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In 2010 I have started Kaleidoscope Software, a company that sells licenses for BoldStroke, an online change management toolkit.
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1 Personalia P. Visser (Paul) Van der Boechorststraat BV Amsterdam Telephone: Mobile: Date of birth: Amsterdam, 28 December 1956 Profile People whom I have worked with tell me my best quality is my ability to listen, react in a calm and tactful way and then start working in a team to create a solution that exactly meets the clients needs. I can analyze situations, work in a structured way and I am flexible enough to adapt to situations without giving up my own integrity. With a long experience as user, supplier and enabler in various ICT disciplines I have specialized in project management. Managing project members as well as motivating them and being a partner for management, I like to be involved in a project from the creation of the business case until the successful implementation and evaluation. I like to make sure that the solution that is offered exactly meets the clients needs. Not just the result but also the way this result was created is very important to me. In the company that I have started with four colleagues, Bologna Adviesgroep, I am the one that makes sure that we carry out what we have invented. I am often called the conscience of the company. In 2010 I have started Kaleidoscope Software, a company that sells licenses for BoldStroke, an online change management toolkit. Professional experience 06/10 until now: Founder/co-owner Kaleidoscope Software 01/10 until now: consultant/project manager Southpaw BV Free lance consultancy and project management assignments for Lukkien. Projects for Lukkien include: Consultant and project manager for the requirements analysis and implementation of a client portal for the Consolidated Groep (Scrum) pagina 1 / 5 1 december 2011
2 Project manager for the implementation of a corporate website for Bison International and four brand websites (Scrum) Project manager for the implementation of Allerhande Online, an online version of a very successful consumer magazine published by Albert Heijn (Scrum). Project manager for the implementation a Digital Asset Management System for Heinz Project manager for the implementation a Digital Asset Management System for Forbo Flooring Project manager for the implementation a Digital Asset Management System for G-Star Project manager for the implementation of EXTRA, a client treatment program of ABN AMRO bank Consultancy assignment for Consolidated, a roofing company that wanted to build a portal to support and bind their customers. Consultancy assignment for TW Steel, a watch company that needed a corporate marketing solution. 01/03 until 12/09: consultant/project manager Bologna Adviesgroep Director/owner of a small consultancy firm that aims at improving the effectiveness in companies. Projects for Bologna Adviesgroep: Implementation manager for pan-european distribitor website for Mitsubishi Motors Europe (April 2008 now) Activities in this role: Project management Requirements analysis, design, interface, integration with other applications, functional/design review committees, SEO and web analytics Implementation in over 30 countries Workshops and training, documentation Setup service a organisation (service desk, SLA) Program manager at LUKKIEN for Marcom X-Change, a Digital Asset Management system that was developed for Philips and is now used by several large globally operating companies (June 2003 present) Activities in this role: Project management Consultancy Software development manager Service manager pagina 2 / 5 1 december 2011
3 Responsible for testing, training and documentation Responsible for the selection and implementation of a content management system that is integrated into Marcom X-Change Project management for the Philips Williams Formula 1 website, including development of a localization application and a liaison role with international stakeholders for content creation and localization Facilitator team trainings and workshops (several occasions Jan. 2003) Coaching senior and junior project managers at Staalbankiers (Jan. April 2003) Facilitating workshops and writing functional specifications for a global Intranet application at Akzo (Jan. April 2003) Activities as director of Bologna Adviesgroep: Co-writer of business plan. Marketing and sales of products and services. Developing and selling a program for a team training. Developing marketing materials for the Rosabeth Moss Kanter Toolkit for Leadership and Change 1 and facilitating workshops for this product. Managed a pilot project at Staalbankiers. 12/99 until 12/02: consultant/project manager Company at Work Responsible for selling and managing projects Assisting the startup and supporting the project organization for the e-business (Airmiles, 2000) Project manager design, develop and implement a Lotus Notes based Decision Support System (Eureko, 2000) Information manager, responsible for daily operations of the infrastructure, user, management and third part relations, project management and innovation. Writing a business case, selecting a supplier and managing a migration project Windows NT to Windows Project manager for designing and implementing a Lotus Domino based infrastructure. Selected a Swiss company for the implementation in Zurich. (EurAPCo, Zurich, 2001) Project manager design, develop and implement an online Who is Who application (EurAPCo, Zurich, 2001) As project manager/consultant facilitating workshops to define the functional demands for an application to improve the processes of a venture capitalist company. Designing and implementing both the infrastructure and the application. (Residex, ) Project manager and product manager for designing, developing and marketing a Lotus Domino based CRM-application, BRICKS. (internal project, ) Demonstrating, selling and implementing this application at several clients. 1 This is an on-line toolkit based on the work of Rosabeth Moss Kanter that supports changing processes in organisations. Bologna Adviesgroep is the only representative of this toolkit in Holland. pagina 3 / 5 1 december 2011
4 04/92 until 11/99: project manager implementations Pica Bibliotheekautomatisering Responsible for the implementation and management of local library applications at several Dutch and German university libraries Designing and implementing processes and procedures for implementation and management of application and infrastructure Professionalize the department (incident management, configuration management, change management) Manage implementation projects, starting with designing the infrastructure. Managing suppliers, local administrators and project team members. Managing system managers, network managers, database managers and a Helpdesk Designing and selling Service Level Agreements Creating an taking part in several user groups 07/90 until 03/92: manager customer support Maatschappij voor Informaticadiensten Responsible for the creation and management of a Customer Support department in a computer centre. Creating a Helpdesk Managing operators, network managers and Helpdesk Designing and implementing ITIL procedures Quality manager Account management 06/88 until 06/90: project coordinator VNU Nieuwe Media Coordination of several new media projects Project management for on on-line hardware catalogue (VNU Computer Data) Production manager for several encyclopedias 07/77 until 05/88: several roles Uitgeverij Het Spectrum Started as manuscript corrector and user of editorial management system. Ended up as macro developer and production manager. Corrector Design data models for editorial management system Develop macros for page layout system Production manager for several encyclopedias pagina 4 / 5 1 december 2011
5 Education and experience : Gymnasium Alpha : Program development Cobol, Volmac : Middle Management, ISW : Management, ISW 1999: Helping Clients Succeed, Franklin Covey 2000: Franklin Covey Project Management 2003: PRINCE2 foundation 2004: ITIL foundation ICT experience IBM VM/MVS VAX/VMS UNIX Lotus Notes Microsoft Windows en Office products MAC OSX Sybase Oracle Java Web services Apache Tomcat several network protocols Morello Web Content Management Ektron CMS400.NET Application expertise Digital Asset Management Languages Dutch English German French - excellent reading and speaking skills - good reading and speaking skills - reading and speaking skills - reading and speaking skills Hobbies Reading Baseball Cycling Traveling Cooking pagina 5 / 5 1 december 2011
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text:
The words ink jet printer and ink cartridges hardly would be synonymous with excitement, but the latest offering from Epson would suggest otherwise.
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A Dog Ear'd Cosmos
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First Interhouse Paperback Edition: In "Dog Ear'd Cosmos" an unlikely discussion with a childhood companion unfolds - as together, a canine Beast and "his boy" investigate and secure a psychic Beach-head, enabling safer Personal journeys into the Heart and Mind of Western Culture.
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Albigensian Albigensian Heresy amount appear embodied authentic beingness blind-spots Brothers and Sisters bubble Buddhist causal comfort Conservation of Energy consider context Cosmic soap-bubble Cosmos cruel intent currently curved space Dark Darth Dave David despair develop dialog disappeared Einstein emotional encourage experience fabric of space-time fear feel fellows Friends function galaxies Gnostic gonna Grand Unified Theory guess habitual happiness healing high entropy Holy Spirit idea identifying indulging Innocence intellectual iridescent patterns kind kinda Language appears lies beneath Light lighten listening looking magic matter and energy Mind ocular tension overwhelmed perceived surface perhaps perspective phonemes physicists physics play pretty Quantum Mechanics red shift remember repressed awareness Sanskrit science appears Science's scientific scientists seduced seems sense shadow short circuit Silence sounds speak spiritual cramp things thought-forms Unconscious undoing unfolding Universe World appears World view Yeah you're Zero-point Zero-Point Energy


text:
Ghost Fest will return in October 2017!
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text:
Face + Neck Lift Q&A
Can; I get a Neck Lift without getting a Face Lift or do they have to be done at the same time?
I Had a Facelift, Neck Lift, Upper and Lower Lids Done, a Nose Tipplasty and Juvederm and I Still Look the Same!
I had all this plastic surgery on my face and after a month its all back. I have a hollow under my eyes which looked great after the surgery because I... READ MORE
Doctor Recommendation in Boston Area for Neck Lift / Facelift
I have seen a few doctors in the Boston area regarding neck lift and possible facelift. They are all board certified, but I would like reccomendations... READ MORE
Face Has Turned Puffy For The Last Month, Is It Lymph Node Damage After Necklift?
I am almost 3 months po. Initial swelling went down beautifully then suddenly my face turned puffy and has remained so for over a month. My... READ MORE
Necklift Re-do, Will It Change my Face?
I had a neck/facelift in 2010. I had a vy plasty done to remove excess skin 6 mos. later. I still have some loose skin under chin % very slight... READ MORE
Neck pleating. Why did this happen? Will it go away? (Photo)
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2 weeks, 3 days post neck/facelift. Super unhappy! (Photo)
I am 2 weeks and 2 days post lower face and neck lift with fat grafting. I was happy until a few days ago. The more the swelling goes down, the more... READ MORE
Is it recommended to clean my face and neck with Betadine Skin Cleanser prior to neck lift and face lift?
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About a year ago in Europe I had a neck lift with Platysma tightening, endoscopic endotine cheek lift and a lower face lift. Please see current photos... READ MORE
Neck + facelift w fat graft to neck 4 1/2 months ago. This is the result. I am anxious about what happened and healing (Photo)
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text:
Global gene expression profiling and histochemical analysis of the developing human fetal pancreas
- First Online:
- Received:
- Accepted:
An immunohistochemical and genomic analysis of human pancreatic development from 9–23 weeks of fetal age was undertaken to provide a comparative analysis of human and murine islet development.
Human fetal pancreases obtained at gestational ages 9–23 weeks were processed in parallel for immunohistochemistry and gene expression profiling by Affymetrix microarrays.
By 9–11 weeks, the pancreas was made up principally of mesenchymal tissue infiltrated by branched epithelial structures containing scattered hormone-negative neurogenin3-positive endocrine cells. Protoacinar structures emerged by 15–19 weeks, along with clusters of endocrine cells producing either glucagon or insulin. By 20–23 weeks, vascularised islet-like structures appeared. More than 70% of endocrine cells produced a single hormone at any age. Analysis of Ki67 immunoreactivity showed that the replicative rate of endocrine cells was low and suggested that the endocrine expansion was derived from hormone-negative precursors. Insulin, glucagon, somatostatin, ghrelin and pancreatic polypeptide transcripts were present at 9–10 weeks and increased progressively, commensurate with the expansion of endocrine cell volume. The human equivalent of a mouse endocrine secondary transition was not evident, neither in terms of morphology nor in dramatic changes in endocrine-specific transcriptional regulators. By contrast, exocrine genes showed a marked transition at around 11 weeks, associated with a greater than sixfold increase in exocrine gene transcripts.
The observed extension of terminal differentiation of human endocrine tissue into late gestation is in contrast with findings in the mouse. It indicates that the human fetal pancreas could provide an abundant islet precursor cell population that could be expanded ex vivo for therapeutic transplantation.
KeywordsFetal pancreas Gene expression profiling Human Immunohistochemistry Islet development Microarray
7-amino-4-methyl-3-coumarinylacetic acid
carboxyester lipase
embryonic day
cytokeratin 19
principal component analysis
self-organising map
tyramine signal amplification
There is a paucity of information on the development of the human pancreas at the morphological and genomic level because of ethical constraints on procurement of fetal tissue and problems with preservation of mRNA. Like the mouse pancreas, the human pancreas develops from two endodermal diverticula, the dorsal and ventral [1], which fuse around 56 days post coitum of development [2]. The morphogenesis of the endocrine tissue, however, is unlikely to be equivalent given the differences in gestation (260 vs 20 days) and the larger relative volume of the human pancreas [3]. Extrapolation from our knowledge of transcriptional regulation of rodent pancreatic development to the human is thus difficult and needs to be evaluated in the context of morphological events. There are also a number of discrepancies in published accounts of endocrine cell development in the human pancreas regarding whether early endocrine cells produce multiple hormones and at which stage the fetal cells are developmentally or functionally 'mature' [2, 4, 5, 6, 7, 8, 9].
Available gene expression data on the human pancreas have tended to focus on subpopulations of endocrine cells [10] or individual transcription factors like neurogenin3 (NGN3) [11] and PDX1 [2, 10, 11] but not the global or dynamic picture. Pancreatic acinar cell development has been documented at the ultrastructural and histochemical level [12] and an early marker of exocrine cell differentiation has been identified as carboxyester lipase (CEL) [13, 14]. However, again, there are discrepant reports on the expression of the genes for major terminal acinar cell markers during human development [15, 16]. We report here microarray profiling of human fetal pancreatic tissue from age 9–23 weeks in conjunction with an immunohistochemical analysis of the same samples. The morphological data presented as high-resolution montages are accessible online along with the microarray data at http://genespeed.ccf.org and http://www.uchsc.edu/misc/diabetes/Sarkar/Sarkar.htm, last accessed in October 2007. Many of the same molecules appear to be involved in human and mouse pancreatic patterning and cellular differentiation. However, an abrupt secondary transition in human endocrine development is not observed and is reflected in differences in the onset and the kinetics of the expression of the genes for key transcriptional regulators. This has implications for the impact of fetal nutrition and intrauterine growth restriction with type 2 diabetes [17, 18] and the use of the tissue as a source of endocrine progenitor cells.
Fetal pancreas procurement
Human fetal pancreases at gestational ages 9–23 weeks were obtained from Advanced Bioscience Resources (Oakland, CA, USA) and the Birth Defect Research Laboratory, University of Washington (Seattle, WA, USA). The procurement centres obtained informed consent for tissue donation and approval by the institutional review boards. Gestational age was determined from biparietal diameter, femur length and fetal foot measurements. Each pancreas was freed of extraneous tissue and divided, one portion for fixation in 4% paraformaldehyde (wt/vol.) in PBS for 30 min at 4°C, the other frozen in liquid nitrogen for isolation of RNA.
Immunohistochemistry of fetal tissue
Paraffin-embedded pancreases were sectioned (6 μm) and de-paraffinated by standard procedures. Antigen retrieval was performed for 30 min at 97°C in 10 mmol/l Tris, 1 mmol/l EDTA (pH 9.0) or 0.01 mol/l citrate buffer (pH 6.0). The antibodies used are listed in the electronic supplementary material (ESM). For immunofluorescence microscopy, sections were incubated for 1 h at room temperature with blocking buffer (tyramine signal amplification [TSA] system; Zymed, Invitrogen Corporation, Carlsbad, CA, USA) and then with primary antibodies overnight in a humid chamber. Secondary antibodies (1:200) conjugated to cyanine 3, cyanine 2 or 7-amino-4-methyl-3-coumarinylacetic acid (AMCA) fluorophores (Jackson Immunoresearch Laboratories, West Grove, PA, USA) were applied at room temperature for 60 min. The sections were rinsed in PBS and mounted in a glycerol-based medium. Adjacent sections were stained either with haematoxylin and eosin for morphology or with Ki67 antibodies followed by immunoperoxidase development to detect dividing cells. The latter were viewed both in bright field and by immunofluorescence. NGN3 was visualised on 9–13 week fetal pancreases with mouse monoclonal (F25A1B3; DSHB, University of Iowa, IA, USA) using the TSA kit before incubation with insulin and β-catenin antibodies. Image panels were acquired with ×40 oil lens using an Olympus 1X70 inverted microscope equipped with a motorised stage and Quantix monochromatic CCD camera (KAF 1400 chip) (Photometrix, Tucson, AZ, USA). Image arrays are accessible at http://genespeed.ccf.org and http://www.uchsc.edu/misc/diabetes/Sarkar/Sarkar.htm, last accessed in October 2007 (including ESM Figs 1, 2, 3 and 4).
RNA isolation and microarray analysis
Total RNA was extracted from fetal pancreases using Trizol reagent (Invitrogen, Carlsbad, CA, USA), purified by RNeasy columns (Qiagen, Valencia, CA, USA) and quantified and assessed for quality by capillary electrophoresis (Agilent-2100 Bioanalyzer; Agilent, Palo Alto, CA, USA). Biotin-labelled cRNA was synthesised from total RNA 6 μg (Batch 1) and 2.6 μg (Batch 2 and 3) according to the standard Affymetrix protocol and 15 μg of the final product hybridised to Human Genome HG U133 Plus 2.0 microarrays (Affymetrix, Santa Clara, CA, USA) containing 54,675 probe-sets representing around 22,000 unique genes.
Genome-wide expression and statistical analysis
False detection rate report
Cut-off p value
Number of significant genes
9–10 weeks vs 11 weeks
9–10 weeks vs 15 weeks
9–10 weeks vs 18–19 weeks
9–10 weeks vs 20–23 weeks
Quantitative RT-PCR
cDNA was prepared from total RNA (1 μg) using an iScript cDNA synthesis kit (Bio-Rad Laboratories, Hercules, CA, USA). Templates (0.1 μg of cDNA) were amplified over the linear range in a 5′ nuclease assay-based system using 6-carboxy-fluorescein dye-labelled Taqman minor groove binding probes (Applied Biosystems, Foster City, CA, USA) on a 96 well ABI 7000 PCR instrument. GAPDH was selected for sample normalisation based on preliminary experiments with the ABI control plate (part number 430 9199). The cycle threshold values were determined in triplicate and the data normalised to 9 week samples (control group/calibrator).
Characterisation of fetal human pancreatic development (morphological and histological)
Endocrine tissue
A progressive increase in the endocrine cell population was evident from 11–23 weeks, reflecting both the progressive expansion of the pancreatic epithelium (Fig. 1) and an increase in the density of endocrine cells within the epithelium (Fig. 3). With increasing fetal age there was evidence of formation of endocrine cell clusters especially from 15 weeks onwards (Fig. 4c,d), although solitary endocrine cells were still observed at all time-points. The endocrine cell clusters at early time-points displayed a significant homotypic association of either insulin- or glucagon-positive cells (Fig. 3e,f). At later time-points, heterotypic endocrine cell clustering and the appearance of typical islet-like structures were a feature. NGN3-positive cells were scattered among these epithelial clusters. Such cells exhibited heterogeneity with respect to the level of staining (9–13 weeks; see Fig. 9b) and were β-catenin and hormone-negative, a striking observation given the suggestion that β-catenin may be required for the development of the exocrine and not endocrine pancreas [21]. The endocrine transcription factor PDX1 was produced within the early pancreatic progenitor epithelium from 9 weeks onwards, although initially with a cytoplasmic localisation. From 19 weeks both nuclear and cytoplasmic PDX1 staining of the pancreatic epithelium and islet-like clusters was seen (see Fig. 9c) more typical of the adult human pancreas (results not shown).
The relationship between cell division and endocrine cell differentiation was evaluated by simultaneous immunoperoxidase staining for Ki67 combined with immunofluorescence for insulin, glucagon and somatostatin (ESM Fig. 1). Ki67-positive nuclei were seen at all time-points in both epithelial and mesenchymal structures with apparent random distribution, except in the region of the mesenchymal–epithelial boundary where it was common to see a string of adjacent cells each with a Ki67-positive nucleus (ESM Fig. 1). None of the latter stained positively for endocrine markers and it was difficult to ascertain whether they were epithelial or mesenchymal in nature. In older fetal ages it was evident that the regions of clustered endocrine cells had far fewer Ki67-positive nuclei than adjacent non-immunoreactive epithelia. Quantitative analyses at 9–10 weeks showed that 2% of the endocrine cells were Ki67-positive (ESM Fig. 1) and increased to 5.2% at 23 weeks. The relative ratio of endocrine to non-endocrine epithelial replication was low at all ages but increased significantly with time from an early (10–11 weeks) value of 0.10–0.29 at later gestation (19–23 weeks; t test p = 0.041). These data suggested that a large majority of endocrine cells are G0-arrested, and thus post-mitotic indicating that the endocrine compartment is predominantly generated through de novo differentiation from a precursor population over the second trimester rather than by replication of an established early set of endocrine cell-type populations.
Exocrine tissue
Amylase, a marker of the mature exocrine pancreas, was detected only at 23 weeks in typical acinar structures (ESM Fig. 2). The protoacinar marker CEL was not detectable at 9 weeks (Fig. 4e) but emerged in the β-catenin-positive epithelium at 11 weeks. It peaked at 15 weeks (Fig. 4f) and thereafter appeared in both luminal and peripheral locations of the epithelium in β-catenin-positive cells (Fig. 4g,h).
Ductal tissue
Cytokeratin 19 (CK19) showed diffuse immunolabelling of all epithelial clusters at 9 weeks but by 11 weeks was associated with cells on the luminal aspects of epithelial clusters. Later, the luminal cells became more columnar in appearance and retained a CK19 staining pattern typical of the adult human pancreas. Triple-positive immunostaining of CK19 with the endocrine markers insulin and chromogranin was observed in the pancreas from early gestational ages; however, the intensity of CK19 staining was lower relative to hormone-negative epithelial structures that had luminal openings and columnar-like epithelium (ESM Fig. 3).
Pancreatic mesenchyme
A proportion of mesenchymal structures showed immunoreactivity for vimentin and smooth muscle actin (data not shown) but no colocalisation of endocrine, exocrine and the mesenchymal markers was observed at any developmental stage. Vascular endothelium detected by CD34 antibodies was observed in the mesenchyme from 9 weeks and by 10–23 weeks was closely associated with large or small islet-like clusters (ESM Fig. 4).
Global gene expression analysis
Expression of genes for endocrine cells
Expression of the genes for exocrine cells
The exocrine-specific genes show a distinct transition around 11–15 weeks (Fig. 6b). At 9–10 weeks low signals were detected for the fetal acinar cell marker CEL and other exocrine markers CPA1, CPA2, CTRB1, CTRC, elastase (ELA) (2A, 3A, 3B), PRSS1, REG1A and REG3G (Figs 6b and 7b). In every case, dramatic increases were observed at 11 weeks reaching a plateau (or saturation) at 15–19 weeks (Figs 6b and 7b). Other markers of differentiated acinar cells such as amylase (AMY2A) are not detected by arrays but could be shown by immunohistochemistry at later gestational ages (20–23 weeks; ESM Fig. 2). PTF1A, a major transcriptional regulator of exocrine cell gene expression and development, was not present on the Affymetrix chip. The expression of other exocrine transcription factors, such as BHLHB8/MIST1 and GATA4, increased with time (Fig. 6b).
Expression of genes for ductal cells
Pancreatic ductal cell functional markers such as carbonic anhydrase (CA1), mucin1 (MUC1), CFTR and several aquaporins (AQP1, AQP8, AQP12B) were detected at all gestational ages and increased from 11 weeks onwards (Fig. 6c). Genes encoding keratins (KRT; 7, 8, 10, 18 and 19) were expressed at 9–10 weeks but declined gradually by 15–23 weeks (Fig. 6c).
Expression of genes for mesenchymal cells
The genes encoding the mesenchymal markers smooth muscle actin (ACTG2), collagen type V1-alpha 2 (COL6A2), alpha 3 (COL6A3) and vimentin (VIM), were highly expressed in 9–10 week fetal tissue and subsequently declined from 11–15 weeks (Fig. 6d). A similar profile was observed for other mesenchymal-specific genes in cluster 8 and presumably reflect the relative decrease in mesenchymal to epithelial mass as development proceeds (Fig. 1).
Developmental transcription factors
Our current knowledge of transcriptional regulation of mammalian pancreatic development is largely derived from studies on mice, in which gene regulation can be manipulated in a conditional and tissue-specific manner to provide information on signalling pathways and cell lineage [23]. The evagination of the human foregut to form the ventral and dorsal pancreas takes place around 4–5 weeks post coitum (Carnegie stage 12-15) corresponding to mouse embryonic day (E)9.5 (six to ten somites) [24, 25]. Significant insulin production would be anticipated in the human at this time but is not observed until 2 weeks later [2]. Conversely the emergence of the four major endocrine cell types in the mouse near term (E18) first occurs at 8.5 weeks in man [2]. The human equivalent of the secondary transition in the mouse (E12.5–13.5) when a wave of NGN3-positive cells differentiate into clusters of insulin and glucagon cells has not been described in man. Such a transition conceivably occurs prior to the earliest time-point in our study (9 weeks); however, our observation of NGN3-positive from 9–23 weeks and in a previous study at 14 weeks [26] argues against this. Nevertheless, many structural features of human endocrine pancreatic development and accompanying patterns of gene expression are reminiscent of processes described in the mouse and we hypothesise that essentially similar transitional events do occur but at multiple foci and without the same temporal coincidence as the mouse. The epithelial thickenings and evaginations that appear to precede the appearance of endocrine cells thus appear to be similar to the multilayer stratified cells previously described in the mouse in the progenitor epithelium that exists prior to the onset of the secondary transition (mouse: E13.5) and which subsequently disappears following terminal differentiation (mouse: E15.5). The cells display a high nuclear/cytoplasm ratio, are β-catenin-positive and diffusely positive for ductal marker CK19 and transcription factor PDX1. Scattered insulin or glucagon cells are evident in the non-luminal areas of these structures [27, 28]. PDX1 production was cytoplasmic at all stages of development in our study except at a later stage (>19 weeks), where nuclear production of PDX1 was observed in endocrine cells (beta cells). In this respect our histochemical results were similar to CK19 and somewhat at variance for PDX1 [2], which the authors localised at 12–13 weeks in non-endocrine epithelial cells.
The abundance of endocrine cells from 9–23 weeks that were Ki67-negative suggested that the endocrine cells are formed by terminal differentiation of actively replicating epithelium. Peak proliferation of glucagon cells (6.5%) occurred at 20 weeks, for insulin (5.4%) and somatostatin cells (5.5%) at 23 weeks. This is in contrast to previous findings [29] where peak proliferation of alpha/beta cells (3%) was noted earlier at 14–16 weeks. The continued expression of endocrine regulatory genes such as IRX2, ISL1, MAFB, NKX2-2, PAX6, PBX1 and PKMYT1 throughout the early to late gestational period is consistent with the focal endocrine developmental hypothesis, as is the maintenance of expression of the NOTCH signalling pathway of HES1, HES4, JAG1, JAG2 and NOTCH (1, 2, 3, 4). High transcript levels of SOX9 were notable in this context as this factor was recently described as pancreatic progenitor-specific factor acting in conjunction with NOTCH to maintain the progenitor state [30]. The persistent expression of NGN3 is likewise consistent with the appearance of foci of progenitor cells at different time-points resulting in the continuous differentiation of endocrine cells in the 9–23 week developmental window. NGN3 has a non-redundant role in mouse endocrine development [31, 32] and further studies aimed at systematic characterisation and isolation these of these putative endocrine precursors are warranted.
Islet formation occurs just prior to birth in the mouse [1] but in the human samples islet-like clusters appeared as early as 11–15 weeks. The continuing genesis of islets over time would account for the cumulative increase in islet number with fetal age. Since abnormal glycaemic control is a typical complication of very early pre-term infants it seems likely that by 25 weeks the pancreatic endocrine cells are not capable of controlling blood glucose if put to the test. This implies that they are developmentally immature as suggested [33] and that although unresponsive to glucose in vitro, they are eventually able in vivo to respond to environmental cues by induction of genes required for glucose sensing and granule exocytosis. After all, at 23 weeks the islets were vascularised and expressed mRNA for GLUT2 and genes that control prohormone conversion and insulin storage such as INS, PCSK1, IAPP and PTPRN.
The development of the fetal acinar compartment in humans also is not synchronised with that of endocrine differentiation following the secondary transition as it is in the mouse [34, 35]. Rather it appeared to be initiated abruptly around week 11 as evidenced by the appearance of transcripts for CEL, CPA1, CTRB1, RNASE2, PRSS1 and ELA3B. The concomitant appearance of transcriptional regulators of exocrine cell formation such as BHLB8, GATA4 and RBPJL suggests a common mechanism of gene regulation in humans as in the mouse. However, only low levels of transcripts for ELA2A and pancreatic lipase were evident at 11 weeks and amylase could only be detected histologically at 20–23 weeks, indicating that the cells may still be immature in terms of the molecular composition of their secretory product.
As in the mouse, the human mesenchyme probably plays an important role in the differentiation of the pancreatic epithelium into endocrine and exocrine components as evidenced by the presence of transcripts for fibroblast growth factor-10 [36] and integrins that coordinate epithelial cell adhesion and movement [37]. Considering the overall architecture of the pancreas at 9–10 weeks and the large volume of the mesenchyme relative to epithelium, it seems unlikely that the mesenchyme would provide strict spatial gradients of extracellular growth factors or morphogens.
The general conclusion that the endocrine precursors are generated continually throughout the second trimester and remain competent in terms of islet production has important implications for the use of fetuses as a source of tissue for therapeutic transplantation in type 1 diabetes. Animal studies have demonstrated that fetal islet-like cell clusters comprise a mixture of hormone-containing cells and undifferentiated epithelial cells may be a better source of functional islet tissue than isolated adult islet tissue [38, 39, 40], possibly because they contain endocrine precursors. This raises the prospect of maintaining such tissue ex vivo to extend the progenitor state and expand the precursor cell population prior to differentiation. The present study provides a framework for further study of the intra-organ environment and discovery of the genes that might orchestrate this process.
The authors would like to thank C. Wright, School of Medicine (Vanderbilt, TN, USA) for PDX1 antibodies and the Developmental Studies Hybridoma Bank under National Institute of Child Health and Human Development, maintained by the University of Iowa (Iowa City, IA, USA), for the NGN3 antibody developed by O. D. Madsen. Funding for the project was provided by the Children's Diabetes Foundation at Denver, the Larry L. Hillbloom Foundation, the Juvenile Diabetes Research Foundation, the Diabetes and Endocrine Research Center (NIH P30 DK57516), the Beta Cell Biology Consortium (NIH U19 DK61248) and the Birth Defect Research Laboratory (University of Washington, WA, USA) (NIH HD 000836). The Islet Cell Research Consortium is thanked for human islet procurement. J. N. Jensen is supported by the Danish Research Council (271-05-0667).
Duality of interest
The authors declare that there is no duality of interest associated with this manuscript.


text: However, for Sirius, it's more than just the buyback program. Liberty Media ( LMCA) is now in full control of the company. Sirius is no longer bleeding subscribers and is now posting record numbers for revenue and cash flow growth. So, not only is the company operating on all cylinders, there are no meaningful signs of slowing down, including its recently announced 15% increase in net subscriber additions last week. What's more, the company just also announced a new partnership with AT&T ( T) to provide connectivity to its telematics platform that will arrive in new Nissan ( NSANY) vehicles. In other words, Sirius is working to become more than "just radio." While there are several unknowns with telematics such as what it will become and how much it will cost, it is clear that Sirius is not sitting idle -- waiting to run out of gas. The company has found a way to profit from the "connected car," which is what Apple and Google are racing to produce. Is it possible that Sirius, which is not seen as a "tech company," will get there first? I wouldn't wait to find out. Shares are getting progressively more expensive. Investors that are looking for ways to play the audio streaming market that are also looking for some safety would do well taking a long ride with Sirius.


text:
Deepali Sathe isn't new to the music world. The songstress started crooning at the age of three and mingling with the stalwarts of the music industry. She is the new voice in 'Humari Adhuri Kahani'.
Deepali Sathe has crooned the track, 'Yeh Kaisi Jagah' with Zubeen Garg, in the Emraan Hashmi and Vidya Balan starrer.
It has been composed by Jeet Ganguly, the music director of 'Hamari Adhuri Kahani' and the lyrics have been written by Rashmi Singh and Virag Mishra.


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2016's most viral fashion moments
- TextTed Stansfield
Presenting 2016's most viral fashion moments. A truly mixed bag, these are a portion of the images that made us gasp, gawp and giggle – ones that were so good that we couldn't help tweet or Instagram them. And before you ask, yes, a lot of these have to do with Vetements or things Rihanna wore to feed pigeons in. 2k16, you've been shit in so many but these moment provided some comfort in the darkest of times – and for that, we thank you. Let's hope that 2017 brings us more memes and less global catastrophes.
Follow Ted Stansfield on Twitter here @ted_stansfield
Get updates direct to your inbox with the Dazed bi-weekly newsletter


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It only takes a minute to get started. Fill out our simple sign up form and login to the website.
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Identified someone who tickles your fancy? Send them a few words or just a wink and wait for their response. With a little luck you'll be on your way to a lifetime of happiness.
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- 1 of 12 Photos | View More Photos
CINCINNATI (AP) -- A man accused of a shooting at a veterans hospital said he intended to intimidate former co-workers he believed were having inappropriate relationships with his wife and daughter, according to court documents.
One person was shot in the ankle when Neil Moore's gun went off in a hospital break room, authorities said.
Moore, 59, of Trotwood, was charged Tuesday in Dayton federal court with single counts of assault with a dangerous weapon and use of a deadly weapon during the commission of a violent crime. His attorney, F. Arthur Mullins, did not immediately return a call Tuesday.
Investigators said Moore entered a room where several people were playing cards and pointed a revolver at them saying something like, "Don't mess with my family."
Authorities said one of the card game participants lunged at Moore, knocking his .38-caliber revolver. The gun went off at least three times, striking another man in the lower leg, federal investigators said.
Moore then went to an elevator, where he pointed the revolver at another person before fleeing the building, according to court documents.
Moore then drove his pickup truck to his sister's Trotwood home and she drove him to a hospital in Dayton for medical evaluation, authorities said. Moore was taken into custody at the hospital.
Moore, a former employee at the VA hospital, told police that he regularly participated in a card game with co-workers when he worked there. He said he went to the hospital Monday intending to brandish the handgun to intimidate two former co-workers he believed were involved in relationships with his wife and daughter, both of whom reportedly work at the hospital, authorities said.
He intended to "hold the ex-co-workers at gunpoint while he punched them with his right hand," according to court documents.
Police identified the wounded man as Paul Burnside, 61, a housekeeping aide. He was "not a target of Moore's attention," said U.S. attorney's spokesman Fred Alverson.
Burnside remained hospitalized Tuesday and requested no further information be released, a hospital spokeswoman said.
The hospital complex has beds for about 450 people and provides veterans with medical, mental health and nursing home care. It doesn't have metal detectors at its entrances, but it does have its own security force.
Each of the counts against Moore carries a maximum sentence of 10 years and a possible fine of up to $250,000.
Moore was behind bars pending a detention hearing Friday, where prosecutors plan to ask that remain in custody pending trial.


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General enquiries
+44 (0) 20 7079 4399
Call HCA from 8am-8pm Mon-Fri and 9am-5pm Sat
HCA Healthcare UK
Our Specialists
Mr Maxim Horwitz
MBChB, FRCS(Orth), Dip Hand Surg
Orthopaedic Surgery - upper limb, Hand Surgery, Paediatric Orthopaedics, Wrist Surgery, Paediatric Genetics/ Congenital Abnormal
Hand and Upper Limb Trauma including fractures and tendon injury. Treatment of hands in people with Cerebral Palsy, Brain and Spinal cord injury
Mr Horwitz was educated and trained in South Africa and London, UK. After completing training in Orthopaedics and Trauma in London he travelled to a centre of global excellence in Sydney, Australia as the Pulvertaft Fellow of the British Society of Hand Surgery. He then undertook a fellowship in children's hand conditions at the world renowned Great Ormond Street Hospital, London. He also undertook an AO fellowship in Trauma in Salzburg, Austria.During these fellowships he received training in advanced techniques including, the management of complex hand and upper limb trauma, wrist and hand arthritis as well as the treatment of congenital hand deformity, complex nerve injuries and microsurgery. He also has as interest in the management of the hand and upper limb in children with cerebral palsy. He has been awarded the BSSH postgraduate diploma in hand surgery and is a member of the British Orthopaedic Association. He has published many book chapters and scientific papers related to hand surgery. Mr Horwitz currently works as a Consultant Hand Surgeon in the Hand Unit at Chelsea and Westminster Hospital. He has previously worked as a Consultant in the Major Trauma Centre at St Mary's Hospital London and still consults to them regarding patients with Complex Injuries. He works very closely with a team of Hand Therapists and at times with fellowship trained Plastic and Reconstructive Surgeon.
© copyright 2008 - 2017 HCA Healthcare UK.
Registered Name: HCA International Limited; The part of the UK in which it is registered: England and Wales;
Registered Number: 03020522; Registered Office Address: 242 Marylebone Road London NW1 6JL.
£500m has been invested by HCA International in the latest medical technologies and facilities over the last 10 years.
Your hospital will be one of our world-class private hospitals: HCA's world-class hospitals are accredited by The CHKS Accreditation Unit, a leading provider of healthcare intelligence and quality improvement services. The accreditation is a measure of the overall quality of a hospital and hospitals with CHKS accreditation have been shown to provide a better quality of service.
Your safety will be protected because we have more critical care beds than any other private hospital group: HCA hospitals achieved 100% compliance with all Care Quality Commission inspected outcomes of care in 2011.
Your treatment will be undertaken using the most advanced diagnostic and treatment facilities: Oliver Wyman, Corporate Accounts: Driving quality and value, January 2012.


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All You Need To Know About Haringey Sixth Form Collegeposted on 17 Apr 2016 21:32 by eroranceilz
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edit @ 17 Apr 2016 21:33:37 by eroranceilz


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Macondo Map
157 E. Houston St. (Allen St.)
212-473-9900 | Make Restaurant Reservations | Menu
Find Macondo with this handy map to the restaurant. If you don't see a pop-up, click on the map's green arrow to get driving directions to and from Macondo.
Find out which restaurants and chefs top the list of GAYOT's 2016 Annual Restaurant Awards.


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http://bit.ly/ClevverGames - Subscribe! http://Twitter.com/ClevverGames - Follow Us! http://www.facebook.com/ClevverGames - Like Us! http://www.clevver.com/games - Check out our blog!
What's up guys and welcome back to Clevver Games I'm Andrea Rene here with the latest news from Activision on their reboot of Goldeneye 007 dubbed Reloaded. The single-player demo is now available on the PlayStation Network and will be coming soon to Xbox Live so if you haven't played now is your chance to test run the game. . If you decide the re-envisioned spy action is up your alley you might want to consider snagging the upcoming downloadable content featuring two new playable characters. First up is the one and only Pussy Galore. Before you take your minds completely to the gutter...oh who am I kidding you went there after reading the title... . She is an actual character that is practiced in Judo so she'll have increased stamina granting her longer sprints and she'll regenerate health 25% faster. She'll also be able to swap weapons twice as fast and reload 25% quicker. And that's not all, Pussy also gets a high capacity magazine that increases her bullets in each clip by 20%. . Also available for download is Emilio Largo, the black marketer. He will have 25% improved accuracy and will also be able to swap weapons twice as fast and reload firearms faster. He'll get access to enhanced frag grenades and hollow point ammunition which increases bullet damage. . Both characters will cost $2 bucks or 160 Microsoft Points and will fit right in to the multiplayer experience. If you want to learn more about Goldeneye 007 Reloaded check out the videos on our channel page and make sure to subscribe to Clevver Games to get all the latest Activision news. I'm Andrea Rene and I'll see you guys later.
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Overview Edit
The Pathways to a National Cyberspace Security Response System (PNCSRS) is a prototype of information infrastructure assurance capability specified in the National Strategy to Secure Cyberspace. The PNCSRS application suite was used to: (1) evaluate off-the-shelf technologies that have the potential to be deployed in more advanced NCSRS pilots; (2) to explore methods of conducting future national scale cyber security exercises; and (3) to generate ideas for new R&D initiatives.
The trial produced key breakthroughs by demonstrating the fusing of cyber security information with other operational intelligence through the DoD's Global Command and Control System (GCCS), and in procedural approaches to integrate cyber security information in the HLS-HLD decision-making process.
Source Edit
- Department of Homeland Security, "Coalition Warrior Interoperability Demonstration (CWID)" (full-text).


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The vibe in Roseville, Minnesota is friendly and familiar to those seeking a close-in location equidistant between Minneapolis and St. Paul. Small towns that turned into suburbs feel welcoming and familiar to me, after having lived in more than half a dozen: Camarillo, San Pedro (CA), Mt. Clemens, Wyoming (MI), Chanhassen, Minnetonka, Deephaven, St. Louis Park, and Maple Grove (MN). It's tempting for self-appointed sophisticates to relegate these communities to anonymity, thinking that they Continue Reading
Home2 Suites by Hilton – Roseville Minneapolis
Home2 Suites by Hilton - Roseville Minneapolis showcases Hilton's new, contemporary extended-stay concept in a great Twin Cities location. Our Experience: We were excited to stay at the brand new Home2 Suites by Hilton - Roseville Minneapolis. A couple of months prior, we had been taken on a pre-opening tour to introduce us to the concept. Now, we couldn't wait to experience the finished product. Home2 Suites by Hilton was envisioned as a stylish option for mid-range, extended-stay Continue Reading
Holiday Inn Express – Roseville-St. Paul
Holiday Inn Express - Roseville-St. Paul delivers a superlative experience for Twin Cities visitors in a newly-renovated, close-in location. Our Experience: We arrived at the Holiday Inn Express - Roseville-St. Paul at midnight local time after a lengthy and somewhat harrowing 24 hours of travel in four different countries. Rising at about 5:30AM Stockholm time on the overnight ferry from Helsinki, we had nabbed the Arlanda Express train to the airport outside Stockholm, changed flights after Continue Reading
A Nostalgic Visit to Paul Bunyan Land
Many Minnesotans have fond memories of visiting Paul Bunyan Land as children. Nowadays, this famous attraction has even more for all ages! "Oh boy!" said Pete to the rest of our group. "One of the highlights for us kids on our summer trips to the cabin was visiting Paul Bunyan Land. You know, he talks to you and everything! He even knew my name!" If you grew up in the Northern United States, chances are you know the mythical legend of Paul Bunyan and Babe the Blue Ox. Formulated out of Continue Reading
Fun Adventures in Central and Northwest Minnesota
With summer brings the opportunity for a variety of fun adventures in Central and Northwest Minnesota on land and water, and even in the air! Summer fun adventures in Central and Northwest Minnesota abound for all ages! We recently rediscovered this region with new eyes after an absence of several years. Active enthusiasts will be amazed at all the options, no matter how you roll. There is no more perfect environment than a Minnesota summer to get your groove on! Come along and be inspired as Continue Reading
Hotel Review: Hampton Inn Minneapolis-Roseville
We discovered a wealth of thoughtfully designed details to please almost every type of traveler at the new Hampton Inn Minneapolis-Roseville. Our Experience: It's not every day you can move into a brand new hotel and be among the first to experience every thoughtful detail it has to offer. We found a variety of amenities and conveniences at the Hampton Inn Minneapolis-Roseville, which proved the brand's commitment to business travelers isn't just lip service. And what's good for business Continue Reading
The Magic of Madden's on Gull Lake
In the perfectly pristine setting of an upstate Minnesota summer, we left the real world behind for the magic of Madden's on Gull Lake. After you turn off highway 371, the upstate Minnesota landscape unfolds as part of a shimmering promise. And that promise is: in the space of the few minutes, you'll leave your real world somewhere back behind you, obscured and protected from intrusion by the perfection only this part of the world can bring. Here is a paradise wrought in a hundred shades of Continue Reading
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No Comment »
Looks tasty to me!
While these analyses may be "technically correct" sometimes, I think these sites overlook interesting recipes from regular folks. I'm not looking for work by food photographers when I browse — I've got cookbooks for that. I'm looking for goodies by real cooks, like me. Your ice cream looks fantastic.
I love this photo and I think you captured the idea that was intended, the scoops look delicious and I love that you can even see swirls in the ceramic bowl that imitate how an ice cream scoop curls the ice cream into a ball. To me, it looks like you thought of that too and that was very clever. You surely made me want a taste—or lick! Keep it up.
Leave a comment!


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Why Invest in a lower priced Hublot Look-alike Watch?
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This article, Magnet Release: Magnetizing Barrier Technique, is the property of User:Boredfan1.
|Magnet Release: Magnetizing Barrier Technique
|Magnet Release: Magnetizing Barrier Technique
|Kekkei Genkei, Hiden & Barrier Ninjutsu
|Chakra Nature
|Magnet Release
|Parent jutsu
|Magnet Release: Hidden Magnetism Technique
Some time after Karura created the Magnet Release: Hidden Magnetism technique, she came to realize that the the extreme difficulty and chakra tax of using the technique makes it impractical at times to use. So she studied barriers and in secret, learned how to apply her Magnet Release to barriers, creating a method of magnetizing enemies secretly as they go through it without such a large drain on her. However, this barrier is draws on the user's chakra whenever someone goes through it to magnetize enemies, transporting the chakra instantaneously over the distance.
The amount depends on how large and dense the thing that goes through as well as the number of things that go through at once. Small objects with low density require such a small amount of chakra that it is practically unnoticable however, high or medium density objects, however small, require a noticable amount of chakra though even a high density small object only amounts to a D ranked technique unless extremely dense then it is equal to either a C or B ranked technique. Medium sized objects depending on how big in the medium range it is will be equal to a D or C ranked technique, even without much of a density while large objects, like Humans are never below the amount of chakra required of C ranked techniques. Normally, this technique can only extend a max of sixty meters away from the user however, it can be extended through a lot of hard work and time to go father out but even Karura's barrier can only go eighty to a hundred meters away.


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