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Find video protocols related to scientific articles indexed in Pubmed.
Mutations in the essential arabinosyltransferase EmbC lead to alterations in Mycobacterium tuberculosis lipoarabinomannan.
J. Biol. Chem.
PUBLISHED: 10-30-2014
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The Mycobacterium tuberculosis cell wall is a complex structure essential for the viability of the organism and its interaction with the host. The glycolipid lipoarabinomannan (LAM) plays an important role in mediating host-bacteria interactions and is involved in modulation of the immune response. The arabinosyltransferase EmbC required for LAM biosynthesis is essential. We constructed recombinant strains of M. tuberculosis expressing a variety of alleles of EmbC. We demonstrated that EmbC has a functional signal peptide in M. tuberculosis. Over- or under-expression of EmbC had no effect on LAM production, but did result in reduced or increased sensitivity to ethambutol respectively. The C-terminal domain of EmbC was essential for activity, since truncated alleles were unable to mediate LAM production in Mycobacterium smegmatis, and were unable to complement an embC deletion in M. tuberculosis. The C-terminal domain of the closely related arabinosyltransferase EmbB was unable to complement the function of the EmbC C-terminal domain. Two functional motifs were identified; the GT-C motif contains two essential aspartate residues in the DDX motif. The proline-rich region contains two highly conserved asparagines (N638 and N652); mutation of these residues was tolerated, but loss of N638 resulted in the synthesis of truncated LAM lacking arabinose branching. All embC alleles that were incapable of complementing LAM production in M. smegmatis were not viable in M. tuberculosis supporting the hypothesis that LAM itself is essential in M. tuberculosis.
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Human herpes simplex virus type 1 in confiscated gorilla.
Emerging Infect. Dis.
PUBLISHED: 10-24-2014
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In 2007, we detected human herpes simplex virus type 1, which caused stomatitis, in a juvenile confiscated eastern lowland gorilla (Gorilla beringei graueri) that had a high degree of direct contact with human caretakers. Our findings confirm that pathogens can transfer between nonhuman primate hosts and humans.
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Efficient stereo image geometrical reconstruction at arbitrary camera settings from a single calibration.
Med Image Comput Comput Assist Interv
PUBLISHED: 10-22-2014
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Camera calibration is central to obtaining a quantitative image-to-physical-space mapping from stereo images acquired in the operating room (OR). A practical challenge for cameras mounted to the operating microscope is maintenance of image calibration as the surgeon's field-of-view is repeatedly changed (in terms of zoom and focal settings) throughout a procedure. Here, we present an efficient method for sustaining a quantitative image-to-physical space relationship for arbitrary image acquisition settings (S) without the need for camera re-calibration. Essentially, we warp images acquired at S into the equivalent data acquired at a reference setting, S(0), using deformation fields obtained with optical flow by successively imaging a simple phantom. Closed-form expressions for the distortions were derived from which 3D surface reconstruction was performed based on the single calibration at S(0). The accuracy of the reconstructed surface was 1.05 mm and 0.59 mm along and perpendicular to the optical axis of the operating microscope on average, respectively, for six phantom image pairs, and was 1.26 mm and 0.71 mm for images acquired with a total of 47 arbitrary settings during three clinical cases. The technique is presented in the context of stereovision; however, it may also be applicable to other types of video image acquisitions (e.g., endoscope) because it does not rely on any a priori knowledge about the camera system itself, suggesting the method is likely of considerable significance.
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CD47 in the Tumor Microenvironment Limits Cooperation between Antitumor T-cell Immunity and Radiotherapy.
Cancer Res.
PUBLISHED: 10-08-2014
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Although significant advances in radiotherapy have increased its effectiveness in many cancer settings, general strategies to widen the therapeutic window between normal tissue toxicity and malignant tumor destruction would still offer great value. CD47 blockade has been found to confer radioprotection to normal tissues while enhancing tumor radiosensitivity. Here, we report that CD47 blockade directly enhances tumor immunosurveillance by CD8(+) T cells. Combining CD47 blockade with irradiation did not affect fibrosarcoma growth in T cell-deficient mice, whereas adoptive transfer of tumor-specific CD8(+) T cells restored combinatorial efficacy. Furthermore, ablation of CD8(+) T cells abolished radiotherapeutic response in immunocompetent syngeneic hosts. CD47 blockade in either target cells or effector cells was sufficient to enhance antigen-dependent CD8(+) CTL-mediated tumor cell killing in vitro. In CD47-deficient syngeneic hosts, engrafted B16 melanomas were 50% more sensitive to irradiation, establishing that CD47 expression in the microenvironment was sufficient to limit tumor radiosensitivity. Mechanistic investigations revealed increased tumor infiltration by cytotoxic CD8(+) T cells in a CD47-deficient microenvironment, with an associated increase in T cell-dependent intratumoral expression of granzyme B. Correspondingly, an inverse correlation between CD8(+) T-cell infiltration and CD47 expression was observed in human melanomas. Our findings establish that blocking CD47 in the context of radiotherapy enhances antitumor immunity by directly stimulating CD8(+) cytotoxic T cells, with the potential to increase curative responses. Cancer Res; 74(23); 1-13. ©2014 AACR.
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Stereovision to MR image registration for cortical surface displacement mapping to enhance image-guided neurosurgery.
Med Phys
PUBLISHED: 10-06-2014
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A surface registration method is presented to align intraoperative stereovision (iSV) with preoperative magnetic resonance (pMR) images, which utilizes both geometry and texture information to extract tissue displacements as part of the overall process of compensating for intraoperative brain deformation in order to maintain accurate neuronavigational image guidance during surgery.
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Self-association of the APC tumor suppressor is required for the assembly, stability, and activity of the Wnt signaling destruction complex.
Mol. Biol. Cell
PUBLISHED: 09-10-2014
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The tumor suppressor adenomatous polyposis coli (APC) is an essential negative regulator of Wnt signaling through its activity in the destruction complex with Axin, GSK3?, and CK1 that targets ?-catenin/Armadillo (?-cat/Arm) for proteosomal degradation. The destruction complex forms macromolecular particles we termed the destructosome. Whereas APC functions in the complex through its ability to bind both ?-cat and Axin, we hypothesize that APC proteins play an additional role in destructosome assembly through self-association. Here we show that a novel N-terminal coil, the APC self-association domain (ASAD), found in vertebrate and invertebrate APCs, directly mediates self-association of Drosophila APC2 and plays an essential role in the assembly and stability of the destructosome that regulates ?-cat degradation in Drosophila and human cells. Consistent with this, removal of the ASAD from the Drosophila embryo results in ?-cat/Arm accumulation and aberrant Wnt pathway activation. These results suggest that APC proteins are required not only for the activity of the destructosome, but also for the assembly and stability of this macromolecular machine.
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CD47 signaling regulates the immunosuppressive activity of VEGF in T cells.
J. Immunol.
PUBLISHED: 09-08-2014
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Thrombospondin-1 (TSP1) inhibits angiogenesis, in part, by interacting with the ubiquitous cell-surface receptor CD47. In endothelial cells, CD47 interacts directly with vascular endothelial growth factor receptor (VEGFR)-2, and TSP1 inhibits VEGFR2 phosphorylation and signaling by disrupting this association. We show that CD47 similarly associates with and regulates VEGFR2 in T cells. TSP1 inhibits phosphorylation of VEGFR2 and its downstream target Src in wild type but not in CD47-deficient human Jurkat and primary murine T cells. VEGFR2 signaling inhibits proliferation and TCR signaling in wild type T cells. However, ligation of CD47 by TSP1 or loss of CD47 expression reverses some inhibitory effects of VEGF on proliferation and T cell activation. We further found that VEGF and VEGFR2 expression are upregulated in CD47-deficient murine CD4(+) and human Jurkat T cells, and the resulting autocrine VEGFR2 signaling enhances proliferation and some TCR responses in the absence of CD47. Thus, CD47 signaling modulates the ability of VEGF to regulate proliferation and TCR signaling, and autocrine production of VEGF by T cells contributes to this regulation. This provides a mechanism to understand the context-dependent effects of TSP1 and VEGF on T cell activation, and reveals an important role for CD47 signaling in regulating T cell production of the major angiogenic factor VEGF.
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Idiosyncratic responses of grizzly bear habitat to climate change based on projected food resource changes.
Ecol Appl
PUBLISHED: 08-27-2014
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Climate change vulnerability assessments for species of conservation concern often use species distribution and ecological niche modeling to project changes in habitat. One of many assumptions of these approaches is that food web dependencies are consistent in time and environmental space. Species at higher trophic levels that rely on the availability of species at lower trophic levels as food may be sensitive to extinction cascades initiated by changes in the habitat of key food resources. Here we assess climate change vulnerability for Ursus arctos (grizzly bears) in the southern Canadian Rocky Mountains using projected changes to 17 of the most commonly consumed plant food items. We used presence-absence information from 7088 field plots to estimate ecological niches and to project changes in future distributions of each species. Model projections indicated idiosyncratic responses among food items. Many food items persisted or even increased, although several species were found to be vulnerable based on declines or geographic shifts in suitable habitat. These included Hedysarum alpinum (alpine sweet vetch), a critical spring and autumn root-digging resource when little else is available. Potential habitat loss was also identified for three fruiting species of lower importance to bears: Empetrum nigrum (crowberry), Vaccinium scoparium (grouseberry), and Fragaria virginiana (strawberry). A general trend towards uphill migration of bear foods may result in higher vulnerability to bear populations at low elevations, which are also those that are most likely to have human-bear conflict problems. Regardless, a wide diet breadth of grizzly bears, as well as wide environmental niches of most food items, make climate change a much lower threat to grizzly bears than other bear species such as polar bears and panda bears. We cannot exclude, however, future alterations in human behavior and land use resulting from climate change that may reduce survival rates.
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Oral or parenteral iron supplementation to reduce deferral, iron deficiency and/or anaemia in blood donors.
Cochrane Database Syst Rev
PUBLISHED: 07-04-2014
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Iron deficiency is a significant cause of deferral in people wishing to donate blood. If iron removed from the body through blood donation is not replaced, then donors may become iron deficient. All donors are screened at each visit for low haemoglobin (Hb) levels. However, some deferred blood donors do not return to donate. Deferred first-time donors are even less likely to return. Interventions that reduce the risk of provoking iron deficiency and anaemia in blood donors will therefore increase the number of blood donations. Currently, iron supplementation for blood donors is not a standard of care in many blood services. A systematic review is required to answer specific questions regarding the efficacy and safety of iron supplementation in blood donors.
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Cortical surface shift estimation using stereovision and optical flow motion tracking via projection image registration.
Med Image Anal
PUBLISHED: 07-03-2014
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Stereovision is an important intraoperative imaging technique that captures the exposed parenchymal surface noninvasively during open cranial surgery. Estimating cortical surface shift efficiently and accurately is critical to compensate for brain deformation in the operating room (OR). In this study, we present an automatic and robust registration technique based on optical flow (OF) motion tracking to compensate for cortical surface displacement throughout surgery. Stereo images of the cortical surface were acquired at multiple time points after dural opening to reconstruct three-dimensional (3D) texture intensity-encoded cortical surfaces. A local coordinate system was established with its z-axis parallel to the average surface normal direction of the reconstructed cortical surface immediately after dural opening in order to produce two-dimensional (2D) projection images. A dense displacement field between the two projection images was determined directly from OF motion tracking without the need for feature identification or tracking. The starting and end points of the displacement vectors on the two cortical surfaces were then obtained following spatial mapping inversion to produce the full 3D displacement of the exposed cortical surface. We evaluated the technique with images obtained from digital phantoms and 18 surgical cases - 10 of which involved independent measurements of feature locations acquired with a tracked stylus for accuracy comparisons, and 8 others of which 4 involved stereo image acquisitions at three or more time points during surgery to illustrate utility throughout a procedure. Results from the digital phantom images were very accurate (0.05 pixels). In the 10 surgical cases with independently digitized point locations, the average agreement between feature coordinates derived from the cortical surface reconstructions was 1.7-2.1mm relative to those determined with the tracked stylus probe. The agreement in feature displacement tracking was also comparable to tracked probe data (difference in displacement magnitude was <1mm on average). The average magnitude of cortical surface displacement was 7.9 ± 5.7 mm (range 0.3-24.4 mm) in all patient cases with the displacement components along gravity being 5.2 ± 6.0 mm relative to the lateral movement of 2.4 ± 1.6 mm. Thus, our technique appears to be sufficiently accurate and computationally efficiency (typically ?15 s), for applications in the OR.
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Testing Models of the APC Tumor Suppressor/?-Catenin Interaction Reshapes Our View of the Destruction Complex in Wnt Signaling.
Genetics
PUBLISHED: 06-14-2014
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The Wnt pathway is a conserved signal transduction pathway that contributes to normal development and adult homeostasis, but is also misregulated in human diseases such as cancer. The tumor suppressor adenomatous polyposis coli (APC) is an essential negative regulator of Wnt signaling inactivated in >80% of colorectal cancers. APC participates in a multiprotein "destruction complex" that targets the proto-oncogene ?-catenin for ubiquitin-mediated proteolysis; however, the mechanistic role of APC in the destruction complex remains unknown. Several models of APC function have recently been proposed, many of which have emphasized the importance of phosphorylation of high-affinity ?-catenin-binding sites [20-amino-acid repeats (20Rs)] on APC. Here we test these models by generating a Drosophila APC2 mutant lacking all ?-catenin-binding 20Rs and performing functional studies in human colon cancer cell lines and Drosophila embryos. Our results are inconsistent with current models, as we find that ?-catenin binding to the 20Rs of APC is not required for destruction complex activity. In addition, we generate an APC2 mutant lacking all ?-catenin-binding sites (including the 15Rs) and find that a direct ?-catenin/APC interaction is also not essential for ?-catenin destruction, although it increases destruction complex efficiency in certain developmental contexts. Overall, our findings support a model whereby ?-catenin-binding sites on APC do not provide a critical mechanistic function per se, but rather dock ?-catenin in the destruction complex to increase the efficiency of ?-catenin destruction. Furthermore, in Drosophila embryos expressing some APC2 mutant transgenes we observe a separation of ?-catenin destruction and Wg/Wnt signaling outputs and suggest that cytoplasmic retention of ?-catenin likely accounts for this difference.
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Comprehensive analysis of forty yeast microarray datasets reveals a novel subset of genes (APha-RiB) consistently negatively associated with ribosome biogenesis.
BMC Bioinformatics
PUBLISHED: 06-10-2014
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The scale and complexity of genomic data lend themselves to analysis using sophisticated mathematical techniques to yield information that can generate new hypotheses and so guide further experimental investigations. An ensemble clustering method has the ability to perform consensus clustering over the same set of genes from different microarray datasets by combining results from different clustering methods into a single consensus result.
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The INTERVAL trial to determine whether intervals between blood donations can be safely and acceptably decreased to optimise blood supply: study protocol for a randomised controlled trial.
Trials
PUBLISHED: 06-10-2014
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Ageing populations may demand more blood transfusions, but the blood supply could be limited by difficulties in attracting and retaining a decreasing pool of younger donors. One approach to increase blood supply is to collect blood more frequently from existing donors. If more donations could be safely collected in this manner at marginal cost, then it would be of considerable benefit to blood services. National Health Service (NHS) Blood and Transplant in England currently allows men to donate up to every 12 weeks and women to donate up to every 16 weeks. In contrast, some other European countries allow donations as frequently as every 8 weeks for men and every 10 weeks for women. The primary aim of the INTERVAL trial is to determine whether donation intervals can be safely and acceptably decreased to optimise blood supply whilst maintaining the health of donors.
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Velocity of climate change algorithms for guiding conservation and management.
Glob Chang Biol
PUBLISHED: 05-23-2014
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The velocity of climate change is an elegant analytical concept that can be used to evaluate the exposure of organisms to climate change. In essence, one divides the rate of climate change by the rate of spatial climate variability to obtain a speed at which species must migrate over the surface of the earth to maintain constant climate conditions. However, to apply the algorithm for conservation and management purposes, additional information is needed to improve realism at local scales. For example, destination information is needed to ensure that vectors describing speed and direction of required migration do not point toward a climatic cul-de-sac by pointing beyond mountain tops. Here, we present an analytical approach that conforms to standard velocity algorithms if climate equivalents are nearby. Otherwise, the algorithm extends the search for climate refugia, which can be expanded to search for multivariate climate matches. With source and destination information available, forward and backward velocities can be calculated allowing useful inferences about conservation of species (present-to-future velocities) and management of species populations (future-to-present velocities).
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Thrombospondin-1 and CD47 signaling regulate healing of thermal injury in mice.
Matrix Biol.
PUBLISHED: 05-07-2014
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More than 2.5 million Americans suffer from burn injuries annually, and burn management is a major public health problem. Treatments have been developed to manage wound injuries employing skin grafts, various dressings and topical and systemic agents. However, these often achieve limited degrees of success. We previously reported that targeting the interaction of thrombospondin-1 with its signaling receptor CD47 or deletion of the genes encoding either of these proteins in mice improves recovery from soft tissue ischemic injuries as well as tissue injuries caused by ionizing radiation. We now demonstrate that the absence of CD47 improves the rate of wound closure for a focal dermal second-degree thermal injury, whereas lack of thrombospondin-1 initially delays wound closure compared to healing in wild type mice. Doppler analysis of the wounded area showed increased blood flow in both CD47 and thrombospondin-1 null mice. Accelerated wound closure in the CD47 null mice was associated with increased fibrosis as demonstrated by a 4-fold increase in collagen fraction. Wound tissue of CD47 null mice showed increased thrombospondin-1 mRNA and protein expression and TGF-?1 mRNA levels. Activation of latent TGF-?1 was increased in thermally injured CD47-null tissue as assessed by phosphorylation of the TGF-?1 receptor-regulated transcription factors SMAD-2 and -3. Overall these results indicate that targeting CD47 may improve the speed of healing thermal injuries, but some level of CD47 expression may be required to limit the long term TGF-?1-dependent fibrosis of these wounds.
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Towards AOP application--implementation of an integrated approach to testing and assessment (IATA) into a pipeline tool for skin sensitization.
Regul. Toxicol. Pharmacol.
PUBLISHED: 04-14-2014
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Since the OECD published the Adverse Outcome Pathway (AOP) for skin sensitization, many efforts have focused on how to integrate and interpret nonstandard information generated for key events in a manner that can be practically useful for decision making. These types of frameworks are known as Integrated Approaches to Testing and Assessment (IATA). Here we have outlined an IATA for skin sensitization which focuses on existing information including non testing approaches such as QSAR and read-across. The IATA was implemented into a pipeline tool using OASIS technology to provide a means of systematically collating and compiling relevant information which could be used in an assessment of skin sensitization potential. A test set of 100 substances with available skin sensitization information was profiled using the pipeline IATA. In silico and in chemico profiling information alone was able to correctly predict skin sensitization potential, with a preliminary accuracy of 73.85%. Information from other relevant endpoints (e.g., Ames mutagenicity) was found to improve the accuracy (to 87.6%) when coupled with a reaction chemistry mechanistic understanding. This pipeline platform could be useful in the assessment of skin sensitization potential and marks a step change in how non testing approaches can be practically applied.
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Fragmentation of care and the use of head computed tomography in patients with ischemic stroke.
Circ Cardiovasc Qual Outcomes
PUBLISHED: 04-08-2014
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Computed tomographic (CT) scans are central diagnostic tests for ischemic stroke. Their inefficient use is a negative quality measure tracked by the Centers for Medicare and Medicaid Services.
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Douglas-fir plantations in Europe: a retrospective test of assisted migration to address climate change.
Glob Chang Biol
PUBLISHED: 03-28-2014
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We evaluate genetic test plantations of North American Douglas-fir provenances in Europe to quantify how tree populations respond when subjected to climate regime shifts, and we examined whether bioclimate envelope models developed for North America to guide assisted migration under climate change can retrospectively predict the success of these provenance transfers to Europe. The meta-analysis is based on long-term growth data of 2800 provenances transferred to 120 European test sites. The model was generally well suited to predict the best performing provenances along north-south gradients in Western Europe, but failed to predict superior performance of coastal North American populations under continental climate conditions in Eastern Europe. However, model projections appear appropriate when considering additional information regarding adaptation of Douglas-fir provenances to withstand frost and drought, even though the model partially fails in a validation against growth traits alone. We conclude by applying the partially validated model to climate change scenarios for Europe, demonstrating that climate trends observed over the last three decades warrant changes to current use of Douglas-fir provenances in plantation forestry throughout Western and Central Europe.
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Human induced pluripotent stem cell derived erythroblasts can undergo definitive erythropoiesis and co-express gamma and beta globins.
Br. J. Haematol.
PUBLISHED: 03-09-2014
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Human induced pluripotent stem cells (hiPSCs), like embryonic stem cells, are under intense investigation for novel approaches to model disease and for regenerative therapies. Here, we describe the derivation and characterization of hiPSCs from a variety of sources and show that, irrespective of origin or method of reprogramming, hiPSCs can be differentiated on OP9 stroma towards a multi-lineage haemo-endothelial progenitor that can contribute to CD144(+) endothelium, CD235a(+) erythrocytes (myeloid lineage) and CD19(+) B lymphocytes (lymphoid lineage). Within the erythroblast lineage, we were able to demonstrate by single cell analysis (flow cytometry), that hiPSC-derived erythroblasts express alpha globin as previously described, and that a sub-population of these erythroblasts also express haemoglobin F (HbF), indicative of fetal definitive erythropoiesis. More notably however, we were able to demonstrate that a small sub-fraction of HbF positive erythroblasts co-expressed HbA in a highly heterogeneous manner, but analogous to cord blood-derived erythroblasts when cultured using similar methods. Moreover, the HbA expressing erythroblast population could be greatly enhanced (44·0 ± 6·04%) when a defined serum-free approach was employed to isolate a CD31(+) CD45(+) erythro-myeloid progenitor. These findings demonstrate that hiPSCs may represent a useful alternative to standard sources of erythrocytes (RBCs) for future applications in transfusion medicine.
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Genome-wide admixture and ecological niche modelling reveal the maintenance of species boundaries despite long history of interspecific gene flow.
Mol. Ecol.
PUBLISHED: 02-27-2014
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The maintenance of species boundaries despite interspecific gene flow has been a continuous source of interest in evolutionary biology. Many hybridizing species have porous genomes with regions impermeable to introgression, conferring reproductive barriers between species. We used ecological niche modelling to study the glacial and postglacial recolonization patterns between the widely hybridizing spruce species Picea glauca and P. engelmannii in western North America. Genome-wide estimates of admixture based on a panel of 311 candidate gene single nucleotide polymorphisms (SNP) from 290 genes were used to assess levels of admixture and introgression and to identify loci putatively involved in adaptive differences or reproductive barriers between species. Our palaeoclimatic modelling suggests that these two closely related species have a long history of hybridization and introgression, dating to at least 21,000 years ago, yet species integrity is maintained by a combination of strong environmental selection and reduced current interspecific gene flow. Twenty loci showed evidence of divergent selection, including six loci that were both Fst outliers and associated with climatic gradients, and fourteen loci that were either outliers or showed associations with climate. These included genes responsible for carbohydrate metabolism, signal transduction and transcription factors.
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The surgical treatment of headache.
Headache
PUBLISHED: 02-11-2014
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Medically refractory headache is an uncommon but difficult-to-treat clinical problem. Patients who fail maximal medical management may be candidates for invasive treatment. In this review, we critically examine the literature on the range of surgical treatments currently available for migraine, trigeminal autonomic cephalalgias, idiopathic intracranial hypertension and Chiari malformation type 1, with particular attention to patient selection, treatment efficacy, and complications.
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Mitochondria directly donate their membrane to form autophagosomes during a novel mechanism of parkin-associated mitophagy.
Cell Biosci
PUBLISHED: 02-06-2014
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Autophagy (macroautophagy), a cellular process of "self-eating", segregates damaged/aged organelles into vesicles, fuses with lysosomes, and enables recycling of the digested materials. The precise origin(s) of the autophagosome membrane is unclear and remains a critical but unanswered question. Endoplasmic reticulum, mitochondria, Golgi complex, and the plasma membrane have been proposed as the source of autophagosomal membranes.
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A mechanistic approach to modeling respiratory sensitization.
Chem. Res. Toxicol.
PUBLISHED: 02-06-2014
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Chemical respiratory sensitization is an important occupational health problem which may lead to severely incapacitated human health, yet there are currently no validated or widely accepted models for identifying and characterizing the potential of a chemical to induce respiratory sensitization. This is in part due to the ongoing uncertainty about the immunological mechanisms through which respiratory sensitization may be acquired. Despite the lack of test method, regulations such as REACH still require an assessment of respiratory sensitization for risk assessment and/or for the purposes of classification and labeling. The REACH guidance describes an integrated evaluation strategy to characterize what information sources could be available to facilitate such an assessment. The components of this include a consideration of well-established structural alerts and existing data (whether it be derived from read-across, (quantitative) structure-activity relationships ((Q)SAR), in vivo studies etc.). There has been some progress in developing SARs as well as a handful of empirical QSARs. More recently, efforts have been focused on exploring whether the reaction chemistry mechanistic domains first characterized for skin sensitization are relevant for respiratory sensitization and to what extent modifications or refinements are needed to rationalize the differences between the two end points as far as their chemistry is concerned. This study has built upon the adverse outcome pathway (AOP) for skin sensitization that was developed and published by the OECD in 2012. We have structured a workflow to characterize the initiating events that are relevant in driving respiratory sensitization. OASIS pipeline technology was used to encode these events as components in a software platform to enable a prediction of respiratory sensitization potential to be made for new untested chemicals. This prediction platform could be useful in the assessment of respiratory sensitization potential or for grouping chemicals for subsequent read-across.
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Hexokinase-II positively regulates glucose starvation-induced autophagy through TORC1 inhibition.
Mol. Cell
PUBLISHED: 01-23-2014
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Hexokinase-II (HK-II) catalyzes the first step of glycolysis and also functions as a protective molecule; however, its role in protective autophagy has not been determined. Results showed that inhibition of HK-II diminished, while overexpression of HK-II potentiated, autophagy induced by glucose deprivation in cardiomyocyte and noncardiomyocyte cells. Immunoprecipitation studies revealed that HK-II binds to and inhibits the autophagy suppressor, mTOR complex 1 (TORC1), and that this binding was increased by glucose deprivation. The TOS motif, a scaffold sequence responsible for binding TORC1 substrates, is present in HK-II, and mutating it blocked its ability to bind to TORC1 and regulate protective autophagy. The transition from glycolysis to autophagy appears to be regulated by a decrease in glucose-6 phosphate. We suggest that HK-II binds TORC1 as a decoy substrate and provides a previously unrecognized mechanism for switching cells from a metabolic economy, based on plentiful energy, to one of conservation, under starvation.
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CD47-dependent immunomodulatory and angiogenic activities of extracellular vesicles produced by T cells.
Matrix Biol.
PUBLISHED: 01-10-2014
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Intercellular communication is critical for integrating complex signals in multicellular eukaryotes. Vascular endothelial cells and T lymphocytes closely interact during the recirculation and trans-endothelial migration of T cells. In addition to direct cell-cell contact, we show that T cell derived extracellular vesicles can interact with endothelial cells and modulate their cellular functions. Thrombospondin-1 and its receptor CD47 are expressed on exosomes/ectosomes derived from T cells, and these extracellular vesicles are internalized and modulate signaling in both T cells and endothelial cells. Extracellular vesicles released from cells expressing or lacking CD47 differentially regulate activation of T cells induced by engaging the T cell receptor. Similarly, T cell-derived extracellular vesicles modulate endothelial cell responses to vascular endothelial growth factor and tube formation in a CD47-dependent manner. Uptake of T cell derived extracellular vesicles by recipient endothelial cells globally alters gene expression in a CD47-dependent manner. CD47 also regulates the mRNA content of extracellular vesicles in a manner consistent with some of the resulting alterations in target endothelial cell gene expression. Therefore, the thrombospondin-1 receptor CD47 directly or indirectly regulates intercellular communication mediated by the transfer of extracellular vesicles between vascular cells.
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Contact and photocontact allergy to octocrylene: a review.
Contact Derm.
PUBLISHED: 01-02-2014
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Octocrylene is an ultraviolet (UV)B and UVAII absorber that was introduced some 15?years ago, and is now widely used in sunscreen agents and skin care cosmetics. Since 2003, several studies, notably from France, Belgium, Spain, and Italy, have reported an increasing number of patients with photocontact allergy to octocrylene. This reaction is seen mainly in adult patients who have previously used topical products containing the non-steroidal anti-inflammatory drug ketoprofen. Photosensitization to ketoprofen leads, in many cases, to photocontact allergy to octocrylene; the mechanism of this reaction is unknown. Contact allergy to octocrylene also occurs, but is far less frequent, and is seen, in most cases, in children, resulting from the use of octocrylene-containing sunscreen products. In this article, (photo)contact allergy to octocrylene is fully reviewed.
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Regulation of soluble guanylate cyclase by matricellular thrombospondins: implications for blood flow.
Front Physiol
PUBLISHED: 01-01-2014
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Nitric oxide (NO) maintains cardiovascular health by activating soluble guanylate cyclase (sGC) to increase cellular cGMP levels. Cardiovascular disease is characterized by decreased NO-sGC-cGMP signaling. Pharmacological activators and stimulators of sGC are being actively pursued as therapies for acute heart failure and pulmonary hypertension. Here we review molecular mechanisms that modulate sGC activity while emphasizing a novel biochemical pathway in which binding of the matricellular protein thrombospondin-1 (TSP1) to the cell surface receptor CD47 causes inhibition of sGC. We discuss the therapeutic implications of this pathway for blood flow, tissue perfusion, and cell survival under physiologic and disease conditions.
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SMART: unique splitting-while-merging framework for gene clustering.
PLoS ONE
PUBLISHED: 01-01-2014
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Successful clustering algorithms are highly dependent on parameter settings. The clustering performance degrades significantly unless parameters are properly set, and yet, it is difficult to set these parameters a priori. To address this issue, in this paper, we propose a unique splitting-while-merging clustering framework, named "splitting merging awareness tactics" (SMART), which does not require any a priori knowledge of either the number of clusters or even the possible range of this number. Unlike existing self-splitting algorithms, which over-cluster the dataset to a large number of clusters and then merge some similar clusters, our framework has the ability to split and merge clusters automatically during the process and produces the the most reliable clustering results, by intrinsically integrating many clustering techniques and tasks. The SMART framework is implemented with two distinct clustering paradigms in two algorithms: competitive learning and finite mixture model. Nevertheless, within the proposed SMART framework, many other algorithms can be derived for different clustering paradigms. The minimum message length algorithm is integrated into the framework as the clustering selection criterion. The usefulness of the SMART framework and its algorithms is tested in demonstration datasets and simulated gene expression datasets. Moreover, two real microarray gene expression datasets are studied using this approach. Based on the performance of many metrics, all numerical results show that SMART is superior to compared existing self-splitting algorithms and traditional algorithms. Three main properties of the proposed SMART framework are summarized as: (1) needing no parameters dependent on the respective dataset or a priori knowledge about the datasets, (2) extendible to many different applications, (3) offering superior performance compared with counterpart algorithms.
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Interleukin-10 regulates hepcidin in Plasmodium falciparum malaria.
PLoS ONE
PUBLISHED: 01-01-2014
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Acute malarial anemia remains a major public health problem. Hepcidin, the major hormone controlling the availability of iron, is raised during acute and asymptomatic parasitemia. Understanding the role and mechanism of raised hepcidin and so reduced iron availability during infection is critical to establish evidence-based guidelines for management of malaria anemia. Our recent clinical evidence suggests a potential role of IL-10 in the regulation of hepcidin in patients with acute P. falciparum malaria.
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Role of receptor activity modifying protein 1 in function of the calcium sensing receptor in the human TT thyroid carcinoma cell line.
PLoS ONE
PUBLISHED: 01-01-2014
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The Calcium Sensing Receptor (CaSR) plays a role in calcium homeostasis by sensing minute changes in serum Ca(2+) and modulating secretion of calciotropic hormones. It has been shown in transfected cells that accessory proteins known as Receptor Activity Modifying Proteins (RAMPs), specifically RAMPs 1 and 3, are required for cell-surface trafficking of the CaSR. These effects have only been demonstrated in transfected cells, so their physiological relevance is unclear. Here we explored CaSR/RAMP interactions in detail, and showed that in thyroid human carcinoma cells, RAMP1 is required for trafficking of the CaSR. Furthermore, we show that normal RAMP1 function is required for intracellular responses to ligands. Specifically, to confirm earlier studies with tagged constructs, and to provide the additional benefit of quantitative stoichiometric analysis, we used fluorescence resonance energy transfer to show equal abilities of RAMP1 and 3 to chaperone CaSR to the cell surface, though RAMP3 interacted more efficiently with the receptor. Furthermore, a higher fraction of RAMP3 than RAMP1 was observed in CaSR-complexes on the cell-surface, suggesting different ratios of RAMPs to CaSR. In order to determine relevance of these findings in an endogenous expression system we assessed the effect of RAMP1 siRNA knock-down in medullary thyroid carcinoma TT cells, (which express RAMP1, but not RAMP3 constitutively) and measured a significant 50% attenuation of signalling in response to CaSR ligands Cinacalcet and neomycin. Blockade of RAMP1 using specific antibodies induced a concentration-dependent reduction in CaSR-mediated signalling in response to Cinacalcet in TT cells, suggesting a novel functional role for RAMP1 in regulation of CaSR signalling in addition to its known role in receptor trafficking. These data provide evidence that RAMPs traffic the CaSR as higher-level oligomers and play a role in CaSR signalling even after cell surface localisation has occurred.
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Predicting inpatient complications from cerebral aneurysm clipping: the Nationwide Inpatient Sample 2005-2009.
J. Neurosurg.
PUBLISHED: 09-13-2013
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Object Precise delineation of individualized risks of morbidity and mortality is crucial in decision making in cerebrovascular neurosurgery. The authors attempted to create a predictive model of complications in patients undergoing cerebral aneurysm clipping (CAC). Methods The authors performed a retrospective cohort study of patients who had undergone CAC in the period from 2005 to 2009 and were registered in the Nationwide Inpatient Sample (NIS) database. A model for outcome prediction based on preoperative individual patient characteristics was developed. Results Of the 7651 patients in the NIS who underwent CAC, 3682 (48.1%) had presented with unruptured aneurysms and 3969 (51.9%) with subarachnoid hemorrhage. The respective inpatient postoperative risks for death, unfavorable discharge, stroke, treated hydrocephalus, cardiac complications, deep vein thrombosis, pulmonary embolism, and acute renal failure were 0.7%, 15.3%, 5.3%, 1.5%, 1.3%, 0.6%, 2.0%, and 0.1% for those with unruptured aneurysms and 11.5%, 52.8%, 5.5%, 39.2%, 1.7%, 2.8%, 2.7%, and 0.8% for those with ruptured aneurysms. Multivariate analysis identified risk factors independently associated with the above outcomes. A validated model for outcome prediction based on individual patient characteristics was developed. The accuracy of the model was estimated using the area under the receiver operating characteristic curve, and it was found to have good discrimination. Conclusions The featured model can provide individualized estimates of the risks of postoperative complications based on preoperative conditions and can potentially be used as an adjunct in decision making in cerebrovascular neurosurgery.
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Neurosurgery in the Byzantine Empire: the contributions of Paul of Aegina (625-690 AD).
J. Neurosurg.
PUBLISHED: 09-13-2013
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Paul of Aegina (625-690 AD) was born on the island of Aegina and was one of the most prominent physician-writers of the Byzantine Empire. His work Epitome of Medicine, comprised of 7 books, was a comprehensive compendium of the medical and surgical knowledge of his time and was subsequently translated into multiple languages. Paul of Aegina made valuable contributions to neurosurgical subjects and described procedures for the treatment of nerve injuries, hydrocephalus, and fractures of the skull and spine. His work combined the ancient knowledge of Hippocrates and Galen with contemporary medical observations and served as a bridge between Byzantine and Arabic medicine. He is considered to be one of the great ancient Greek medical writers and his work has influenced the subsequent evolution of Western European and Arab medicine. This paper provides an account of his contribution to the management of neurosurgical pathologies during the Byzantine era, as described in his medical compendium, Epitome of Medicine.
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APC2 and Axin promote mitotic fidelity by facilitating centrosome separation and cytoskeletal regulation.
Development
PUBLISHED: 09-11-2013
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To ensure the accurate transmission of genetic material, chromosome segregation must occur with extremely high fidelity. Segregation errors lead to chromosomal instability (CIN), with deleterious consequences. Mutations in the tumor suppressor adenomatous polyposis coli (APC) initiate most colon cancers and have also been suggested to promote disease progression through increased CIN, but the mechanistic role of APC in preventing CIN remains controversial. Using fly embryos as a model, we investigated the role of APC proteins in CIN. Our findings suggest that APC2 loss leads to increased rates of chromosome segregation error. This occurs through a cascade of events beginning with incomplete centrosome separation leading to failure to inhibit formation of ectopic cleavage furrows, which result in mitotic defects and DNA damage. We test several hypotheses related to the mechanism of action of APC2, revealing that APC2 functions at the embryonic cortex with several protein partners, including Axin, to promote mitotic fidelity. Our in vivo data demonstrate that APC2 protects genome stability by modulating mitotic fidelity through regulation of the cytoskeleton.
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Pulsed-light imaging for fluorescence guided surgery under normal room lighting.
Opt Lett
PUBLISHED: 08-31-2013
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Fluorescence guided surgery (FGS) is an emerging technology that has demonstrated improved surgical outcomes. However, dim lighting conditions required by current FGS systems are disruptive to standard surgical workflow. We present a novel FGS system capable of imaging fluorescence under normal room light by using pulsed excitation and gated acquisition. Images from tissue-simulating phantoms confirm visual detection down to 0.25 ?M of protoporphyrin IX under 125 ?W/cm2 of ambient light, more than an order of magnitude lower than that measured with the Zeiss Pentero in the dark. Resection of orthotopic brain tumors in mice also suggests that the pulsed-light system provides superior sensitivity in vivo.
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System and methods for wide-field quantitative fluorescence imaging during neurosurgery.
Opt Lett
PUBLISHED: 08-02-2013
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We report an accurate, precise and sensitive method and system for quantitative fluorescence image-guided neurosurgery. With a low-noise, high-dynamic-range CMOS array, we perform rapid (integration times as low as 50 ms per wavelength) hyperspectral fluorescence and diffuse reflectance detection and apply a correction algorithm to compensate for the distorting effects of tissue absorption and scattering. Using this approach, we generated quantitative wide-field images of fluorescence in tissue-simulating phantoms for the fluorophore PpIX, having concentrations and optical absorption and scattering variations over clinically relevant ranges. The imaging system was tested in a rodent model of glioma, detecting quantitative levels down to 20 ng/ml. The resulting performance is a significant advance on existing wide-field quantitative imaging techniques, and provides performance comparable to a point-spectroscopy probe that has previously demonstrated significant potential for improved detection of malignant brain tumors during surgical resection.
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Integrated testing and assessment approaches for skin sensitization: a commentary.
J Appl Toxicol
PUBLISHED: 07-18-2013
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A Bayesian integrated testing strategy (ITS) approach, aiming to assess skin sensitization potency, has been presented, in which data from various types of in vitro assays are integrated and assessed in combination for their ability to predict in vivo skin sensitization data. Here we discuss this approach and compare it to our quantitative mechanistic modeling (QMM) approach based on physical organic chemistry. The main findings of the Bayesian study are consistent with our chemistry-based approach and our previously published assessment of the key determinants of sensitization potency, in particular the relatively high predictive value found for chemical reactivity data and the relatively low predictive value for bioavailability parameters. As it stands at present the Bayesian approach does not utilize the full range of predictive capability that is already available, and aims only to assign potency categories rather than numerical potency values per se. In contrast, for many chemicals the QMM approach can already provide numerical potency predictions. However, the Bayesian approach may have potential for those chemicals where a chemistry modeling approach cannot provide a complete answer (e.g. pro-electrophiles whose in cutaneo activation cannot currently be modeled confidently). Nonetheless, our main message is of the importance of leveraging chemistry insights and read-across approaches to the fullest extent possible. Copyright © 2013 John Wiley & Sons, Ltd.
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Akt phosphorylates HK-II at Thr-473 and increases mitochondrial HK-II association to protect cardiomyocytes.
J. Biol. Chem.
PUBLISHED: 07-08-2013
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Hexokinase II (HK-II) is an enzyme that catalyzes the first step in glycolysis and localizes not only in the cytosol but also at mitochondria. Akt, activated by insulin-like growth factor 1 (IGF-1) treatment in neonatal rat ventricular myocytes, translocates to mitochondria and increases mitochondrial HK-II binding. Expression of an HK-II-dissociating peptide diminished IGF-1-induced increases in mitochondrial HK-II as well as protection against hydrogen peroxide treatment, suggesting an important role of mitochondrial HK-II in IGF-1/Akt-mediated protection. We hypothesized, on the basis of an Akt phosphorylation consensus sequence present in HK-II, that Thr-473 is the target of Akt kinase activity. Indeed, recombinant kinase-active Akt robustly phosphorylates WT HK-II, but not Thr-473 mutants. Phosphomimetic (T473D)HK-II, but not non-phosphorylatable (T473A)HK-II, constitutively increased mitochondrial binding compared with WT HK-II and concomitantly confers greater protection against hydrogen peroxide. Glucose 6-phosphate (G-6P), a product of the catalytic activity of HK-II, is well known to dissociate HK-II from mitochondria. Addition of G-6P to isolated mitochondria dose-dependently dissociates WT HK-II, and this response is inhibited significantly in mitochondria isolated from cardiomyocytes expressing T473D HK-II. Pretreatment with IGF-1 also inhibits G-6P-induced overexpressed or endogenous HK-II dissociation, and this response was blocked by Akt inhibition. These results show that Akt phosphorylation of HK-II at Thr-473 is responsible for the Akt-mediated increase in HK-II binding to mitochondria. This increase is, at least in part, due to the decreased sensitivity to G-6P-induced dissociation. Thus, phosphorylation-mediated regulation of mitochondrial HK-II would be a critical component of the protective effect of Akt.
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Loss of MCL-1 leads to impaired autophagy and rapid development of heart failure.
Genes Dev.
PUBLISHED: 06-22-2013
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Myeloid cell leukemia-1 (MCL-1) is an anti-apoptotic BCL-2 protein that is up-regulated in several human cancers. MCL-1 is also highly expressed in myocardium, but its function in myocytes has not been investigated. We generated inducible, cardiomyocyte-specific Mcl-1 knockout mice and found that ablation of Mcl-1 in the adult heart led to rapid cardiomyopathy and death. Although MCL-1 is known to inhibit apoptosis, this process was not activated in MCL-1-deficient hearts. Ultrastructural analysis revealed disorganized sarcomeres and swollen mitochondria in myocytes. Mitochondria isolated from MCL-1-deficient hearts exhibited reduced respiration and limited Ca(2+)-mediated swelling, consistent with opening of the mitochondrial permeability transition pore (mPTP). Double-knockout mice lacking MCL-1 and cyclophilin D, an essential regulator of the mPTP, exhibited delayed progression to heart failure and extended survival. Autophagy is normally induced by myocardial stress, but induction of autophagy was impaired in MCL-1-deficient hearts. These data demonstrate that MCL-1 is essential for mitochondrial homeostasis and induction of autophagy in the heart. This study also raises concerns about potential cardiotoxicity for chemotherapeutics that target MCL-1.
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Hippocampal interictal epileptiform activity disrupts cognition in humans.
Neurology
PUBLISHED: 05-17-2013
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We investigated whether interictal epileptiform discharges (IED) in the human hippocampus are related to impairment of specific memory processes, and which characteristics of hippocampal IED are most associated with memory dysfunction.
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Proteases in Mycobacterium tuberculosis pathogenesis: potential as drug targets.
Future Microbiol
PUBLISHED: 05-07-2013
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TB is still a major global health problem causing over 1 million deaths per year. An increasing problem of drug resistance in the causative agent, Mycobacterium tuberculosis, as well as problems with the current lengthy and complex treatment regimens, lends urgency to the need to develop new antitubercular agents. Proteases have been targeted for therapy in other infections, most notably these have been successful as antiviral agents in the treatment of HIV infection. M. tuberculosis has a number of proteases with good potential as novel drug targets and developing drugs against these should result in agents that are effective against drug-resistant and drug-sensitive strains. In this review, the authors summarize the current status of proteases with potential as drug targets in this pathogen, particularly focusing on proteases involved in protein secretion (signal peptidases LepB and LspA), protein degradation and turnover (ClpP and the proteasome) and virulence (mycosins and HtrA).
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The proteasome cap RPT5/Rpt5p subunit prevents aggregation of unfolded ricin A chain.
Biochem. J.
PUBLISHED: 04-27-2013
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The plant cytotoxin ricin enters mammalian cells by receptor-mediated endocytosis, undergoing retrograde transport to the ER (endoplasmic reticulum) where its catalytic A chain (RTA) is reductively separated from the holotoxin to enter the cytosol and inactivate ribosomes. The currently accepted model is that the bulk of ER-dislocated RTA is degraded by proteasomes. We show in the present study that the proteasome has a more complex role in ricin intoxication than previously recognized, that the previously reported increase in sensitivity of mammalian cells to ricin in the presence of proteasome inhibitors simply reflects toxicity of the inhibitors themselves, and that RTA is a very poor substrate for proteasomal degradation. Denatured RTA and casein compete for a binding site on the regulatory particle of the 26S proteasome, but their fates differ. Casein is degraded, but the mammalian 26S proteasome AAA (ATPase associated with various cellular activities)-ATPase subunit RPT5 acts as a chaperone that prevents aggregation of denatured RTA and stimulates recovery of catalytic RTA activity in vitro. Furthermore, in vivo, the ATPase activity of Rpt5p is required for maximal toxicity of RTA dislocated from the Saccharomyces cerevisiae ER. The results of the present study implicate RPT5/Rpt5p in the triage of substrates in which either activation (folding) or inactivation (degradation) pathways may be initiated.
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Long-term seizure, cognitive, and psychiatric outcome following trans-middle temporal gyrus amygdalohippocampectomy and standard temporal lobectomy.
J. Neurosurg.
PUBLISHED: 04-26-2013
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Previous comparisons of standard temporal lobectomy (STL) and selective amygdalohippocampectomy (SelAH) have been limited by inadequate long-term follow-up, variable definitions of favorable outcome, and inadequate consideration of psychiatric comorbidities.
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Electrical stimulation-evoked dopamine release in the primate striatum.
Stereotact Funct Neurosurg
PUBLISHED: 04-17-2013
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Primate studies demonstrate that high-frequency electrical stimulation (HFS) of the caudate can enhance learning. Importantly, in these studies, stimulation was applied following the execution of behavior and the effect persisted into subsequent trials, suggesting a change in plasticity rather than a momentary facilitation of behavior.
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Intraoperative Fluorescence-Guided Resection of High-Grade Gliomas: A Comparison of the Present Techniques and Evolution of Future Strategies.
World Neurosurg
PUBLISHED: 04-15-2013
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Fluorescence guidance has a demonstrated potential in maximizing the extent of high-grade glioma resection. Different fluorophores (fluorescent biomarkers), including 5-aminolevulinic acid (5-ALA) and fluorescein, have been examined with the use of several imaging techniques. Our goal was to review the state of this technology and discuss strategies for more widespread adoption.
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Institutional charges and disparities in outpatient brain biopsies in four US States: the State Ambulatory Database (SASD).
J. Neurooncol.
PUBLISHED: 03-21-2013
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Several groups have demonstrated the safety of ambulatory brain biopsies, with no patients experiencing complications related to early discharge. Although they appear to be safe, the reasons factoring into the selection of patients have not been investigated. We performed a cross-sectional study involving 504 patients who underwent outpatient and 10,328 patients who underwent inpatient brain biopsies and were registered in State Ambulatory Surgery Databases and State Inpatient Databases respectively for four US States (New York, California, Florida, North Carolina). In a multivariate analysis private insurance (OR 2.45, 95 % CI, 1.85, 3.24), was significantly associated with outpatient procedures. Higher Charlson Comorbidity Index (OR 0.16, 95 % CI, 0.08, 0.32), high income (OR 0.37, 95 % CI, 0.26, 0.53), and high volume hospitals (OR 0.30, 95 % CI, 0.23, 0.39) were associated with a decreased chance of outpatient procedures. No sex, or racial disparities were observed. Institutional charges were significantly less for outpatient brain biopsies. There was no difference in the rate of 30-day postoperative readmissions among inpatient and outpatient procedures. The median charge for inpatient surgery was 51,316 as compared to 12,266 for the outpatient setting (P < 0.0001, Students t test). Access to ambulatory brain biopsies appears to be more common for patients with private insurance and less comorbidities, in the setting of lower volume hospitals. Further investigation is needed in the direction of mapping these disparities in resource utilization.
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Selective depletion of FOXP3(high) cells by Fas-Fas-L-induced apoptosis occurs in CD4(+)CD25(+)-enriched populations during repeated expansion.
Cytotherapy
PUBLISHED: 03-14-2013
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Expansion of anti-CD25 bead-isolated human Tregs culture has paradoxically resulted in reduced suppressive activity, but the mechanism(s) responsible for these observations are poorly defined.
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Outcome prediction in intracranial tumor surgery: the National Surgical Quality Improvement Program 2005-2010.
J. Neurooncol.
PUBLISHED: 02-17-2013
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Accurate knowledge of individualized risks is crucial for decision-making in the surgical management of patients with brain tumors. Precise delineation of those risks remains a topic of debate. We attempted to create a predictive model of outcomes in patients undergoing craniotomies for tumor resection (CTR). We performed a retrospective cohort study involving patients who underwent CTR from 2005 to 2010 and were registered in the American College of Surgeons National Quality Improvement Project database. A model for outcome prediction based on individual patient characteristics was developed. Of the 1,834 patients, 457 had meningiomas (24.9 %) and 1377 had non-meningioma tumors (75.1 %). The respective 30-day postoperative risks were 2.1 % for stroke, 1.3 % for MI, 2.7 % for death, 2.4 % for deep surgical site infection, and 6.6 % for return to the OR. Multivariate analysis demonstrated that pre-operative tumor-related neurologic deficit, stroke, altered mental status, and weight loss, were independently associated with most outcomes, including post-operative MI, death, and deep surgical site infection. An additive effect of the variables on the risk of all outcomes was observed. A validated model for outcome prediction based on individual patient characteristics was developed. The accuracy of the model was estimated by the area under the receiver operating characteristic curve, which was 0.687, 0.929, 0.749, 0.746, and 0.679 for postoperative risk of stroke, MI, death, infection, and return to the OR, respectively. Our model can provide individualized estimates of the risks of post-operative complications based on pre-operative conditions, and can potentially be utilized as an adjunct in the decision-making for surgical intervention in brain tumor patients.
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Thrombospondin-1 is a CD47-dependent endogenous inhibitor of hydrogen sulfide signaling in T cell activation.
Matrix Biol.
PUBLISHED: 02-15-2013
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Thrombospondin-1 is a potent suppressor of T cell activation via its receptor CD47. However, the precise mechanism for this inhibition remains unclear. Because H2S is an endogenous potentiator of T cell activation and is necessary for full T cell activation, we hypothesized that thrombospondin-1 signaling through CD47 inhibits T cell activation by antagonizing H2S signaling. Primary T cells from thrombospondin-1 null mice were more sensitive to H2S-dependent activation assessed by proliferation and induction of interleukin-2 and CD69 mRNAs. Exogenous thrombospondin-1 inhibited H2S responses in wild type and thrombospondin-1 null T cells but enhanced the same responses in CD47 null T cells. Fibronectin, which shares integrin and glycosaminoglycan binding properties with thrombospondin-1 but not CD47 binding, did not inhibit H2S signaling. A CD47-binding peptide derived from thrombospondin-1 inhibited H2S-induced activation, whereas two other functional sequences from thrombospondin-1 enhanced H2S signaling. Therefore, engaging CD47 is necessary and sufficient for thrombospondin-1 to inhibit H2S-dependent T cell activation. H2S stimulated T cell activation by potentiating MEK-dependent ERK phosphorylation, and thrombospondin-1 inhibited this signaling in a CD47-dependent manner. Thrombospondin-1 also limited activation-dependent T cell expression of the H2S biosynthetic enzymes cystathionine ?-synthase and cystathionine ?-lyase, thereby limiting the autocrine role of H2S in T cell activation. Thus, thrombospondin-1 signaling through CD47 is the first identified endogenous inhibitor of H2S signaling and constitutes a novel mechanism that negatively regulates T cell activation.
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Thrombospondin-1 signaling through CD47 inhibits self-renewal by regulating c-Myc and other stem cell transcription factors.
Sci Rep
PUBLISHED: 02-11-2013
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Signaling through the thrombospondin-1 receptor CD47 broadly limits cell and tissue survival of stress, but the molecular mechanisms are incompletely understood. We now show that loss of CD47 permits sustained proliferation of primary murine endothelial cells, increases asymmetric division, and enables these cells to spontaneously reprogram to form multipotent embryoid body-like clusters. c-Myc, Klf4, Oct4, and Sox2 expression is elevated in CD47-null endothelial cells, in several tissues of CD47- and thrombospondin-1-null mice, and in a human T cell line lacking CD47. CD47 knockdown acutely increases mRNA levels of c-Myc and other stem cell transcription factors in cells and in vivo, whereas CD47 ligation by thrombospondin-1 suppresses c-Myc expression. The inhibitory effects of increasing CD47 levels can be overcome by maintaining c-Myc expression and are absent in cells with dysregulated c-Myc. Thus, CD47 antagonists enable cell self-renewal and reprogramming by overcoming negative regulation of c-Myc and other stem cell transcription factors.
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A systematic review of factors associated with the deferral of donors failing to meet low haemoglobin thresholds.
Transfus Med
PUBLISHED: 01-15-2013
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Blood donors attending a donation session may be deemed ineligible to donate blood due to a failure to meet low haemoglobin (Hb) thresholds. Several studies have identified factors associated with a donor falling below these Hb thresholds. A review of these factors will inform future prospective studies and form the basis for predictive models of deferral due to low Hb.
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Blockade of CD47 increases survival of mice exposed to lethal total body irradiation.
Sci Rep
PUBLISHED: 01-08-2013
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Accidental or therapeutic total body exposure to ionizing radiation has profound pathophysiological consequences including acute radiation syndrome. Currently only investigational drugs are available in case of radiological or nuclear accidents or terrorism. Lack of selective radioprotectants for normal tissues also limits the therapeutic doses that can be delivered to treat cancers. CD47 is a receptor for the secreted protein thrombospondin-1. Blockade of thrombospondin-1 or CD47 provides local radioprotection of soft tissues and bone marrow. We now report that suppression of CD47 using an antisense morpholino increases survival of mice exposed to lethal total body irradiation. Increased survival is associated with increased peripheral circulating blood cell counts and increased proliferative capacity of bone marrow derived cells. Moreover, CD47 blockade decreased cell death while inducing a protective autophagy response in radiosensitive gastrointestinal tissues. Thus, CD47 is a new target for radiomitigation that prevents both hematopoietic and gastrointestinal radiation syndromes.
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MRI confirms loss of blood-brain barrier integrity in a mouse model of disseminated candidiasis.
NMR Biomed
PUBLISHED: 01-02-2013
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Disseminated candidiasis primarily targets the kidneys and brain in mice and humans. Damage to these critical organs leads to the high mortality associated with such infections, and invasion across the blood-brain barrier can result in fungal meningoencephalitis. Candida albicans can penetrate a brain endothelial cell barrier in vitro through transcellular migration, but this mechanism has not been confirmed in vivo. MRI using the extracellular vascular contrast agent gadolinium diethylenetriaminepentaacetic acid demonstrated that integrity of the blood-brain barrier is lost during C. albicans invasion. Intravital two-photon laser scanning microscopy was used to provide the first real-time demonstration of C. albicans colonizing the living brain, where both yeast and filamentous forms of the pathogen were found. Furthermore, we adapted a previously described method utilizing MRI to monitor inflammatory cell recruitment into infected tissues in mice. Macrophages and other phagocytes were visualized in kidney and brain by the administration of ultrasmall iron oxide particles. In addition to obtaining new insights into the passage of C. albicans across the brain microvasculature, these imaging methods provide useful tools to study further the pathogenesis of C. albicans infections, to define the roles of Candida virulence genes in kidney versus brain infection and to assess new therapeutic measures for drug development.
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Age-associated induction of cell membrane CD47 limits basal and temperature-induced changes in cutaneous blood flow.
Ann. Surg.
PUBLISHED: 01-01-2013
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We tested the hypothesis that the matricellular protein thrombospondin-1 (TSP1), through binding to and activation of the cell receptor CD47, inhibits basal and thermal-mediated cutaneous blood flow.
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Hydrogen sulfide is an endogenous potentiator of T cell activation.
J. Biol. Chem.
PUBLISHED: 12-13-2011
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H(2)S is an endogenous signaling molecule that may act via protein sulfhydrylation to regulate various physiological functions. H(2)S is also a byproduct of dietary sulfate metabolism by gut bacteria. Inflammatory bowel diseases such as ulcerative colitis are associated with an increase in the colonization of the intestine by sulfate reducing bacteria along with an increase in H(2)S production. Consistent with its increased production, H(2)S is implicated as a mediator of ulcerative colitis both in its genesis or maintenance. As T cells are well established mediators of inflammatory bowel disease, we investigated the effect of H(2)S exposure on T cell activation. Using primary mouse T lymphocytes (CD3+), OT-II CD4+ T cells, and the human Jurkat T cell line, we show that physiological levels of H(2)S potentiate TCR-induced activation. Nanomolar levels of H(2)S (50-500 nM) enhance T cell activation assessed by CD69 expression, interleukin-2 expression, and CD25 levels. Exposure of T cells to H(2)S dose-dependently enhances TCR-stimulated proliferation with a maximum at 300 nM (30% increase, p < 0.01). Furthermore, activation increases the capacity of T cells to make H(2)S via increased expression of cystathionine ?-lyase and cystathionine ?-synthase. Disrupting this response by silencing these H(2)S producing enzymes impairs T cell activation, and proliferation and can be rescued by the addition of 300 nM H(2)S. Thus, H(2)S represents a novel autocrine immunomodulatory molecule in T cells.
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Combined fluorescence and reflectance spectroscopy for in vivo quantification of cancer biomarkers in low- and high-grade glioma surgery.
J Biomed Opt
PUBLISHED: 11-25-2011
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Biomarkers are indicators of biological processes and hold promise for the diagnosis and treatment of disease. Gliomas represent a heterogeneous group of brain tumors with marked intra- and inter-tumor variability. The extent of surgical resection is a significant factor influencing post-surgical recurrence and prognosis. Here, we used fluorescence and reflectance spectral signatures for in vivo quantification of multiple biomarkers during glioma surgery, with fluorescence contrast provided by exogenously-induced protoporphyrin IX (PpIX) following administration of 5-aminolevulinic acid. We performed light-transport modeling to quantify multiple biomarkers indicative of tumor biological processes, including the local concentration of PpIX and associated photoproducts, total hemoglobin concentration, oxygen saturation, and optical scattering parameters. We developed a diagnostic algorithm for intra-operative tissue delineation that accounts for the combined tumor-specific predictive capabilities of these quantitative biomarkers. Tumor tissue delineation achieved accuracies of up to 94% (specificity = 94%, sensitivity = 94%) across a range of glioma histologies beyond current state-of-the-art optical approaches, including state-of-the-art fluorescence image guidance. This multiple biomarker strategy opens the door to optical methods for surgical guidance that use quantification of well-established neoplastic processes. Future work would seek to validate the predictive power of this proof-of-concept study in a separate larger cohort of patients.
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Ribosomal RNA processing in Candida albicans.
RNA
PUBLISHED: 10-25-2011
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Ribosome assembly begins with conversion of a polycistronic precursor into 18S, 5.8S, and 25S rRNAs. In the ascomycete fungus Candida albicans, rRNA transcription starts 604 nt upstream of the 18S rRNA junction (site A1). One major internal processing site in the 5 external transcribed spacer (A0) occurs 108 nt from site A1. The A0-A1 fragment persists as a stable species during log phase growth and can be used to assess proliferation rates. Separation of the small and large subunit pre-rRNAs occurs at sites A2 and A3 in internal transcribed spacer-1 Saccharomyces cerevisiae pre-rRNA. However, the 5 end of the 5.8S rRNA is represented by only a 5.8S (S) form, and a 7S rRNA precursor of the 5.8S rRNA extends into internal transcribed spacer 1 to site A2, which differs from S. cerevisiae. External transcribed spacer 1 and internal transcribed spacers 1 and 2 show remarkable structural similarity with S. cerevisiae despite low sequence identity. Maturation of C. albicans rRNA resembles other eukaryotes in that processing can occur cotranscriptionally or post-transcriptionally. During rapid proliferation, U3 snoRNA-dependent processing occurs before large and small subunit rRNA separation, consistent with cotranscriptional processing. As cells pass the diauxic transition, the 18S pre-rRNA accumulates into stationary phase as a 23S species, possessing an intact 5 external transcribed spacer extending to site A3. Nutrient addition to starved cells results in the disappearance of the 23S rRNA, indicating a potential role in normal physiology. Therefore, C. albicans reveals new mechanisms that regulate post- versus cotranscriptional rRNA processing.
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Genetics of glioblastoma: a window into its imaging and histopathologic variability.
Radiographics
PUBLISHED: 10-15-2011
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Glioblastoma is a highly malignant brain tumor that relentlessly defies therapy. Efforts over the past decade have begun to tease out the biochemical details that lead to its aggressive behavior and poor prognosis. There is hope that this new understanding will lead to improved treatment strategies for patients with glioblastoma, in the form of targeted, molecularly based therapies that are individualized to specific changes in individual tumors. However, these new therapies have the potential to fundamentally alter the biologic behavior of glioblastoma and, as a result, its imaging appearance. Knowledge about common genetic alterations and the resultant cellular and tissue changes (ie, induced angiogenesis and abnormal cell survival, proliferation, and invasion) in glioblastomas is important as a basis for understanding imaging findings before treatment. It is equally critical that radiologists understand which genetic pathway is targeted by each specific therapeutic agent or class of agents in order to accurately interpret changes in the imaging appearances of treated tumors.
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Therapeutic Targeting of CD47 to Modulate Tissue Responses to Ischemia and Radiation.
J Genet Syndr Gene Ther
PUBLISHED: 09-26-2011
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CD47 is a widely expressed cell surface receptor that serves as a counter-receptor for signal regulatory protein-? and as a receptor for the secreted matricellular protein thrombospondin-1. Thrombospondin-1 signaling through CD47 regulates cellular signaling pathways that control cell survival, growth, motility, mitochondrial biogenesis, arterial vasoactive responses to physiologic vasodilators and blood flow, and responsiveness to growth factors. Studies employing mice lacking either thrombospondin-1 or CD47 have revealed an important role for this receptor-ligand interaction in tissue responses to injury and stress. These null mice show enhanced recovery from soft tissue fixed ischemic injuries, ischemia reperfusion injuries, and radiation injuries. These studies have led to development of antisense strategies to locally or globally suppress CD47 gene expression. A translation-blocking CD47 morpholino improves tissue survival in skin flap and hindlimb fixed ischemia models, full thickness skin grafts, and a liver ischemia/reperfusion model of organ transplantation in mice. Furthermore, the benefits of morpholino treatment extend to aged mice and mice with dysregulated fat metabolism that characteristically exhibit impaired recovery from ischemic injuries. Activity of the morpholino was also demonstrated for treatment of ischemic injury in miniature pigs. Treatment with the CD47 morpholino protects mice from major effects of ionizing radiation including alopecia, deterioration of muscle function, soft tissue and cutaneous fibrosis, and loss of hematopoietic stem cells in bone marrow. Remarkably, the same treatment does not protect tumors but instead enhances their ablation by irradiation. We discuss prospects for further development of CD47 antisense therapeutics for clinical applications including reconstructive surgery, organ transplantation, angioplasty, and cancer.
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Status of dairy cow management and fertility in smallholder farms in Malawi.
Trop Anim Health Prod
PUBLISHED: 08-29-2011
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A review of the smallholder dairy production in Malawi was conducted using livestock annual reports and other literature that was supplemented with primary data from a baseline survey conducted in December 2009. Smallholder dairy farming in Malawi operates with support from institutions that facilitate access to initial stock and dairy production technologies. Most farmers (94%) keep the animals in pens where feed is provided throughout the year. Results indicated unsatisfactory feeding, housing and health management practices, which negatively impact cow fertility. Dairy population trends suggest low replacement rates, which could be associated to low cow fertility and inadequate management skills. There are challenges related to access to breeding and health services, which further contribute to low productivity. Low fertility is evidenced by low calving rates (22-61%) and long calving interval (405-549 days). Existence of programmes on farmer capacity building provides an opportunity for improved management skills and cow productivity. It is concluded that dairy cow management and fertility have challenges and opportunities that are influenced by the extent to which farmers have access to important services such as extension, health, breeding and finance.
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Human platelet antigen 1a epitopes are dependent on the cation-regulated conformation of integrin ?(IIb)?(3) (GPIIb/IIIa).
J. Immunol. Methods
PUBLISHED: 08-06-2011
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The HPA-1a (Leu(33)) polymorphism of platelet integrin ?IIb?3 is the target of alloantibodies in 70-80% cases of neonatal alloimmune thrombocytopenia (NAIT) in Caucasians and reliable detection of these antibodies is essential for appropriate clinical management. However, the ability to detect such antibodies is highly variable between laboratories and, in a number of clinical cases where there is a HPA-1 genotype mismatch between mother and neonate, HPA-1a antibodies are undetectable. Furthermore, some studies have not shown a consistent relationship between maternal anti-HPA-1a level and neonatal platelet count. Since the integrity and conformation of the ?IIb?3 complex are dependent on divalent cations, we investigated whether HPA-1a epitope integrity and/or conformation might be affected by the presence of the cation chelator EDTA in patient samples or in assay buffers, thus providing a possible explanation for the variable sensitivity of current assays.
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Outcomes of cervical and lumbar disk herniations in Major League Baseball pitchers.
Orthopedics
PUBLISHED: 08-02-2011
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The effects of disk herniations on the career and performance outcomes of Major League Baseball (MLB) pitchers are unknown. The purpose of this study is to determine the outcomes after a cervical or lumbar disk herniation for MLB pitchers. Forty MLB pitchers from 1984 to 2009 with a cervical disk herniation or lumbar disk herniation were identified using a previously established protocol. Cervical disk herniation was identified in 11 pitchers, 8 of which were treated operatively. The majority of pitchers with cervical disk herniation (8/11) returned to play at an average of 11.6 months. Lumbar disk herniation was identified in 29 pitchers, 20 of which were treated operatively. All pitchers with lumbar disk herniation (29/29) returned to play at an average of 7.3 months after diagnosis.
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?-aminolevulinic acid-induced protoporphyrin IX concentration correlates with histopathologic markers of malignancy in human gliomas: the need for quantitative fluorescence-guided resection to identify regions of increasing malignancy.
Neuro-oncology
PUBLISHED: 07-30-2011
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Extent of resection is a major goal and prognostic factor in the treatment of gliomas. In this study we evaluate whether quantitative ex vivo tissue measurements of ?-aminolevulinic acid-induced protoporphyrin IX (PpIX) identify regions of increasing malignancy in low- and high-grade gliomas beyond the capabilities of current fluorescence imaging in patients undergoing fluorescence-guided resection (FGR). Surgical specimens were collected from 133 biopsies in 23 patients and processed for ex vivo neuropathological analysis: PpIX fluorimetry to measure PpIX concentrations (C(PpIX)) and Ki-67 immunohistochemistry to assess tissue proliferation. Samples displaying visible levels of fluorescence showed significantly higher levels of C(PpIX) and tissue proliferation. C(PpIX) was strongly correlated with histopathological score (nonparametric) and tissue proliferation (parametric), such that increasing levels of C(PpIX) were identified with regions of increasing malignancy. Furthermore, a large percentage of tumor-positive biopsy sites (?40%) that were not visibly fluorescent under the operating microscope had levels of C(PpIX) greater than 0.1 µg/mL, which indicates that significant PpIX accumulation exists below the detection threshold of current fluorescence imaging. Although PpIX fluorescence is recognized as a visual biomarker for neurosurgical resection guidance, these data show that it is quantitatively related at the microscopic level to increasing malignancy in both low- and high-grade gliomas. This work suggests a need for improved PpIX fluorescence detection technologies to achieve better sensitivity and quantification of PpIX in tissue during surgery.
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High frequency stimulation abolishes thalamic network oscillations: an electrophysiological and computational analysis.
J Neural Eng
PUBLISHED: 05-27-2011
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Deep brain stimulation (DBS) of the thalamus has been demonstrated to be effective for the treatment of epilepsy. To investigate the mechanism of action of thalamic DBS, we examined the effects of high frequency stimulation (HFS) on spindle oscillations in thalamic brain slices from ferrets. We recorded intracellular and extracellular electrophysiological activity in the nucleus reticularis thalami (nRt) and in thalamocortical relay (TC) neurons in the lateral geniculate nucleus, stimulated the slice using a concentric bipolar electrode, and recorded the level of glutamate within the slice. HFS (100 Hz) of TC neurons generated excitatory post-synaptic potentials, increased the number of action potentials in both TC and nRt neurons, reduced the input resistance, increased the extracellular glutamate concentration, and abolished spindle wave oscillations. HFS of the nRt also suppressed spindle oscillations. In both locations, HFS was associated with significant and persistent elevation in extracellular glutamate levels and suppressed spindle oscillations for many seconds after the cessation of stimulation. We simulated HFS within a computational model of the thalamic network, and HFS also disrupted spindle wave activity, but the suppression of spindle activity was short-lived. Simulated HFS disrupted spindle activity for prolonged periods of time only after glutamate release and glutamate-mediated activation of a hyperpolarization-activated current (I(h)) was incorporated into the model. Our results suggest that the mechanism of action of thalamic DBS as used in epilepsy may involve the prolonged release of glutamate, which in turn modulates specific ion channels such as I(h), decreases neuronal input resistance, and abolishes thalamic network oscillatory activity.
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Smallholder dairy production in Northern Malawi: production practices and constraints.
Trop Anim Health Prod
PUBLISHED: 05-25-2011
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Milk production in Malawi is still unsatisfactory despite efforts by different stakeholders to boost the dairy sector. To investigate the roots of the problem, a survey on the current production practices and constraints on smallholder dairy farming was conducted in the Northern Region of the country. A total of 210 farmers were interviewed. The results revealed that farmers had small herd sizes in the region with an average of 2.2 ± 0.6 cattle per farmer. Average herd size was larger in male-managed farms than in female-managed farms (2.6 ± 2.8 vs. 1.8 ± 1.3), farmers with more than 5 years of dairy farming experience had larger herds than those with less experience (2.6 ± 2.8 vs. 1.9 ± 1. 2) and farmers who grazed their animals tended to have larger herds than those that stall-fed their animals (4.4 ± 5.1 vs. 1.9 ± 1.3). Average milk production was 8.2 ± 6.5 l per cow per day. Higher average daily milk production was observed in farmers with above primary school education (10.3 ± 8.3 vs. 7.7 ± 5.6), those with dairy farming as main activity (9.3 ± 6.6 vs. 6. 5 ± 6.1) and farmers with more than 2 years of experience in dairy farming (9.3 ± 6.3 vs. 6.1 ± 6.4). Unreliable supply of improved animal genetics, poor animal health, feed shortage and poor prices for milk were considered to be the most important constraints to smallholder dairy farming in descending order.
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Antenatal interventions for fetomaternal alloimmune thrombocytopenia.
Cochrane Database Syst Rev
PUBLISHED: 05-13-2011
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Fetomaternal alloimmune thrombocytopenia results from the formation of antibodies by the mother which are directed against a fetal platelet alloantigen inherited from the father. The resulting fetal thrombocytopenia (reduced platelet numbers) may cause bleeding, particularly into the brain, before or shortly after birth. Antenatal treatment of fetomaternal alloimmune thrombocytopenia includes the administration of intravenous immunoglobulin (IVIG) and/or corticosteroids to the mother to prevent severe fetal thrombocytopenia. IVIG and corticosteroids both have short-term and possibly long-term side effects. IVIG is also costly and optimal regimens need to be identified.
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Analysis of the glucagon receptor first extracellular loop by the substituted cysteine accessibility method.
Peptides
PUBLISHED: 05-05-2011
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Glucagon is an important hormone for the prevention of hypoglycemia, and contributes to the hyperglycemia observed in diabetic patients, yet very little is known about its receptor structure and the receptor-glucagon interaction. In related receptors, the first extracellular loop, ECL1, is highly variable in length and sequence, suggesting that it might participate in ligand recognition. We applied a variant of the SCAM (Substituted Cysteine Accessibility Method) to the glucagon receptor ECL1 and sequentially mutated positions 197 to 223 to cysteine. Most of the mutations (15/27) affected the glucagon potency, due either to a modification of the glucagon binding site, or to the destabilization of the active receptor conformation. We reasoned that side chains accessible to glucagon must also be accessible to large, hydrophilic cysteine reagents. We therefore evaluated the accessibility of the introduced cysteines to maleimide-PEO(2)-biotin ((+)-biotinyl-3-maleimido-propionamidyl-3,6-dioxa-octanediamine), and tested the effect of pretreatment of intact cells with a large cationic cysteine reagent, MTSET ([2-(trimethylammonium)ethyl]methanethiosulfonate bromide), on glucagon potency. Our results suggest that the second and third transmembrane helices (TM2 and TM3) are extended to position 202 and from position 215, respectively, and separated by a short ? stretch (positions 203-209). Glucagon binding induced a conformational change close to TM2: L198C was accessible to the biotin reagent only in the presence of glucagon. Most other mutations affected the receptor activation rather than glucagon recognition, but S217 and D218 (at the top of TM3) were good candidates for glucagon recognition and V221 was very close to the binding site.
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Quantitative and qualitative 5-aminolevulinic acid-induced protoporphyrin IX fluorescence in skull base meningiomas.
Neurosurg Focus
PUBLISHED: 05-03-2011
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Complete resection of skull base meningiomas provides patients with the best chance for a cure; however, surgery is frequently difficult given the proximity of lesions to vital structures, such as cranial nerves, major vessels, and venous sinuses. Accurate discrimination between tumor and normal tissue is crucial for optimal tumor resection. Qualitative assessment of protoporphyrin IX (PpIX) fluorescence following the exogenous administration of 5-aminolevulinic acid (ALA) has demonstrated utility in malignant glioma resection but limited use in meningiomas. Here the authors demonstrate the use of ALA-induced PpIX fluorescence guidance in resecting a skull base meningioma and elaborate on the advantages and disadvantages provided by both quantitative and qualitative fluorescence methodologies in skull base meningioma resection.
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The Ras activator RasGRP3 mediates diabetes-induced embryonic defects and affects endothelial cell migration.
Circ. Res.
PUBLISHED: 04-07-2011
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Fetuses that develop in diabetic mothers have a higher incidence of birth defects that include cardiovascular defects, but the signaling pathways that mediate these developmental effects are poorly understood. It is reasonable to hypothesize that diabetic maternal effects are mediated by 1 or more pathways activated downstream of aberrant glucose metabolism, because poorly controlled maternal glucose levels correlate with the frequency and severity of the defects.
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JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

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We use abstracts found on PubMed and match them to JoVE videos to create a list of 10 to 30 related methods videos.

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In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.