Physiological Electrical Signals Promote Chain Migration of Neuroblasts by Up-Regulating P2Y1 Purinergic Receptors and Enhancing Cell Adhesion

Acknowledgments This work was supported by a grant from NHS Grampian. Open Access This article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are creditedPeer reviewedPublisher PD

Is tumour thickness measurement required for MOLES scoring of melanocytic choroidal tumours?

Introduction: It can be challenging to distinguish between choroidal naevi and melanomas in the community setting, particularly without access to ultrasonography, required to measure the thickness of melanocytic choroidal tumours. We aimed to determine whether thickness measurement is required for MOLES scoring of melanocytic choroidal tumours. Methods: The dataset of a recent MOLES evaluation was reviewed. Patients were selected for the present study if their MOLES tumour size category was determined by tumour thickness measured with ultrasonography (US). The largest basal tumour diameter and tumour thickness were then measured from ultra-widefield fundus images and optical coherence tomography (OCT) images, respectively. Results: The tumour size category was determined by tumour diameter in 203/222 (91.4%) with no influence of tumour thickness. The tumour thickness influenced the MOLES score in 19/222 (8.6%) patients. In 11/19 patients with OCT measurements of tumour thickness, the US measurement exceeded the OCT by more than 25% in 5 patients, more than 50% in 2 patients and more than 75% in 1 patient. As a result, the revised tumour thickness based on OCT determined the size category in 4/216 (1.8%) patients. The Optos measurements increased the diameter score by 1 in 5 patients. As a result, the revised tumour thickness determined the size category in 4/216 (1.8%) patients. If both the revised diameter and thickness scores were considered, the MOLES score reduced in 4 patients. If both the diameter and thickness scores were considered, the MOLES score reduced in 5 and increased in 1. Only 0.94% (2/211) of melanocytic choroidal tumours assessed with MOLES when using Optos ultra-widefield fundus images diameter and OCT to measure tumour diameter and thickness, respectively, required a change in management from a reduction in MOLES score from 1 to 0. Discussion/Conclusion: This study suggests that the MOLES category for size is influenced more by the tumour diameter, if it can be measured accurately, than by the thickness. This study suggests ignoring tumour thickness if this cannot be measured accurately with OCT, unless the tumour has a mushroom shape

Responsive Algorithms for Defending Recon gurable Networks

We present algorithms to self-heal reconfigurable networks when they are under attack. These algorithms reconfigure the network during attack to protect two critical invariants. First, they insure that the network remains connected. Second, they insure that no node increases its degree by more than O(log n). We show both theoretically and empirically that our algorithms can successfully maintain these invariants even for large networks under massive attack by a computationally unbounded adversary

Activation of a prophage‐encoded tyrosine kinase by a heterologous infecting phage results in a self‐inflicted abortive infection

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/87011/1/j.1365-2958.2011.07847.x.pd

Multimodal MRI can identify perfusion and metabolic changes in the invasive margin of glioblastomas.

PURPOSE: To use perfusion and magnetic resonance (MR) spectroscopy to compare the diffusion tensor imaging (DTI)-defined invasive and noninvasive regions. Invasion of normal brain is a cardinal feature of glioblastomas (GBM) and a major cause of treatment failure. DTI can identify invasive regions. MATERIALS AND METHODS: In all, 50 GBM patients were imaged preoperatively at 3T with anatomic sequences, DTI, dynamic susceptibility perfusion MR (DSCI), and multivoxel spectroscopy. The DTI and DSCI data were coregistered to the spectroscopy data and regions of interest (ROIs) were made in the invasive (determined by DTI), noninvasive regions, and normal brain. Values of relative cerebral blood volume (rCBV), N-acetyl aspartate (NAA), myoinositol (mI), total choline (Cho), and glutamate + glutamine (Glx) normalized to creatine (Cr) and Cho/NAA were measured at each ROI. RESULTS: Invasive regions showed significant increases in rCBV, suggesting angiogenesis (invasive rCBV 1.64 [95% confidence interval, CI: 1.5-1.76] vs. noninvasive 1.14 [1.09-1.18]; P < 0.001), Cho/Cr (invasive 0.42 [0.38-0.46] vs. noninvasive 0.35 [0.31-0.38]; P = 0.02) and Cho/NAA (invasive 0.54 [0.41-0.68] vs. noninvasive 0.37 [0.29-0.45]; P = < 0.03), suggesting proliferation, and Glx/Cr (invasive 1.54 [1.27-1.82] vs. noninvasive 1.3 [1.13-1.47]; P = 0.028), suggesting glutamate release; and a significantly reduced NAA/Cr (invasive 0.95 [0.85-1.05] vs. noninvasive 1.19 [1.06-1.31]; P = 0.008). The mI/Cr was not different between the three ROIs (invasive 1.2 [0.99-1.41] vs. noninvasive 1.3 [1.14-1.46]; P = 0.68). In the noninvasive regions, the values were not different from normal brain. CONCLUSION: Combining DTI to identify the invasive region with perfusion and spectroscopy, we can identify changes in invasive regions not seen in noninvasive regions.This study was funded from a National Institutes of Health Research Clinician Scientist FellowshipThis is the final version of the article. It first appeared from Wiley via http://dx.doi.org/10.1002/jmri.2499

Protrudin functions from the endoplasmic reticulum to support axon regeneration in the adult CNS

Funder: Bill and Melinda Gates Foundation (Bill & Melinda Gates Foundation); doi: https://doi.org/10.13039/100000865Funder: Christopher and Dana Reeve Foundation (Christopher & Dana Reeve Foundation); doi: https://doi.org/10.13039/100001305Funder: International Foundation for Research in Paraplegia (Internationale Stiftung für Forschung in Paraplegie); doi: https://doi.org/10.13039/501100001708Funder: Foundation for the National Institutes of Health (Foundation for the National Institutes of Health, Inc.); doi: https://doi.org/10.13039/100000009Funder: Christopher and Dana Reeve Foundation (Christopher & Dana Reeve Foundation)Abstract: Adult mammalian central nervous system axons have intrinsically poor regenerative capacity, so axonal injury has permanent consequences. One approach to enhancing regeneration is to increase the axonal supply of growth molecules and organelles. We achieved this by expressing the adaptor molecule Protrudin which is normally found at low levels in non-regenerative neurons. Elevated Protrudin expression enabled robust central nervous system regeneration both in vitro in primary cortical neurons and in vivo in the injured adult optic nerve. Protrudin overexpression facilitated the accumulation of endoplasmic reticulum, integrins and Rab11 endosomes in the distal axon, whilst removing Protrudin’s endoplasmic reticulum localization, kinesin-binding or phosphoinositide-binding properties abrogated the regenerative effects. These results demonstrate that Protrudin promotes regeneration by functioning as a scaffold to link axonal organelles, motors and membranes, establishing important roles for these cellular components in mediating regeneration in the adult central nervous system

Proteomic identification, cDNA cloning and enzymatic activity of glutathione S-transferases from the generalist marine gastropod, Cyphoma gibbosum

Author Posting. © Elsevier B.V., 2008. This is the author's version of the work. It is posted here by permission of Elsevier B.V. for personal use, not for redistribution. The definitive version was published in Archives of Biochemistry and Biophysics 478 (2008): 7-17, doi:10.1016/j.abb.2008.07.007.Glutathione S-transferases (GST) were characterized from the digestive gland of Cyphoma gibbosum (Mollusca; Gastropoda), to investigate the possible role of these detoxification enzymes in conferring resistance to allelochemicals present in its gorgonian coral diet. We identified the collection of expressed cytosolic Cyphoma GST classes using a proteomic approach involving affinity chromatography, HPLC and nanospray liquid chromatography-tandem mass spectrometry (LC-MS/MS). Two major GST subunits were identified as putative mu-class GSTs; while one minor GST subunit was identified as a putative theta-class GST, apparently the first theta-class GST identified from a mollusc. Two Cyphoma GST cDNAs (CgGSTM1 and CgGSTM2) were isolated by RT-PCR using primers derived from peptide sequences. Phylogenetic analyses established both cDNAs as mu-class GSTs and revealed a mollusc-specific subclass of the GST-mu clade. These results provide new insights into metazoan GST diversity and the biochemical mechanisms used by marine organisms to cope with their chemically defended prey.Support was provided by the WHOI-Cole Ocean Ventures Fund (KEW), the WHOI Ocean Life Institute (KEW and MEH), a grant from Walter A. and Hope Noyes Smith (MEH), the National Science Foundation Graduate Research Fellowship (KEW), and by the National Institutes of Health (P42-ES007381 and R01-ES015912 to JVG)

Variants of the EAAT2 Glutamate Transporter Gene Promoter Are Associated with Cerebral Palsy in Preterm Infants

© 2017, The Author(s). Preterm delivery is associated with neurodevelopmental impairment caused by environmental and genetic factors. Dysfunction of the excitatory amino acid transporter 2 (EAAT2) and the resultant impaired glutamate uptake can lead to neurological disorders. In this study, we investigated the role of single nucleotide polymorphisms (SNPs; g.-200CCloseSPigtSPiA and g.-181ACloseSPigtSPiC) in the EAAT2 promoter in susceptibility to brain injury and neurodisability in very preterm infants born at or before 32-week gestation. DNA isolated from newborns’ dried blood spots were used for pyrosequencing to detect both SNPs. Association between EAAT2 genotypes and cerebral palsy, cystic periventricular leukomalacia and a low developmental score was then assessed. The two SNPs were concordant in 89.4% of infants resulting in three common genotypes all carrying two C and two A alleles in different combinations. However, in 10.6% of cases, non-concordance was found, generating six additional rare genotypes. The A alleles at both loci appeared to be detrimental and consequently, the risk of developing cerebral palsy increased four- and sixfold for each additional detrimental allele at -200 and -181bp, respectively. The two SNPs altered the regulation of the EAAT2 promoter activity and glutamate homeostasis. This study highlights the significance of glutamate in the pathogenesis of preterm brain injury and subsequent development of cerebral palsy and neurodevelopmental disabilities. Furthermore, the described EAAT2 SNPs may be an early biomarker of vulnerability to neurodisability and may aid the development of targeted treatment strategies

The genetic architecture of type 2 diabetes

The genetic architecture of common traits, including the number, frequency, and effect sizes of inherited variants that contribute to individual risk, has been long debated. Genome-wide association studies have identified scores of common variants associated with type 2 diabetes, but in aggregate, these explain only a fraction of heritability. To test the hypothesis that lower-frequency variants explain much of the remainder, the GoT2D and T2D-GENES consortia performed whole genome sequencing in 2,657 Europeans with and without diabetes, and exome sequencing in a total of 12,940 subjects from five ancestral groups. To increase statistical power, we expanded sample size via genotyping and imputation in a further 111,548 subjects. Variants associated with type 2 diabetes after sequencing were overwhelmingly common and most fell within regions previously identified by genome-wide association studies. Comprehensive enumeration of sequence variation is necessary to identify functional alleles that provide important clues to disease pathophysiology, but large-scale sequencing does not support a major role for lower-frequency variants in predisposition to type 2 diabetes