2 Plants Affecting the Central Nervous System
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Electrophysiologic Evidence for Increased Endogenous Gabaergic but Not Glycinergic Inhibitory Tone in the Rat Spinal Nerve Ligation Model of Neuropathy Vesa K
Anesthesiology 2001; 94:333–9 © 2001 American Society of Anesthesiologists, Inc. Lippincott Williams & Wilkins, Inc. Electrophysiologic Evidence for Increased Endogenous GABAergic but Not Glycinergic Inhibitory Tone in the Rat Spinal Nerve Ligation Model of Neuropathy Vesa K. Kontinen, M.D., Ph.D.,* Louise C. Stanfa, Ph.D.,† Amlan Basu,‡ Anthony H. Dickenson, Ph.D.§ Background: Changes in the inhibitory activity mediated by There is evidence that both GABA and glycinergic inter- ␥-aminobutyric acid (GABA) and glycine, acting at spinal GABA A neurons are preferentially associated with the control of receptors and strychnine-sensitive glycine receptors, are of in- 6–9 terest in the development of neuropathic pain. There is ana- low-threshold afferent input to the spinal cord. Con- Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/94/2/333/402482/0000542-200102000-00024.pdf by guest on 29 September 2021 tomic evidence for changes in these transmitter systems after sistent with this, intrathecal administration of the 10 nerve injuries, and blocking either GABAA or glycine receptors GABAA-receptor antagonist bicuculline or the glycine- has been shown to produce allodynia-like behavior in awake receptor antagonist strychnine10,11 produces segmen- normal animals. tally localized tactile allodynia-like behavior in conscious Methods: In this study, the possible changes in GABAergic and glycinergic inhibitory activity in the spinal nerve ligation rats and increased responses to mechanical stimulation 12 model of neuropathic pain were studied by comparing the in anesthetized cats. Intrathecal strychnine has also effects of the GABAA-receptor antagonist bicuculline and the been shown to produce in anesthetized rats reflex re- glycine-receptor antagonist strychnine in neuropathic rats to sponses similar to those produced by nociceptive stim- their effects in sham-operated and nonoperated control rats. -
(12) Patent Application Publication (10) Pub. No.: US 2016/017.4603 A1 Abayarathna Et Al
US 2016O174603A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2016/017.4603 A1 Abayarathna et al. (43) Pub. Date: Jun. 23, 2016 (54) ELECTRONIC VAPORLIQUID (52) U.S. Cl. COMPOSITION AND METHOD OF USE CPC ................. A24B 15/16 (2013.01); A24B 15/18 (2013.01); A24F 47/002 (2013.01) (71) Applicants: Sahan Abayarathna, Missouri City, TX 57 ABSTRACT (US); Michael Jaehne, Missouri CIty, An(57) e-liquid for use in electronic cigarettes which utilizes- a TX (US) vaporizing base (either propylene glycol, vegetable glycerin, (72) Inventors: Sahan Abayarathna, MissOU1 City,- 0 TX generallyor mixture at of a 0.001 the two) g-2.0 mixed g per with 1 mL an ratio. herbal The powder herbal extract TX(US); (US) Michael Jaehne, Missouri CIty, can be any of the following:- - - Kanna (Sceletium tortuosum), Blue lotus (Nymphaea caerulea), Salvia (Salvia divinorum), Salvia eivinorm, Kratom (Mitragyna speciosa), Celandine (21) Appl. No.: 14/581,179 poppy (Stylophorum diphyllum), Mugwort (Artemisia), Coltsfoot leaf (Tussilago farfara), California poppy (Eschscholzia Californica), Sinicuichi (Heimia Salicifolia), (22) Filed: Dec. 23, 2014 St. John's Wort (Hypericum perforatum), Yerba lenna yesca A rtemisia scoparia), CaleaCal Zacatechichihichi (Calea(Cal termifolia), Leonurus Sibericus (Leonurus Sibiricus), Wild dagga (Leono Publication Classification tis leonurus), Klip dagga (Leonotis nepetifolia), Damiana (Turnera diffiisa), Kava (Piper methysticum), Scotch broom (51) Int. Cl. tops (Cytisus scoparius), Valarien (Valeriana officinalis), A24B 15/16 (2006.01) Indian warrior (Pedicularis densiflora), Wild lettuce (Lactuca A24F 47/00 (2006.01) virosa), Skullcap (Scutellaria lateriflora), Red Clover (Trifo A24B I5/8 (2006.01) lium pretense), and/or combinations therein. -
Unnamed Document
Mutations M287L and Q266I in the Glycine Receptor ␣1 Subunit Change Sensitivity to Volatile Anesthetics in Oocytes and Neurons, but Not the Minimal Alveolar Concentration in Knockin Mice Cecilia M. Borghese, Ph.D.,* Wei Xiong, Ph.D.,† S. Irene Oh, B.S.,‡ Angel Ho, B.S.,§ S. John Mihic, Ph.D.,ʈ Li Zhang, M.D.,# David M. Lovinger, Ph.D.,** Gregg E. Homanics, Ph.D.,†† Edmond I. Eger 2nd, M.D.,‡‡ R. Adron Harris, Ph.D.§§ ABSTRACT What We Already Know about This Topic • Inhibitory spinal glycine receptor function is enhanced by vol- Background: Volatile anesthetics (VAs) alter the function of atile anesthetics, making this a leading candidate for their key central nervous system proteins but it is not clear which, immobilizing effect if any, of these targets mediates the immobility produced by • Point mutations in the ␣1 subunit of glycine receptors have been identified that increase or decrease receptor potentiation VAs in the face of noxious stimulation. A leading candidate is by volatile anesthetics the glycine receptor, a ligand-gated ion channel important for spinal physiology. VAs variously enhance such function, and blockade of spinal glycine receptors with strychnine af- fects the minimal alveolar concentration (an anesthetic What This Article Tells Us That Is New EC50) in proportion to the degree of enhancement. • Mice harboring specific mutations in their glycine receptors Methods: We produced single amino acid mutations into that increased or decreased potentiation by volatile anesthetic in vitro did not have significantly altered changes in anesthetic the glycine receptor ␣1 subunit that increased (M287L, third potency in vivo transmembrane region) or decreased (Q266I, second trans- • These findings indicate that this glycine receptor does not me- membrane region) sensitivity to isoflurane in recombinant diate anesthetic immobility, and that other targets must be receptors, and introduced such receptors into mice. -
Studies on the Pharmacology of Conopharyngine, an Indole Alkaloid of the Voacanga Series
Br. J. Pharmac. Chemother. (1967), 30, 173-185. STUDIES ON THE PHARMACOLOGY OF CONOPHARYNGINE, AN INDOLE ALKALOID OF THE VOACANGA SERIES BY P. R. CARROLL AND G. A. STARMER From the Department of Pharmacology, University of Sydney, New South Wales, Australia (Received January 17, 1967) Conopharyngine, the major alkaloid present in the leaves of Tabernaemontana (Conopharyngia) pachysiphon var. cumminsi (Stapf) H. Huber was isolated and identified by Thomas & Starmer (1963). The same alkaloid has also been found in the stem bark of a Nigerian variety of the same species by Patel & Poisson (1966) and in the stem bark of Conopharyngia durissima by Renner, Prins & Stoll (1959). Conopharyn- gine is an indole alkaloid of the voacanga type, being 18-carbomethoxy-12,13- dimethoxyibogamine (Fig. 1) and is thus closely related to voacangine and coronaridine. Me.0OC Fig. 1. Conopharyngine (18-carbomethoxy-12,13-dimethoxyibogamine). Some confusion exists in that an alkaloid with an entirely different structure, but also named conopharyngine, was isolated from a cultivated variety of Conopharyngia pachysiphon by Dickel, Lucas & Macphillamy (1959). This compound was shown to be the 3-D-9-glucoside of 55-20a-amino-3 8-hydroxypregnene, and was reported to possess marked hypotensive properties. The presence of steroid alkaloids in the Tabernaemontaneae was hitherto unknown and it was suggested by Raffauf & Flagler (1960) and Bisset (1961) that the plant material was open to further botanical confir- mation. The roots of the conopharyngia species are used in West Africa to treat fever (Kennedy, 1936), including that of malaria (Watt & Breyer-Brandwijk, 1962). The only report on the pharmacology of conopharyngine is that of Zetler (1964), who included it in a study of some of the effects of 23 natural and semi-synthetic alkaloids 174 P. -
表 2.7.6.25-143 鉄剤の投与を受けた被験者の割合(Fas) (続き)
2.7.6 個々の試験のまとめ 表 2.7.6.25-143 鉄剤の投与を受けた被験者の割合(FAS)(続き) 5.3.5.1―8 表 11.4.1―8 より引用 1282 Page 460 of 1887 2.7.6 個々の試験のまとめ (8) 血清フェリチン値 100 ng/mL 以上又は TSAT 20%以上の被験者の割合 血清フェリチン値 100 ng/mL 以上又は TSAT 20%以上の被験者の割合を表 2.7.6.25-144 に示した.血清フェリチン値 100 ng/mL 以上又は TSAT 20%以上の被験者の割合は,全集 団を対象に記載した. 血清フェリチン値 100 ng/mL 以上又は TSAT 20%以上の被験者の割合は,MT-6548 群に おいてベースラインで 94.7%に対し,52 週後では 93.6%であり,darbepoetin 群においてベ ースラインで 90.8%に対し,52 週後では 96.7%であった. 1283 Page 461 of 1887 2.7.6 個々の試験のまとめ 表 2.7.6.25-144 血清フェリチン値 100 ng/mL 以上又は TSAT 20%以上の被験者の割合(FAS) 5.3.5.1―8 表 14.2.3.8.1 より引用 1284 Page 462 of 1887 2.7.6 個々の試験のまとめ (9) 血球関連評価項目 MMRM を用いた MCV,MCH,ヘマトクリット,RBC,網状赤血球数及び網状赤血球 率のベースラインからの変化量を表 2.7.6.25-145,表 2.7.6.25-146,表 2.7.6.25-147, 表 2.7.6.25-148,表 2.7.6.25-149 及び表 2.7.6.25-150 に示した.血球関連評価項目は, 全集団を対象に記載した. MMRM を用いた MCV の 52 週後のベースラインからの変化量の LSMean 及びその 95%CI は,MT-6548 群で 2.7 fL 及び 2.2~3.2 fL,darbepoetin 群で 0.1 fL 及び -0.3~0.6 fL であった.MMRM を用いた MCV の 52 週後のベースラインからの変化量の MT-6548 群 と darbepoetin 群の差の LSMean 及びその 95%CI は,2.6 fL 及び 1.9~3.3 fL であり,統計 学的に有意な差が認められた(p<0.001). MMRM を用いた MCH の 52 週後のベースラインからの変化量の LSMean 及びその 95%CI は,MT-6548 群で 1.06 pg 及び 0.86~1.26 pg,darbepoetin 群で 0.01 pg 及び -0.19~ 0.20 pg であった.MMRM を用いた MCH の 52 週後のベースラインからの変化量の MT- 6548 群と darbepoetin 群の差の LSMean 及びその 95%CI は,1.05 pg 及び 0.77~1.34 pg で あり,統計学的に有意な差が認められた(p<0.001). -
Investigation of Photoprotective, Anti-Inflammatory, Antioxidant
foods Article Investigation of Photoprotective, Anti-Inflammatory, Antioxidant Capacities and LC–ESI–MS Phenolic Profile of Astragalus gombiformis Pomel Sabrina Lekmine 1 , Samira Boussekine 1, Salah Akkal 2 , Antonio Ignacio Martín-García 3 , Ali Boumegoura 4, Kenza Kadi 5, Hanene Djeghim 4, Nawal Mekersi 5, Samira Bendjedid 6 , Chawki Bensouici 4 and Gema Nieto 7,* 1 Laboratory of Bioactive Molecules and Applications, Larbi Tébessi University, Tébessa 12000, Algeria; [email protected] (S.L.); [email protected] (S.B.) 2 Valorization of Natural Resources, Bioactive Molecules and Biological Analysis Unit, Department of Chemistry, University of Mentouri Constantine 1, Constantine 25000, Algeria; [email protected] 3 Estación Experimental del Zaidín (CSIC), ProfesorAlbareda 1, 18008 Granada, Spain; [email protected] 4 Biotechnology Research Center (C.R.Bt), Ali Mendjeli, Nouvelle Ville, UV 03 BP E73, Constantine 25000, Algeria; [email protected] (A.B.); [email protected] (H.D.); [email protected] (C.B.) 5 Biotechnology, Water, Environment and Health Laboratory, Abbes Laghrour University, Khenchela 40000, Algeria; [email protected] (K.K.); [email protected] (N.M.) 6 Research Laboratory of Functional and Evolutionary Ecology, Department of Biology, Faculty of Natural Sciences and Life, Chadli Bendjedid University, El Tarf 36000, Algeria; [email protected] 7 Department of Food Technology, Food Science and Nutrition, Faculty of Veterinary Sciences, Regional Campus of International Excellence “Campus Mare Nostrum”, Espinardo, 30071 Murcia, Spain Citation: Lekmine, S.; Boussekine, S.; * Correspondence: [email protected]; Tel.: +34-(86)-8889694 Akkal, S.; Martín-García, A.I.; Boumegoura, A.; Kadi, K.; Djeghim, Abstract: Plant-derived compounds have recently been gaining popularity as skincare factors due to H.; Mekersi, N.; Bendjedid, S.; their ability to absorb ultraviolet radiations and their anti-inflammatory, and antioxidant properties. -
Survey of Roadside Alien Plants in Hawai`I Volcanoes National Park and Adjacent Residential Areas 2001–2005
Technical Report HCSU-032 SURVEY OF ROADSIDE ALIEN PLANts IN HAWAI`I VOLCANOES NATIONAL PARK AND ADJACENT RESIDENTIAL AREAS 2001–2005 Linda W. Pratt1 Keali`i F. Bio2 James D. Jacobi1 1 U.S. Geological Survey, Pacific Island Ecosystems Research Center, Kilauea Field Station, P.O. Box 44, Hawaii National Park, HI 96718 2 Hawai‘i Cooperative Studies Unit, University of Hawai‘i at Hilo, P.O. Box 44, Hawai‘i National Park, HI 96718 Hawai‘i Cooperative Studies Unit University of Hawai‘i at Hilo 200 W. Kawili St. Hilo, HI 96720 (808) 933-0706 September 2012 This product was prepared under Cooperative Agreement CA03WRAG0036 for the Pacific Island Ecosystems Research Center of the U.S. Geological Survey. Technical Report HCSU-032 SURVEY OF ROADSIDE ALIEN PLANTS IN HAWAI`I VOLCANOES NATIONAL PARK AND ADJACENT RESIDENTIAL AREAS 2001–2005 1 2 1 LINDA W. PRATT , KEALI`I F. BIO , AND JAMES D. JACOBI 1 U.S. Geological Survey, Pacific Island Ecosystems Research Center, Kīlauea Field Station, P.O. Box 44, Hawai`i Volcanoes National Park, HI 96718 2 Hawaii Cooperative Studies Unit, University of Hawai`i at Hilo, Hilo, HI 96720 Hawai`i Cooperative Studies Unit University of Hawai`i at Hilo 200 W. Kawili St. Hilo, HI 96720 (808) 933-0706 September 2012 This article has been peer reviewed and approved for publication consistent with USGS Fundamental Science Practices ( http://pubs.usgs.gov/circ/1367/ ). Any use of trade, firm, or product names is for descriptive purposes only and does not imply endorsement by the U.S. Government. -
Enantioenriched Positive Allosteric Modulators Display Distinct Pharmacology at the Dopamine D1 Receptor
molecules Article Enantioenriched Positive Allosteric Modulators Display Distinct Pharmacology at the Dopamine D1 Receptor Tim J. Fyfe 1, Peter J. Scammells 1, J. Robert Lane 2,3,* and Ben Capuano 1,* 1 Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC 3052, Australia; tim.fyfe@griffithhack.com (T.J.F.); [email protected] (P.J.S.) 2 Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC 3052, Australia 3 School of Life Sciences, Queen’s Medical Centre, University of Nottingham, Nottingham NG7 2UH, UK * Correspondence: [email protected] (J.R.L.); [email protected] (B.C.) Abstract: (1) Background: Two first-in-class racemic dopamine D1 receptor (D1R) positive allosteric modulator (PAM) chemotypes (1 and 2) were identified from a high-throughput screen. In particular, due to its selectivity for the D1R and reported lack of intrinsic activity, compound 2 shows promise as a starting point toward the development of small molecule allosteric modulators to ameliorate the cognitive deficits associated with some neuropsychiatric disease states; (2) Methods: Herein, we describe the enantioenrichment of optical isomers of 2 using chiral auxiliaries derived from (R)- and (S)-3-hydroxy-4,4-dimethyldihydrofuran-2(3H)-one (D- and L-pantolactone, respectively); (3) Results: We confirm both the racemate and enantiomers of 2 are active and selective for the D1R, but that the respective stereoisomers show a significant difference in their affinity and magnitude of positive allosteric cooperativity with dopamine; (4) Conclusions: These data warrant further investigation Citation: Fyfe, T.J.; Scammells, P.J.; of asymmetric syntheses of optically pure analogues of 2 for the development of D1R PAMs with Lane, J.R.; Capuano, B. -
(19) United States (12) Patent Application Publication (10) Pub
US 20130289061A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2013/0289061 A1 Bhide et al. (43) Pub. Date: Oct. 31, 2013 (54) METHODS AND COMPOSITIONS TO Publication Classi?cation PREVENT ADDICTION (51) Int. Cl. (71) Applicant: The General Hospital Corporation, A61K 31/485 (2006-01) Boston’ MA (Us) A61K 31/4458 (2006.01) (52) U.S. Cl. (72) Inventors: Pradeep G. Bhide; Peabody, MA (US); CPC """"" " A61K31/485 (201301); ‘4161223011? Jmm‘“ Zhu’ Ansm’ MA. (Us); USPC ......... .. 514/282; 514/317; 514/654; 514/618; Thomas J. Spencer; Carhsle; MA (US); 514/279 Joseph Biederman; Brookline; MA (Us) (57) ABSTRACT Disclosed herein is a method of reducing or preventing the development of aversion to a CNS stimulant in a subject (21) App1_ NO_; 13/924,815 comprising; administering a therapeutic amount of the neu rological stimulant and administering an antagonist of the kappa opioid receptor; to thereby reduce or prevent the devel - . opment of aversion to the CNS stimulant in the subject. Also (22) Flled' Jun‘ 24’ 2013 disclosed is a method of reducing or preventing the develop ment of addiction to a CNS stimulant in a subj ect; comprising; _ _ administering the CNS stimulant and administering a mu Related U‘s‘ Apphcatlon Data opioid receptor antagonist to thereby reduce or prevent the (63) Continuation of application NO 13/389,959, ?led on development of addiction to the CNS stimulant in the subject. Apt 27’ 2012’ ?led as application NO_ PCT/US2010/ Also disclosed are pharmaceutical compositions comprising 045486 on Aug' 13 2010' a central nervous system stimulant and an opioid receptor ’ antagonist. -
Traditional Medicine
MINISTRY OF HEALTH DEPARTMENT OF MEDICAL RESEARCH (LOWER MYANMAR) -4 rf,"d .1, l,.ifr M '\t $.,iJ+j AI{I{OTATED BIBLIOGRAPHY OF TRADITIOI{AL MEDTCII\E RESEARCH CARRTED OUT AT DMR (LM) nURIf{G 196s-2011 f# #a# €€# 6rdffi t u 6 l6'6 ktibilicetidiT \ &, ft Ministry of Health Department of Medical Research (Lower Myanmar) Central Biomedical Library ANNOTATED BIBLIOGRAPHY OF TRADITIONAL MEDICINE RESEARCH CARRIED OUT AT DMR (LM) DURING 1965-2011 Compiled by Cho Mar Oo BA (Economics); DipLibSc Librarian, Central Biomedical Library Staff of Central Biomedical Library May Aye Than MBBS, MMedSc (Pharmacology) Deputy Director & Head Pharmacology Research Division Staff of Pharmacology Research Division Aung Myo Min BSc (Physics); DipLibSc; RL Librarian & Head (Retd.) Central Biomedical Library Ye Htut MBBS, MSc (Medical Parasitology) (London) DLSHTM, FRCP (Edin) Deputy Director-General Myo Khin MBBS, MD (New South Wales), DCH, FRCP (Edin) Acting Director General PREFACE Throughout recorded history, people of various cultures have relied on traditional medicine. Worldwide, only an estimated ten to thirty percent of human health care is delivered by conventional, biomedically oriented practitioners. The remaining seventy to ninety percent ranges from self-care according to folk principles, to care given in an organized health care system based on traditional medicine. Likewise, in Myanmar health care system, the existence of traditional medicine along with allopathic medicines is well recognized. Myanmar traditional medicine dates back 2,000 years and is well accepted and widely used by the people throughout history. Burma Medical Research Institute since it was established in 1963 had started a program of research on traditional medicinal plants including laboratory screening tests on animal models of herbs with reputed pharmacological properties-such as anti-dysentery, bronchodilator, hypoglycemic effects. -
TO COPE with Stress…
TO COPE WITH Stress ….. For the majority of the population life throws us unexpected curves, short or long lasting, in which we are forced to deal with and move on. This is an inevitable fact of life. Unfortunately, these stressors of life take their tole on our physiology, stripping us of some of our most precious resources...b vitamins. This is one of the reasons why sometimes after dealing with prolonged stress we feel like we just finished the Tour de France on foot. Interestingly, the nutraceutical universe does in fact provide a means to replenish these precious resources and at the same time, help ease the potential of flying off the handle when the stress volcano is on the verge of eruption. _____________________________________________________________________________ What do B Vitamins do? One of the major physiological damage pathways that stress initiates is activation of slight to moderate Our bodies have the amazing ability to convert sympathetic responses. This initiates the fight-or- macronutrients from food into usable potential and flight response and activation of the hypothalamic- kinetic energy through myriads of biochemical pituitary-adrenal axis, producing catecholamines and pathways. We know that these reactions are catalyzed cortisol, respectively. Catecholamine (adrenaline and by enzymes (globular proteins that speed up reaction noradrenaline) and corticosteroid secretion ultimately rates), but do enzymes have on/off switches? As ends up in glycogenolysis, lipolysis, proteinolysis, much as enzymes have the ability to speed up and activation of myriads of different biochemical reactions, most enzymes require coenzymes and pathways. As previously stated, the majority of the cofactors (small organic and inorganic molecules that enzymes involved in these pathways require b are required by enzymes to carry out their catalytic vitamins as coenzymes. -
WO 2013/142184 Al 26 September 2013 (26.09.2013) P O P C T
(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2013/142184 Al 26 September 2013 (26.09.2013) P O P C T (51) International Patent Classification: DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, A61K 33/16 (2006.01) A61K 31/7048 (2006.01) HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, A61K 33/14 (2006.01) A61K 31/70 (2006.01) KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, A61K 33/18 (2006.01) A61K 31/4196 (2006.01) ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, (21) International Application Number: RW, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, PCT/US20 13/030788 TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, (22) International Filing Date: ZM, ZW. 13 March 2013 (13.03.2013) (84) Designated States (unless otherwise indicated, for every (25) Filing Language: English kind of regional protection available): ARIPO (BW, GH, GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, SZ, TZ, (26) Publication Language: English UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, (30) Priority Data: TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, 61/612,689 19 March 2012 (19.03.2012) US EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, (71) Applicant: YALE UNIVERSITY [US/US]; Two Whitney TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, Avenue, New Haven, CT 065 10 (US).