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Career mentoring
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Edward Hugh Hebern (ur. 23 kwietnia 1869, zm. 10 lutego  1952) – amerykański wynalazca nowoczesnej maszyny szyfrującej. Prawdopodobnie miało to miejsce w 1915 roku, zaś w roku 1919, wkrótce po trzech wynalazcach europejskich, którymi byli Artur Scherbius (Niemcy), Hugo Koch (Holandia) i A Damm – Szwecja, uzyskał na nią patent. Niedługo potem na rynek trafiła jego maszyna o nazwie Hebern Rotor Machine. Była ona mniej bezpieczna w użyciu niż sądził wynalazca, co potem wykazał William F. Friedman znajdując dla niej co najmniej jedną metodę skutecznego ataku kryptologicznego.

Linki zewnętrzne

Amerykańscy kryptolodzy
Amerykańscy wynalazcy
Urodzeni w 1869
Zmarli w 1952

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Replaced my origional pump due to a bad bearing. New pump never built pressure. Not the easiest thing to do and now have to do it again.


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Community Notices 8th December, 2017
December 26, 2021 December 8, 2017 by Susan O'Donnell
Church Coffee Morning: Everything from cakes to jams, pictures to novelty items and much more, will be on sale at the annual St. Conal's Church coffee morning which takes place this Friday, December 8th at Teague's Bar, Ardara from 10.30am. The event will also include a raffle. The Reverend Robert Wray and church members would like to thank all those who, once again, attended the annual dinner-dance at the Nesbitt Arms Hotel, Ardara, last Friday, November 24th.Save Our Fisheries: The Ardara GAP Heritage & History Group and Loughros Heritage Group have organised a public petition against the closure of The Channel (Loughros More Estuary) and against making the Owenea and Owentocker 'catch and release' rivers for the 2018 fishing season. If implented, these changes will have a huge impact on our heritage, tourism and local communities. Copies of the petition are available to sign until Tuesday next, 12th December at Diver's Newsagents, Charlie's West End Café, Young's General Store, Maloney's Texaco and Darnell's Mace. It is crucial that as many people as possible sign this petition. Big Turn Out in Ardara: Last Sunday was a big day in Ardara. One of the biggest crowds for years attended the Children's Party and meeting Santa. At 5.30pm Imelda Heena and her wonderful young choir were joined by the Glenties Brass Band for some delightful carols, and at 6.00 pm our local Councillor Terence Slowey introduced and welcomed to the stage Conal Big Francie, who was this years guest to switch on the lights for Christmas 2017. Thanks to all involved,especially Shane Mulreany for doing a great job organising the lights again this year. There will be a church gate collection on the weekend of 16th/17th December also and baubles are still available in all local shops.Duchas Magazine: The Duchas Magazine is now on sale in the local shops. It is a great production with lots of articles and photographs and will make an ideal Christmas present for family living in Ireland and abroad.Ardara has new and exciting Festival: "South of the Border" is the new Festival taking place on Valentines Weekend next year from 16th to 18th February. This Festival incorporates the music of Jimmy Kennedy and the stories of Packie Manus Byrne. There will be a Song Contest which is now open for entries. The Contest is for amateur song writers i.e. people who have no competition recorded. The prize for the winner is €1000.00 and the inaugural scroll in the Jimmy Kennedy Song Contest. More details will follow but anyone interested in competing in the Contest must send link to lyricsardara@gmail.com but also all details of this Festival can be found on www.ardara.ie.Ulster Bank Service: Ulster Bank's Community Banker, Eve Curran is holding drop in sessions Every Monday 11-1 at the Heritage Centre and every Wednesday 11-1 at St Shanaghan House in Ardara. She will attend on Monday 11th December. She will be assisting with online banking set up or queries, One to One Personal Financial Review, helping you plan your financial goals, Assisting with your individual account queries, products and services, Arranging one to one appointments if you prefer a home visit. Eve can be contacted on 087 1926529 Or eve.c.curran@ulsterbank.com Please do avail of this service and call in. All welcome!Please take a moment – Please take a moment to fill out the following short survey, which has been designed to help us gather relevant information on what makes your stay with us here in Ardara special and fulfilling. We appreciate your support as we continue to grow and improve on these services, and your feedback is very important to us as a way to meet your future needs. We look forward to seeing you all back with us again soon. Please click on the following link to open the survey: https://www.surveymonkey.com/r/Y2Y2DX2
Categories News Tags Events, News
Songs For Grace
Community Notices 12th December 2017


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ANNEXIN DERIVATIVES SUITABLE FOR PRETARGETING IN THERAPY AND DIAGNOSIS
The present invention provides methods and compositions for the treatment and diagnosis of diseases such as neoplastic diseases, neurodegenerative diseases, cardiovascular diseases, autoimmune diseases, and inflammatory diseases. The methods are based on the concept of pretargeting and include the administration of complexes comprising a recognizable compound A coupled to annexins, and the administration of complexes comprising of pharmaceutical or diagnostic compounds coupled to a compound B recognizing and binding to compound A to subjects. The compositions include annexins, annexin variants, that are not internalized by the target cells, derivatives thereof, and complexes thereof.
FORM-2 THE PATENTS ACT, 1970
(39 of 1970)
THE PATENTS RULES, 2003
Provisional /Complete specification
[See Section 10 and rule 13]
1	Title of the Invention.
2	Applicant (s)
1	Applicant	MOSAMEDIX B.V.
Nationality	The Netherlands
Address	Monnikendijk 4, NL-4474 ND Kattendijke, The Netherlands
The following specification particularly describes the invention and the manner in which it is to be performed.
The present invention relates generally to the field of annexins. More particularly, it relates to compositions and methods for treating and diagnosing a subject by delivering compounds to a specified target using novel annexins, variants of annexins, and derivatives thereof that do not form trimers and 2-dimensionaI networks.
Cells are enveloped by a plasma membrane ("PM") that consists of a bilayer of phospholipid molecules and several protein molecules. Various phospholipid molecules form the building blocks of the bilayer. The phospholipid molecules are distributed asymmetrically over the two leaflets of the bilayer. Phosphatidylcholine for example is present in both layers, whereas sphingomyeline can be found only in the outer leaflet facing the environment. Aminophospholipids. like phosphatidylserine ("PS"), on the other hand, are predominantly present in the inner leaflet facing the cell's cytosol (Zwaal and Schroit. Blood 89:1121-32 (1997)). Aminophospholipid translocases transport PS from the outer to the inner layer, or leaflet, of the plasma membrane to create an asymmetric distribution of PS. The asymmetric architecture of the PM is a feature of living cells. They expend energy to generate and maintain the uneven distribution of the phospholipid species in their PM's.
A cell can change the phospholipid architecture of its PM under certain circumstances, which lead to activation and perturbation of the cell. Programmed cell death ("PCD") is associated with the appearance of PS in the outer leaflet of the PM (Fadok et al., J. Immunol. 148:2207-16 (1992)). On the basis of morphology and biochemistry, at least four types of PCD have been identified: (1) apoptosis. (2) apoptosis-like PCD, (3) necrosis-like PCD. and necrosis. Each type is accompanied by a change in the asymmetry of the PM characterized by exposure of PS to the outer layer of the eell surface. PS exposure at the outer layer of the PM is a good indication of a variety of activated and perturbed states of a cell. PS exposure, however, is not exclusively associated with cellular processes culminating in cell death. Transient and reversible PS exposure has been reported for several cell types, including activated B cells, undifferentiated muscle cells prone to form syncytium, chlamydia infected cells, endothelial cells of tumour vasculature (United States Patent 6,312,694), and engulfing macrophages (Kenis et al. J. Biol Chem. 2004 279: 52623-9). In addition, several cellular processes and conditions have been found that are associated with an expression of PS at the outer leaflet of the PM. These include platelet activation, red blood cell ageing, stimulation of the immune system, muscle cell syncytium formation, new blood vessel formation in tumors (US 6,312,694), and tumor growth (Rao et al., Thromb. Res. 67:517-31 (1992)).
In addition, cells can dissipate portions of themselves from their surface resulting in membrane encapsulated microparticles. These microparticles have aminophospholipids such as PS exposed at the outer layer of the membranes. These microparticles have been associated with diseases like infection, AIDS, atherosclerosis. Therefore, aminophospholipids
at the ceil surface are indicators of a variety of activated and perturbed states of a cell. Moreover, microparticles that exhibit exposed aminophospholipids reflect distant cell activation and perturbation. Hence, phospholipids at the surface of a Pm constitute attractive targets for a variety of purposes including research, diagnosis, prevention and treatment of diseases. Preferably, PS in the outer leaflet of a PM constitutes a target for research, diagnosis, prevention and treatment of diseases.
Pharmacological and genetic treatments of diseases are based on the delivery of pharmacologically active compounds to diseased cells where the compounds act preferably intracellularly. Current therapeutic treatments employ systemic delivery of a drug, where the drug circulates through the entire body before reaching its desired target. This method of drug delivery results in systemic dilution of the compound. As a result higher concentrations of the drug are required to achieve a therapeutic efficacy. This is associated with undesired toxic side-effects and increased costs of drugs.
Solutions to these problems are provided by targeted drug deliver)' systems. The targeting agent, which is coupled to the drugs directly or indirectly, guides the drugs to the diseased cells where they accumulate.
Recently we described annexins, derivatives thereof and annexin-Cys variants as targeting and cell-entry agents and their uses for therapeutic and diagnostic applications (WO 2006/003488, published 12 January 2006). The predominant target of annexins is phosphatidylserine (PS,, which is exposed by cells that execute programmed cell death or are submitted to stress such as metabolic stress. The annexins, derivates and annexin-Cys variants as described in WO 2006/003488 bind to cell surface exposed PS and are subsequently internalized. The internalization results in a depletion of surface-bound annexins. This phenomenon disfavours the use of annexins in therapeutic and diagnostic procedures that employ the concept of pretargeting.
Pretargeting is a strategy of targeting a reporting compound for diagnostic purposes and/or a drug for therapeutic purposes to the diseased tissue in a multi-step procedure in order to reduce the background signal and the systemic toxic burden respectively. The pretargeting concept employs two compounds A and B which have a high affinity for each other. Compound A encompasses the targeting function and compound B contains the reporter and/or therapeutic function. Firstly, compound A with the targeting function is administered to the subject. After a certain period of time when the circulating compound A is cleared sufficiently, compound B with the reporter and/or therapeutic drug is given to the subject. The latter compound will accumulate at sites where compound A is retained due to its targeting function. This strategy reduces the amount of compound B that needs to be administered in order to obtain the desired effect. Moreover, it will circumvent background signals and undesired toxic side-effects that are related to compound A if the reporter and/or therapeutic drug were directly coupled to compound A.
Examples of combinations of A and B compounds that have high affinity for each other and that are suitable for pretargeting include the streptavidin/avidin and biotin combination,
combination of complementary DNA and RNA oligonucleotides, complementary DNA and RNA analogs such as morpholinos (synthetic oligonucleotide analogues containing morpholino-phosporodiimidate chains instead of deoxyribose-phosphodiester chains), peptide nucleic acids (synthetic oligonucleotide analogues containing N-aminoethyl-glycine chains instead of deoxyribose-phosphodiester chains, PNA) and aptamers (specifically binding oligonucleotides or oligopeptides), the antibody and hapten combination, and the receptor and ligand combination. These combinations have been used in delivery of radionuclides for imaging and therapy of cancer through the pretargeting strategy (Sharkey et al,Clin. Cancer Res. 200, 11:7109-21).
The prerequisite for successful implementation of the pretargeting strategy is the accessibility of compound A for compound B. internalization of compound A by the target cell would reduce the efficacy of this strategy.
Patent application WO 2006/003488, describes that annexins, derivatives thereof, and annexin-Cys variants are internalized by cells that expose PS at their surface. The mechanism of internalization is based on the formation of annexin-trimers and the organization of the annexin-trimers in large 2-dimensional networks (kenis et al. J. Biol. Chem. 2004 279: 52623-9). This mechanism, thus, diminishes the efficient use of annexin, derivatives thereof, and annexin-Cys variants as targeting parts of compound A in pretargeting strategies.
Mira et al.. J. Biol. Chem. 1997, 272: 10474-82, describe annexin mutants M1-M4, which affect Ca2-4 binding and the effect thereof on inhibition of cytosolic phospholipase A2.
In accordance with one embodiment of the invention there is provided annexin variants that are suitable for pretargeting strategies for diagnosing and treating diseases. These annexin variants bind PS with sufficient affinity and are unable to form trimers and 2-dimensional networks on the cellular surface and, hence, they do not induce their own internalization.
Another embodiment of the invention concerns annexins and variants thereof that are derivatised with affinity compounds A for pretargeting strategies. Such affinity compounds include biotin, compounds containing one or- more biotin groups, streptavidin, avidin, DNA oligonucleotides, RNA oligonucleotides, morpholinos, PNA's. aptamers, receptors, compounds with high affinity for receptors and immunoglobulins or parts thereof. In the present invention, affinity compound A is also referred to as recognizable compound (A), or as compound A, with the same meaning.
A further embodiment of the invention comprises annexins, derivatives thereof and annexin-Cys variants according to patent application WO 2006/003488 that are derivatised with affinity compounds A via conjugation to the cysteine residue.
One embodiment of the invention relates to the use of affinity compounds B that are conjugated with fluorescent compounds, radionuclides. MRI contrast agents, CT contrast agents, cytostatics, and therapeutic biologicals including cytokines, complement factors, toxins, and immunoglobulins in combination with the annexin derivatives and complexes.
Affinity compounds B have a high affinity for affinity compounds A of other embodiments of the invention. In the present invention, affinity compound B is also referred to as compound (	B) recognizing compound A. or as recognizing compound B, or compound B, with the same meaning.
One embodiment of the present invention is a kit that includes at least one complex of annexin derivative with affinity compound A described above and. optionally at least one pharmaceutical ly acceptable excipient.
Another embodiment of the invention relates to a method for delivering a pharmaceutical compound to a target cell that includes administering firstly a targeting complex of the composition that is described above and secondly a therapeutic complex of the composition that is described above. More specifically, this embodiment encompasses a method to treat or prevent a disease, where the pharmaceutical compound is a therapeutic compound that is effective to treat or prevent the disease.
One embodiment of the invention relates to a method for delivering a diagnostic compound to a target cell that includes administering firstly a targeting complex of the composition that is described above and secondly a diagnostic complex of the composition that is described above. More specifically this embodiment encompasses a method to diagnose a disease and to determine the efficacy of a therapeutic treatment, where the diagnostic compound is a molecular imaging compound that can be detected by imaging modalities comprising optical imaging, nuclear imaging, MRI, CT and ultrasound.
For a better understanding of the present invention, together with other and further objects thereof, reference is made to the following description, taken in conjunction with the accompanying drawings, and its scope will be pointed out in the appending claims.
The present invention is based in part on the directed search to identify' those amino acids that are involved in the inter-molecular interactions between annexin molecules. Molecular modelling and docking of the crystal structures available in the Protein Database (PDB, IAVR and ANX) revealed amino acids that are involved in the trimer formation. These amino acids are found in the helices 1A, ID, IIA, 1ID. I1IC, HID and IVE and in the stretches connecting helices IC and ID, HE and 1IIA, IIIC and HID, HID and HIE, and IVA and IVB (for localization of these helices in the annexin A5 molecule see Huber et al. EMBO J. 12:3867-74 (1990)). The annexin variants of one of the embodiments of the invention have onE or more amino acids replaced in the helices IA, ID, IIA, IID. IIIC, HID and IVE and in the stretches connecting helices IC and ID, HE and IIIA, IIIC and HID. HID and HIE, and IVA and IVB so as to impair their ability to form trimers and a 2-dimensional network on the ce)\u)ar surface and consequently to impair their internalization into the cell. The annexin variants will remain longer on the cellular surface and are, thus, suitable for pretargeting strategies.
Thus, the invention generally pertains to an annexin variant, a) that binds to at least one phospholipid, in particular to phosphatidylserine (PS), and b) that is not internalized into a cell. The term "annexin" refers to any protein capable of binding to phospholipids, especially phosphatidylserine, and member of the so-called annexin family. The family covers many members; information thereon and on the protein and nucleotide sequences can for example be found on http://snoops.bch.ed.ac.uk/annexins/seq/search.php. By way of example, reference is made herein to annexin A5, having the amino acid sequence of SEQ ID No. 1, but other annexins can equally be used for producing and using the annexin variants of the invention. Figure 2 contains an alignment of human annexins Al to All and A13. Some of the annexins, such as Al, A6, A7 and A1 1 have long extensions at the N-terminus. These parts have not been included in Figure 2, and are believed to be less relevant for the purpose of the invention. Here below, reference is made to the amino acid sequence and the positions of annexin A5, but what applies to A5 also applies to the other annexins, especially human annexins, by choosing the corresponding position found with the alignment of Figure 2 or corresponding alignment of any annexins not represented in Figure 2.
Specific annexin variants according to the invention have amino acid sequences according to Figure 1 (SEQ ID NO:l), which are modified to inhibit the internalization into a cell in that one or more amino acids within the helices and connecting stretches indicated above are replaced by different amino acids. These amino acids are located at positions 16-29, 59-74, 88-102, 135-145, 156-169, 202-231, 259-266, and 305-317 in annexin A5, and these positions are underlined in SEQ ID No. I and in Figure 2. Where the annexin variant contains one or more of these modifications, the feature of the annexin not being internalized into a cell is considered as being fulfilled. Thus, the invention also comprises an annexin variant that a) binds to at least one phospholipids and b) contains one or more of the amino acid modifications as described herein.
Preferred modifications are substitutions, especially substitutions of polar amino acids by non-polar amino acids. Thus, preferred amino acids for substitution include arginine (R), lysine (K), aspartate (D), glutamate (E). asparagine (N) and glutamine (Q). They may be substituted e.g. by alanine (A) or glycine (G), or by a non-polar amino acid that is located in the corresponding position of another annexin (cf. Figure 2). Suitable examples of substituted amino acids include E21, K25 (e.g. by G, T), R62 (e.g. G, A), D63 (e.g. G, A, P), K69, D91, K96, H97. K10, E137 (e.g. A, G. V). D138, D139, N159 (e.g. A, G, S), R160, R206, K207, Q2I9, D225, R226, D264, K308, K309. The modifications MI-M4, at positions £71, D143, E227 and D302, are less preferred according to the invention.
li is preferred to have at least two. or even at least three, substitutions in different regions, for example R62A + E137G, or K69A + KIOOA + N159S etc, in order to further decrease the trimerisation of the annexin at the site of the cell.
The annexin variants according may further comprise one or more amino acid substitutions, deletions, or additions, wherein the amino acid substitutions, deletions, or additions do not substantially affect the ability of the annexin variant to bind to at least one phospholipid, and
to bind at least on recognizable compound A, and wherein the amino acid substitutions, deletions, or additions do not substantially affect the inhibited internalization of the recognizable compound A into a cell.
The substitution must be such that the annexin still binds sufficiently to the phospholipid. Sufficient binding means a dissociation constant of approximately 10"6 M or less in the presence of Ca2-1-ions.
The invention further pertains to annexin molecules or variants as defined above to which a recognizable compound A, wherein the annexin variant is not internalized by the target cell. The recognizable compound A may for example be a biotin or a complex of multiple biotins. Other suitable examples include avidin or streptavidin, an oligonucleotide or a nuclease-resistant oligonucleotide analogue in the form of a morpholino compound or a PNA or an aptamer.
In another embodiment the recognizable compound A is a receptor or a part thereof, or a receptor ligand or a part thereof. Other examples of recognizable compounds A include an antibody or a fragment thereof, for example a nanobody - a truncated antibody from camel-like origin -. or an antigen.
The recognizable compound can be bound to the annexin by methods known per se. One method consists in covalently binding the recognizable compound to specific amino acids, possibly in derivatised form. Especially suitable is binding to a cysteine residu of the annexin, for example in the case of biotin. which can be derivatised with a maleimide group. In order not to interfere with functional properties of the annexin, the amino acid to which the recognizable compound is coupled is located at the concave sides of the annexin molecule. These are represented by italic amino acid symbols in SEQ ID NO. 1. Moreover, these positions may or may not be located in the regions selected above for preventing trimerisation and internalization of the annexin. Thus the preferred sites are the bold italic positions in SEQ ID No. 1, i.e. the stretches 1-15, 46-58, 86-87, 118-134, (170), 245-248 and 280-294 of annexin A5 and the corresponding stretches in other annexins (see Figure 2), but underlined italic positions (16-19, 24, 28, 59-64, 88-89, 135, 157-169, 203-219) can llso be used for introducing cysteine residues.
It is furthermore preferred that any cysteine residues naturally present outside these stretches, especially those which are present in the parts where amino acids are substituted according to the invention for the purpose of preventing trimerisation, are replaced by other amino acids. Such other amino acid can be a neutral small amino acid such as G, A or S, or an amino acid that is present at the same position ion of another annexin. For example, C107 of annexin A4 can suitably be replaced by V or A, C201 of annexin A3 (and the counterparts in many other annexins) can be replaced by G or A, and C315 in annexin A5 (and the counterparts in many other annexins) can be replaced by V, A or S. The C292 of annexin A8 need not be replaced as it is in a position suitable for derivatisation. The amino acid substitutions can be performed by recombinant techniques well-known in the art and illustrated in the examples below.
Thus the invention pertains to an annexin variant which contains a cysteine residue at one of the amino acid positions 1-19, 24, 28, 46-64, 86-89, 118-135, 149-150, 157-170, 203-219, 245-248 and 280-294, and does not contain a cysteine residue outside these positions, and which furthermore contains substitution of one or more amino acids Lys, Arg, GIn, Asn, Glu, Asp or His at positions 16-29, 59-74, 88-102, 135-145, 156-169, 202-231, 259-266 and 305-317 by Gly. Ala, Va, He, Leu, Ser. Thr, Met, Pro, Phe, or Tyr, preferably Gly. Ala, Val or Ser; herein the corresponding amino acid positions in other annexins apply, e.g. as depicted in Figure 2. The annexins may be the proteins as such, or the conjugates with spacers and/or recognizable compounds. The cysteine residue(s) may be substituted, e.g. with a recognizable group (A).
The complexes of the annexin variant and the recognizable compound A can be used in a therapeutic or diagnostic method for targeting a medicament or a diagnostic agent to a specific site, in particular to cells which expose PS. In such a method, a composition containing the complex of the annexin variant and the recognizable compound A is first administered to a subject for which such therapeutic or diagnostic method is intended, followed by administering to the subject a composition comprising at least one complex. comprising a compound B recognizing and binding to compound A and a diagnostic or therapeutic compound. Compound B is especially a specific counterpart of compound A, for example streptavidin or avidin, in case compound A is biotin. Likewise, compound B may be biotin or a complex of multiple biotins. especially if compound A is streptavidin or avidin. Compound B may also be an oligonucleotide, a morpholino, a PNA or an aptamer which have high affinity for the oligonucleotide, morpholino, PNA or aptamer counterpart bound to the annexin molecule as described above. It may also be a receptor or a part thereof, where compound A is the receptor ligand, or vice versa. Also compound may be an antigen to an antibody as compound A or fragment thereof or vice versa.
The diagnostic agent that can be used in the diagnostic method of the invention, can be selected from a fluorescent group, a radionuclide, an MRI contrast agent, a CT contrast agent, an ultrasound agent, and a combination thereof. Suitable examples of fluorescent groups are fluoresceines, Alexas, Phycoerythrines, Cy-compounds, Nanocrystals and a combination thereof. Suitable examples of radionuclides include Carbon-11, Fluorine-18, Indium-Ill, Iodine-123, Iodine-131, Nitrogen-13, Oxygen-15, Technetium-99m, Zirconium-89, Ga-67, Ga-68, Cu-64 and a combination thereof, which are incorporated in suitable molecules bound to compound B or in compound B itself. An MRI contrast agent may be selected from Gadolinium, magnetic particles and paramagnetic particles.
Therapeutic compounds that can be used in the therapeutic method of the invention, can for example be a toxin, an enzyme, enzyme inhibitors, a lipid, a carbohydrate, an immunoglobulin or a fragment thereof, an immunoconjugate, a chemotherapeutic compound, a photosensitizer, a radionuclide, a cell death inducing agent, a cell death inhibiting agent, a fibrinolytic compound, and a combination thereof. The toxin can be selected from Dt, PE, P38, P40. ricin, abrin, diphtheria toxin, cholera toxin, gelonin, pseudomonas, exotoxin, shigella toxin, pokeweed antiviral protein, and a combination thereof. Examples of enzymes
that can be coupled to compound B include peroxidases, alkalases. caspases. and a combination thereof. Lipids can e.g. be selected from phospholipids, fatty acids, terpenes, steroids, and a combination thereof. The lipid can be embedded in the membrane of a liposome.
Examples of chemotherapeutic agents include BiCNU, bleomycin, busulfan, CCNU, carboplatin, carmustine. cisplatin, cisplatinum, chlorambucil, 2-cholrodeoxyadenosine, cladirabine, cytarabine, cyclophosphamide, dacarbazitie, daunorubicin, docetaxel, doxorubicin, DTIC, etoposide, 5-flourouracil, fludarabine, gemcitabine, hydroxyurea, idarubicin. ifosfamide: irinotecan, lomustine, melphelan, methotrexate, mithramycin, mitomycin, mitoxantrone, nitrogen mustard, oxaliplatin. paclitaxel. plicamycin, procarbazine, raltritexed, semustine, tomudex, topotecan, vinblastine, vincristine, vinorelbine. and combinations thereof.
Examples of photosensitizers include phthalocyanines, rhodoporphyrins, rhodochlorins, mesorhodochlorins, phylloerythrin and its derivatives, porphorin and its derivatives, metal-pyrollic compounds, and combinations thereof.
Cell death inducing agents that can advantageously be used in the method of the invention can be selected from the group of apoptosis inducers, kinase inhibitors, activators of mitochondrial permeability transition activators, polynucleotides encoding for a cell death inducing protein, activators of ion-transport across the membrane, polynucleotides being an anti-sense to polynucleotides encoding for cell death inhibiting proteins, polynucleotides interacting with and inhibiting cell death inhibiting proteins, and a combination thereof.
The therapeutic and diagnostic compounds can be bound to compound B by methods known in the art. For example, when the therapeutic or diagnostic Compound is a protein, it can be coupled through a lysine or arginine residue, optionally after activation using cyanogen bromide or other chemical or physical methods. If the compound is a lipid, such as phosphatidylethanolamine, it can be coupled to the amino group using methods known in the art. If the compound is a polynucleotide it can be coupled for example to hydroxyl groups thereof using methods known in the art. If the compound is a radionuclide, it can be coupled either directly or indirectly by coupling a chelator to compound B that chelates the radionuclide of choice.
The complex can also be used for detecting the presence or absence of cells or cell particles expressing phospholipids comprising:
a)	administering to a subject a composition comprising at least one complex comprising a recognizable compound A and an annexin or an annexin variant, and :
b)	administering to a subject a composition comprising at least one complex comprising a compound B recognizing compound A and a diagnostic agent: and:
c) submitting a subject to a detecting step such as optical imaging, SPECT imaging, PET imaging, MRI imaging, CT imaging, and ultrasound imaging.
The invention also pertains to a diagnostic kit suitable for carrying out the diagnostic method as described above, which comprises at least a complex of an annexin variant and an affinity compound A, and optionally a complex of a detectable (reporter) compound and an affinity compound B, and optionally diluents and further components necessary for carrying a diagnostic method. Preferably, the complex of the annexin variant and the complex of the detectable compound are conditioned separately.
The invention also pertains to a pharmaceutical kit suitable for carrying out the therapeutic method as described above, which comprises at least a complex of an annexin variant and an affinity compound A combined with a pharmaceuticaly acceptable excipient, and optionally a complex of a therapeutic compound and an affinity compound B, and optionally diluents and further components necessary for carrying a therapeutic method. Preferably, the complex of the annexin variant and the complex of the therapeutic compound are conditioned separately.
The present invention provides methods and compositions for the treatment diagnosis, prevention, and research of diseases, such as neoplastic diseases, neurodegenerative diseases, cardiovascular diseases, autoimmune diseases, and inflammatory diseases. The methods include the administration to subjects of targeting complexes comprising annexins and annexin variants and diagnostic and therapeutic complexes comprising molecular imaging agents and pharmaceutical compounds respectively.
The present invention relates to the ability of annexins to bind to PS expressing cells. The present invention relates to the use of annexins in pretargeting methods to diagnose and treat diseases. It is known that annexins are taken up by liver, spleen and kidneys and by the reticuloendothelial system of the bone marrow. Injecting annexins conjugated to diagnostic compounds and therapeutic compounds will result in high background signals and undesired toxic side-effects respectively. Therefore, the present invention provides methods in which annexins will be conjugated neither to diagnostic compounds such as fluorescent groups, radionuclides, MRI contrast agents, CT contrast agents and ultrasound agents nor to therapeutic compounds such as a toxin, an enzyme, a lipid, a carbohydrate, an immunoglobulin or a fragment thereof, an immunoconjugate, a chemotherapeutic compound, a photosensitizer, a radionuclide, a cell death inducing agent, a cell death inhibiting agent, a fibrinolytic compound prior to their administration into the subject. Instead, the present invention provides methods in which annexins be coupled to recognizable compounds A. which are selected from the set comprising but not restricted to biotin, multiple biotins, streptavidin, avidin, DNA, RNA, morpholinos, PNAs, aptamers, receptors and receptor ligands and antibodies. The present invention provides methods for delivering a diagnostic or a therapeutic compound to a target cell by delivering a complex of an annexin and a recognizable compound A to the target cell and by delivering subsequently a complex of a compound B that recognizes compound A and a diagnostic compound or a therapeutic
compound to the target cell. The conjugated annexins will be administered to the subject. After a period of time, for example between 1 h and 24 h, the diagnostic or the therapeutic complex with compound B, which has a high affinity for compound A, will be injected into the same subject Compound B will accumulate at sites where annexins conjugated to compound A are bound to cellular surfaces.
Annexins constitute a multigene family of proteins that share structural and functional features. The annexin polypeptide is organized in domains that form the so-called Annexin fold in space (Gerke and Moss, Physiol. Rev. 82:331-71 (2002)). The domains contain calcium binding sites through which an interaction with phospholipid membranes can occur. Once bound to a phospholipid surface the annexins can form a two-dimensional lattice through protein-protein interactions (Oling et al.. J. 304: 561-73 (2001)). The
physiological significances of the annexins are poorly understood but are thought to be related to their phospholipid binding activity. The annexins do not have a signal sequence and are therefore thought to play a role within the cell. Extracellular localization of annexins has been reported but it is unknown whether this has happened by a selective process or by an aspecific event such as cell lysis. According to WO 2006/003488, annexins and annexin-Cys variants will induce their own internalization after binding to cell surface expressed PS. The phenomenon of internalization reduces the efficacy of the pretargeting strategy. The present invention relates to annexins that are not internalized by the target cells. Jn order to find annexin variants that are less internalized the mechanism of internalization was inspected on its structure-function relationships. The internalization is induced by the formation of annexin trimers that form a 2-dimensional network on the phospholipid bilayer (Kenis et al., J. Biol. Chem. 279:52623-9 (2004)); The annexin trimers arise from non-covalent interactions between annexin molecules.
Example 1: Production of Annexin A5-2D variants having one or more amino acids at positions , 137,138 and 159 replaced by Alanine and Glycine.
The human annexin A5 cDNA was prepared from a white blood cell cDNA library from a healthy volunteer with standard techniques known in the art. The cDNA sequence encoded the amino acid sequence presented in Figure 1. Primers were designed to mutate annexin A5 by PCR techniques such that the resulting cDNA encoded the amino acid sequence of Figure 1 with the exception of the following substitutions, that were performed singularly, but also jn combinations thereof in the cDNA: R62A, K69A. K100A, E137A, D138G, and N159A. The annotation employs the single letter code for amino acids and the numerical position in the amino acid sequence where the substitution occurs with left to the number presenting the original amino acid and right to the number presenting the substitute.
The annexin A5-2D cDNA was cloned into a bacterial expression vector with standard techniques known in the art. E. coli transformed with the resulting bacterial expression vectors were grown in a fermentor. The annexin A5-2D variants that were produced by the bacteria were isolated and purified from E. coli lysates with standard chromatography techniques known to persons skilled in the art.
The purified annexin A5-2D variant appeared as a homogenous band of around 34kDa on SDS-PAGE and exhibited full calcium-dependent phosphatidylserine binding activity as measured by plasmon surface resonance technique using the BiaCore.
Example 2: Production of Annexin A5-2D variants having one or more amino acids at positions 62, 69, 100, 137, 138 and 159 replaced by Alanine and Glycine and having Glutamine at position 2 replaced by Cysteine.
The annexin A5-2D cDNA was prepared as described in Example 1 of the present invention. Primers were designed to mutate annexin A5-2D cDNA by PCR techniques such that the resulting cDNA encoded the amino acid sequence of an annexin A5-2D variant with the exception that the amino acid Glutamine at position 2 was replaced by the amino acid Cysteine.
The purified annexin A5-2D-Cys2 variant appeared as a homogenous band of around 34kDa on SDS-PAGE and exhibited full calcium-dependent phosphatidylserine binding activity as measured by plasmon surface resonance technique using the BiaCore.
Example 3: Production of Annexin A5-2D variants having one or more amino acids at positions 62, 69, 100, 137, 138 and 159 replaced by Alanine and Glycine and having Glycine at position 165 replaced by Cysteine.
The annexin A5-2D cDNA was prepared as described in Example 1 of the present invention. Primers were designed to mutate annexin A5-2D cDNA by PCR techniques such that the resulting cDNA encoded the amino acid sequence of an annexin A5-2D variant with the exception that the amino acid Glycine at position 165 was replaced by the amino acid Cysteine.
The purified annexin A5-2D-Cysl65 variant appeared as a homogenous band of around 34kDa on SDS-PAGE and exhibited full calcium-dependent phosphatidylserine binding activity as measured by plasmon surface resonance technique using the BiaCore.
Example 4: Binding of Annexin A5-2D variants having one or more amino acids at positions 62, 69,100, 137, 138 and 159 replaced by Alanine and Glycine to phospholipid bi layers.
This example demonstrates that the annexin A5-2D variant has a calcium-dependent ability to
bind to PS of phospholipid bilayers like annexin A5 but lacks the ability to form a 2-
dimensional network on the phospholipid surface and is not internalized into a ceil.
The binding of annexin A5-2D to a phospholipid bilayer containing PS was studied by
ellipsometry (Andree et al., J. Biol Chem. 265:4923-4928 (1990)). In the absence of calcium
the annexin A5-2D variant did not bind to the phospholipid surface by increasing the calcium
concentration an increase in binding was observed similar to the calcium-dependent binding
isotherm of annexin A5.
Annexin A5-2D bound to a phospholipid surface was analysed by electron microscopy
(Mosser et al., J. Mol. Biol. 271:241-5 (1991)). Unlike annexin A5, the annexin A5-2D
variant did not form an ordered 2-dimensional network.
Jurkat cells were co-incubated with fluorescent annexin A5-2D or fluorescent annexin A5. and the apoptotic stimulus. Trie cells were analysed for the localization of fluorescent annexin A5-2D or fluorescent annexin A5 by confocal scanning laser microscopy (Kenis et al., J. Biol Chem. 279:52623-9 (2004)). Annexin A5 was internalized. Annexin A5-2D was not internalized but remained bound to the plasma membrane.
Example 5: The coupling of maleimide-activated biotin to the Annexin A5-2D variant having amino acids at positions 62,69,100, 137,138 and 159 replaced by Alanine and Glycine and having Glutamine at position 2 and Cysteine at position 315 replaced by Cysteine and Serine respectively.
The annexin A5-2D variant was prepared as described by example 2. The Cysteine was removed at position 315 and incorporated at position 2 in order to be able to couple compounds easily to the annexin A5-2D variant through thiol-chemistry without affecting the PS binding activity of the annnexin A5-2D variant.
The resulting conjugate was assayed on its PS binding activity by ellipsometry and tested for the accessibility of the biotin group using avidin (Pierce). The biotinylated annexin A5-2D showed no impaired PS binding, while the avidin readily bound to the biotinylated annexin A5-2D on the phospholipid surface.
Example 6: The coupling of maleimide-activated avidin to the Annexin A5-2D variant having amino acids at positions 62, 69,100,37,138 and 159 replaced by Alanine and Glycine and having Glutamine at position 2 and Cysteine at position 315 replaced by Cysteine and Serine respectively.
The annexin A5-2D variant was prepared as described by example 2. The Cysteine was removed at position 315 and incorporated at position 2 in order to be able to couple compounds easily to the annexin A5-2D variant through thiol chemistry without affecting the PS binding activity of the annnexin A5-2D variant.
Immunopure avidin (Pierce) was dissolved in 25 mM Hepes/NaOH, pH 7.4, 140 MM NaCL at a concentration of 8 mg/ml. 1 mg of Sulfo-SMCC (Pierce) was added to the avidin solution and the mixture was incubated for 60 minutes at room temperature. The excess cross-linker was removed by gel-filtration on a PD10 column (GE-Amersham/Pharmacia). The maleimide activated avidin was added to 1 mg/ml of annexin A5-2D variant that was dialysed into 25 mM Hepes/NaOH, pH 7.0, 140 mM NaCl, 1 mM EDTA. The mixture was incubated for 120 minutes at 3700cThe conjugate between avidin and the annexin A5-2D variant was tested on its ability to bind to PS by ellipsometry. The conjugate showed no imapired PS binding properties.
Example 7: A procedure to visualize a tumor in vivo using annexin A5-2D variant and pretargeting.
Annexin A5-2D variants having a Cysteine at position 2 or 165 were engineered and produced as presented in examples 2 and 3, respectively. The Cys-annexin A5-2D variants were biotinylated using maleimide-biotin as described by example 5.
Biotinylated annexin A5-2D was injected intravenously into a tumor-bearing mouse. Levels of circulating biotinylated annexin A5-2D were decreased either by time-lapsed spontaneous clearance or by forced clearance with for example intravenously administered avidin. Streptavidin conjugated to a molecular imaging probe such as for example a fluorescent compound or a radionuclide was injected intravenously. The mouse was then subjected to imaging using a whole body optical imager if streptavidin conjugated to a fluorescent probe was used or using a SPECT, PET, SPECT/CT or PET/CT imager if streptavidin conjugated to a radionuclide was used.
This visualization procedure can be applied for localizing and quantifying tumors and metastases and for determination of the efficacy of an anti-tumor therapy.
Example 8: A procedure to visualize unstable atherosclerotic plaques in vivo using annexin A5-2D variant and pretargeting.
Biotinylated annexin A5-2D was injected intravenously into a mouse suffering from atherosclerotic lesions. Levels of circulating biotinylated annexin A5-2D were decreased either by time-lapsed spontaneous clearance or by forced clearance with for example intravenously administered avidin. Streptavidin conjugated to a molecular imaging probe such as for example a fluorescent compound or a radionuclide was injected intravenously. The mouse was then subjected to imaging using a whole body optical imager if streptavidin conjugated to a fluorescent probe was used or using a SPECT, PET. SPECT/CT or PET/CT imager if streptavidin conjugated to a radionuclide was used.
This visualization procedure can be applied for localizing unstable atherosclerotic plaques and distinguishing unstable atherosclerotic plaques from stable atherosclerotic plaques. The visualization procedure can be applied to determine the efficacy of drugs that stabilize unstable atherosclerotic plaques.
Example 9: A procedure to treat a tumor in vivo using annexin A5-2D variant and pretargeting.
Biotinylated annexin A5-2D was injected intravenously into a tumor-bearing mouse. Levels of circulating biotinylated annexin A5-2D were decreased either by time-lapsed spontaneous
clearance or by forced clearance with for example intravenously administered avidin. Streptavidin conjugated to an antic-cancer compound such as for example doxorubicin and cisplatin, or conjugated to a carrier of anti-cancer compounds such as for example liposomes encapsulating for example doxorubicin and cisplatin was injected intravenously. This pretargeting therapeutic procedure can be applied to delivering locally anti-cancer drugs to the tumor.
Example 10: A procedure to treat unstable atherosclerotic plaques in vivo using annexin A5-2D variant and pretargeting.
Biotinylated annexin A5-2D was injected intravenously into a mouse suffering from atherosclerotic lesions. Levels of circulating biotinylated annexin A5-2D were decreased either by time-lapsed spontaneous clearance or by forced clearance with for example intravenously administered avidin. Streptavidin conjugated to atherosclerotic plaque stabilizing compound such as for example statins and anti-inflammatory compounds, or conjugated to a carrier of atherosclerotic plaque stabilizing compounds such as for example liposomes encapsulating for example statins and anti-inflammatory compounds was injected intravenously.
This pretargeting therapeutic procedure can be applied to delivering locally atherosclerotic plaque stabilizing compounds to the atherosclerotic plaques.
All of the examples, methods and/or compositions disclosed, and claimed herein can be made and executed without undue experimentation in light of the present disclosure. While the methods and compositions of this invention have been described in terms of preferred embodiments, it will be apparent to those skilled in the art that variations may be applied to the methods and/or compositions and in the steps or in the sequence of steps of the methods described herein without departing from the concept, spirit arid scope of the invention. It will be apparent to those skilled in the art that compositions with compounds which are structurally and functionally related may be substituted for compositions with the compounds described herein.
1.	An annexin variant:
a)	that binds to at least one phospholipid;
b)	wherein one or more amino acids in the helices IA, ID, IIA, I1D, IIIC, HID and IVE and in the stretches connecting helices IC and ID, HE and IHA, IIIC and HID, HID and HIE, and IVA and IVB are replaced by other amino acids, so as to impair internalisation of the annexin variant into a cell,
c)	that is bound to a recognizable compound.
2.	The annexin variant according to claim I. wherein the annexin comprises SEQ ID NO:l for annexin A5 or the corresponding sequences for other annexins, wherein one or amino acids are replaced by other amino acids to inhibit the internalization into a cell.
3.	The annexin variant according to claim 2, wherein the one or more amino acids are located at positions 16-29, 59-74, 88-102, 135-145, 156-169, 202-231, 259-266 and 305-317, or the corresponding sequences for other annexins.
4.	The annexin variant according to claim 2 or 3, wherein the one or more amino acids are polar amino acids Glu, Gin, Asp, Asn, Arg and/or Lys. and are replaced by a non-polar amino acid.
5.	The annexin variant according to any one of claims 1-4, wherein the affinity compound is selected from one or more biotin,, avidin or streptavidin, oligonucleotides or morpholinos, peptide nucleic acids and aptamers, receptors or parts thereof, receptor ligands or parts thereof, antibodies or fragments thereof, and antigens.
6.	The annexin variant according to any one of claims 1-5, wherein the annexin is bound through a cysteine residue at one of the amino acid positions 1-15, 46-58, 86-87, 118-134, 162-167, 245-248 and 280-294 of annexin A5, and the annexin does not have a cysteine residue at the positions 20-23. 25-27, 29-45, 65-85, 90-117, 136-148, 151-156, 171-202, 220-244, 249-279 and 295-319 of annexin A5.
7.	An annexin variant wherein the annexin comprises SEQ ID NO:l for annexin A5 or the corresponding sequences for other annexins, wherein one or more amino acids at positions 16-29, 59-74, 88-102, 135-145, 156-169, 202-231, 259-266 and 305-317, or the corresponding sequences for other annexins, are replaced by other amino acids, and wherein one or amino acids at positions 1-19, 24, 28, 46-64, 86-89, 118-135, 149-150, 157-170, 203-219, 245-248 and 280-294 has been replaced by a cysteine residue, which is optionally substituted.
A method for delivering a diagnostic compound to a target cell in a subject comprising:
a)	administering to the subject a composition comprising at least one annexin
variant according to any one of claims 1-6,
b)	administering to the subject a composition comprising at least one complex
of a compound (B) recognizing and binding to the recognizable compound (A)
bound to the annexin variant, and a diagnostic compound.
The method according to claim 8, wherein the diagnostic agent is selected from the group consisting of a fluorescent group, a radionuclide, an MRI contrast agent, a CT contrast agent, an ultrasound agent, and a combination thereof.
A method for delivering a pharmaceutical compound to a target cell in a subject comprising:
bound to the annexin variant, and a pharmaceutical compound.
The method according to claim 10, wherein the pharmaceutical compound is selected from the group consisting of a toxin, an enzyme, an enzyme inhibitor, a lipid, a carbohydrate, an immunoglobulin or a fragment thereof, an immunoconjugate, a chemotherapeutic compound, a photosensitizer, a radionuclide, a cell death inducing agent, a cell death inhibiting agent, a fibrinolytic compound, and a combination thereof.
The method according to any one of claims 8-11. wherein the recognizing compound (B) is selected from streptavidin or avidin, biotin or a complex of multiple biotins. an oligonucleotide or a morpholino, peptide nucleic acids and aptamers, a receptor or a part thereof, a receptor ligand or a part thereof, an antibody or a fragment thereof, and an antigen.
A method for detecting the presence or absence of cells or cell particles expressing phospholipids comprising:
a)	administering to a subject a composition comprising at least one complex comprising a recognizable compound A and an annexin or an annexin variant, and
b)	administering to a subject a composition comprising at least one complex comprising a compound B recognizing compound A and a diagnostic agent,
c) submitting a subject to a detecting step selected from the group consisting of optical imaging, SPECT imaging, PET imaging, MRI imaging, CT imaging, and ultrasound imaging.
A kit comprising:
a)	at least one annexin variant according to any one of claims 1 -7: and,
b)	a diagnostic or therapeutic compound capable of recognizing the annexin variant.
Use of an annexin variant according to any one of claims 1-7 in diagnosis.
Use of an annexin variant according to any one of claims 1-7 in therapy.
1221-MUMNP-2008-ABSTRACT(GRANTED)-(21-3-2012).pdf
1221-mumnp-2008-abstract.doc
1221-mumnp-2008-abstract.pdf
1221-MUMNP-2008-CANCELLED PAGES(29-2-2012).pdf
1221-MUMNP-2008-CLAIMS(AMENDED)-(23-2-2011).pdf
1221-MUMNP-2008-CLAIMS(GRANTED)-(21-3-2012).pdf
1221-MUMNP-2008-CLAIMS(MARKED COPY)-(29-2-2012).pdf
1221-mumnp-2008-claims.doc
1221-mumnp-2008-claims.pdf
1221-mumnp-2008-corespondence.pdf
1221-MUMNP-2008-CORRESPONDENCE(11-6-2008).pdf
1221-MUMNP-2008-CORRESPONDENCE(14-11-2008).pdf
1221-MUMNP-2008-CORRESPONDENCE(2-12-2011).pdf
1221-mumnp-2008-correspondence(ipo)-(16-6-2008).pdf
1221-mumnp-2008-description(complete).doc
1221-mumnp-2008-description(complete).pdf
1221-MUMNP-2008-DESCRIPTION(GRANTED)-(21-3-2012).pdf
1221-mumnp-2008-drawing(16-6-2008).pdf
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1221-mumnp-2008-form 1.pdf
1221-MUMNP-2008-FORM 13(24-2-2012).pdf
1221-MUMNP-2008-FORM 18(14-11-2008).pdf
1221-MUMNP-2008-FORM 2(GRANTED)-(21-3-2012).pdf
1221-MUMNP-2008-FORM 2(TITLE PAGE)-(GRANTED)-(21-3-2012).pdf
1221-mumnp-2008-form 2(tittle page).pdf
1221-mumnp-2008-form 2.doc
1221-MUMNP-2008-FORM 26(2-12-2011).pdf
1221-mumnp-2008-international publication report a1.pdf
1221-MUMNP-2008-MARKED COPY(24-2-2012).pdf
1221-mumnp-2008-pct-ib-304.pdf
1221-mumnp-2008-pct-request form.pdf
1221-MUMNP-2008-POWER OF ATTORNEY(24-2-2012).pdf
1221-MUMNP-2008-REPLY TO EXAMINATION REPORT(23-2-2011).pdf
1221-MUMNP-2008-REPLY TO HEARING(24-2-2012).pdf
1221-mumnp-2008-sequence listing(16-6-2008).pdf
1221-MUMNP-2008-SPECIFICATION(AMENDED)-(24-2-2012).pdf
abstract1.jpg
1221/MUMNP/2008
MOSAMEDIX B.V.
MONNIKENDIJK 4, NL-4474 ND KATTENDIJKE,
1 REUTELINGSPERGER, CHRISTIAAN, PETER, MARIA ST. LAMBERTUSLAAN 2, NL-6211 KB MAASTRICHT,
2 MOONEN, PETER OUDE RIJKSWEG ZUID 21, NL-6114 RC SUSTEREN,
3 VERMAIRE, AD MONNIKENDIJK 4, NL-4474 ND KATTENDIJKE,
A61K47/42, G01N33/68
PCT/NL2006/050315
1 05111982.4 2005-12-12 EUROPEAN UNION


text:
Privacy in Tunisia: Legislation, Application, and Public Outreach
Dhouha Ben Youssef
Translated by	Vanessa Szakal
The Tunisian constitution of 2014 enshrines (via Article 24) the protection of privacy at home and in the domains of communications correspondence and personal data. The text itself conforms with European case law, but what about current legislation, its application, and its impact on Tunisians?
Chawki Gaddes Noomane Fehri
A legal framework in need of reform
Although the organic law of 2004 is considered to reflect international standards, it is in need of reforms in three specific areas.
● Independence of the National Authority for Protection of Personal Information (INPDP): The procedures for appointing the members of this organism are ambiguous as is the nature of its current member-base. The selection process is carried out by government officials whose choice of members is formalized by decree. Moreover—and in spite of the fact that the Authority exists under the Ministry of Justice—there are no measures in place to ensure members' independence from external powers or lobbies.
Organizational chart of the composition of the National Authority for the Protection of Personal Information (INPDP) INPDP Facebook page1. Click on image to enlarge.
● Public sector adherence: Tunisian legislation requires actors of the private sector to follow a preliminary declarations procedure in order to use personal information. These same actors must fill out an authorization request for the use of or access to information including health records (which constitute "sensitive information"), and for the transfer of information abroad. The public sector, in contrast, is not subject to any control procedures prior to the treatment of information, with the exception of the Tunisian postal service which voluntarily signed a memorandum of understanding with the INPDP.2 Other public institutions remain silent concerning what they intend to do with citizens' personal information, whether for the purposes of security, surveillance, or, more worrisome, the project Identifiant Unique du Citoyen.3
Thus the most urgent reforms are to:
● amend the INPDP to ensure its financial and administrative autonomy;
● ensure the independence of its members;
● apply standards and control procedures to the public sector which holds the greatest proportion of personal information.
Key concepts such as "sensitive information" should be better defined in the new draft law. Additionally, it will be necessary to add more restrictive rules governing the use of information in the project Identifiant Unique du Citoyen; in both cases, reforms must adhere to the standards of European case law.4
Reform of the law of 2004 is prerequisite for Tunisia's adherence the European Council's Convention 108 concerning the Protection of Individuals with regard to Automatic Processing of Personal Data. As these changes are realized, it will be important to simplify and to effectively communicate procedures —which remain highly bureaucratic— through a single online outlet. If these changes cannot be implemented, it will be worth creating a new authority at the constitutional level that will be independent and driven by the principle mission to regulate the right to privacy.
Enforcing application of the law
During his first public appearance, INPDP president Chawki Gaddes declared his intention to apply the current law and to "render effective the application of penal measures in the law of 2004 against recalcitrant parties." Gaddes even went so far as to designate a deadline on 30 September 2015.5 With the exception of a handful of actors (private operators, administrations, clinics), there has been little response to the INPDP's call for compliance.
The protection of personal information, however, represents a comparative advantage for businesses looking to attract investors or grow their client bases. If officials are not yet aware of the importance of consumer confidence, lobbying for this advantage might prove to be more effective than a coercive approach.
Indeed, a participatory process might, for instance, include informative meetings with key actors in the private sector and then those in the public sector; such a strategy could employ an information guide defining procedures, and an online platform where authorization requests and declarations can be submitted. Such measures and many others are likely to encourage concerned actors to adhere to the principle of protecting personal information.
An Ill-adapted outreach approach
Raising public awareness about citizens' right to privacy, and the discourse and actions undertaken by those who handle private information are currently ill-adapted to the Tunisian context. Like its predecessors, the current government employs a security-driven discourse that emphasizes the fight against terrorism and criminality. Mainstream media has only served to reinforce this vision. Rare are those in the sphere of civil society who have contradicted this fear-based communication strategy to emphasize instead the right to privacy.
Like citizens throughout the world, Tunisians do not bother to read the famous "Conditions of Use" for social media networks, nor do they protect themselves by adjusting the functions provided for this purpose. Furthermore, they share all kinds of information pertaining to lifestyle, the places they frequent, health, and other private and sensitive data. This lack of vigilance on the part of internet users is often justified by the fallacious nothing to hide argument. In the West, this justification has been deconstructed and rejected6 by those who defend the right to privacy.
Faced with biased discourse, a lack of information and awareness, the INPDP is hard-pressed to accomplish its mission. This much was apparent on 22 October 2015, the would-be launching of the Authority's awareness campaign. An invitation to the event was posted on the INPDP Facebook page7 and officially addressed to designated public authorities including the Technical Telecommunications Agency (ATT), the Tunisian Internet Agency (ATI), and the National Agency for Computer Security (ANSI). After opening statements were made by event organizers, sponsors, and government officials, the INPDP faced a nearly empty conference room to discuss the intrusion of businesses into the private life of citizens8 and the procedures associated with applying the legal framework.9 Even the few media outlets in attendance had little more to relay about the conference than the address of Noomane Fehri, Minister of Information and Communication Technologies, who spoke about the draft law on cybercrime.10
The topic of targeted or mass surveillance carried out by state institutions was avoided, as well as its impact on public confidence and the promotion of innovative technologies. The Authority's silence on these issues is all the more concerning given that the country's many years of dictatorship are intimately associated with digital policing. Both the new counterterrorism law11 and Identifiant Unique du Citoyen project12 forebode a precipitous return to former surveillance practices.
The INPDP should have engaged in a partnership with actors of civil society and national media agencies in order to fine-tune its interaction with the public and dissemination of information regarding "the democratic and economic imperative" in the protection of personal information.
Indeed, the INPDP would do well to establish a multi-stakeholder advisory committee composed of experts in the protection of personal information and related domains. Such a committee might assemble civil society representatives and actors from the public and private sectors to develop initiatives to inform internet-users about the importance of encrypting their personal information.
1. INPDP Facebook page.
2. Tunisian postal services signs with INPDP.
3. IUC, pourra-t-on éviter le pire?
4. Données personnelles : La CJUE invalide le Safe Harbor des Etats-Unis.
5. Présentation 27 août 2015.
6. EFF: how to respond to 'I have Nothing To Hide'.
7. Facebook page event 22 October 2015.
8. Presentation: Conference 1. 22 October 2015.
9. Presentation: Conference 2. 22 oct 2015.
10. MTCEN 22 October 2015.
11. Terrorism and ITC: Keeping surveillance alive in Tunisia.
12. IUC entre les mains du MI.
INPDP	personal information	privacy	reform	Security	Surveillance
Dhouha Ben Youssef est une professionnelle des métiers de la Communication et TICs. Socialement, Dhouha consacre la plus part de son temps à plaidoyer pour la défense de la liberté d'Internet et la protection des données personnelles.
Tous les articles Blog @_dby_
Économie numérique: retour à la case départ
Data Privacy Day : comment protéger les données personnelles ?
Identifiant Unique du Citoyen : la fuite en avant
(Will not be publishd)
Home Nawaat in English Privacy in Tunisia: Legislation, Application, and Public Outreach


text:
"""
Compatibility with Python 2 and 3.

This module exposes aliases and functions that make it easier to write Python
code that is compatible with Python 2 and Python 3.

.. data:: basestring

   Alias for :func:`python2:basestring` (in Python 2) or :class:`python3:str`
   (in Python 3). See also :func:`is_string()`.

.. data:: HTMLParser

   Alias for :class:`python2:HTMLParser.HTMLParser` (in Python 2) or
   :class:`python3:html.parser.HTMLParser` (in Python 3).

.. data:: interactive_prompt

   Alias for :func:`python2:raw_input()` (in Python 2) or
   :func:`python3:input()` (in Python 3).

.. data:: StringIO

   Alias for :class:`python2:StringIO.StringIO` (in Python 2) or
   :class:`python3:io.StringIO` (in Python 3).

.. data:: unicode

   Alias for :func:`python2:unicode` (in Python 2) or :class:`python3:str` (in
   Python 3). See also :func:`coerce_string()`.

.. data:: monotonic

   Alias for :func:`python3:time.monotonic()` (in Python 3.3 and higher) or
   `monotonic.monotonic()` (a `conditional dependency
   <https://pypi.org/project/monotonic/>`_ on older Python versions).
"""

__all__ = (
    'HTMLParser',
    'StringIO',
    'basestring',
    'coerce_string',
    'interactive_prompt',
    'is_string',
    'is_unicode',
    'monotonic',
    'name2codepoint',
    'on_macos',
    'on_windows',
    'unichr',
    'unicode',
    'which',
)

# Standard library modules.
import sys

# Differences between Python 2 and 3.
try:
    # Python 2.
    unicode = unicode
    unichr = unichr
    basestring = basestring
    interactive_prompt = raw_input
    from distutils.spawn import find_executable as which
    from HTMLParser import HTMLParser
    from StringIO import StringIO
    from htmlentitydefs import name2codepoint
except (ImportError, NameError):
    # Python 3.
    unicode = str
    unichr = chr
    basestring = str
    interactive_prompt = input
    from shutil import which
    from html.parser import HTMLParser
    from io import StringIO
    from html.entities import name2codepoint

try:
    # Python 3.3 and higher.
    from time import monotonic
except ImportError:
    # A replacement for older Python versions:
    # https://pypi.org/project/monotonic/
    try:
        from monotonic import monotonic
    except (ImportError, RuntimeError):
        # We fall back to the old behavior of using time.time() instead of
        # failing when {time,monotonic}.monotonic() are both missing.
        from time import time as monotonic

def coerce_string(value):
    """
    Coerce any value to a Unicode string (:func:`python2:unicode` in Python 2 and :class:`python3:str` in Python 3).

    :param value: The value to coerce.
    :returns: The value coerced to a Unicode string.
    """
    return value if is_string(value) else unicode(value)

def is_string(value):
    """
    Check if a value is a :func:`python2:basestring` (in Python 2) or :class:`python3:str` (in Python 3) object.

    :param value: The value to check.
    :returns: :data:`True` if the value is a string, :data:`False` otherwise.
    """
    return isinstance(value, basestring)

def is_unicode(value):
    """
    Check if a value is a :func:`python2:unicode` (in Python 2) or :class:`python2:str` (in Python 3) object.

    :param value: The value to check.
    :returns: :data:`True` if the value is a Unicode string, :data:`False` otherwise.
    """
    return isinstance(value, unicode)

def on_macos():
    """
    Check if we're running on Apple MacOS.

    :returns: :data:`True` if running MacOS, :data:`False` otherwise.
    """
    return sys.platform.startswith('darwin')

def on_windows():
    """
    Check if we're running on the Microsoft Windows OS.

    :returns: :data:`True` if running Windows, :data:`False` otherwise.
    """
    return sys.platform.startswith('win')

redpajama_set_name: RedPajamaGithub


text:
History: Although a substantial decrease in vaccine-serotype invasive pneumococcal disease (IPD) incidence was observed following a intro of pneumococcal conjugate vaccines (PCV), the estimated range of thirteen-valent conjugate vaccine (PCV13) performance for serotype 3 disease is wide and includes zero
Hector Austin Laminin October 20, 2020
History: Although a substantial decrease in vaccine-serotype invasive pneumococcal disease (IPD) incidence was observed following a intro of pneumococcal conjugate vaccines (PCV), the estimated range of thirteen-valent conjugate vaccine (PCV13) performance for serotype 3 disease is wide and includes zero. post-PCV13 serotype 3 IPD instances occurred among fully vaccinated children. Age distribution, medical syndrome and presence of Big Endothelin-1 (1-38), human comorbidities among serotype 3 IPD instances were related before and after PCV13 intro. There was no association between the date of the last PCV13 dose and time to IPD to suggest waning of immunity. Conclusions: seven years following PCV 13 we found no significant changes in serotype 3 IPD incidence or disease characteristics in children in Massachusetts. = 25)= 18)(%) 14 (56%)11 (61%) Race/ethnicity (%) Asian 0 (0.0%)1 (5.6%) African American 1 (4.0%)4 (22.2%) Hispanic 7 (28.0%)4 (22.2%) Light 11 (44.0%)8 (44.4%) Other/Unknown 6 (24.0%)1 (5.6%) Immunization position with PCV 13 (%) Fully immunized * 0 (0.0%)14 (77.8%) Partially immunized + Big Endothelin-1 (1-38), human 0 (0.0%)0 (0.0%) Zero vaccination with PCV 13 25 (100%)4 (22.2%) IPD symptoms (%) Bacteremia with out a concentrate 7 (28.0%)5 (27.7%) Bacteremia with concentrate 0 (0.0%)1 (5.6%) Bacteremic pneumonia/Empyema 14 (56.0%)10 (55.6%) Meningitis 3 (12%)2 (11.1%) Osteoarthritis 1 (4%)0 (0.0) Mortality (%) 0(0.0%)2 (11.1%) Comorbidities #(%) 2 (8.0%)3 (16.7%) Open up in another screen PCV1313-valent Pneumococcal conjugated vaccine; IPDInvasive pneumococcal disease. * immunized is normally thought as 2C3 dosages of vaccine at 2 Completely, 4, six months old and one dosage after a year old OR at least one dosage after two years old (according to CDC suggestions). + Partly immunized is thought as receipt of at least one dosage of PCV 13, without being immunized fully. # Comorbidities included cerebral palsy, persistent lung disease, congenital cardiovascular disease, prematurity/low delivery fat and sickle cell disease. Twenty-five situations of serotype 3 IPD happened within the eight-year period before the launch of PCV13 (January 2002 to Dec 2009). Eighteen situations occurred within the seven-year period following launch of PCV13 (January 2011 to Dec 2017). Four serotype 3 situations happened during 2010, the entire calendar year PCV 13 was presented, and had been NOS3 excluded out of this evaluation. Among the post- PCV13 situations, 14 situations (78%) happened in kids who were completely vaccinated because of their age group, two (11%) happened in newborns aged 0C2 a few months who hadn't however received their regular two-month vaccine, and two (11%) situations were in old unvaccinated Big Endothelin-1 (1-38), human kids. The occurrence of serotype 3 IPD per 100,000 kids didn't considerably transformation over time. The mean incidence rate after PCV13 and before PCV13 was 0.19 and 0.21, respectively, with an incidence rate percentage [IRR] of 0.86 (95% CI 0.41C1.82). The yearly tendency of serotype 3 IPD was reducing [?0.04 (95% CI ?0.09, 0.0051)] prior to PCV 13 and increasing [0.07 (95% CI ?0.0087, 0.14)] in the years following PCV13. The switch in tendency of serotype 3 IPD incidence before and after PCV13 was not significant [post-PCV13 vs. Pre-PCV13 was 0.00017 (95% CI ?0.37, 0.37)]. The characteristics of children who experienced serotype 3 IPD were generally similar across the two time periods. The age distribution at the time of IPD was related before and after PCV13, with the majority of cases happening in the young population (Table 1). There was also a similar distribution of IPD medical syndromes before and after PCV13 (56% and 55.6% of cases were bacteremic pneumonia/empyema, 28% and 27.7% isolated bacteremia, 12% and 11.1% meningitis before and after the introduction of PCV13, respectively). The time from your last PCV7 dose to serotype 3 IPD ranged from 9 to 1521 days (median 222 days), and from last PCV13 dose to serotype 3 IPD day ranged from 23 to 1243 days (median 432 days) and was not statistically different between the two study periods (Wilcoxon twoCsample test = 0.26). Within the population of children that experienced serotype 3 IPD in the post-PCV13 era, three (16.7%) had an underlying comorbidity compared to two (8%) children with underlying comorbidities in the pre-PCV13 era (these comorbidities include cerebral palsy, chronic lung disease, congenital heart disease, prematurity/low birth excess weight and sickle cell disease), family member risk percentage [RR] = 2.08 (CI 95% 0.39C11.22). 3. Conversation.
← Supplementary MaterialsAdditional document 1
Supplementary MaterialsFig S1 CAS-111-2052-s001 →


text:
Denmark
South Greenland – Carl Peter Holbøll, Inspector of South Greenland (1828–1856)

Portugal
Angola –
 José Xavier Bressane Leite, Governor-General of Angola (1842–1843)
 Temporarily vacant (1843–1844)

United Kingdom
 Malta Colony
Henry Bouverie, Governor of Malta (1836–1843)
Patrick Stuart, Governor of Malta (1843–1847)
 New South Wales – Major George Gipps, Governor of New South Wales (1838–1846)
 South Australia – Sir George Grey, Governor of South Australia (1841–1845)
 Western Australia – John Hutt, Governor of Western Australia (1839–1846)

Colonial governors
Colonial governors
1843


text:
20% impact fee ends in Lee with big jump
HEATHER WYSOCKI
HWYSOCKI@NEWS-PRESS.COM
Lee County's impact fees the last two years may have been a whimper compared to full prices, but that discount went out with a bang.
At 4:30 p.m. Friday, Lee County's two-year impact fee reduction ended.
And the explosive ending some predicted for the last few days of the discount was proven true, according to Lee County data.
On Friday alone, the county received permit applications for 95 single-family homes and 136 multifamily units.
Since March 1, the county has received applications to build 299 single-family homes and around 90 multifamily permits totaling 1,201 units.
Commercial numbers were not available Friday.
"It was a big jump, it really was," said Joan LaGuardia, communications manager for the Lee County Department of Community Development.
By comparison, the county took in applications for just 34 single-family homes and 365 units.
In a typical month, the office receives 65-100 applications to build single family homes, LaGuardia said.
Lee County Commissioners voted in March 2013 to reduce impact fees to 20 percent for two years.
The fees are collected on home and commercial construction projects and can be used for new capital projects but not improvements.
On March 3, after nearly a year of discussion, commissioners voted 4-1 to increase the fees to 45 percent.
That's about $5,840 to build a single-family home — or nearly double the $2,942 impact fee paid under the 20 percent reduction.
Lee County saw a similar scramble right before it last increased fees.
In June 2007, road impact fees almost tripled in most areas of the county, and many builders waiting to see what the economy held scrambled to apply at the last minute.
But the boost in June 2007, when road impact fees almost tripled in most areas of the county, was much higher, LaGuardia said.
The jump in applications in March didn't surprise Mark Stevens, president of commercial builder Stevens Construction. His company had several potential projects on hold until commissioners decided how high fees would go.
"We can't say for certain they wouldn't have proceeded, but out of five projects two of them probably would not have if it went up to the past rate," Stevens said.
Before Lee County board's decision to create a grace period, which allowed builders to apply by Friday but go through the full process within six months, many developers were already working on applications to meet the deadline, Stevens said.
But some were still scrambling.
"Pretty much every architectural firm I know of has been feverishly working on completing plans the last couple months, and even this week," he said.
Now, LaGuardia said, the county will look to see if the spike will really increase permitting for the year, or if it was just a temporary boost.
That's what happened in 2007, before "the feared recession became economic fact," she added.
"What you'll see now is we'll have really low numbers the next month and the month after that. … So by the end of the year that'll be the question, did we really have more or was everyone just rushing to get them in to beat the deadline?"


text:
Nepali Goddess Wants To Be A Banker
by Derek Loosvelt | April 08, 2010
Chanira Bajracharya, a 15-year-old whose resume includes blessing devotees, riding atop chariots and being an incarnation of the Hindu goddess Kali, says when she grows up she wants to work in finance, explaining in a recent interview with Reuters that she'd like to "study commerce or accounting and be engaged in the banking sector."
The goddess, who has not been allowed to "mingle with outsiders" and thus does not have any friends or playmates (though she does have two brothers), also told Reuters that if she had her choice of places to work, she would want to be hired by Bear Stearns because it's known for its renegade entrepreneurial bent. Reuters then told the goddess that Bear was no longer in existence, that the former cowboy of Wall Street was acquired by J.P. Morgan a couple years ago. Then I think I would like to work for Lehman Brothers, the goddess said to Reuters, because of their incredible team-oriented culture that I've heard so much about. Reuters then told the goddess that the Brothers went bankrupt a couple years ago for making some extremely bad bets and because its CEO turned out to be not such a great manager. Oh, the goddess said, then I guess I'll work for Merrill Lynch, because I love bulls and I think having the largest retail sales force on Wall Street will be essential to thriving in the investment banking sector during the next two decades.
The Reuters reporter began to respond to the goddess, telling her about Morgan Stanley Smith Barney, a man named Kenny Lewis, another called Thain, a bank known as America and billions of dollars in losses, but was cut short and ushered out of the palace by the goddess' mother, who said it was time for her daughter's afternoon pooja.
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Filed Under: Finance


These intensely flavored, sun-kissed beauties are a concentrated source of nutrients. They provide vitamins C and K, iron, and lycopene, an antioxidant associated with lower risk of certain cancers.
Sun-dried tomatoes are common pizza toppings. You can add them to salads and use them to make bruschetta with variations using additional ingredients such as feta cheese or chicken. You can use sun-dried tomatoes to increase the acidity in pesto, hummus and other condiments, and toss them into pasta dishes to add a chewy texture.


text:
<?php

/**
 * @namespace
 */
namespace Zend\Tool\Framework\Metadata;

/**
 * @category   Zend
 * @package    Zend_Tool
 * @copyright  Copyright (c) 2005-2010 Zend Technologies USA Inc. (http://www.zend.com)
 * @license    http://framework.zend.com/license/new-bsd     New BSD License
 */
interface Attributable
{
    public function getAttributes();
}


text:
František Hák (27. května 1886, Studenec – 1. března 1974) byl český fotograf působící na Novopacku.

Život a dílo
Přibližně v roce 1908 si otevřel fotografický ateliér v Klášterní ulici (naproti lékárně). Provozoval obvyklý fotografický ateliér orientovaný na portrétní fotografii a na dokumentaci lokálních událostí. Na popud Aloise Boudy začal ve dvacátých letech dokumentovat lidovou architekturu. V této činnosti jej podporovalo Městské muzeum v Nové Pace, Okrašlovací spolek v Nové Pace a Okresní sdružení agrárního dorostu v Nové Pace. Rovněž pracoval jako dokumentarista Uměleckoprůmyslového musea v Praze. Dále jsou jeho fotografie ve sbírkách Etnologického ústavu AV ČR. Jedná se o 951 fotografií formátu 9×14 cm z let 1927 a 1928. Z dokumentace ale vyplývá, že fotografie pocházejí ve skutečnosti i z dřívějších let. Jejich nákup z prostředků Ministerstva školství a národní osvěty zorganizoval Zdeněk Wirth. Další Hákovy fotografie s touto tematikou vznikly během Zaměřovací akce České akademie věd a umění, která proběhla v letech 1941–1946 a kterou vedl jako předseda komise opět Zdeněk Wirth. Dnes je sbírka uložena v Generálním archivu AV ČR.

Vedle dokumentace venkovských stavení jsou na fotografiích zachyceny i městské domy z Nové Paky, Jilemnice a Lázní Bělohrad. Na snímcích jsou zachyceny i krajinné pohledy nebo na druhé straně detaily konstrukcí a výzdoby, sakrální a technické objekty (vodní a větrné mlýny).

Jeho synem byl fotograf Miroslav Hák.

Odkazy

Literatura

Reference

Externí odkazy

Čeští fotografové
Narození 27. května
Narození v roce 1886
Narození ve Studenci (okres Semily)
Úmrtí 1. března
Úmrtí v roce 1974
Muži


This topic describes the minimum privileges required by the vSphere BOSH CPI. A vSphere admin must grant the following privileges to the vSphere service account that Pivotal Cloud Foundry (PCF) uses to manage vSphere resources.
The PCF account needs privileges at both the vCenter server level and the Datacenter level. See Hierarchical Inheritance of Permissions in the VMware documentation for how permission levels and inheritance work in vSphere.
Ops Manager assigns custom attributes to the virtual machines (VMs) it deploys to identify BOSH releases and job index information about each VM. vCenter APIs require vCenter server level access to manage these custom attributes.
Ops Manager creates a folder for VMs, stemcells, and persistent disks during installation. The folder contents change frequently as Ops Manager applies changes.
When using vAppImport to clone a VM, BOSH requires the resource migration privileges to create a new, powered-off VM based on a given stemcell. BOSH migrates the VM to the destination datastore, where Ops Manager deploys the VM and powers it on.
When cloning a stemcell, BOSH sets custom specifications, such as hostnames and network configurations, based on the stemcell operating system.
The VM download privilege allows BOSH to modify files within a VM, including links between VMs and persistent disks. When vMotion migrates disks in vSphere, BOSH uses these links to maintain the connections between VMs and their persistent disks.
Before Ops Manager deploys a new VM, it uses a snapshot to clone the stemcell image to the destination.
These privileges must be set at the resource pool level. VApp.ApplicationConfig is required when attaching or detaching persistent disks.


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