CD34 marks angiogenic tip cells in human vascular endothelial cell cultures

The functional shift of quiescent endothelial cells into tip cells that migrate and stalk cells that proliferate is a key event during sprouting angiogenesis. We previously showed that the sialomucin CD34 is expressed in a small subset of cultured endothelial cells and that these cells extend filopodia: a hallmark of tip cells in vivo. In the present study, we characterized endothelial cells expressing CD34 in endothelial monolayers in vitro. We found that CD34-positive human umbilical vein endothelial cells show low proliferation activity and increased mRNA expression of all known tip cell markers, as compared to CD34-negative cells. Genome-wide mRNA profiling analysis of CD34-positive endothelial cells demonstrated enrichment for biological functions related to angiogenesis and migration, whereas CD34-negative cells were enriched for functions related to proliferation. In addition, we found an increase or decrease of CD34-positive cells in vitro upon exposure to stimuli that enhance or limit the number of tip cells in vivo, respectively. Our findings suggest cells with virtually all known properties of tip cells are present in vascular endothelial cell cultures and that they can be isolated based on expression of CD34. This novel strategy may open alternative avenues for future studies of molecular processes and functions in tip cells in angiogenesis

Structural Extremes in a Cretaceous Dinosaur

Fossils of the Early Cretaceous dinosaur, Nigersaurus taqueti, document for the first time the cranial anatomy of a rebbachisaurid sauropod. Its extreme adaptations for herbivory at ground-level challenge current hypotheses regarding feeding function and feeding strategy among diplodocoids, the larger clade of sauropods that includes Nigersaurus. We used high resolution computed tomography, stereolithography, and standard molding and casting techniques to reassemble the extremely fragile skull. Computed tomography also allowed us to render the first endocast for a sauropod preserving portions of the olfactory bulbs, cerebrum and inner ear, the latter permitting us to establish habitual head posture. To elucidate evidence of tooth wear and tooth replacement rate, we used photographic-casting techniques and crown thin sections, respectively. To reconstruct its 9-meter postcranial skeleton, we combined and size-adjusted multiple partial skeletons. Finally, we used maximum parsimony algorithms on character data to obtain the best estimate of phylogenetic relationships among diplodocoid sauropods. Nigersaurus taqueti shows extreme adaptations for a dinosaurian herbivore including a skull of extremely light construction, tooth batteries located at the distal end of the jaws, tooth replacement as fast as one per month, an expanded muzzle that faces directly toward the ground, and hollow presacral vertebral centra with more air sac space than bone by volume. A cranial endocast provides the first reasonably complete view of a sauropod brain including its small olfactory bulbs and cerebrum. Skeletal and dental evidence suggests that Nigersaurus was a ground-level herbivore that gathered and sliced relatively soft vegetation, the culmination of a low-browsing feeding strategy first established among diplodocoids during the Jurassic

Inhibitor recurrence after immune tolerance induction: a multicenter retrospective cohort study

Immune tolerance induction (ITI) in patients with congenital hemophilia A is successful in up to 70%. Although there is growing understanding of predictors of response to ITI, the probability and predictors of inhibitor recurrence following successful ITI are not well understood

Relationships between paranoid thinking, self-esteem and the menstrual cycle.

This study aimed to investigate whether paranoid experiences and levels of self-esteem fluctuate over the menstrual cycle and whether levels of self-esteem are lower when perceived persecution is felt to be deserved. Measures of anxiety, depression, persecution, deservedness and self-esteem were completed on-line by 278 women over their menstrual cycle. Responses were compared at the paramenstrual (3 days before and after menses onset) and mid-cycle phase. At the paramenstrual phase persecution, negative self-esteem, anxiety and depression were higher and positive self-esteem was lower than at mid-cycle. A greater proportion of women experienced persecution as deserved at the paramenstrual phase. This was associated with higher depression and negative self-esteem scores. Increased levels of deservedness significantly strengthened the relationship between persecution and negative, but not positive, self-esteem. These findings suggest that the paramenstrual phase is a time of vulnerability to increased paranoid experiences, an increased likelihood that feelings of persecution will feel deserved and lowered self-esteem. The findings support the view that interpersonal sensitivities may be key to menstrual cycle symptoms and have an impact on relationships. Further, the study illustrated that ideas developed for psychosis could make a valuable contribution to understanding and managing this aspect of menstruation-related distress

Binding and neutralization of vascular endothelial growth factor (VEGF) and related ligands by VEGF Trap, ranibizumab and bevacizumab

Pharmacological inhibition of VEGF-A has proven to be effective in inhibiting angiogenesis and vascular leak associated with cancers and various eye diseases. However, little information is currently available on the binding kinetics and relative biological activity of various VEGF inhibitors. Therefore, we have evaluated the binding kinetics of two anti-VEGF antibodies, ranibizumab and bevacizumab, and VEGF Trap (also known as aflibercept), a novel type of soluble decoy receptor, with substantially higher affinity than conventional soluble VEGF receptors. VEGF Trap bound to all isoforms of human VEGF-A tested with subpicomolar affinity. Ranibizumab and bevacizumab also bound human VEGF-A, but with markedly lower affinity. The association rate for VEGF Trap binding to VEGF-A was orders of magnitude faster than that measured for bevacizumab and ranibizumab. Similarly, in cell-based bioassays, VEGF Trap inhibited the activation of VEGFR1 and VEGFR2, as well as VEGF-A induced calcium mobilization and migration in human endothelial cells more potently than ranibizumab or bevacizumab. Only VEGF Trap bound human PlGF and VEGF-B, and inhibited VEGFR1 activation and HUVEC migration induced by PlGF. These data differentiate VEGF Trap from ranibizumab and bevacizumab in terms of its markedly higher affinity for VEGF-A, as well as its ability to bind VEGF-B and PlGF

Validation of a low-cost virtual reality system for training street-crossing. A comparative study in healthy, neglected and non-neglected stroke individuals

Unilateral spatial neglect is a common consequence of stroke that directly affects the performance of activities of daily living. This impairment is traditionally assessed with paper-and-pencil tests that can lack correspondence to real life and are easily compensated. Virtual reality can immerse patients in more ecological scenarios, thus providing therapists with new tools to assess and train the effects of this impairment in simulated real tasks. This paper presents the clinical validation and convergent validity of a low-cost virtual reality system for training street-crossing in stroke patients with and without neglect. The performance of neglect patients was significantly worse than the performance of non-neglect and healthy participants. In addition, several correlations between the scores in the system and in the traditional scales were detected.This study was funded in part by Ministerio de Educacion y Ciencia Spain, Projects Consolider-C (SEJ2006-14301/PSIC), "CIBER of Physiopathology of Obesity and Nutrition, an initiative of ISCIII" and the Excellence Research Program PROMETEO (Generalitat Valenciana. Conselleria de Educacion, 2008-157).Navarro, MD.; Llorens Rodríguez, R.; Noé, E.; Ferri, J.; Alcañiz Raya, ML. (2013). Validation of a low-cost virtual reality system for training street-crossing. A comparative study in healthy, neglected and non-neglected stroke individuals. Neuropsychological Rehabilitation. 23(4):597-618. https://doi.org/10.1080/09602011.2013.806269S597618234Allegri, R. F. (2000). Atención y negligencia: bases neurológicas, evaluación y trastornos. Revista de Neurología, 30(05), 491. doi:10.33588/rn.3005.99645Appelros, P., Karlsson, G. M., Seiger, Åke, & Nydevik, I. (2002). Neglect and Anosognosia After First-Ever Stroke: Incidence and Relationship to Disability. Journal of Rehabilitation Medicine, 34(5), 215-220. doi:10.1080/165019702760279206Baheux, K., Yoshizawa, M., & Yoshida, Y. (2007). Simulating hemispatial neglect with virtual reality. Journal of NeuroEngineering and Rehabilitation, 4(1). doi:10.1186/1743-0003-4-27Boian, R. F., Burdea, G. C., Deutsch, J. E. and Winter, S. H. Street crossing using a virtual environment mobility simulator.Paper presented at 3rd Annual International Workshop on Virtual Reality. Lausanne, Switzerland.Broeren, J., Samuelsson, H., Stibrant-Sunnerhagen, K., Blomstrand, C., & Rydmark, M. (2007). Neglect assessment as an application of virtual reality. Acta Neurologica Scandinavica, 116(3), 157-163. doi:10.1111/j.1600-0404.2007.00821.xBuxbaum, L. J., Ferraro, M. K., Veramonti, T., Farne, A., Whyte, J., Ladavas, E., … Coslett, H. B. (2004). Hemispatial neglect: Subtypes, neuroanatomy, and disability. Neurology, 62(5), 749-756. doi:10.1212/01.wnl.0000113730.73031.f4Buxbaum, L. J., Palermo, M. A., Mastrogiovanni, D., Read, M. S., Rosenberg-Pitonyak, E., Rizzo, A. A., & Coslett, H. B. (2008). Assessment of spatial attention and neglect with a virtual wheelchair navigation task. Journal of Clinical and Experimental Neuropsychology, 30(6), 650-660. doi:10.1080/13803390701625821Castiello, U., Lusher, D., Burton, C., Glover, S., & Disler, P. (2004). Improving left hemispatial neglect using virtual reality. Neurology, 62(11), 1958-1962. doi:10.1212/01.wnl.0000128183.63917.02Conners, C. K., Epstein, J. N., Angold, A., & Klaric, J. (2003). Journal of Abnormal Child Psychology, 31(5), 555-562. doi:10.1023/a:1025457300409Folstein, M. F., Folstein, S. E., & McHugh, P. R. (1975). «Mini-mental state». Journal of Psychiatric Research, 12(3), 189-198. doi:10.1016/0022-3956(75)90026-6Fordell, H., Bodin, K., Bucht, G., & Malm, J. (2011). A virtual reality test battery for assessment and screening of spatial neglect. Acta Neurologica Scandinavica, 123(3), 167-174. doi:10.1111/j.1600-0404.2010.01390.xGupta, V., Knott, B. A., Kodgi, S., & Lathan, C. E. (2000). Using the «VREye» System for the Assessment of Unilateral Visual Neglect: Two Case Reports. Presence: Teleoperators and Virtual Environments, 9(3), 268-286. doi:10.1162/105474600566790Hartman-Maeir, A., & Katz, N. (1995). Validity of the Behavioral Inattention Test (BIT): Relationships With Functional Tasks. American Journal of Occupational Therapy, 49(6), 507-516. doi:10.5014/ajot.49.6.507Jannink, M. J. A., Aznar, M., de Kort, A. C., van de Vis, W., Veltink, P., & van der Kooij, H. (2009). Assessment of visuospatial neglect in stroke patients using virtual reality: a pilot study. International Journal of Rehabilitation Research, 32(4), 280-286. doi:10.1097/mrr.0b013e3283013b1cJehkonen, M., Laihosalo, M., & Kettunen, J. (2006). Anosognosia after stroke: assessment, occurrence, subtypes and impact on functional outcome reviewed. Acta Neurologica Scandinavica, 114(5), 293-306. doi:10.1111/j.1600-0404.2006.00723.xKatz, N., Ring, H., Naveh, Y., Kizony, R., Feintuch, U., & Weiss, P. L. (2005). Interactive virtual environment training for safe street crossing of right hemisphere stroke patients with Unilateral Spatial Neglect. Disability and Rehabilitation, 27(20), 1235-1244. doi:10.1080/09638280500076079Kim, D. Y., Ku, J., Chang, W. H., Park, T. H., Lim, J. Y., Han, K., … Kim, S. I. (2010). Assessment of post-stroke extrapersonal neglect using a three-dimensional immersive virtual street crossing program. Acta Neurologica Scandinavica, 121(3), 171-177. doi:10.1111/j.1600-0404.2009.01194.xKim, J., Kim, K., Kim, D. Y., Chang, W. H., Park, C.-I., Ohn, S. H., … Kim, S. I. (2007). Virtual Environment Training System for Rehabilitation of Stroke Patients with Unilateral Neglect: Crossing the Virtual Street. CyberPsychology & Behavior, 10(1), 7-15. doi:10.1089/cpb.2006.9998Kim, K., Kim, J., Ku, J., Kim, D. Y., Chang, W. H., Shin, D. I., … Kim, S. I. (2004). A Virtual Reality Assessment and Training System for Unilateral Neglect. CyberPsychology & Behavior, 7(6), 742-749. doi:10.1089/cpb.2004.7.742Kim, Y. M., Chun, M. H., Yun, G. J., Song, Y. J., & Young, H. E. (2011). The Effect of Virtual Reality Training on Unilateral Spatial Neglect in Stroke Patients. Annals of Rehabilitation Medicine, 35(3), 309. doi:10.5535/arm.2011.35.3.309Krakauer, J. W. (2006). Motor learning: its relevance to stroke recovery and neurorehabilitation. Current Opinion in Neurology, 19(1), 84-90. doi:10.1097/01.wco.0000200544.29915.ccMcComas, J., MacKay, M., & Pivik, J. (2002). Effectiveness of Virtual Reality for Teaching Pedestrian Safety. CyberPsychology & Behavior, 5(3), 185-190. doi:10.1089/109493102760147150Myers, R. L., & Bierig, T. A. (2000). Virtual Reality and Left Hemineglect: A Technology for Assessment and Therapy. CyberPsychology & Behavior, 3(3), 465-468. doi:10.1089/10949310050078922Peskine, A., Rosso, C., Box, N., Galland, A., Caron, E., Rautureau, G., … Pradat-Diehl, P. (2010). Virtual reality assessment for visuospatial neglect: importance of a dynamic task. Journal of Neurology, Neurosurgery & Psychiatry, 82(12), 1407-1409. doi:10.1136/jnnp.2010.217513Romero, M., Sánchez, A., Marín, C., Navarro, M. D., Ferri, J., & Noé, E. (2012). Utilidad clínica de la versión en castellano del Mississippi Aphasia Screening Test (MASTsp): validación en pacientes con ictus. Neurología, 27(4), 216-224. doi:10.1016/j.nrl.2011.06.006Rose, F. D., Brooks, B. M., & Rizzo, A. A. (2005). Virtual Reality in Brain Damage Rehabilitation: Review. CyberPsychology & Behavior, 8(3), 241-262. doi:10.1089/cpb.2005.8.241Schwebel, D. C., & McClure, L. A. (2010). Using virtual reality to train children in safe street-crossing skills. Injury Prevention, 16(1), e1-e1. doi:10.1136/ip.2009.025288Simpson, G., Johnston, L., & Richardson, M. (2003). An investigation of road crossing in a virtual environment. Accident Analysis & Prevention, 35(5), 787-796. doi:10.1016/s0001-4575(02)00081-7Smith, J., Hebert, D., & Reid, D. (2007). Exploring the effects of virtual reality on unilateral neglect caused by stroke: Four case studies. Technology and Disability, 19(1), 29-40. doi:10.3233/tad-2007-19104Sugarman, H., Weisel-Eichler, A., Burstin, A. and Brown, R.Use of novel virtual reality system for the assessment and treatment of unilateral spatial neglect: A feasibility study. Paper presented at International Conference on Virtual Rehabilitation. Zürich.Tanaka, T., Sugihara, S., Nara, H., Ino, S., & Ifukube, T. (2005). Journal of NeuroEngineering and Rehabilitation, 2(1), 31. doi:10.1186/1743-0003-2-31Thomson, J. A., Tolmie, A. K., Foot, H. C., Whelan, K. M., Sarvary, P., & Morrison, S. (2005). Influence of Virtual Reality Training on the Roadside Crossing Judgments of Child Pedestrians. Journal of Experimental Psychology: Applied, 11(3), 175-186. doi:10.1037/1076-898x.11.3.175Weiss, P. L. (Tamar), Naveh, Y., & Katz, N. (2003). Design and testing of a virtual environment to train stroke patients with unilateral spatial neglect to cross a street safely. Occupational Therapy International, 10(1), 39-55. doi:10.1002/oti.176Witmer, B. G., & Singer, M. J. (1998). Measuring Presence in Virtual Environments: A Presence Questionnaire. Presence: Teleoperators and Virtual Environments, 7(3), 225-240. doi:10.1162/105474698565686Wu, H., Ashmead, D. H. and Bodenheimer, B.Using immersive virtual reality to evaluate pedestrian street crossing decisions at a roundabout. Paper presented at 6th Symposium on appied perception in Graphics and Visualization. Chania

Relationships of Cetacea (Artiodactyla) Among Mammals: Increased Taxon Sampling Alters Interpretations of Key Fossils and Character Evolution

BACKGROUND: Integration of diverse data (molecules, fossils) provides the most robust test of the phylogeny of cetaceans. Positioning key fossils is critical for reconstructing the character change from life on land to life in the water. METHODOLOGY/PRINCIPAL FINDINGS: We reexamine relationships of critical extinct taxa that impact our understanding of the origin of Cetacea. We do this in the context of the largest total evidence analysis of morphological and molecular information for Artiodactyla (661 phenotypic characters and 46,587 molecular characters, coded for 33 extant and 48 extinct taxa). We score morphological data for Carnivoramorpha, Creodonta, Lipotyphla, and the raoellid artiodactylan Indohyus and concentrate on determining which fossils are positioned along stem lineages to major artiodactylan crown clades. Shortest trees place Cetacea within Artiodactyla and close to Indohyus, with Mesonychia outside of Artiodactyla. The relationships of Mesonychia and Indohyus are highly unstable, however--in trees only two steps longer than minimum length, Mesonychia falls inside Artiodactyla and displaces Indohyus from a position close to Cetacea. Trees based only on data that fossilize continue to show the classic arrangement of relationships within Artiodactyla with Cetacea grouping outside the clade, a signal incongruent with the molecular data that dominate the total evidence result. CONCLUSIONS/SIGNIFICANCE: Integration of new fossil material of Indohyus impacts placement of another extinct clade Mesonychia, pushing it much farther down the tree. The phylogenetic position of Indohyus suggests that the cetacean stem lineage included herbivorous and carnivorous aquatic species. We also conclude that extinct members of Cetancodonta (whales+hippopotamids) shared a derived ability to hear underwater sounds, even though several cetancodontans lack a pachyostotic auditory bulla. We revise the taxonomy of living and extinct artiodactylans and propose explicit node and stem-based definitions for the ingroup

The mismeasure of ape social cognition

In his classic analysis, The Mismeasure of Man, Gould (1981) demolished the idea that intelligence was an inherent, genetic trait of different human groups by emphasizing, among other things, (a) its sensitivity to environmental input, (b) the incommensurate pre-test preparation of different human groups, and (c) the inadequacy of the testing contexts, in many cases. According to Gould, the root cause of these oversights was confirmation bias by psychometricians, an unwarranted commitment to the idea that intelligence was a fixed, immutable quality of people. By virtue of a similar, systemic interpretive bias, in the last two decades, numerous contemporary researchers in comparative psychology have claimed human superiority over apes in social intelligence, based on two-group comparisons between postindustrial, Western Europeans and captive apes, where the apes have been isolated from European styles of social interaction, and tested with radically different procedures. Moreover, direct comparisons of humans with apes suffer from pervasive lapses in argumentation: Research designs in wide contemporary use are inherently mute about the underlying psychological causes of overt behavior. Here we analyze these problems and offer a more fruitful approach to the comparative study of social intelligence, which focuses on specific individual learning histories in specific ecological circumstances

‘In vivo’ optical approaches to angiogenesis imaging

In recent years, molecular imaging gained significant importance in biomedical research. Optical imaging developed into a modality which enables the visualization and quantification of all kinds of cellular processes and cancerous cell growth in small animals. Novel gene reporter mice and cell lines and the development of targeted and cleavable fluorescent “smart” probes form a powerful imaging toolbox. The development of systems collecting tomographic bioluminescence and fluorescence data enabled even more spatial accuracy and more quantitative measurements. Here we describe various bioluminescent and fluorescent gene reporter models and probes that can be used to specifically image and quantify neovascularization or the angiogenic process itself