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Research Executive Agency
THE 2012 PEOPLE PROGRAMME
GUIDE FOR APPLICANTS Marie Curie Actions (Common Part)
This document contains information common to the Marie Curie Actions. It is to be read in conjunction with the Guides for Applicants, Ethics and Call-Specific Parts Date of publication: 28/11/2011 Version Number: 2012.2
Please note The 2012 Marie Curie Actions are: FP7-PEOPLE-2012-CIG FP7-PEOPLE-2012-COFUND FP7-PEOPLE-2012-IAPP FP7-PEOPLE-2012-IEF FP7-PEOPLE-2012-IIF FP7-PEOPLE-2012-IOF FP7-PEOPLE-2012-IRSES FP7-PEOPLE-2012-ITN Guides for Applicants for any other action in the PEOPLE programme, or indeed in any FP7 programme, can be found by following the links at http://ec.europa.eu/research/participants/portal This Guide is based on the rules and conditions contained in the legal documents relating to FP7 (in particular the Seventh Framework Programme, Specific Programmes, Rules for Participation, and the Work Programmes), all of which can be consulted via the Participant Portal. This Guide does not in itself have any legal value, and thus does not supersede those documents.
Marie Curie Actions, Guide for Applicants (Common Part) – 2012
Changes since Version 2012.1 The Republic of Moldova has been added to the list of Associated Countries
1. Introduction Funding decisions in the Seventh Framework Programme (FP7) are made on the basis of calls published by the Commission or its agencies, which solicit proposals. The proposals must be submitted using a special web-based service before a strictly enforced deadline. The Research Executive Agency (REA) evaluates all eligible proposals in order to identify those whose quality is sufficiently high for possible funding. The basis for this evaluation is a peer review carried out by independent experts. The REA then negotiates with some or all of those whose proposals have successfully passed the evaluation stage, depending on the budget available. If negotiations are successfully concluded, grant agreements providing for an EU financial contribution are established with the beneficiaries. This Guide for Applicants contains the essential information to guide applicants through the mechanics of preparing and submitting a proposal. It contains information that is common to all of the Marie Curie Actions, and must be read in conjunction with the Call-Specific Guides and the Ethics Guide. Applicants must also refer to the People Work Programme 2012. This includes a detailed description of the Marie Curie Actions, their objectives and scope, the eligibility criteria, the European Union contribution and the evaluation criteria. Work Programmes are revised each year, so it is important to refer to the latest version before preparing a proposal. This Guide and the Work Programme are essential reading. In addition, applicants may wish to consult other reference and background documents, in particular those relating to negotiation and the grant agreements, which are available on the Participant Portal: http://ec.europa.eu/research/participants/portal
2. How to apply Turning your idea into an effective proposal The coordinator The REA refers to the participant who is taking the lead in the preparation of the proposal as the "proposal coordinator". The coordinator acts as the single point of contact between the participants and the REA. For Intra-European Fellowships (IEF), International Outgoing Fellowships (IOF), International Incoming Fellowships (IIF) and Career Integration Grants (CIG) the experienced researcher can act as the proposal coordinator before the call deadline, in particular in order to submit the proposal. However after the call deadline the scientist in charge at the host organization will be the single contact point. The experienced researcher and the scientist in charge cannot be the same person. Please note that the Acknowledgement of Receipt of the proposal, which is sent after the call deadline, will be sent to the coordinator. Further, the evaluation results will be sent to the coordinator. Focusing your planned work Refer to the description of the Marie Curie Action in the Call-Specific Guide and the Work Programme to check the eligibility criteria and any other special conditions that apply. Refer also to the evaluation criteria against which your proposal will be assessed. These are given in the Work Programme and the Call-Specific Guide. The independent experts are instructed that proposals submitted must be evaluated exclusively against the published criteria.
National Contact Points A network of National Contact Points (NCPs) has been established to provide advice and support to organisations which are preparing proposals. You are highly recommended to get in touch with your NCP at an early stage. (Contact details are given on CORDIS http://cordis.europa.eu/fp7/get-support_en.html .) Please note that, after the applicants have been informed, the Commission will also give the NCPs statistics and information on the outcome of the call and of the evaluation for each proposal. This information is supplied to support the NCPs in their service role, and is given under strict conditions of confidentiality. Other sources of help The Call-Specific Guides give references to further sources of help for this call. In particular: •
The Commission's general enquiry service on any aspect of FP7. Questions can be sent to a single email address and will be directed to the most appropriate department for reply. Please see http://ec.europa.eu/research/enquiries
A dedicated help desk has been set up to deal with technical questions related to the Electronic Proposal Submission Service (EPSS). See below
The European Charter for Researchers and the Code of Conduct for their recruitment can be downloaded from http://ec.europa.eu/euraxess/rights
A help desk providing assistance on intellectual property matters (see CORDIS under http://cordis.europa.eu/fp7/how_en.html#ipr)
Any other guidance documents or background information related specifically to this call
The date and contact address for any 'information day' that the REA may be organising for this call.
Other services, including partner search facilities, provided via the CORDIS web site (see http://cordis.europa.eu/fp7/partners_en.html). Ethics principles Please remember that research activities in FP7 should respect fundamental ethics principles, including those reflected in the Charter of Fundamental Rights of the European Union1. These principles include the need to ensure the freedom of research and the need to protect the physical and moral integrity of individuals and the welfare of animals. For this reason, the REA and the European Commission carry out an ethics review on research proposals when appropriate. The following fields of research will not be financed under this Framework Programme: • • •
research activity aiming at human cloning for reproductive purposes research activity intended to modify the genetic heritage of human beings which could make such changes heritable2 research activities intended to create human embryos solely for the purpose of research or for the purpose of stem cell procurement, including by means of somatic cell nuclear transfer.
For human embryonic stem cell research, European Union financial support for research activities involving destroying human embryos is excluded, including for the procurement of stem 1
Charter of Fundamental Rights of the European Union, http://www.europarl.europa.eu/charter/default_en.htm Research relating to cancer treatment of the gonads can be financed.
2000/C
364/01.
cells. The exclusion of funding of this step of research will not prevent the European Union funding of subsequent steps involving human embryonic stem cells. More comprehensive details can be found in the Guide for Applicants (Ethics). This guide must be read by all applicants, even if they believe that no ethics concerns arise in their proposal; failure to complete the Ethics section of the proposal can lead to the proposal being declared ineligible. Presenting your proposal A proposal has two parts: Part A consists of several administrative forms which contain information about the proposal and the applicant. The information requested includes a summary of the proposed project, contact details of the host organisation and the researcher, and information related to the funding requested (please see the Call-Specific Guide). This information will be encoded in a structured database for further processing to produce, for example, statistics, and evaluation reports. This information will also be used by the experts and the REA staff during the evaluation process. The information in Part A is entered through a set of online forms. Part B is a "template", or list of headings, rather than an administrative form (please see the CallSpecific Guide). Applicants should follow this structure strictly when presenting the scientific and technical content of their proposal. The template is designed to highlight those aspects that will be assessed against the evaluation criteria. It covers, among other things, the nature of the proposed work, the participants and their roles in the project proposed, and the impacts that might be expected to arise from the proposed work. The information given will be the basis on which the experts will evaluate the proposal, so ensure that it is precise and complete. References to web pages will not be taken into account as part of the proposal during evaluation, unless specified in the Call-Specific Guide. Part B of the proposal is uploaded by the applicant in the EPSS system described below. A maximum length may be specified for the different sections of Part B, or for Part B as a whole (see the Call-Specific Guide). Applicants must keep their proposal within these limits. Experts will be instructed to disregard any excess pages. Proposal language The working language of the expert evaluators is English and it is recommended that proposals are prepared in English. However, proposals may be prepared in any official language of the European Union. If your proposal is not in English, a translation of the full proposal would be of assistance to the experts.
3. Proposal submission About the EPSS Proposals must be submitted electronically using the REA's Electronic Proposal Submission Service (EPSS). Proposals arriving by any other means are regarded as 'not submitted', and will not be evaluated3. All the data that you upload is securely stored on a server to which only you 3
In exceptional cases, when a proposal coordinator has absolutely no means of accessing the EPSS, and when it is impossible to arrange for another person, an applicant may request permission from the REA to submit on paper. A request should be sent via the FP7 enquiry service (see the Call-Specific Guide), indicating in the subject line
and the other participants in the proposal have access until the deadline. This data is encrypted until the close of the call. Please note that this also means that the REA does not have access to the proposal data (except that entered in the EPSS registration form) until after the call deadline. You can access the EPSS from the call page https://www.epss-fp7.org/epss. Full instructions are found in the "EPSS preparation and submission guide", available from the EPSS entry page (click on "EPSS user guide"). The most important points are explained below. Use of the EPSS system by the proposal coordinator The EPSS refers to the participant who is taking the lead in the preparation of the proposal as the "proposal coordinator" Only one login and password is provided which must then be shared as appropriate. As coordinator you can: • register an interest in submitting a proposal to a particular call • complete Part A of the proposal • download the document template for writing Part B of the proposal, and when it is completed, upload the finished Part B • submit the complete proposal Part A and Part B • nominate referees. Participant Identification Codes (PICs) Participants possessing a Participant Identification Code (PIC) can use this number to identify themselves in the EPSS. On entering the PIC, parts of the A forms will be filled in automatically. Please note that in the cases where a PIC is not available it will always be possible to submit a proposal by entering the organisation details manually. However, the use of PICs will lead to more efficient handling of the proposal. The process for assigning a PIC is triggered by a selfregistration of an organisation at the Unique Registration Facility website: http://ec.europa.eu/research/participants/urf. On the following website you will find a search tool for checking if your organisation is already registered http://ec.europa.eu/research/participants/portal/page/searchorganisations. Referees' assessments For individual actions (IEF, IOF, IIF, CIG), up to three referees can be nominated in order to provide assessments of the experienced researcher. A special facility within the EPSS system permits referees to create their assessment for the proposal. The creation of the referee happens from the "Set Up Proposal" page. Once the proposal coordinator has nominated a referee the EPSS system will automatically send a login and password to the referee's email address. Due to potential problems with SPAM filters, however, when a mail is sent to the referee, an instruction mail is also sent to the person who has registered, requesting the applicant to cross-check with the referee if he or she has received the email from the EPSS system.
"Paper submission request". (You can call the enquiry service if the web access is not possible: +800 6 7 8 9 10 11 from inside Europe; or +32 2 299 96 96 from the rest of the world. A postal or email address will then be given to you). Such a request, which must clearly explain the circumstances of the case, must be received by the REA no later than one month before the call deadline. The REA will reply within five working days of receipt. If derogation is granted, a proposal on paper may be submitted by mail, courier or hand delivery. The delivery address will be given in the derogation letter.
When the nominated referee uploads a referee's assessment the proposal coordinator will receive an email to confirm that an assessment has been uploaded but the assessment itself will not be visible to the coordinator. The referees' assessments are automatically added to the proposal package by the EPSS system but will only become accessible to the REA when (if) the proposal is submitted. Referees' assessments can be submitted any time between the issue of a password and login for the referee and the call closure (even before the main proposal is submitted). Referees' assessments cannot be submitted after the call closure. Please note that if you nominate referees close to the call deadline then this leaves them very little time to submit their assessments. Submitting the proposal Only the coordinator is authorised to submit the proposal. Completing the Part A forms in the EPSS system and uploading a Part B does not mean that your proposal is submitted. Once there is a consolidated version of the proposal, the coordinator must press the button "SUBMIT NOW". (If you don't see the button "SUBMIT NOW", first select the "SUBMIT" tag at the top of the screen). Please note that "SUBMIT NOW" starts the final steps for submission; it does not in itself cause the proposal to be submitted. After reading the information page that then appears, it is possible to submit the proposal using the button marked "PRESS THIS BUTTON TO SUBMIT THE PROPOSAL". The EPSS then performs an automatic validation of the proposal. A list of any problems such as missing data, viruses, wrong file format or excessive file size will then appear on the screen. Submission is blocked until these problems are corrected. Once corrected, the coordinator must then repeat the above steps to submit. Please note that if a proposal is validated it does not imply that it is eligible or that the page limits have been respected. It is also the case that not all eligibility conditions are checked at validation, for example any restriction on the minimum number of participants is checked manually by the REA. If successfully submitted, the coordinator receives a message that indicates the proposal has been received. This automatic message is not the official acknowledgement of receipt which is sent after the call deadline has passed. Please note that in very rare cases there have been problems with uploaded files mainly due to errors in the conversion to PDF format before uploading. Applicants are thus strongly advised to verify, by downloading the file from the EPSS server before the call deadline, that the part B of the proposal they uploaded is the right file, that it has not been corrupted, is complete, printable and readable. The coordinator may continue to modify the proposal and submit revised versions, overwriting the previous one, until the deadline. Please note that the sequence above must be repeated each time. If the submission sequence described above is not followed, the REA considers that no proposal has been submitted. As each successive submission overwrites the previous version, it is a good idea to submit a draft well before the deadline. For the proposal Part B you must use exclusively PDF ("portable document format", compatible with Adobe version 3 or higher, with embedded fonts). Irrespective of any page limits specified in the Call-Specific Guide, there is an overall limit of 10MB to the size of proposal file Part B. There Marie Curie Actions, Guide for Applicants (Common Part) – 2012
are also restrictions to the name you give to the Part B file. You should only use alphanumeric characters. Special characters and spaces must be avoided. Applicants are advised to clean their document before converting to PDF (e.g. accept any track changes). Check that your conversion software successfully converts all pages of the original document (e.g. there is no problem with page limits or margins). Please note that the REA prints proposals on plain A4 paper. The printable zone on the print engine is bounded by 1.5 cm right, left, top and bottom. No scaling is applied to make the page "fit" the window. Printing is done at 300 dots per inch. About the deadline Proposals must be submitted on or before the deadline specified in the Call fiche. The EPSS will be closed for the call at the call deadline. After this moment, access to the EPSS for this call will be impossible. Do not wait until the last moment before submitting your proposal. Call deadlines are absolutely final and are strictly enforced Leaving your first submission attempt to the last few minutes of the call will give you no time to overcome even the smallest technical difficulties, proposal verification problems or communications delays which may arise. Such events are never accepted as extenuating circumstances; your proposal will be regarded as not having been submitted. Submission is deemed to occur at the moment when the proposal coordinator completes the submission sequence described above. It is not the point at which you start the upload. If you wait until too near to the close of the call to start uploading your proposal, there is a serious risk that you will not be able to submit in time. If you have registered and submitted your proposal in error to another call which closes after this call, the REA will not be aware of it until it is discovered among the downloaded proposals for the later call. It will therefore be classified as ineligible because of late arrival. The submission of a proposal requires some knowledge of the EPSS system, a detailed knowledge of the contents of the proposal and the authority to make lastminute decisions if problems arise. Applicants are advised not to delegate the job of submitting their proposal. In the unlikely event of a failure of the EPSS service due to breakdown of the server during the last 24 hours of a call, the deadline will be extended by a further 24 hours. This will be notified by email to all proposal coordinators who had registered for this call by the time of the original deadline, and also by a notice on the Call page on the Participant Portal (see http://ec.europa.eu/research/participants/portal/page/searchorganisations) Such a failure is an exceptional event, therefore do not assume that there will be an extension to the Call. If you have difficulty in submitting your proposal, you should not assume that it is because of a problem with the server, since this is rarely the case. Contact the EPSS help desk if in doubt. Please note that the REA will not extend deadlines for system failures that are not its own responsibility. In all circumstances, applicants should aim to submit their proposal well before the deadline to have time to solve any problems. Marie Curie Actions, Guide for Applicants (Common Part) – 2012
Correcting or revising your proposal Errors discovered by the applicant in proposals submitted to the EPSS can be rectified by simply submitting a corrected version. As long as the Call has not yet closed, the new submission will overwrite the old one. Once the deadline has passed, however, the REA can accept no further additions, corrections or resubmissions. The last version of your proposal received before the deadline is the one which will be evaluated, and no later material can be submitted. Ancillary material Only a single PDF file comprising the complete Part B can be uploaded. Unless specified in the call, any hyperlinks to other documents, embedded material, and any other documents (company brochures, supporting documentation, reports, audio, video, multimedia etc.) sent electronically or by post, will be disregarded. Withdrawing a proposal Before the deadline, applicants may withdraw a proposal by submitting a revised version with an empty Part B section, with the following words entered in the abstract field of Part A: "The applicants wish to withdraw this proposal. It should not be evaluated by the REA". After the deadline, applicants may send an email to EPSS Helpdesk: [email protected] Multiple Submissions Applicants are reminded that only one proposal may be submitted in an evaluation procedure at any one time for any of the following actions: •
Marie Curie Intra-European Fellowships for Career Development (IEF),
Marie Curie International Outgoing Fellowships for Career Development (IOF),
Marie Curie International Incoming Fellowships (IIF). Please note that the Research Executive Agency will not conclude more than one grant agreement for the same project.
In case of multiple submissions by a research or research funding organisation, the applicant entity may be asked to demonstrate the capacity to participate in more than one of those projects simultaneously, in terms of research staff, infrastructure and management.
Countries that can participate in, or be funded by the PEOPLE programme
4. Countries that can participate in, or be funded by the PEOPLE programme Please be aware that the information in this section cannot be regarded as definitive, and participants should refer to the CORDIS website before making an application http://cordis.europa.eu/fp7/who_en.html. In general all EU member states and countries associated to the 7th Framework Programme can participate in all calls, although in some calls other countries must be included in order to form an eligible consortium. The European Union Member States are: Austria, Belgium, Bulgaria, Cyprus, Czech Republic, Denmark, Estonia, Finland, France, Germany, Greece, Hungary, Ireland, Italy, Latvia, Lithuania, Luxembourg, Malta, Netherlands, Poland, Portugal, Romania, Slovakia, Slovenia, Spain, Sweden, United Kingdom. The Associated countries are4: Albania, Bosnia and Herzegovina, Croatia, the Faroe Islands, FYR Macedonia, Iceland, Israel, Liechtenstein, Moldova, Montenegro, Norway, Serbia, Switzerland, Turkey. Other countries may become associated during the course of FP7. The latest news will be posted on the CORDIS web site: http://cordis.europa.eu/fp7/who_en.html.
4 Please consult list at http://cordis.europa.eu/fp7/who_en.html
Preparing your proposal • • •
Are you applying for the correct action? Check that your proposed work falls within the scope of this call, and that you have applied for the correct action (see the "PEOPLE" Work Programme). Is your proposal eligible? The eligibility criteria are given in the Work Programme. For detailed information, please refer to the Call-Specific Guide. Any proposal not meeting the eligibility requirements will be considered ineligible and will not be evaluated. Is your proposal complete? Proposals must comprise a Part A, containing the administrative information; and a Part B containing the description of your proposal as described in the Call-Specific Guide. A proposal that does not contain both parts will be considered ineligible and will not be evaluated. If the call allows referees' assessments and you intend to use them to support your application, have you defined the referees well in advance so that they can submit their recommendation letter before the deadline? Does your proposed work raise ethics issues? Clearly indicate any potential ethics, safety or regulatory aspects of the proposed research and the way they will be dealt with in your proposed project. An ethics check will take place during the evaluation and an ethics review will take place for proposals dealing with sensitive issues. Proposals may be rejected on ethics grounds if such issues are not dealt with satisfactorily. Does your proposal follow the required structure? Proposals should be precise and concise, and must follow the proposal structure described in the Call-Specific Guide, which is designed to correspond to the evaluation criteria which will be applied. This structure varies for different calls. Omitting requested information will almost certainly lead to lower scores and possible rejection. Have you maximised your chances? Please be aware that there will be strong competition. Therefore, edit your proposal carefully, strengthen or eliminate weak points. Put yourself in the place of an expert evaluator; please refer to the evaluation criteria given in the CallSpecific Guide. Arrange for your draft to be evaluated by experienced colleagues, use their advice to improve it before submission. Do you need further advice and support? You are strongly advised to inform your National Contact Point of your intention to submit a proposal (please see the Call-Specific Guide). Remember the Enquiry service listed in the Call-Specific Guide.
Final checks before submission • • • • • • • •
If you are submitting for a Marie Curie Intra European, International Outgoing or International Incoming Fellowship or for a Marie Curie Career Integration Grant, please be certain that this is agreed upon by the respective host organisation Check once more the eligibility criteria described in the call. Remember – the information given in part A is considered definitive and eligibility decisions will be based on it. Please ensure that the information in part A does not contradict that in part B. Is your Part B in portable document format (PDF), including no material in other formats? Is the filename made up of the letters A to Z, and numbers 0 to 9? You should avoid special characters and spaces. Have you printed out your Part B PDF file, to check that it really is the file you intend to submit, and that it is complete, printable and readable? Proposals that cannot be printed will not be evaluated. After the call deadline it will not be possible to replace your Part B file. Double check that you respect the minimum font size and the page limitations for the different sections (if any) given in the Call-Specific Guide. Is your Part B (PDF file) within the size limit of 10 MB? Have you virus-checked your computer? The EPSS will automatically block the submission of any file containing a virus.
The deadline: very important! • • • •
Have you taken the responsibility to submit your proposal? Have you made yourself familiar with the EPSS in good time? Have you allowed time to submit a first version of your proposal well in advance of the deadline (at least several days before), and then to continue to improve it with regular resubmissions? Have you completed the submission process for your latest version?
Following submission • • •
Information submitted to the EPSS remains encrypted until the deadline and can only be viewed by the applicant; It is strongly recommended that you check that all your material has been successfully uploaded and submitted, that you have submitted the correct Part B file and that it is readable and printable, by downloading and printing it; You can revise and resubmit your proposal up to the call deadline.
EUROPEAN COMMISSION RESEARCH EXECUTIVE AGENCY Unit P2 – Marie Curie Actions – International fellowships
Brussels, 17/08/2012 Ares(2012)54288
Alexander Kharlamov Westblaak 92 3012KM Rotterdam Netherlands (NL)
7th Framework Programme – acknowledgement of receipt of proposal Dear co-ordinator Thank you for submitting your proposal
Development of bioresorbable scaffolds and nanotechnologies for reversal of atherosclerosis
under the call FP7-PEOPLE-2012-IIF which has been recorded as having arrived on 15/08/2012 19:23:47 Your proposal has been given the following reference number: Proposal reference number: FP7- 329728
Please make sure that you quote this reference number in all future correspondence related to this proposal. Also make sure that all of your partners are aware of this reference number. Your proposal will be checked for eligibility, including confirmation of the time and date of arrival. All eligible proposals will go forward for evaluation. Guidance on when the Commission will decide on successful proposals for funding can be found in the original call for proposals. You will be notified as soon as possible after this of whether your proposal has been successful or not. Disclaimer: Please note that this acknowledgement of receipt letter may in no way be taken to prejudge the Research Executive Agency's check of eligibility criteria nor the outcome of the evaluation process related to this call for proposals. On behalf of the Research Executive Agency, I would like to thank you for your interest in the 7th Framework Programme.
Yours sincerely, Brito FERREIRA Call Coordinator
Research Executive Agency, B-1049 Brussels, Belgium. Telephone (32-2)299 11 11. Office: COVE2 15/58. Telephone: direct line (32-2)2992388.
Proposal Number
Proposal Acronym
Marie Curie action-code
International Incoming Fellowships (IIF)
Scientific Panel
Life Sciences (LIF)
Duration in months
Keywords (up to 200 characters)
Call identifier
FP7-PEOPLE-2012-IIF
LIF, development of technology, nanomedicine, bioresorbable scaffolds, interventional cardiology, atheroregression, Glagovian threshold, translational research training
Abstract (up to 2000 characters) Reversal of atherogenesis is a holy grail of the state-of-the-art cardiology. We have a unique chance to revolutionize interventional vascular medicine and understanding of natural history of atherosclerosis, improve standards of clinical practice, reconsider international guidelines of treatment, and save millions of lives worldwide. The anticipated breakthroughs arising from this project are: 1) Identification of molecular and cellular mechanisms of bioresorbable scaffold (BRS)-promoted atheroregression; 2) Strategy for optimal use of mTORC1 inhibition in promoting reversal of atherosclerosis; 3) Design transient vessel scaffolding with BRS amenable to biological and pharmacological modulation; 4) Change the clinical paradigm to temporary scaffolding with BRS; 5) Progress in theranostics of atherosclerosis; 6) Unprecedented atheroregression below a Glagovian threshold of 40% with dramatical reduction in major adverse cardiovascular events using nanotechnologies; 7) Development of the close scientific relations with exchange of knowledge and advanced technologies between Western society and countries in Eastern Europe. Research aims with related work packages (WP) are: a) To elucidate the key molecular and cellular mechanisms of atheroregression and atheroprotection by transient scaffolding using mTORC1 inhibition (correspondent to WP1); b) To perform in vivo bench-to-bedside studies relevant to the central research questions (correspondent to WP2); c) To test BRS and adjunctive pharmacological treatment for the reversal of atherogenesis (correspondent to WP3); d) To transfer, examine and optimize technology of the plasmonic photothermic therapy (PPTT) of atherosclerosis (correspondent to WP4); e) To implement BRS to the Russian clinical practice, and develop optimal approach utilizing nanotechnologies (correspondent to WP5 – a "return phase"); f) To synergistically foster translational science, interdisciplinary and international partnerships.
Has a similar proposal been submitted to a Marie Curie Action under this Framework Programme?
IF YES Programme name(s) and year
Proposal number(s)
Does this proposal include any of the sensitive ethical issues detailed in the Research Ethical Issues table of Part B?
If your organisation has already registered for FP7, enter your Participant Identification Code Legal name
Participant Number
ERASMUS UNIVERSITAIR MEDISCH CENTRUM ROTTERDAM
Organisation short name
Internet homepage
Postal Code/Cedex
www.erasmusmc.nl
Certain types of organisations benefit from special conditions under the FP7 participation rules. The Commission also collects data for statistical purposes. The guidance notes will help you complete this section. Please 'tick' the relevant box(es) if your organisation falls into one or more of the following categories Non-profit organisation
Public body
Higher or secondary education establishment
International organisation
International organisation of European Interest
Joint Research Center of the European Commission
Entities composed of one or more legal entities [European Economic no
Interest Group (Unité mixte de recherche) / Enterprise groupings] Commercial Enterprise
Main area of activity (NACE code) 80.3
230 3015CE
1. Is your number of employees smaller than 250? (full time equivalent)
2. Is your annual turnover smaller than € 50 million?
3. Is your annual balance sheet total smaller than € 43 million?
4. Are you an autonomous legal entity?
You are NOT an SME if your answer to question 1 is "NO" and/or your answer to both questions 2 and 3 is "NO". In all other cases, you might conform to the Commission's definition of an SME.
Following this check, do you conform to the Commission's definition of an SME
Person in charge (For the co-ordinator (participant number 1) this person is the one who the Commission will contact in the first instance) Family name
Serruys
Position in the organisation
head of the Department
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Department of Interventional Cardiology
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Ural Institute of Cardiology
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Gabinsky
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Sveshnikova
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Kharlamov
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PROPOSAL: DREAM
EUROPEAN HOST: ERASMUS MC, ROTTERDAM, NL
THIRD COUNTRY HOST: RU
PEOPLE MARIE CURIE ACTIONS
MARIE CURIE INTERNATIONAL INCOMING FELLOWSHIPS (IIF) CALL: FP7-PEOPLE-2012-IIF
PART B IIF MARIE CURIE
FELLOW: ALEXANDER KHARLAMOV
B1. RESEARCH AND TECHNOLOGICAL QUALITY THE STATE-OF-THE-ART AND OBJECTIVES THE STATE-OF-THE-ART IN INTERVENTIONAL CARDIOLOGY 1) Bioresorbable scaffolds – potentially the "fourth revolution" in interventional cardiology Effective prevention of atherosclerosis and the treatment of its complications remain a major clinical challenge. Current percutaneous coronary intervention (PCI) with drug-eluting (DES) stents is associated with delayed healing, late stent thrombosis, abnormal vasomotor function and neoatherosclerosis1, 2. New devices such as the fully bioresorbable scaffolds (BRS) have been tested in only 600 humans. The device scaffolds the diseased coronary vessels and elutes an anti-proliferative drug that counteracts constrictive remodeling, excessive neointimal hyperplasia and delays re-endothelialization. Preclinical studies in the porcine model and clinical ABSORB trial have demonstrated that within 4 years the polymeric struts have totally disappeared - having become completely indiscernible on histology, optical coherence tomography (OCT) and virtual histology intravascular ultrasound (VH-IVUS) - and become fully incorporated into the vessel wall3, Moreover a circumferential evaluation of the healing process by OCT after BRS implantation showed a minimal amount of neointima forming a neocap of 170 μm, which should contribute to plaque stability 4. As observed in the porcine model late lumen enlargement, plaque media reduction (12.7%) with wall thinning were also observed in humans by IVUS3. By comparison, in the most recent study of plaque regression in patients treated with rosuvastatin, the relative percentage reduction in plaque media volume was 8.5% over a period of 2 years 5. Notably within this study vasomotion testing demonstrated restored normal vasodilatory response to acetylcholine within the previously scaffolded area, when necrotic core was absent or minimal. Thus this transient scaffolding technology may introduce the "fourth revolution" in interventional cardiology3, 6. 2) mTORC1 molecular pathways – unresolved mechanistic questions in vascular biology mTOR inhibitors remain the key compound of BRS. Target of rapamycin (TOR) is a key mediator of growth, metabolism, and inflammation. mTOR is part of two distinct multiprotein complexes, mTOR complex 1 (mTORC1), which is sensitive to rapamycin, and mTOR complex 2 (mTORC2), which is not. Preclinical systemic application of mTOR inhibitors decreases atherosclerotic plaque formation in both apolipoprotein E knockout (ApoE-/-) and low-density lipoprotein-receptor knockout (LDL-R-/-) mice7. However systemic mTOR inhibitors also increase plasma triglycerides and LDL cholesterol levels. Most recent findings imply a novel role of mTOR in aging: chronic rapamycin treatment prolongs life span in C. elegans, drosophila and mice. At the molecular level, the following questions related to mTORC1 inhibition remains unanswered: the effects of mTOR inhibitors on vascular healing, foam cell formation, autophagy, cholesterol metabolism and reverse cholesterol transport as well as their effects on vascular aging. 3) The Glagov concept of regression of atherosclerosis – translation to bioresorbable scaffolds in PCI Glagov's observation9 in 1987 suggests that coronary arteries are not inanimate pipes, but dynamic structures that change shape and size to adapt to plaque accumulation and shear stress. This vascular remodeling, maintains the arterial lumen10, up to a plaque burden of 40% to 55% of the external elastic membrane (EEM). Thereafter the lumen becomes compromised due to the inability of the artery to further expand. This limited process of EEM enlargement to accommodate the plaque and maintain the lumen is referred to as the Glagov phenomenon, which appears to be a cornerstone principle of the atheroprotection. 4) Unmet clinical needs related to atheroregression and PCI Our previous bench and bedside findings (ABSORB team, Erasmus MC, Rotterdam, The Netherlands, 60 articles, 2006-2012) support the concept that BRS enhances the natural reversal of the atherosclerosis8. It is unknown whether this 'plaque and media regression' on IVUS is a true atherosclerotic regression, with changes in vessel wall composition and plaque morphology or a pseudo-regression due to bioresorption of the polymeric struts. True atherosclerotic regression can only be assessed when the unresolved mechanistic questions are answered in vitro and in vivo, assuming that mTOR inhibition blocks central pathways in progression of atherosclerosis8. 5) Nanotechnologies - herald "the next revolution" in cardiology?! The reversal of atherogenesis becomes a new attractive target for cardiovascular therapy and coronary device development11. Some clinical trials11 have demonstrated that lowering LDL levels through intensive statin therapy can partially reduce the total atheroma volume (TAV) up to 6.38 mm3. Of note, plaque regression was associated only with a 30% relative reduction in events. By way of comparison, recombinant ApoA-I Milano demonstrated a 14.1 mm3 reduction in TAV. Plasmonic photothermal therapy (PPTT) using near-infrared (NIR) laser irradiation1314 is the novel invasive approach in cardiology, and noble-metal nanoparticles are a new type of optically active composite spherical particles on the nanoscale15. Our previous bench studies PLASMONICS12 documented acceptable level of safety and significant efficacy of PPTT with unprecedented plaque burden reduction up to 79.4 mm3. First-in-man trial of PPTT (NANOM FIM) showed16 the mean TAV reduction at 12 months up to 60.3 mm3.
References 1. Windecker S, et al. Clinical end points in coronary stent trials. Circulation 2007;115(17):2344-51. 2. Nakazawa G, et al. The pathology of neoatherosclerosis in human coronary implants bare-metal and drug-eluting stents. JACC 2011;57(11):1314-22. 3. Serruys PW, et al. A bioabsorbable everolimus-eluting coronary stent system (ABSORB): 2-year outcomes and results from multiple imaging methods. Lancet 2009;373:897-910. 4. Brugaletta S, et al,. Circumferential evaluation of neointima by optical coherence tomography after ABSORB bioresorbable vascular scaffold implantation: can the scaffold cap the plaque? Atherosclerosis 2011[Epub ahead of print]. 5. Nissen SE, et al. Effect of very high-intensity statin therapy on regression of coronary atherosclerosis: the ASTEROID trial. JAMA 2006;295(13):1556-65. 6. Onuma Y, et al. Bioresorbable scaffold: the advent of a new era in percutaneous coronary and peripheral revascularization. Circulation 2011;123(7):779-97. 7. Stein S, Matter CM, et al. SIRT1 decreases Lox-1-mediated foam cell formation in atherogenesis. Eur Heart J 2010;31(18):2301-9. 8. Serruys PW, et al. From metallic cages to transient bioresorbable scaffolds: change a paradigm of coronary revascularization in the upcoming decade? Eur Heart J 2011;33(1):16-25. 9. Glagov S, et al. Compensatory enlargement of human atherosclerotic coronary arteries. NEJM 1987;316(22):1371-5. 10. Korshunov VA, et al. Vascular remodeling: hemodynamic and vascular mechanisms underlying Glagov's phenomenon. Arterioscler Thromb Vasc Biol 2007;27(8):1722-8. 11. Onuma Y, Muramatsu T, Kharlamov A, Serruys PW. Freeling the vessel from metallic cage: what can we achieve with bioresorbable vascular scaffolds? Cardiovasc Interv Ther 2012 [ahead of print]. 12. Kharlamov A, Gabinsky J. Plasmonic nanophotothermal and stem cell therapy of atherosclerotic plaque as the novel tool for angioplasty and artery remodeling. Rejuvenation Research 2012;15(2): 222-230. 13. Tang J, Lobatto ME, Read JC, Mieszawska AJ, Fayad ZA, Mulder WJ. Nanomedical Theranostics in Cardiovascular Disease. Curr Cardiovasc Imaging Rep. 2012 Feb;5(1):19-25. 14. Yu SS, Ortega RA, Reagan BW, McPherson JA, Sung HJ, Giorgio TD. Emerging applications of nanotechnology for the diagnosis and management of vulnerable atherosclerotic plaques. WIREs Nanomed Nanobiotechnol 2011;3:620-646. 15. Lapotko D. Plasmonic nanoparticle-generated photothermal bubbles and their biomedical applications. Nanomedicine (Lond) 2009;4(7):813-845. 16. Kharlamov A, Veselova V, Filatova A, et al. Plasmonic photothermal therapy of flow-limiting atherosclerotic lesions with silica-gold nanoparticles: a first-in-man-study. Lancet 2012;NA;NA. [submitted; under the peer review].
CENTRAL RESEARCH QUESTIONS 1) How do BRS eluting mTORC1 inhibitor pave the way towards atheroregression? 2) What mode of the PPTT of atherosclerosis has the optimal level of feasibility, efficacy and safety for the further clinical development of nanotechnologies? SYNERGISTIC GOALS 1) To reverse the atherogenesis according to Glagov paradigm using BRS/ mTORC1 inhibition and systemic treatment of flow-limiting atherosclerotic plaque. 2) To reduce plaque burden below Glagovian threshold with the use of silica-gold nanoparticles and nearinfrared (NIR) laser technologies for PPTT and imaging of atherosclerosis. 3) To create international research network in order to merge and exchange knowledge, strengthen multinational scientific collaboration, and develop advanced technologies in nanomedicine and colloidal chemistry for purposes of interventional cardiology. ANTICIPATED BREAKTHROUGHS (BEYOND OF THE STATE-OF-THE-ART) 1. Identification of molecular and cellular mechanisms of BRS-promoted atheroregression. 2. Strategy for optimal use of mTORC1 inhibition in promoting reversal of atherosclerosis. 3. Design transient vessel scaffolding with BRS amenable to biological and pharmacological modulation, to allow for the potential reopening of critical arterial stenosis. 4. Change the clinical paradigm from caging the vessel with a permanent metal prosthesis to temporary scaffolding with a BRS and transient drug elution. 5. Progress in theranostics of atherosclerosis using NIR laser with noble metal nanoparticles for imaging, angioplasty and atherodestruction instead of conventional imaging, PCI and coronary artery bypass surgery (CABG). 6. Unprecedented atheroregression below a Glagovian threshold of 40% with dramatical reduction in major adverse cardiovascular events using nanotechnologies. 7. Development of the close scientific relations with exchange of knowledge and advanced technologies between Western society and former soviet countries in Eastern Europe. ADDED VALUE OF THE GROUP
The Synergy Project is scientifically and logistically firmly based in a single host institution, Erasmus Medical Centre, The Netherlands. The Coordinator (Professor Patrick W. Serruys) of the project is amongst the five worldleading experts and innovators in stent technology for CAD. His team and the Thorax Center Rotterdam have a highly successful track record spanning more than three decades. The development of new and innovative technology, including in vivo and ex vivo imaging, is strongly promoted by the fact that engineers and biophysicists are involved in all five work packages, working alongside immunologists, vascular biologists, specialists in nanobiology, colloidal chemistry, and interventional cardiologists. Hence, the Synergy team will join experts from basic and translational sciences to clinical cardiology, thus favoring interdisciplinary and international partnerships and education among participants. RESEARCH AIMS 1. To elucidate the key molecular and cellular mechanisms of atheroregression and atheroprotection by transient scaffolding using mTORC1 inhibition (correspondent to WP1) – with total duration of WP while 24 months; 2. To perform in vivo bench-tobedside studies relevant to the central research question; to test novel imaging tools, scaffolding materials, shear stress, pharmacokinetics and biomarkers supporting effective mTOR1C1 inhibition (correspondent to WP2) – 24 months; 3. To test BRS and adjunctive pharmacological treatment for the reversal of atherogenesis on the basis of the discovered molecular, cellular and tissue mechanisms leading to atheroregression; optimize imaging tools and biomarkers for quantification of atherosclerotic burden and non-invasive monitoring and risk stratification of patients; develop and test novel proof-of-concept technologies; compare/monitor effects of local vs. systemic mTORC1 inhibition in patients (correspondent to WP3) – 36 months. 4. To transfer technology of the plasmonic photothermic therapy (PPTT) of atherosclerosis from Russia to the Netherlands; pre-clinically examine different approaches for delivery of nanoparticles to atheroma in order to test feasibility and safety; optimize the laser mode for theranostics, and features of PPTT in order to further develop nanotechnologies relevant to the real clinical practice (correspondent to WP4) – 30 months. 5. To implement transient scaffolding with BRS and tailored scheme of mTORC1 inhibition to the real clinical practice, and develop optimal approach utilizing nanotechnologies with balanced level of safety and efficacy (correspondent to WP5 – a "return phase") – 12 months. 6. To synergistically foster translational science, interdisciplinary and international partnerships between participants to optimize PCI-based coronary revascularization and corresponding technologies (drug, imaging, scaffolding) with exchange of knowledge and mutual transfer of technologies.
METHODOLOGY The outlined scientific approach is feasible and realistic, and the strong centralization in a single center with multidisciplinary teams having longstanding collaborations will be key to its success. All resources required are present and operational, and some will be further innovated as part of the project (e.g. spectral histology in WP2 and cross-applied in the other two WP). The possibility of a major breakthrough from this project is sufficiently high to justify novel methodology as part of the high-gain/high risk balance. Specifically, this concerns the development of novel drug regimens in conjunction with the BRS. Since mTOR signaling is so central in human physiology, rational and cautious application of systemic mTOR regimens will allow circumventing and controlling side effects. Another crucial target is the development of nanotechnologies with special focus on the testing of the most realistic and feasible approaches. Work package 1 (leader - Prof. J.D. Laman): Molecular mechanisms. PART B IIF MARIE CURIE
Goals for WP1: (1) Assess mechanisms by which BRS-everolimus affects macrophage and foam cell innate immunity; (2) Determine pathways by which BRS-everolimus acts on dendritic cells to change adaptive immunity; (3) Assess the mechanisms by which BRS-everolimus affects endothelial repair; (4) Determine whether shear stress levels and its molecular pathways control BRS-everolimus plaque regression; (5) Identify vascular cell specific markers associated with progression and regression of intimal thickening in relation to scar maturation and shear stress regulation, including exercise; (6) Assess molecular mechanisms by which mTORC1 inhibition decreases foam cell formation, delays vascular aging, and promotes endothelial regeneration. These 6 complementary goals are addressed in parallel in close collaboration of the groups involved in WP 1, to optimally benefit from the operational distinct technologies and models. In addition, groups contribute to activities of another WP, promoting efficient cross flow of expertise between work packages. Methodology of WP1: Task 1: Human macrophages as well as mouse and Watanabe rabbit models will be employed to identify functional macrophage and foam cell subsets in response to mTORC1 inhibition. Inibition of autophagy by targeting mTOR and cholesterol transport will be investigated, using autophagy deficient mice. Adaptive immune function for memory T-cell responses by macrophages and foam cells will be addressed in conjunction with WP2. Task 2: Dendritic cell activation by BRS-everolimus and subsequent development of functional T helper cell subsets will be addressed in vitro, and in vivo by means of a murine vulnerable plaque model. Plaque and vessel wall composition upon DC exposure to BRS will also be addressed in the Watanabe rabbit. Task 3: Using in vitro assays in conjunction with the Watanabe rabbit model, effects of mTORC1 inhibition on proliferation, endothelial cell differentiation, vessel formation and sprouting will be assessed. Laser capture of endothelial cells and genome wide transcriptomic screen will be used to identify new molecular mechanisms. Task 4: In vitro, human endothelial cells will be exposed to different levels of shear stress and BRS-everolimus. Readouts include micro-array and ROS detection. In vivo, a flow-altering cast generating differential shear stress in the mouse aorta will be used with local and systemic everolimus application. Task 5: Stents will be implanted in healthy and diseased porcine coronary arteries. Neointimal growth will be imaged longitudinally using the imaging suite described in WP2. Upon several time points prior to and following intimal regression, animals will be sacrificed to study the vasculature by routine and spectral histology (WP2). Microarray technology will be used to address mRNA and microRNA profiles of these subsets. Task 6: Employing cultured cells, mice and sorted human peripheral blood monocytic cells, inhibition of mTORC1 will be addressed with respect to inflammation, lipid metabolism, vascular aging and regeneration, with focus on selected signaling pathways. Work package 2 (leader - Prof. van der Steen): Biomedical engineering. This work package focuses on the interaction between the intervention, the drug, metabolism of carrier and drug, shear stress including modulation by tailored exercise, and artery wall pathology. It addresses the core question: Which mechanisms — physiological and systemic, as well as the cellular and molecular as studied in WP1 — promote atheroregression, and how can these mechanisms be exploited for patient-specific, tailored therapy? Goals for WP2: (1) Understanding the relation between pharmacokinetics, carrier degradation, drug metabolism and vascular response to the intervention; (2) Developing new technologies for tissue characterization analysis for (multi-modality) intravascular imaging; (3) Developing a validated numerical models of stent degradation, drug elution and drug distribution; (4) Optimize PCI strategies based on in vivo imaging and 3D patient specific modeling. Methodology of WP2: Central to this WP is an intervention study in a large-animal model of coronary atherosclerosis. The animals undergo PCI with bioresorbable scaffold (BRS) implantation and a subsequent tailored exercise program. We employ a multimodality in vivo imaging suite including Lipiscan, IVUS, OCT and FFR at several time points pre- and post-intervention. This study translates the findings of WP1 to a context of systemic disease, modulated by a tailored exercise program, and will translate to mechanism for inducing regression of atherosclerosis in patients. The WP is partitioned into three tasks, studying (1) where does the eluted drug go; (2) how does BRS interact with the vascular biology; and (3) how can we image this process for improved therapeutic interventions?. Task 1: Spectral histology (MS-Imaging) will be used to localize and quantify drug and scaffold material (including metabolites) in histological sections. This enables correlation between intravascular imaging, plaque pathology (lipids, reactive oxygen species, inflammation) and scaffold/drug distribution and metabolism. It also enables the determination of the spatial distribution of the biomarkers as studied in the different wp1 tasks, This data will be used as input for numerical modelling and optical (in vivo) tissue characterization. Task 2: Using data and numerical models developed in task 1 we will study how drug and scaffold metabolism affect vascular healing and atheroma regression. A tailored exercise program will be implemented to further modulate the two main phases of plaque regression: fibrous tissue development (neointima regression) and lipid
efflux (atheroma regression). This will be studied longitudinally by invasive and non-invasive imaging. The role of lipid modulation by mTOR inhibitors and exercise will be monitored. Task 3: Data sets from task 1 and 2, we will be integrated to cross-reference tissue characterization analysis to (multi-modality) intravascular imaging. Understanding the vascular response to drug and scaffold metabolism, and being able to characterize the lesion through validated imaging techniques will allow a tailored therapy for specific lesion types, yielding a PCI strategy optimization tool based on 3D patient specific modeling and in vivo imaging. Work package 3 (leader - Prof. Serruys): Human intervention. This work package aims to analyze the completed and ongoing BRS trials to unravel the leading reversal mechanism with focus on mechanic and biologic response of the vessel wall to BRS/ mTOR inhibitor implantation in human, and to test newly developed transient scaffolding product, local and systemic multi-target treatment and imaging on the basis of earlier discovered (WP1 and WP2) pathology mechanisms in new human trials in order to ultimately reverse the atherogenesis in humans. Goals for WP3: (1) To analyze the previous experience and perform meta-analysis of the BRS/ mTOR inhibition trials; (2) To analyze mechanic and biologic response to shear stress with advanced imaging for assessment of vessel architecture, inflammation, plaque burden, dynamics of the vessel remodeling, and available biomarkers in patients with BRS implantation; (3) To analyze why BRS is superior to metal stent with validation of the optimal dosage, drug elution, main effects and duration of mTOR inhibition with verification of pharmacodynamics and – kinetics; (4) To test and validate existing and novel imaging technologies, supporting the identification of the main working mechanisms of atheroregression as determined in WP2.3; Methodology of WP3: We will conduct serial observational and clinical randomized trials in parallel and sequential designs based on results of completed and ongoing BRS trials as well as discovered working mechanisms and novel products for atheroregression: 1) Observational Retrospective Study and meta-analysis of eight BRS studies – subjects will be stratified and taken in the statistical multi-variate handling, and main parameters of artery remodeling, clinical outcomes with probable prospective examination by advanced imaging technologies will be analyzed; 2) Clinical Randomized Trials (CRT) – serial CRT will be performed in patients with one or two vessel disease, who will be allocated in comparative trials of BRS platform (n=110) vs everolimus DES (EES) (n=110), with multi-factorial analysis of standard (conventional) vs advanced therapy. Task 1: We will perform a number of studies in order to clarify efficacy and safety of the main lipid modulation therapy: advanced therapy with concomitant mTOR inhibition and conventional administration of rosuvastatin; conventional prescription of LpLPA2 inhibitors (oral darapladib), standard administration of CETP inhibitor dalcetrapib; selected new developed substances as a standard therapy in coming years (PCSK9 inhibitors and antibodies, monoclonal antibodies against oxLDL, ApoA1-Milano), which are relevant to the explored targets in the working mechanisms of the scaffolding-mediated atheroregression. Task 2: Human studies of shear stress will be performed. Shear stress will be calculated using finite element modeling based on 3D reconstruction as can be obtained using a combination of non-invasive imaging and catheter-based devices and doppler flow measurements. Available biomarkers relevant to endothelial function, including ROS will be used when analyzing the results. Conditioning of the shear stress with tailored physical training in patients with intact vessels and flow limiting lesions, blood pressure, and diabetes mellitus will be performed. Work package 4 (leader - Prof. Serruys): Nanomedicine. This work package aims to analyze our previous achievements in the development of nanotechnologies and preclinically test the most realistic and feasible approaches with optimal level of safety and efficacy for the further implementation in the real clinical practice. Goals for WP4: (1) To optimize the technology that uses noble-metal nanoparticles and stem cells for PPTT and theranostics of atherosclerosis with testing of feasibility in the series of pre-clinical studies; (2) To perform bench studies of the main technology in order to examine safety of the PPTT. Methodology of WP4: Task 1: We will perform some animal studies in order to optimize and test feasibility of the existing technology (nanoparticles and carrier cells (SCs and macrophages) for PPTT and imaging of atherosclerosis. a) Synthesis of composite NP with silica-gold core and/ or silica-graphene-polymeric shell; assessment their chemical, physical and cell-biological properties, including stability in biological media and uptake by cells. b) Recovery, purification, culturing and profiling of stem cells, monocytes, and macrophages with verification of migrative, paracrine, metabolic and differentiative properties. c) Modulating composite NP accumulation in the carrier cells with analysis of nano(cyto)toxicity impact, differentiation potential, activity state and phagocytotic capacity.
d) Modulating PPTT in vitro and in vivo (animal studies with swines or rabbits) for assessment and confirmation of the direct destructive effect in tissue (size of destruction and behavior of NP while nanodetonation and afterwards). e) Adaptation of existing (OCT, IVUS) and development of novel technology (photo-acoustics) to measure and track NP in atherosclerotic vessels. f) Technology development of InfraredX IVUS - Lipiscan with both NIR scanner for spectrometry of the vessel wall, and NIR high-energy laser for nanodetonation. g) Scaffolding of the few-layers low-vascularized bioengineered structure with bovine decellularized and polymeric platforms to develop an optimal generation approach and clarify a time for a growing process potentially for clinical development of CABG. h) Developing targeted NP on the basis of targets obtained from microarray studies of a unique atherosclerotic mouse model with in-house developed antibodies. Task 2: To perform bench studies of the main technology in order to test safety and efficacy of the technology for the further clinical development. a) Optimizing existing animal models of atherosclerosis in small and large animals. b) To screen newly developed targeted NP in a unique mouse plaque model for their effect to target macrophage subsets, followed by NIR study to modify the M1/M2 balance in vulnerable and stable plaques. c) Verification of InfraRedX IVUS, OCT, photo-acoustics, MRI features in pigs and rabbits for a subsequent development of this technology for objectives of interventional cardiology. d) Modulation of PPTA (as preclinical study) with different NIR laser modes and concentration of NP in atherosclerotic pig or rabbit models with the use of catheter-based micro-injection of NP to the plaque or open heart surgery transplantation of the grown bioengineered patch on targeted artery under the IVUS follow-up (in comparison with stenting control) with monitoring its effect on plaque stability, rupture and rupture-related thrombosis, distal atheroembolism, total atheroma volume, degradation of adventitia, total lumen volume, total vessel volume, plaque composition, apoptosis, inflammation, neovascularization immune-staining assessment with special focus on complications, including major cardiovascular events, and mortality. e) Assessment of the nano(cyto)toxic effects of PPTT, underlying nanokinetics and nanodynamics parameters, distribution and accumulation of NP in the entire body with profiling of in situ oxidative stress, proapoptotic, pro-fibrotic, pro-inflammative potentials and influence on platelet activity. f) Supporting the vessel wall against necrosis and destructive processes with stem cells (iPS, MSCs) to promote the restoration of the artery wall after the intervention and rejuvenation of artery, clarifying mechanisms of the vascular repair with transplanted, resident and circulating stem and progenitor cells. g) Preparation of a phase-I clinical trial with detection of the main eligibility criteria and an optimal clinical strategy model for an intervention. Work package 5 (leader – Prof. Gabinsky): Implementation to the real clinical practice (a "return phase"). This work package aims to implement received knowledge and experience in the bench and bedside science to the scientific methodology and clinical practice in Russia. We would like to follow this research project in Russia in the close collaboration with the Netherlands, and launch the clinical use of BRS for transient scaffolding of artery as well as utilize nanotechnologies for theranostics of atherosclerosis in humans. Goals for WP5: (1) To test new developed BRS and study the response of the treated vessel wall to studied drugs, and tailored exercise in analogy to WP2.2; (2) To assess safety and efficacy of systemic short- and long-term mTOR-inhibition in BRS-treated patients with ACS; (3) To conduct pre-clinical studies in order to verify efficacy and translational parameters of PPTT for the further development in interventional cardiology; (4) To launch firstin-man trial with optimized nanotechnology for atherodestruction. Methodology of WP5: Task 1: We will conduct human studies with systemic and local mTOR inhibitor treatment. Blood samples will be collected from the patients at coinciding timepoints of micro-OCT and molecular spectroscopy evaluation. Blood analysis by flow cytometry will be conducted to assess the composition of the mono-nuclear cell fraction including functional macrophage subsets. Blood serum will be evaluated for CD4-Th1 and CD4-Treg specific cytokine profiles. The pilot or CRT studies with acute and chronic administration of everolimus will be used with main focus on vascular remodeling, shear stress, vulnerability of plaque and immune response, pharmacokinetics as well as safety of the long-term mTOR inhibition. Task 2: Series of human studies will be performed with the main focus on repair response and following developments: (a) new drug inside the BRS backbone or in coating; (b) new drug for systemic mTOR inhibitor treatment or locally with conventional therapy by LpLPA2 inhibitor and rosuvastatin; (c) new design of device – modified and improved BRS with nanotechnologies; (d) new imaging; (e) endothelial progenitor cells and repair response – advanced imaging technologies, flow cytometry and sorting of circulating stem-progenitors cells with molecular profiling. Mitochondrial function will be indirectly assessed by reactive oxygen species analyses.
Task 3: To conduct a phase-I multi-center pilot clinical studies and primary clinical development of PPTA and regenerative therapy of arteries. Clarification of the short- and long-term PPTA clinical efficacy, including analysis of total atheroma volume, total vessel volume, lumen volume, restenosis, plaque composition, and other interventional-related markers of the impact on plaque, conducting phase-I multi-center trial for the further clinical development. Task 4. Assessment of the PPTA impact on the vessel functions immediately after the intervention and during follow-up. Verification of the short- and long-term influence on safety of PPTA, including all-cause mortality, major cardiovascular events (MACE), readmission rate, acute 'fatal' on-site thrombosis, and TIMI dynamics. Task 5. Characterization of nano(cyto)toxic effects throughout the body including the organ function and clinical follow-up of blood, liver, spleen, heart, brain, bone marrow, etc. Confirmation of the delivery techniques with catheter-based approach implying intramural and transmural micro-injection of NP into the plaque or in perivascular tissues under the IVUS follow-up/ open heart surgery transplantation of the grown bioengineered patch on targeted artery, and NIR nanodetonation from out-of-the-body with transcutaneous laser irradiation or invasively with percutaneous catheter-related activation for patients with PCI indications in comparison with sirolimus DES stenting control with monitoring its effect on the plaque. In conclusion, the scientific and medical advancement provided by the current Synergy project is a true and concrete revolution in clinical practice, replacing metallic stents by BRS/drug combinations or nanotechnologies, based on a mechanistic understanding of the underlying biology and physics.
QUALITY OF HOST RESEARCH Erasmus MC is active worldwide in the fields of patient care, research and education. International collaboration is a precondition for achieving our strategic ambitions. Collaboration can take many forms: from medical student exchange programs to research consortiums in which labs around the world consolidate their strengths. Erasmus MC's position in the world also means that foreign students and employees feel welcome here. This is a brief overview of the main focus areas of Erasmus MC's internationalization policy, of which more details can be found on these international pages (http://www.erasmusmc.nl/internationalization/?lang=en). The International Office is the physical location from which support services are offered. The following excerpts have been taken from Erasmus University Rotterdam's strategic document, Erasmus 2013: 1) New groups of students are signing up; 2) Different nationalities; 3) International mobility. Over the coming years, EUR intends to invest heavily in internationalization for both students and staff. Where possible, Erasmus MC will liaise and cooperate closely with EUR. With regard to an active core internationalization policy, Erasmus MC particularly focuses on areas that are best suited for long-term programs and where short-term opportunism, important for departments, is less evident. To this end, Erasmus MC is especially active outside Europe and the US, where the departments themselves need no extra help in highlighting the opportunities. The Thoraxcenter of the Erasmus MC (http://www.erasmusmc.nl/thoraxcentrum/?lang=en) was founded in 1971 and is an integrated organization of the Cardiology and Cardiothoracic Surgery departments. The head of the Cardiology department is Prof. Dr. F. Zijlstra. The Thoraxcenter is divided into six medical units and three scientific units. The Thoraxcenter wants to stand out both nationally and internationally by the continuous promotion of the quality of patient care, scientific research and education in the field of cardiology and cardiothoracic surgery. The Thoraxcenter is often the birthplace of great modernization and innovations in the field of cardiology and cardiothoracic surgery. Doing scientific research, next to patient care and education, is a core task of the Thoraxcenter. The research focuses in particular on a better understanding of the functioning of the heart and the circulation and direct improvement in patient care (prevention, diagnosis and treatment). The Thoraxcenter among other things carries out research into congenital heart diseases, atherosclerosis and coronary heart disease, heart failure and heart rhythm disorders and into medical technology, advanced catheter technology and cardiac imaging (echocardiography). The Thoraxcenter has three scientific units where fundamental research is carried out from which the bridge is laid to patient-related research: Experimental Cardiology, Biomedical Engineering, Clinical Epidemiology. The Department of Biomedical Engineering is pioneering development of nanotechnologies since 2009. The Department of Interventional Cardiology and Prof. Patrick Serruys are the leaders in the clinical studies of BRS. Extensive research is also carried out in the clinical units of the Thoraxcenter. New research is being set up regarding improved peri-procedural support for heart surgery and interventional cardiology, in cooperation with anesthesia and intensive care. Part of the large-scale (multicenter) clinical research, led by staff from the Thoraxcenter, is co-ordinated by the independent organization for clinical trials: Cardialysis B.V. (Rotterdam, The Netherlands). Interventional cardiology focuses on investigation into and treatment of coronary heart disease. The clinical activities of this department consist of carrying out heart catheterizations, angiograms and intracoronary interventions. The department also carries out pacemaker implants and replacements and takes biopsies for heart PART B IIF MARIE CURIE
transplant patients. This unit has the use of four intervention rooms and a magnetic navigation room and consists of two parts: electrophysiology and heart catheterization. The heart catheterization team treats patients using dottering and stent implants. Around 30 people work here. The team is led by Prof. Dr. Patrick W. Serruys. The interventional cardiology unit is very innovative. For example, this unit, the second in Europe, has a magnetic navigation room. Many new techniques are used and the unit plays a very important part in the care of patients with acute myocardial infarction.
QUALITY OF THE SCIENTIST IN CHARGE Scientist in charge is Prof. Dr. Patrick W. Serruys with respected h-index - 111, a head of the Department of Interventional Cardiology, Erasmus MC, Rotterdam, The Netherlands. Patrick W. Serruys is Professor of Interventional Cardiology at the Interuniversity Cardiological Institute of the Netherlands (1988-1998), and the Erasmus University. Since 1980 he has been Director of the Clinical Research Program of the Catheterization Laboratory, Thoraxcenter, Erasmus University, Rotterdam, The Netherlands and since 1997 the Head of the Interventional Department, Heart Center Rotterdam. He is a Fellow of the American College of Cardiology and a Fellow of the European Society of Cardiology and scientific council of the International College of Angiology. He is the author or coauthor of over 1600 papers and editor or coeditor of 37 books, and a member of 20 Editorial Boards of Scientific Journals. Dr. Serruys received the M.D. degree (1972) from the Catholic University of Louvain, Louvain, Belgium and his PhD degree (1986) from the Erasmus University, Rotterdam, The Netherlands. He has been associate editor of Circulation for Europe for five years and he co-edited the Textbook of Cardiology of the European Society of Cardiology. In 1996 he received the TCT Career Achievement Award and in 1997 he was awarded the Wenkebach Prize of the Dutch Heart Foundation. In 2000 he was awarded the Gruentzig Award of the European Society of Cardiology. In 2001 he held the Paul Dudley White Lecture at the American Heart Association in the USA. In 2004 he received the Andreas Gruentzig Award of the Swiss Society of Cardiology. In 2005 he held the 4th International Lecture at the AHA and Mikamo Lecture at the Japanese heart Association. In 2006 he received the highest award of the Clinical Council of the American Heart Association: the James Herrick Award. In 2007 he received the Arrigo Recordati International Prize (Italy) and the ICI Achievement Award (bestowed by the President of Israel – Shimon Perez). In 2008 he received the Einthoven Penning (Leiden). In 2009 he became Doctor Honoris Causa from the University of Athens. In 2011 he received the Lifetime Achievement Award, bestowed by the American College of Cardiology, in recognition of many years of service and invaluable contributions to the ACC. At the end of 2011 Dr. Serruys received the Ray C. Fish Award, bestowed by the Texas Heart Institute, for outstanding achievement and contribution to cardiovascular medicine, Golden Medal of the European Society of Cardiology 2012. The group of Prof. Serruys first in the world pioneered studies of bioresorbable scaffolds (BRS) that have been tested in almost 1000 humans (BVS – bioresorbable vascular scaffold, Abbott Vascular, Santa Clara, CA, USA). These devices scaffold the diseased coronary artery and elute an anti-proliferative drug that counteracts constrictive remodeling, and excessive neointimal hyperplasia. BRS technologies have been tested in some clinical studies (see fig. 1). The pioneering experimental studies using a non-biodegradable polyethylene-terephthalate braided mesh stents in porcine animal models were published by our group in 1992. The first two publications on BVS eluting everolimus in patients (ABSORB trial - a BioABSORBable Everolimuseluting Coronary Stent System) have reported seminal observations made respectively at 6-month and 2-year follow-up: a) a complete resorption documented by optical coherence tomography (OCT), intravascular ultrasound (IVUS) grey scale and IVUS radiofrequency backscattering; b) physiologically or pharmacologically induced restoration of vasomotion in the scaffolded area; c) late luminal enlargement with plaque/ media regression documented by IVUS and OCT between 6 and 24 month follow up. Our previous bench and bedside findings (ABSORB publication compendium, Erasmus University Medical Center Library, Rotterdam, The Netherlands, 60 articles, 2006-2012). The group of Prof. Serruys is one of the leading groups in the research of the coronary devices, stent and scaffolds utilizing nanotechnologies. The Focus NP (Envision Pvt. Ltd., Surat, India) platform, one of the first tested nanostents, bears a novel carrier which is a phospholipid bilayer nanoparticle that encapsulates sirolimus. The drug content of the nanocarrier sirolimus DES+balloon (108 μg of drug on a 3.0x16 mm stent), and the catheter standalone sirolimus-eluting balloon (180 μg of drug on a 3.0 x 15 mm balloon), is comparable to the drug load of Cypher sirolimus-eluting stent (153 μg of drug on a 3.0x18 mm stent). A compatible technology of manufacturing a controlled porosity stent with utilization of three technologies (nanofilm, microporous stent or scaffold, microporous hydroxyapatite, polymer-free lipid-based drug eluting) is under development, pre-clinical and clinical studies in collaboration with our team at Medtronic Vascular Inc. (Santa Rosa, CA, USA), Translumina (YUKON Choice stent; Hechingen, Germany), Biosensors International Ltd (BioFreedom; Singapore), and MIV Therapeutics, Inc. (VESTAsync; Atlanta, U.S.), CID S.r.l. (Optima stent; Saluggia, Italy).
B2. TRANSFER OF KNOWLEDGE In our current knowledge-driven translational synergistic project, knowledge transfer focuses on the transfer of ideas, research methodology, research results and skills between research organizations in Europe and Russia. Knowledge transfer is about using research knowledge to stimulate people to think or act differently, which have very high impact on the strategy and development of technologies in the current clinical practice. The effective transfer of technology is vital in order to inform, influence decision-making, market, technology and policy development. OBJECTIVES FOR TRANSFER OF KNOWLEDGE: 1) To synergistically address disengagement between researchers of the different specialties, decision-makers and demands of patients in Europe and Russia exchanging knowledge between countries and forcing international collaboration in the field of the research and development of BRS as well as nanomedicine; 2) To bridge the gap between those who produce the knowledge and information (researchers possessing knowledge about nanotechnologies in Russia, or researchers who have broad experience with bioresorbable scaffolds in The Netherlands) and those who are in a position to put it to use (physicians and researchers with advanced facility in Europe for the further development of nanomedicine, or physicians and researchers expecting implementation of BRS to the real clinical practice in Russia); 3) To facilitate the dissemination of Russian knowledge, expertise (methodology) and skills in the field of the PPTT of atherosclerosis with theranostic utilization of noble-metal nanoparticles and near-infrared light as the relatively novel approach in cardiology for Europe; 4) To communicate the Dutch science of the transient scaffolding of arteries with BRS as an alternative to the conventional coronary artery devices such as drug-eluting stents to target groups in Russia and promote its use in the wider management, policy and scientific communities to influence the debate and action on issues relevant to the impacts of the diagnostics and treatment of atherosclerosis with BRS on morbidity and mortality of the targeted deceased population. 5) To provide solution-based actionable scientific information with methodology and raw data of the previous preclinical and clinical studies of PPTT in Russia to the research team, including bench and clinical researchers in Erasmus MC; 6) To deliver messages in a highly-scientific way that utilizes a range of appropriate methods for the research and clinical development of transient scaffolding of arteries as well as nanotechnologies; 7) To understand the difference in epidemiology of cardiovascular disease in Europe and Russia, and needs of market and population in the field of the coronary artery device development and invasive treatment of atherosclerosis; 8) To provide timely information (information must be targeted to the right people at the right time); 9) To transfer knowledge and technology within the network between Erasmus MC and UIC. Within generating network knowledge transfer can only be achieved through a two way process of transmission and exchange. Promotion and exchange of information within the project will promote collaborative efforts and facilitate in the transfer of knowledge externally. A number of activities are in place to facilitate internal communication and exchange of knowledge as the following: conferences, web discussion forums, workshops, email exchange, exchange of hardcopy data, training with exchange of the research skills and methodology. 10) To facilitate exchange between researchers and the policy community. Knowledge could be effectively transferred through collaborative partnerships and engagement with decision-makers. The project facilitates exchange of knowledge and interaction between its scientists and decision-makers through participation in worldwide meetings, workshops, and working groups. Such events will facilitate the transfer of the knowledge directly to the scientific and clinical community. The research team in Erasmus MC will facilitate the use of BRS and PPTT science to influence European and global decision-making and research development in theranostics of atherosclerosis, management of artery remodeling and vascular reparative therapy. Russia possesses quite unique data of the nanotechnology utilization with unprecedented reduction of plaque burden below so called Glagovian threshold (see Russian experience in table 1). The transfer of this knowledge (exchange of the raw data – essential and primary documentation of studies, expertise of the imaging analysis in a CoreLab of Erasmus MC, exchange of methodology and training to scientific skills) from Russia to Europe is able to give a new chance for the further development of this technology for the needs of the real clinical practice and can potentially revolutionize cardiology becoming an alternative to the well-known conventional methods such as stenting or coronary artery bypass surgery. The exchange of knowledge in case of the BRS development and new coronary artery devices (exchange of the hardcopy information, cooperative participation at the pre-clinical and clinical studies) may accelerate the progress of the abovementioned technology, dramatically enhance the efficacy, and reduce complication rate as well as mortality in patients with coronary artery disease. PART B IIF MARIE CURIE
The access to these data and methodology of nanotechnologies is limited by the Russian government. The only way to transfer this knowledge and technology from Russia to Europe is to invite a Russian researcher to the Netherlands in order to exchange knowledge and launch a project in Europe and/ or other parties of the Western scientific community. Moreover, our project has the aim to transfer knowledge of the clinical application of BRS in Russia. Abbott Vascular will launch a project of the clinical implementation of BRS in the Russian clinical practice in December, 2012. Unfortunately, Russian clinicians do not have any real experience with biodegradable devices. Mutual exchange of the knowledge and technology between our institutes, particularly between the key Russian cardiologist Prof. Gabinsky and global leading expert in interventional cardiology Prof. Patrick Serruys, will help to the development of coronary devices and improve the standards of Health Care. Table 1: Ongoing Russian pre-clinical and clinical studies of plasmonic nanotheranostics in the management of atherosclerosis considered for transfer of knowledge and technology. Title/ name of the study Clinicaltrials.gov
Ethical committee
Date of launch Date of completion Status
Intravascular Imaging Protocol was approved by the Texas University at Austin (Austin, Texas, the U.S.) 2009-2010
PLASMONICS
NANOM FIM
NANOM PCI
Protocol approved by the Senate of the Ural State Medical Academy (Yekaterinburg, Russia) Sep, 2004
NANOM CABG -
Ural Institute of Cardiology (Yekaterinburg, Russia)
NANOPLASTY
ANGIOBLASTY
NANODREAM#
Running, not recruiting/ follow-up
Not started yet
Department of Biomedical Engineering, The University of Texas at Austin (Austin, Texas)
Ural State Medical Academy (Yekaterinburg, Russia)
Randomized single-blind two arms clinical trial, n=60 (patients with SYNTAX score 22)
Randomized single-blind two arms clinical trial, n=60 (patients with SYNTAX score
Report "guide for applicants"


text:
'Connectomics' provide a map of the wonder that is the brain
By Abigail Prendergast Apr 8, 2012 in Science
The human brain is a highly complex piece of biological human architecture. With a field of study known as "connectomics," scientists hope to decipher the synapses and ultimately the overall makeup of the mind and possibly the source of mental diseases.
Professor of MIT's Department of Brain and Cognitive Sciences, Sebastian Seung, was never classically trained in neuroscience, but is now a first-year professor in said field. His work delves into a concept known as connectomics, which is "the mapping and study of neural networks," says Wired.
In his book, entitled Connectome, Seung explores the idea that brain cells develop their distinct personalities by the other neurons they communicate with.
Connectomics, for the most part, maps the neural network of the brain by looking at a person's chunk of gray matter through an electron microscope, but is a lethargic process as the cells and their synapses have to be examined manually. In fact it took 12 years for scientists to map the associations in a tiny worm's minimal set of 300 neurons. The human brain has quite a bit more brain cells than that, closer to 100 billion of them. In order to accelerate the process, Seung started developing "computer-vision algorithms" that locate various borders between each neuron.
In an April 2011 article from Reuters, an explanation of connectomics was given comparing it to genomics to some degree. The latter pretty much lays out our genetic make-up, where as the former creates a layout of the brain cells connections.
With this in mind, scientists hope that by pinpointing various flaws in these synapses, that they can discover the causes for cognitive diseases such as schizophrenia, stroke and Alzheimer's Disease.
More about Computers, Brain, Mapping, cognitive
Computers Brain Mapping cognitive

redpajama_set_name: RedPajamaCommonCrawl


Unravelling: "I Make Nice Things"
Corresponding with Cally propelled me to behave more weavery, (shouldn't it be weaverly?) not quite all the way to the loom bench, but: a) in reminding me of an idea I've really wanted to work on, with tied weave of some sort, and the idea came more developed than when I left it on the back burner; b) in making me realize I was actually sick of not weaving; and c) in making me work on the pop-up store some more. Even though just four days ago I wasn't feeling it, handling my stuff was nice. As well, I saw one of my wobbly-selvedge culprits; a pale green, (one I call "lime sherbet",) in spite of the label, may have been be thicker or fulled differently from other 2/26s, although this discovery is far from "solving" my technical problems.
But my cashmeres felt bloody marvelous.
I've been thinking of Pop-Up since I was in Japan in Feb last year. It's a lot of work, (oh, dear me!) but I enjoy the direct interaction with prospective customers. I can sure use some income, and let's face it, being remunerated is one way of validating one's work, and if your work represents your person, then your life, in these modern times.
Early April, Mrs Cady had a significant birthday at the end of their holiday. Dr Cady had hinted it would be fun if we could fly up to the North Island to celebrate. It was a lovely invite, but also expensive; Ben couldn't go but I dithered. I couldn't justify the cost, but I wanted to go because of an exhibition in Auckland, because I'd been so stuck in my making and cities do me good, and I wanted to take part in a significant birthday when normally the Cadys would be surrounded by their many friends and family. So I went. And had a great time.
I tried to suss out Ben's opinion on this new plan, and for the first time he expressed concerns with the expense. I never imagined there was anything we don't talk about whenever, and I thought he'd become such a home body he gave up travelling. Not so. It was the money, and my lack of income, (how embarrasing!), his dental work, our increasing medical bills, and rising cost of living.
Then someone reminded me of van Gogh and the Seasons, not in Japan but in Melbourne!
We haven't had a holiday together since 2003 in Scotland and Ireland. We have been to Japan several times together but they involved family illnesses/death so we only had a day here and there. We've been on one or two road trips in New Zealand but they were all connected to my attending workshops, so Ben was on his own during the day.
So we bit the bullet and decided to have a week in Melbourne.
Melbourne is one heck of an attractive city, beautiful, full of places of foody interest, with the CBD/downtown area relatively small and easy to get around either on foot or by public transport. I am drawing a list of art and craft supply shops; Ben, of coffee equipment shops, and both of us specialty bookshops. And our accommodation is near many theaters, I would so love to squeeze in a play. But our main goal is always walking around town, looking at architecture, stopping to refuel, and this trip, Ben will take pictures but I may try some drawing/sketching. And meet up with two sets of friends. Oh, we can't stop talking about Melbourne. And a proper holiday.
I would still like to go to Japan Oct/Nov if at all possible, but we'll play that by ear. There is also a good chance of a road trip down south in November. Ergo, the Pop-Up sales.
And here are some raw, (not in RAW format, but untreated,) pics from today. I'm so out of practice, I had to relearn a few things. Aside from the selvedge, though, I do make nice things, even if there is always room for improvement.
Nowhere in my house makes a good backdrop, but the entrance hallway gets good light in the late morning/early afternoon. I practiced using different white balance settings to capture the truest colors of the pieces. Except colors on the camera's LCD panel are quite different colors from those on the laptop, so... there we have it.
I have four red pieces, the hardest color to capture.
After 2-ish/3-ish only harsh light comes in from the living room.
But I liked the dark/light photos today. I might experiment more of this style for detail/moody shots.
A self-portrait of my thumb.
I read every word, Meg. Always a pleasure. You make me think. No fluff here.
See what I mean about lack of inspiration?
Jade suggested "Caressable " and I'm ever so partial to that for now!
Caressable is an excellent suggestion.
I went ahead with it. Hee hee.


text:
Q: Spring Boot - Gradle - Eclipse project I am new to SpringBoot and trying to build a basic hello world application with SpringBoot and gradle in eclipse.
In eclipse, when I create a gradle project , it adds src/main/java folder but I don't see a src/main/resources folder. is this something that needs to be added manually or do I need to change some setting to get the folder structure created? I am trying to create a simple JSP and need the web-inf and properties folders for it.

A: Use https://start.spring.io/  to create your Spring boot project , This will generate proper folder structure

A: Assuming that ur trying to build one spring boot application from scratch. You dont really need to do build one from scratch when srping provides spring boot boiler plate which is very handy and easy to use. https://start.spring.io/
Few things you need to know when ur starting a spring boot project. 1.application.properties file contains all the configuration related date.Wondering how to read this property from java class below code can help
Java class
@Configuration
public class JMSSQSConfig {
@Value("${queue.endpoint}")
private String endpoint;

application.properties file
#AWS Endpoint
queue.endpoint=https://sqs.us-west-2.amazonaws.com/

Now spring boot reads this value dynamically from application.properties file.
Above link also provides you the way u want to build ur project gradle/maveen.
Above boiler plate has testing frame work assosiated with it too.. It just makes work easy.
Check this link https://spring.io/guides/gs/spring-boot/

redpajama_set_name: RedPajamaStackExchange


This is a work-in-progress as I figure out what are the necessary steps one has to take to go from a scratch installation of Ubuntu (or Kubuntu, or Xubuntu) to a building environment for source packages of hugin and its related tools (autopano-sift-c, libpano13, enblend). This has been tested in Kubuntu Edgy Eft and Feisty Fawn, but of course no installation is ever the same and I would welcome your comments as to what packages you had to install, or what error messages you are facing.
Hugin is a very versatile software to merge different photos into panoramas. It is open source and its development is quite active so people might benefit from building from the sources. This post is part of a recent push to try to get frequent builds in most operating systems (Linux, Mac OSX and Windows).
Installation of needed components. This is the most difficult part, since once you have all the components you will be able to build hugin as often as you want.
Here is the list as I could work it out from objdump -p /usr/local/bin hugin. Some sound strange, probably because I am building in 64bit linux.
I tried to compile enblend on 64 bit gutsy.
What's going on in a recursive picture?