A convergent solution-phase synthesis of the macrocycle Ac-Phe-[Orn-Pro-D-Cha-Trp-Arg], a potent new antiinflammatory drug

Relatively few cyclic peptides have reached the pharmaceutical marketplace during the past decade, most produced through fermentation rather than made synthetically. Generally, this class of compounds is synthesized for research purposes on milligram scales by solid-phase methods, but if the potential of macrocyclic peptidomimetics is to be realized, low-cost larger scale solution-phase syntheses need to be devised and optimized to provide sufficient quantities for preclinical, clinical, and commercial uses. Here, we describe a cheap, medium-scale, solution-phase synthesis of the first reported highly potent, selective, and orally active antagonist of the human C5a receptor. This compound, Ac-Phe[Orn-Pro-D-Cha-Trp-Arg], known as 3D53, is a macrocyclic peptidomimetic of the human plasma protein C5a and displays excellent antiinflammatory activity in numerous animal models of human disease. In a convergent approach, two tripeptide fragments Ac-Phe-Orn-(Boc)-Pro-OH and H-D-Cha-Trp(For)-Arg-OEt were first prepared by high-yielding solution-phase couplings using a mixed anhydride method before coupling them to give a linear hexapeptide which, after deprotection, was obtained in 38% overall yield from the commercially available amino acids. Cyclization in solution using BOP reagent gave the antagonist in 33% yield (13% overall) after HPLC purification. Significant features of the synthesis were that the Arg side chain was left unprotected throughout, the component Boe-D-Cha-OH was obtained very efficiently via hydrogenation Of D-Phe with PtO2 in TFA/water, the tripeptides were coupled at the Pro-Cha junction to minimize racemization via the oxazolone pathway, and the entire synthesis was carried out without purification of any intermediates. The target cyclic product was purified (>97%) by reversed-phase HPLC. This convergent synthesis with minimal use of protecting groups allowed batches of 50100 g to be prepared efficiently in high yield using standard laboratory equipment. This type of procedure should be useful for making even larger quantities of this and other macrocyclic peptidomimetic drugs.

Normal state tunneling conductance of perovskite oxides: Implications for high-Tc superconductors

We have investigated tunneling conductances in disordered, normally conducting perovskite oxides close to the metal�insulator transition. We show that the normal state tunneling conductance of perovskite oxides can be cast in a general form G(V) = G0[1 + curly logical orV/V*curly logical orn] with 1?n?0.5 and where V* is an intrinsic energy scale. The exponent n graduall y increases from 0.5 to 1 as the metal-insulator (M-I) transition is approached. In the high-Tc Bi(2212) cuprates, the normally observed, linear G(V)(n=1) can be made sub-linear (n<1) by substitution of Ca with Y. From the similarity of the linear conductances, we suggest proximity to the M-I transition as a likely cause for this G(V)logical or, bar below V dependence. In systems showing linear conductances (nreverse similar, equals1), we find that ?G/?Vreverse similar, equalsG?0 with ?reverse similar, equals 1 and the intrinsic energy scale V*reverse similar, equals25�75 meV in the different oxides investigated.

Oxidative DNA cleavage, cytotoxicity and antimicrobial studies of L-ornithine copper (II) complexes

New ternary copper (II) complexes, Cu(L-orn)(B)(Cl)](Cl center dot 2H(2)O) (1-2) where L-orn is L-ornithine, B is an N,N-donor heterocyclic base, viz. 2,2'-bipyridine (bpy, 1) and 1,10-phenanthroline (phen, 2), were synthesized and characterized by various spectroscopic techniques. Complex 2 is characterized by the X-ray single crystallographic method. The complex shows a distorted square-pyramidal (4 + 1) CuN3OCl coordination sphere. Binding interactions of the complexes with calf thymus DNA (CT-DNA) were investigated by UV-Vis absorption titration, ethidium bromide displacement assay, viscometric titration experiment and DNA melting studies. Complex 2 shows appreciable chemical nuclease activity in the presence of 3-mercaptopropionic acid (MPA). The complexes were subjected to in vitro cytotoxicity studies against carcinomic human alveolar basal epithelial cells (A-549) and human epithelial (HEp-2) cells. The IC50 values of 1 and 2 are less than that of cisplatin against HEp-2 cell lines. MIC values for 1 against the bacterial strains Streptococcus mutans and Pseudomonas aeruginosa are 0.5 mM. (C) 2012 Elsevier Ltd. All rights reserved.

XXXI Semana de Teología de la Sociedad Argentina de Teología

La XXXI Semana de Teología tuvo lugar en la diócesis de Lomas de Zamora del 16 al 19 de Julio y contó con la participación de 89 teólogos y teólogas de diferentes provincias de nuestro país. Los participantes recibieron la visita de Mons. Jorge Rubén Lugones SJ, quien fuera Obispo de Orán y actualmente se desempeña como Obispo de Lomas de Zamora (Buenos Aires) y Miembro de la Comisión Episcopal de Comunicación Social y de Pastoral Aborigen...

Sustentabilidad de la Pesquería Artesanal del Río Bermejo.

Este trabajo es el resultado de la tesis de Maestría en Recursos Naturales y Medio Ambiente (Orientación Recursos Faunísticos), realizada por el autor en la Facultad de Ciencias Naturales de la Universidad Nacional de Salta y bajo la dirección del Dr. Sergio Gustavo Mosa. La pesca artesanal con fines comerciales es practicada en el sector salteño del Río Bermejo desde hace décadas, por pobladores de localidades ribereñas como Orán, Embarcación y Rivadavia Banda Sur, los cuales pescan hasta el límite Salta – Chaco, dependiendo de la época del año. Esta pesquería se desarrolló por más de 50 años fuera del marco de las normas legales vigentes en la provincia (Ley 5513), siendo una actividad marginal perseguida por la justicia, y mal vista por la opinión pública en general. Entre Julio de 2001 y Julio de 2003, la Cooperativa de Pescadores Artesanales “La Unión” fue habilitada como empresa pesquera comercial de tipo artesanal por la Secretaria de Medio Ambiente y Desarrollo Sustentable de Salta. El monitoreo de esta actividad fue efectuado por la Cátedra de Piscicultura y Pesquerías (IRNED) de la Facultad de Ciencias Naturales de la Universidad Nacional de Salta. Las reglamentaciones y regulaciones legales de esta actividad se tomaron originariamente bajo el principio de precaución ante la falta de conocimiento científico. A la luz de la nueva información colectada, algunas de ellas resultan contrarias al principio prioritario de la gestión pesquera, el cual propone: Obtener la mejor utilización posible del recurso en provecho de la comunidad, recordando que mejor utilización implica mayor captura, mejor precio, más ganancias y más empleo. La presente Tesis de Maestría demuestra la sustentabilidad de la pesquería artesanal en el Bermejo, tanto desde a) el punto de vista biológico, analizando las capturas en función de las normas y reglamentaciones legales vigentes y de la biología y hábitos reproductivos de cada especie, como desde b) el punto de vista económico, teniendo en cuenta la relación costo-beneficio y las posibles alternativas para optimizar la misma. Asimismo, formula una serie de recomendaciones destinadas a mejorar la gestión pesquera. Para las 4 especies más importantes de la pesquería: sábalo Prochilodus lineatus, surubí Pseudoplatystoma coruscans, dorado Salminus brasiliensis y bagre blanco Pimelodus albicans, a) los cupos asignados para la captura anual por especie no son alcanzados; b) las tallas mínimas de captura observadas superan las tallas mínimas de captura autorizadas; c) las tallas medias de captura se encuentran muy por encima de las tallas medias de madurez sexual; d) la captura exclusiva de ejemplares maduros para todas las especies prueba que el grueso del stock pesquero ha podido superar por lo menos un evento reproductivo antes de ser capturado; e) el actual período de veda resulta demasiado amplio por lo que uno de dos meses, de mediados de noviembre a mediados de enero resultaría biológicamente adecuado. En cuanto a la sustentabilidad económica de la actividad, cada unidad económica de pesca debe realizar entre 45 y 50 excursiones de pesca anuales para obtener rendimientos económicos equivalentes a un ingreso mensual de aproximadamente $ 1000. (PDF tiene 92 paginas.)

Le Brésil, ou, Histoire, moeurs, usages et coutumes des habitans de ce royaume

Segundo Rubens Borba de Moraes, tratam-se de relatos acerca do Rio de Janeiro, Pernambuco, Maranhão, Sergipe, Espírito Santo, São Paulo, Santa Catarina, Rio Grande do Sul, Minas Gerais, Mato Grosso, Goyas, Bahia, Rio Grande do Norte, Pará e outras províncias. Contém excertos de autores renomados como Southey, Beauchamp, Herrera, Barleus, Piso, Marcgraf, Hans Staden, d'Abeville, Vaz de Caminha, Léry, Cazal, Barrow, Lindley, Macartney, Mawe, Koster, Wied-Neuwied e outros. Grande parte das gravuras são reproduções, mas excelentes. O texto não é apenas uma mera compilação. Os seis volumes absolutamente completos, com todas as ilustrações, são raríssimos.

One sound or two? Object-related negativity indexes echo perception.

The ability to isolate a single sound source among concurrent sources and reverberant energy is necessary for understanding the auditory world. The precedence effect describes a related experimental finding, that when presented with identical sounds from two locations with a short onset asynchrony (on the order of milliseconds), listeners report a single source with a location dominated by the lead sound. Single-cell recordings in multiple animal models have indicated that there are low-level mechanisms that may contribute to the precedence effect, yet psychophysical studies in humans have provided evidence that top-down cognitive processes have a great deal of influence on the perception of simulated echoes. In the present study, event-related potentials evoked by click pairs at and around listeners' echo thresholds indicate that perception of the lead and lag sound as individual sources elicits a negativity between 100 and 250 msec, previously termed the object-related negativity (ORN). Even for physically identical stimuli, the ORN is evident when listeners report hearing, as compared with not hearing, a second sound source. These results define a neural mechanism related to the conscious perception of multiple auditory objects.

Examination of Endogenous Rotund Expression and Function in Developing Drosophila Olfactory System Using CRISPR-Cas9-Mediated Protein Tagging.

The zinc-finger protein Rotund (Rn) plays a critical role in controlling the development of the fly olfactory system. However, little is known about its molecular function in vivo. Here, we added protein tags to the rn locus using CRISPR-Cas9 technology in Drosophila to investigate its subcellular localization and the genes that it regulates . We previously used a reporter construct to show that rn is expressed in a subset of olfactory receptor neuron (ORN) precursors and it is required for the diversification of ORN fates. Here, we show that tagged endogenous Rn protein is functional based on the analysis of ORN phenotypes. Using this method, we also mapped the expression pattern of the endogenous isoform-specific tags in vivo with increased precision. Comparison of the Rn expression pattern from this study with previously published results using GAL4 reporters showed that Rn is mainly present in early steps in antennal disc patterning, but not in pupal stages when ORNs are born. Finally, using chromatin immunoprecipitation, we showed a direct binding of Rotund to a previously identified regulatory element upstream of the bric-a-brac gene locus in the developing antennal disc.

El rol del facilitador más allá del de ingeniero agrónomo : una experiencia de intervención comunitaria con pueblos originarios

La intervención de un extensionista - ingeniero agrónomo de la Agencia de Extensión Rural Orán, del Instituto Nacional de Tecnología Agropecuaria/INTA- en el territorio de una Comunidad Tupí Guaraní del norte salteño, exige una profunda revisión de antecedentes dando lugar a reflexiones, interrogantes y propuestas relacionadas con distintos aspectos del trabajo de campo que trascienden a esta situación en particular. Esto está aquí directamente relacionado a la evolución y al desarrollo de esta zona de históricos conflictos de intereses, desigualdad social creciente y fuertes procesos de aculturación. Incluso existen contradicciones dentro de las instancias del Estado relacionadas con el desarrollo rural, en donde el INTA no constituye una excepción, generándose arduas discusiones internas. En este escenario, la praxis destaca la importancia de las técnicas participativas como la mejor metodología para sustentar procesos de desarrollo local, ya que es en terreno se debe trabajar dentro de un proceso de pérdida de la percepción social -pero más importante aún, de la propia percepción- en la que los pueblos originarios se consideren como un actor más. Entonces es desde la revalorización de las propias capacidades y posibilidades de la comunidad que se analiza una experiencia que refleja cómo, a partir del único agente del estado presente en terreno, se intenta avanzar en la trasformación de la realidad en donde se ve naturalizada y no problematizada la diferencia en la distribución de los ingresos y la pobreza estructural. El comienzo de la intervención, por lo tanto, se inició con la identificación clara de una amenaza -el avance de la erosión del río sobre la seguridad y posesiones de los campesinos/aborígenes- lo cual creó la necesidad ineludible de trabajar comunitariamente. Esta coyuntura generó la necesidad de organizarse para llevar a cabo el proyecto necesario para superar la emergencia, que gracias a la forma participativa de encarar el trabajo, así como el trabajo inter-institucional de los técnicos del INAI (Instituto Nacional de Asuntos Indígenas) y del INTA, confluyeron en crear un capital social entre productores y técnicos/instituciones. La articulación interinstitucional lograda hizo posible la formulación y ejecución en forma participativa de un proyecto evaluado satisfactoriamente -social e institucionalmente-, ya que posibilitó controlar la erosión fluvial evitando nuevas pérdidas de tierras, fortaleciendo a la vez a la organización comunitaria y los vínculos con distintos actores públicos, revalorizando sus propias capacidades.

New records of interesting xenophytes in the Iberian Peninsula. V

As a continuation of previous research on the naturalization of non-native vascular plants in the Iberian Peninsula new chorological data are presented for 16 xenophytes recorded between 2010 and 2014, mostly in the provinces of Huelva and Barcelona (Spain) and in the Algarve and Estremadura (Portugal). For each taxon details about distribution, habitats occupied, previous records, degree of naturalization, etc. are provided. Lachenalia bulbifera and Cyperus albostriatus are probably reported for the first time in the wild in Europe, as are Gamochaeta filaginea, and Dysphania anthelmintica and Oenothera lindheimeri for Portugal and Spain respectively. Cosmos bipinnatus is cited as a novelty for the Algarve (Portugal). Newly reported or confirmed for the province of Huelva are: Amaranthus hypochondriacus, Epilobium brachycarpum, Nephrolepis cordifolia, Ficus microcarpa, Tamarix parviflora and Tamarix ramosissima, while Atriplex semibaccata, Chloris truncata, and Elymus elongatus subsp. ponticus are new for Barcelona. Finally, Passiflora caerulea is a novelty for both Barcelona and Huelva provinces.

Antimicrobial activity of short, synthetic cationic lipopeptides.

The increasing emergence of multidrug-resistant micro-organisms presents one of the greatest challenges in the clinical management of infectious diseases. Therefore, novel antimicrobial agents are urgently required to address this issue. In this report, we describe the solid phase synthesis, characterization, microbiological and toxicological evaluation of a library of ultrashort cationic antimicrobial lipopeptides based on the previously described tetrapeptide amide H-Orn-Orn-Trp-Trp-NH2 conjugated with saturated fatty acids which have inherent antimicrobial activity. The microbiological activity of these ultrashort cationic lipopeptides, which exhibit excellent, broad-spectrum antimicrobial activity against a number of clinically important pathogenic bacteria and fungi, including multidrug resistant micro-organisms in both planktonic and sessile (biofilm) cultures is reported.

Antimicrobial peptide incorporated poly(2-hydroxyethyl methacrylate) hydrogels for the prevention of Staphylococcus epidermidis-associated biomaterial infections

The effectiveness of the antimicrobial peptide maximin-4, the ultrashort peptide H-Orn-Orn-Trp-Trp-NH(2) , and the lipopeptide C(12) -Orn-Orn-Trp-Trp-NH(2) in preventing adherence of pathogens to a candidate biomaterial were tested utilizing both matrix- and immersion-loaded poly(2-hydroxyethyl methacrylate) (poly(HEMA)) hydrogels. Antiadherent properties correlated to both the concentration released and the relative antimicrobial concentrations of each compound against Staphylococcus epidermidis ATCC 35984, at each time point. Immersion-loaded samples containing C(12) -Orn-Orn-Trp-Trp-NH(2) exhibited the lowest adherence profile for all peptides studied over 1, 4, and 24 h. The results outlined in this article show that antimicrobial peptides have the potential to serve as an important weapon against biomaterial associated infections. © 2012 Wiley Periodicals, Inc. J Biomed Mater Res Part A, 2012.

Biofilm Eradication Kinetics of the Ultrashort Lipopeptide C12-OOWW-NH2 Utilizing a Modified MBEC Assay™

In this study, we report the antimicrobial planktonic and biofilm kill kinetics of ultrashort cationic lipopeptides previously demonstrated by our group to have a minimum biofilm eradication concentration (MBEC) in the microgram per mL (μg/mL) range against clinically relevant biofilm-forming micro-organisms. We compare the rate of kill for the most potent of these lipopeptides, dodecanoic (lauric) acid-conjugated C₁₂-Orn-Orn-Trp-Trp-NH₂ against the tetrapeptide amide H-Orn-Orn-Trp-Trp-NH₂ motif and the amphibian peptide Maximin-4 via a modification of the MBEC Assay™ for Physiology & Genetics (P&G). Improved antimicrobial activity is achieved upon N-terminal lipidation of the tetrapeptide amide. Increased antimicrobial potency was demonstrated against both planktonic and biofilm forms of Gram-positive micro-organisms. We hypothesize rapid kill to be achieved by targeting of microbial membranes. Complete kill against established 24-h Gram-positive biofilms occurred within 4 h of exposure to C₁₂-OOWW-NH₂ at MBEC values [methicillin-resistant Staphylococcus epidermidis (ATCC 35984): 15.63 μg/mL] close to the values for the planktonic minimum inhibitory concentration (MIC) [methicillin-resistant Staphylococcus epidermidis (ATCC 35984): 1.95 μg/mL]. Such rapid kill, especially against sessile biofilm forms, is indicative of a reduction in the likelihood of resistant strains developing with the potential for quicker resolution of pathogenic infection. Ultrashort antimicrobial lipopeptides have high potential as antimicrobial therapy.

Anti-biofilm activity of ultrashort cinnamic acid peptide derivatives against medical device-related pathogens

The threat of antimicrobial resistance has placed increasing emphasis on the development of innovative approaches to eradicate multidrug-resistant pathogens. Biofilm-forming microorganisms, for example, Staphylococcus epidermidis and Staphylococcus aureus, are responsible for increased incidence of biomaterial infection, extended hospital stays and patient morbidity and mortality. This paper highlights the potential of ultrashort tetra-peptide conjugated to hydrophobic cinnamic acid derivatives. These peptidomimetic molecules demonstrate selective and highly potent activity against resistant biofilm forms of Gram-positive medical device-related pathogens. 3-(4-Hydroxyphenyl)propionic)-Orn-Orn-Trp-Trp-NH2 displays particular promise with minimum biofilm eradication concentration (MBEC) values of 125 µg/ml against methicillin sensitive (ATCC 29213) and resistant (ATCC 43300) S. aureus and activity shown against biofilm forms of Escherichia coli (MBEC: 1000 µg/ml). Kill kinetics confirms complete eradication of established 24-h biofilms at MBEC with 6-h exposure. Reduced cell cytotoxicity, relative to Gram-positive pathogens, was proven via tissue culture (HaCaT) and haemolysis assays (equine erythrocytes).

Existing in nature as part of the immune response, antimicrobial peptides display great promise for exploitation by the pharmaceutical industry in order to increase the library of available therapeutic molecules. Ultrashort variants are particularly promising for translation as clinical therapeutics as they are more cost-effective, easier to synthesise and can be tailored to specific functional requirements based on the primary sequence allowing factors such as spectrum of activity to be varied.

The Pirates of Penzance, March 10, 1987

Concert Program for The Pirates of Penzance, March 10, 1987