Strategic Group Analysis of U.S. Food Businesses Using the Two-step Clustering Method

strategic group, planning, strategy, performance, Agribusiness, Institutional and Behavioral Economics, Marketing, Productivity Analysis, M0, M14, M2, M30,

Profits and Principles: An Economic Framework

Keywords: profit; business ethics; business responsibility; D45; D59; D63; L21; M14; Z13;

Pūrva Mīmāṃsā: Non-Natural, Moral Realism (Ethics-1, M14)

In this module I set out the Moral Non-Naturalism of Pūrva Mīmāṃsā as a version of Deontology that defines duty in terms of its beneficent properties. It elucidates the scheme of right living according to ordinance or command. Whereas natural accounts of moral terms suffer from circularity (by merely re-naming of a natural property with a moral term, which then serves to justify its moral appraisal), proponents of Mīmāṃsā defend their position by offering the Vedas as constituting independent evidence about what yields goodness. In some ways, the argument provided by the defenders of Mīmāṃsā prefigure Moore's complaint of the Naturalistic Fallacy, but the Mīmāṃsā approach doesn't claim that defining natural properties by ethical terms is a fallacy: it is simply circular

Binaries among low-mass stars in nearby young moving groups

The solar galactic neighbourhood contains a number of young co-moving associations of stars (so-called `young moving groups') with ages of ~10--150 Myr, which are prime targets for a range of scientific studies, including direct imaging planet searches. The late-type stellar population of such groups still remain in their pre-main sequence phase, and are thus well suited for purposes such as isochronal dating. Close binaries are particularly useful in this regard, since they allow for a model-independent dynamical mass determination. Here we present a dedicated effort to identify new close binaries in nearby young moving groups, through high-resolution imaging with the AstraLux Sur Lucky Imaging camera. We surveyed 181 targets, resulting in the detection of 61 companions or candidates, of which 38 are new discoveries. An interesting example of such a case is 2MASS J00302572-6236015 AB, which is a high-probability member of the Tucana-Horologium moving group, and has an estimated orbital period of less than 10 years. Among the previously known objects is a serendipitous detection of the deuterium burning boundary circumbinary companion 2MASS J01033563-5515561 (AB)b in the z'-band, thereby extending the spectral coverage for this object down to near-visible wavelengths.Comment: 12 pages, 3 figures, accepted for publication in A&

Discovery and characterizatopn of small molecular weight metallocarboxypeptidase inhibitors

Descripció del recurs: el 02 de novembre de 2010Las hidrolasas son enzimas que catalizan la ruptura del enlace amida o peptódico, y por lo tanto son denominadas también proteasas o peptidasas. Las proteasas constituyen cerca del 2 % del genoma humano, lo que representa unos 600 productos génicos. De acuerdo con el residuo catalóticamente activo, existen seis grandes grupos de peptidasas. En este trabajo nos centraremos en la familia M14 de peptidasas, también denominadas metalocarboxipeptidasas (CPs) debido a que su actividad catalótica reside en el ion zinc presente en el sitio activo de la enzima. En el genoma humano, se han identificado al menos 26 genes que codifican carboxipeptidasas. Las peptidasas de la familia M14 que actúan en el tracto gastrointestinal son las principales metaloproteasas responsables de la obtención de aminoácidos libres de la proteína de la dieta. En otros compartimientos corporales, las CPs pueden llevar a cabo tareas especializadas y altamente reguladas como ser la maduración de neuropéptidos, citokinas y hormonas peptódicas. En algunos casos, una actividad catalótica fuera de control puede conducir a enfermedades. Cada vez existe una mayor evidencia experimental que demuestra la actividad carboxipeptidasa en procesos como la pancreatitis aguda, la diabetes, la inflamación, la fibrinólisis y el cáncer. A pesar de ciertos avances en algunos aspectos, la actividad específica de las CPs es pobremente conocida. Además, las carboxipeptidasas son blancos terapéuticos interesantes para el desarrollo de fármacos, y por lo tanto se ha decidido emplear una aproximación multi-disciplinaria para la identificación y caracterización de nuevas moléculas de bajo peso molecular capaces de interferir la actividad carboxipeptidasa. Así, en este trabajo se han combinado modernas herramientas computacionales, screening in vitro, modelado molecular y cristalografía de rayos X con el fin de obtener nuevas entidades quφmicas como base para el desarrollo de fármacos. Con base en herramientas computacionales, aplicando el método de Optimal Docking Areaö, se han caracterizado sitios de unión proteína-proteína y proteína-ligando en la superficie de las peptidasas de la familia M14. A partir de aquí, se identificó una nueva clase de compuestos químicos capaces de explotar las diferencias existentes entre enzimas de la familia por unión a regiones hidrofóbicas. Otros inhibidores fueron identificados mediante un screening in silico de grandes colecciones de compuestos. Ensayos in vitro demostraron que los compuestos líderes inhibieron de manera potente a las carboxipeptidasas blanco con otras características interesantes como la posibilidad de coordinación del ion zinc catalítico por intermedio de un anillo oxadiazol. A través de una colaboración con el Departamento de Química Orgánica se obtuvieron y caracterizaron nuevos compuestos químicos con conectividades atómicas novedosas que, inesperadamente, demostraron ser potentes inhibidores de carboxipeptidasas. Una clase adicional de molécula de bajo peso molecular caracterizada corresponde a inhibidores que se unen covalentemente al enzima blanco. En este caso, se logró obtener la estructura tridimensional del complejo a resolución atómica mediante cristalografφa de rayos X, lo que ha permitido el dise±o basado en la estructura de una nueva generación de compuestos. Basados en otros datos de cristalografía de rayos X y análisis computacional, se ha revisado y ampliado el mecanismo de acción catalítica de las peptidasas de la familia M14 a partir de una nueva forma cristalina de CPB a alta resolución. En conjunto, nuestro trabajo ha permitido la obtención de nuevas moléculas líderes de bajo peso molecular que podrían servir como base para futuros desarrollos en el diseño de fármacos y agentes de diagnóstico o imaginería dirigidos a metalocarboxipeptidasas fisiológicamente activas.Hydrolases are enzymes catalyzing the breakdown of the amide or peptide bond, and are therefore called proteases or peptidases as well. In the human genome, proteases made up about 2% of the genome, or about 600 gene products. There are six major groups of peptidases according to the catalytic residue. In our work we focused on the M14 family of peptidases, also called metallocarboxypeptidases (CPs) because of their catalytic activity hinges on the zinc ion present in the active site of the enzyme. In the human genome there are identified at least 26 genes encoding for CPs. M14 peptidases in the gastrointestinal tract are the main metalloproteases responsible of the liberation of free aminoacids from the protein content of the diet. In other compartments of the body, CPs may perform specialized and tightly controlled tasks such as neuropeptide, cytokine and hormone maturation. In some instances an imbalance in their activity leads to disease states in man. Increasing evidence shows carboxypeptidase involvement in acute pancreatitis, diabetes, inflammation, fibrinolysis and cancer. Although some aspects have become clearer, much of their activity remain poorly understood. Besides, carboxypeptidases are interesting targets for drug development, and therefore we pursued a multidisciplinary approach to identify and characterize novel small molecular weight compounds able to interfere carboxypeptidase activity. In this work we combined modern computational tools, in vitro screening, molecular modelling and X-ray crystallography to obtain new chemical entities useful as scaffolds for drug design. Based on a bioinformatics tools, the Optimal Docking Area method, we identified protein-protein and protein-ligand binding sites over the surface of M14 peptidases. This knowledge was employed to find out a new class of small molecular weight inhibitors which exploit the differential binding provided by hydrophobic patches. A further class of inhibitors was identified from in silico screening of collections of compounds. In vitro analysis revealed that the leads were potent inhibitors against the target proteases with interesting features like an oxadiazole zinc-chelating moiety. Compounds obtained from the Organic Chemistry Department were also screened, and unexpectedly, afforded some good inhibitors with unprecedented atomic bonding. One further class involved inhibitors that attach covalently to the target enzyme. In this case the structure of the complex obtained at high resolution by X-ray crystallography allowed the structure-guided design of new generation of compounds. The catalytic mechanism of M14 peptidases was also revisited based on our crystallographic and computational analysis of a new CPB crystal form at high resolution. Overall, our study provided new lead small molecular weight inhibitors which can be the foundation for further developments in the design of drugs and bioimaging or diagnostic agents targeted to physiologically-relevant metallocarboxypeptidases

Identification of galaxy cluster substructures with the Caustic method

We investigate the power of the caustic technique for identifying substructures of galaxy clusters from optical redshift data alone. The caustic technique is designed to estimate the mass profile of galaxy clusters to radii well beyond the virial radius, where dynamical equilibrium does not hold. Two by-products of this technique are the identification of the cluster members and the identification of the cluster substructures. We test the caustic technique as a substructure detector on two samples of 150 mock redshift surveys of clusters; the clusters are extracted from a large cosmological $N$-body simulation of a $\Lambda$CDM model and have masses of $M_{200} \sim 10^{14} h^{-1} M_{\odot}$ and $M_{200} \sim 10^{15} h^{-1} M_{\odot}$ in the two samples. We limit our analysis to substructures identified in the simulation with masses larger than $10^{13} h^{-1} M_{\odot}$. With mock redshift surveys with 200 galaxies within $3R_{200}$, (1) the caustic technique recovers $\sim 30-50$\% of the real substructures, and (2) $\sim 15-20$\% of the substructures identified by the caustic technique correspond to real substructures of the central cluster, the remaining fraction being low-mass substructures, groups or substructures of clusters in the surrounding region, or chance alignments of unrelated galaxies. These encouraging results show that the caustic technique is a promising approach for investigating the complex dynamics of galaxy clusters.Comment: 13 pages, 15 figures. Accepted for publication in Ap

HSP90 inhibitors stimulate DNAJB4 protein expression through a mechanism involving N6-methyladenosine.

Small-molecule inhibitors for the 90-kDa heat shock protein (HSP90) have been extensively exploited in preclinical studies for the therapeutic interventions of human diseases accompanied with proteotoxic stress. By using an unbiased quantitative proteomic method, we uncover that treatment with three HSP90 inhibitors results in elevated expression of a large number of heat shock proteins. We also demonstrate that the HSP90 inhibitor-mediated increase in expression of DNAJB4 protein occurs partly through an epitranscriptomic mechanism, and is substantially modulated by the writer, eraser, and reader proteins of N6-methyladenosine (m6A). Furthermore, exposure to ganetespib leads to elevated modification levels at m6A motif sites in the 5'-UTR of DNAJB4 mRNA, and the methylation at adenosine 114 site in the 5'-UTR promotes the translation of the reporter gene mRNA. This m6A-mediated mechanism is also at play upon heat shock treatment. Cumulatively, we unveil that HSP90 inhibitors stimulate the translation of DNAJB4 through an epitranscriptomic mechanism