning D′ to A3 domains. Mutations did not alter VWF secretion by HEK293T cells, multimeric structure, or static collagen binding. The T1255A, Clus1, and DC variants caused increased ristocetin-mediated GPIbα binding to VWF. Platelet translocation rate on OLG mutants was increased because of reduced numbers of GPIbα binding sites but without effect on bond lifetime. In contrast, OLG mutants mediated increased platelet capture on collagen under high shear stress that was associated with increased adhesion of these variants to the collagen under flow. These findings suggest that removal of OLGs increases the flexibility of the hinge linker region between the D3 and A1 domain, facilitating VWF unfolding by shear stress, thereby enhancing its ability to bind collagen and capture platelets. These data demonstrate an important functional role of VWF OLGs under shear stress conditions. © 2012 by The American Society of Hematology.


Sharp P.S.,Hammersmith Hospital Campus | Bye-A-Jee H.,Hammersmith Hospital Campus | Wells D.J.,Hammersmith Hospital Campus | Wells D.J.,Royal Veterinary College
Molecular Therapy | Year: 2011

Antisense-induced exon skipping can restore the open reading frame, and thus correct the dystrophin deficiency that causes Duchenne muscular dystrophy (DMD), a lethal muscle wasting condition. Successful proof-of-principle in preclinical models has led to human clinical trials. However, it is still not known what percentage of dystrophin-positive fibers and what level of expression is necessary for functional improvement. This study directly address these key questions in the mdx mouse model of DMD. To achieve a significant variation in dystrophin expression, we locally administered into tibialis anterior muscles various doses of a phosphorodiamidate morpholino oligomer (PMO) designed to skip the mutated exon 23 from the mRNA of murine dystrophin. We found a highly significant correlation between the number of dystrophin-positive fibers and resistance to contraction-induced injury, with a minimum of 20% of dystrophin-positive fibers required for meaningful improvement. Furthermore, our results also indicate that a relatively low level of dystrophin expression in muscle fibers may have significant clinical benefits. In contrast, improvements in muscle force were not correlated with either the number of positive fibers or total dystrophin levels, which highlight the need to conduct appropriate functional assessments in preclinical testing using the mdx mouse. © The American Society of Gene & Cell Therapy.


Hellyer P.J.,Hammersmith Hospital Campus | Leech R.,Hammersmith Hospital Campus | Ham T.E.,Hammersmith Hospital Campus | Bonnelle V.,Hammersmith Hospital Campus | And 2 more authors.
Annals of Neurology | Year: 2013

Objective: Traumatic brain injury (TBI) often results in traumatic axonal injury (TAI). This can be difficult to identify using conventional imaging. Diffusion tensor imaging (DTI) offers a method of assessing axonal damage in vivo, but has previously mainly been used to investigate groups of patients. Machine learning techniques are increasingly used to improve diagnosis based on complex imaging measures. We investigated whether machine learning applied to DTI data can be used to diagnose white matter damage after TBI and to predict neuropsychological outcome in individual patients. Methods: We trained pattern classifiers to predict the presence of white matter damage in 25 TBI patients with microbleed evidence of TAI compared to neurologically healthy age-matched controls. We then applied these classifiers to 35 additional patients with no conventional imaging evidence of TAI. Finally, we used regression analyses to predict indices of neuropsychological outcome for information processing speed, executive function, and associative memory in a group of 70 heterogeneous patients. Results The classifiers discriminated between patients with microbleeds and age-matched controls with a high degree of accuracy, and outperformed other methods. When the trained classifiers were applied to patients without microbleeds, patients having likely TAI showed evidence of greater cognitive impairment in information processing speed and executive function. The classifiers were also able to predict the extent of impairments in information processing speed and executive function. Interpretation: The work provides a proof of principle that multivariate techniques can be used with DTI to provide diagnostic information about clinically significant TAI. © 2013 American Neurological Association.


Nijjer S.S.,Hammersmith Hospital Campus | Watson G.,Hammersmith Hospital Campus | Athanasiou T.,Imperial College London | Malik I.S.,Hammersmith Hospital Campus
European Heart Journal | Year: 2011

Aims Guidelines suggest that patients should discontinue clopidogrel for 5 days prior to coronary artery bypass grafting (CABG) where possible. Those with acute coronary syndrome (ACS) are at elevated risk of further myocardial infarction (MI) and death without clopidogrel. This meta-analysis Aims to determine the risk of CABG in ACS patients while continuing clopidogrel. Method and results Thirty-four studies with 22 584 patients undergoing CABG were assessed. Patients with recent clopidogrel exposure (CL) were compared with those without recent clopidogrel (NC). Although mortality is increased in CL vs. NC [odds ratio (OR) 1.6, 95 CI 1.301.96, P < 0.00001], it is influenced by the ACS status and case urgency in these mainly non-randomized studies. In ACS patients, there is no significant difference in mortality (OR 1.44, 95 CI 0.972.1, P = 0.07) or in postoperative MI (OR 0.57, 95 CI 0.311.07, P = 0.08) and stroke rates (OR 1.23, 95 CI 0.662.29, P = 0.52). Combined major adverse cardiovascular event (stroke, MI, and death) was not different in the two groups (OR 1.10, 95 CI 0.871.41, P = 0.43). Reoperation rates are elevated on clopidogrel but have reduced over time, and were specifically not different in ACS patients (OR 1.5, 95 CI 0.882.54, P = 0.13). Conclusion Previous studies focused on surrogate endpoints and compared higher risk ACS patients with elective cases. However, many patients have safely undergone CABG on clopidogrel and surgical expertise is growing. Multinational trials are required to fully determine the balance of ischaemia and bleeding. While results are awaited we suggest ACS patients requiring urgent CABG proceed with surgery without delay for a clopidogrel-free period. © 2011 The Author.


Gil J.,Hammersmith Hospital Campus | Rodriguez T.,Imperial College London
Current Biology | Year: 2016

The tumour-host microenvironment plays key roles in cancer, but the mechanisms involved are not fully understood. Two new studies provide insight into this problem by showing that through cell competition, a fitness-sensing process that usually eliminates defective cells, pre-cancerous lesions signal the death of surrounding tissue that in turn promotes their neoplastic transformation. © 2016 Elsevier Ltd.


Leech R.,Hammersmith Hospital Campus | Braga R.,Hammersmith Hospital Campus | Braga R.,Imperial College London | Sharp D.J.,Hammersmith Hospital Campus
Journal of Neuroscience | Year: 2012

There is considerable uncertainty about the function of the posterior cingulate cortex (PCC). The PCC is a major node within the default mode network (DMN) and has high metabolic activity and dense structural connectivity to widespread brain regions, which suggests it has a role as a cortical hub. The region appears to be involved in internally directed thought, for example, memory recollection. However, recent nonhuman primate work provides evidence for a more active role in the control of cognition, through signaling an environmental change and the need to alter behavior. For an organism to flexibly react to a changing environment, information processed in functionally distinct brain networks needs to be integrated by such a cortical hub. If the PCC is involved in this process, its brain activity should show a complex and dynamic pattern that partially reflects activity in other brain networks. Using fMRI in humans and a multivariate analysis, we demonstrate that the PCC shows this type of complex functional architecture, where echoes of multiple other brain networks are seen in separable yet overlapping subregions. For example, a predominantly ventral region shows strong functional connectivity to the rest of the DMN, whereas two subregions within the dorsal PCC show high connectivity to frontoparietal networks involved in cognitive control. PCC subregions showed distinct patterns of activity modulation during the performance of an attentionally demanding task, suggesting that parts of the dorsal PCC interact with frontoparietal networks to regulate the balance between internally and externally directed cognition. ©2012 the authors.


De Giorgio A.,Hammersmith Hospital Campus | Castellano L.,Hammersmith Hospital Campus | Krell J.,Hammersmith Hospital Campus | Stebbing J.,Hammersmith Hospital Campus
Oncogene | Year: 2014

A molecular environment that promotes vascularization around human carcinomas can materialise rapidly, and has been termed the angiogenic switch. Turning this switch toward a proangiogenic state involves an altered interplay between tumor cells and multiple components of the surrounding stroma. The regulatory landscape of these interactions in cervical cancer is now investigated by Huang et al. in this issue of Oncogene, who demonstrate that the microRNA miR-126 is downregulated during cancer progression, particularly in stromal cells. Such a reduction of miR-126 is shown to free at least one target, the proangiogenic adrenomedullin, from repression, enhancing vascular growth especially at the in situ to invasive carcinoma transition. The study implicates the temporal, spatial and progressive nature of tumor-stroma interactions during carcinogenesis, while in turn suggesting therapeutic strategies. © 2014 Macmillan Publishers Limited.


Reynolds R.,Hammersmith Hospital Campus | Roncaroli F.,Hammersmith Hospital Campus | Nicholas R.,Hammersmith Hospital Campus | Radotra B.,Hammersmith Hospital Campus | And 2 more authors.
Acta Neuropathologica | Year: 2011

Multiple sclerosis is the major inflammatory condition affecting the central nervous system (CNS) and is characterised by disseminated focal immune-mediated demyelination. Demyelination is accompanied by variable axonal damage and loss and reactive gliosis. It is this pathology that is thought to be responsible for the clinical relapses that often respond well to immunomodulatory therapy. However, the later secondary progressive stage of MS remains largely refractory to treatment and it is widely suggested that accumulating axon loss is responsible for clinical progression. Although initially thought to be a white matter (WM) disease, it is increasingly apparent that extensive pathology is also seen in the grey matter (GM) throughout the CNS. GM pathology is characterised by demyelination in the relative absence of an immune cell infiltrate. Neuronal loss is also seen both in the GM lesions and in unaffected areas of the GM. The slow progressive nature of this later stage combined with the presence of extensive grey matter pathology has led to the suggestion that neurodegeneration might play an increasing role with increasing disease duration. However, there is a paucity of studies that have correlated the pathological features with clinical milestones during secondary progressive MS. Here, we review the contributions that the various types of pathology are likely to make to the increasing neurological deficit in MS. © 2011 Springer-Verlag.


Surani M.A.,University of Cambridge | Hajkova P.,Hammersmith Hospital Campus
Cold Spring Harbor Symposia on Quantitative Biology | Year: 2010

Primordial germ cells (PGCs), the precursors of sperm and eggs, are the route to totipotency and require establishment of a unique epigenome in this lineage. The genetic program for PGC specification in the mouse also initiates epigenetic reprogramming that continues when PGCs migrate into the developing gonads. Among these later events is active and genomewide DNA demethylation, which is linked to extensive chromatin remodeling. These extensive epigenetic changes erase most, if not all, of the existing epigenetic information, which resets the epigenome for totipotency. Recent evidence suggests that active DNA demethylation involves a base excision repair (BER) pathway. BER is mechanistically linked to DNA demethylation, but what triggers BER is currently under investigation. The methylated cytosine (5mC) could be modified by deamination or to 5hmC, which could induce BER. Detection of Tet1 expression specifically and coincidentally, at the time of BER in PGCs, suggests that conversion of 5mC to 5hmC might be involved, at least in part, during epigenetic reprogramming and DNA demethylation in germ cells. © 2010 Cold Spring Harbor Laboratory Press.

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