Exact time correlation functions for N classical Heisenberg spins in the `squashed' equivalent neighbor model

We present exact integral representations of the time-dependent spin-spin correlation functions for the classical Heisenberg N-spin `squashed' equivalent neighbor model, in which one spin is coupled via the Heisenberg exchange interaction with strength $J_1$ to the other N-1 spins, each of which is coupled via the Heisenberg exchange coupling with strength $J_2$ to the remaining N-2 spins. At low temperature T we find that the N spins oscillate in four modes, one of which is a central peak for a semi-infinite range of the values of the exchange coupling ratio. For the N=4 case of four spins on a squashed tetrahedron, detailed numerical evaluations of these results are presented. As $T\to\infty$, we calculate exactly the long-time asymptotic behavior of the correlation functions for arbitrary N, and compare our results with those obtained for three spins on an isosceles triangle.Comment: 9 pages, 8 figures, submitted to Phys. Rev.

Regulatory Circuit of Human MicroRNA Biogenesis

miRNAs (microRNAs) are a class of endogenous small RNAs that are thought to negatively regulate protein production. Aberrant expression of many miRNAs is linked to cancer and other diseases. Little is known about the factors that regulate the expression of miRNAs. We have identified numerous regulatory elements upstream of miRNA genes that are likely to be essential to the transcriptional and posttranscriptional regulation of miRNAs. Newly identified regulatory motifs occur frequently and in multiple copies upstream of miRNAs. The motifs are highly enriched in G and C nucleotides, in comparison with the nucleotide composition of miRNA upstream sequences. Although the motifs were predicted using sequences that are upstream of miRNAs, we find that 99% of the top-predicted motifs preferentially occur within the first 500 nucleotides upstream of the transcription start sites of protein-coding genes; the observed preference in location underscores the validity and importance of the motifs identified in this study. Our study also raises the possibility that a considerable number of well-characterized, disease-associated transcription factors (TFs) of protein-coding genes contribute to the abnormal miRNA expression in diseases such as cancer. Further analysis of predicted miRNA–protein interactions lead us to hypothesize that TFs that include c-Myb, NF-Y, Sp-1, MTF-1, and AP-2α are master-regulators of miRNA expression. Our predictions are a solid starting point for the systematic elucidation of the causative basis for aberrant expression patterns of disease-related (e.g., cancer) miRNAs. Thus, we point out that focused studies of the TFs that regulate miRNAs will be paramount in developing cures for miRNA-related diseases. The identification of the miRNA regulatory motifs was facilitated by a new computational method, K-Factor. K-Factor predicts regulatory motifs in a set of functionally related sequences, without relying on evolutionary conservation

Plan de desarrollo de turismo rural en la localidad de Las Calles, Departamento San Alberto, Provincia de Córdoba, Argentina. Identificación y análisis de las características socioeconómicas, culturales y ambientales

Ponencia presentada en el 2º Congreso Internacional de Turismo en Serranías: Investigación y Gestión del Patrimonio. Villa de Merlo, San Luis, Argentina, 16 al 18 de mayo de 2018.Ponencia presentada en la 49° Reunión Anual de la Asociación Argentina de Economía Agraria (AAEA): “Hacia una mayor competitividad del sector agroindustrial”. Santa Fe, Argentina, 17 al 19 de octubre de 2018.Fil: Da Riva, Mariano Danilo. Universidad Nacional de Córdoba. Facultad de Ciencias Agropecuarias. Centro de Transferencia de Turismo Rural; Argentina.Fil: Pasquali, María Marcela. Universidad Nacional de Córdoba. Facultad de Ciencias Agropecuarias. Centro de Transferencia de Turismo Rural; Argentina.Fil: Manera, Gabriel Augusto. Universidad Nacional de Córdoba. Facultad de Ciencias Agropecuarias. Centro de Transferencia de Turismo Rural; Argentina.Fil: Carbelo, Leandro. Universidad Nacional de Córdoba. Facultad de Ciencias Agropecuarias. Centro de Transferencia de Turismo Rural; Argentina.Fil: Bino Raya, Rosanna E. Universidad Blas Pascal. Instituto de Investigaciones en Turismo; Argentina.Fil: Bino Raya, Rosanna E. Universidad Provincial de Córdoba; Argentina.El turismo rural se visualiza como una posible estrategia para el desarrollo rural aunque no todos los territorios disponen de condiciones para establecer una oferta competitiva y en muchos casos los actores locales desconocen la forma de aprovechar y gestionar con mayor eficiencia, calidad y de manera sostenible el potencial turístico. Un plan de desarrollo turístico sostenible e inclusivo, que involucre a los actores locales (sector público y privado) en su planeamiento y ejecución es una herramienta que brinda lineamientos generales para la gestión turística en un territorio y garantiza en cierta medida que las acciones y decisiones surjan del conjunto de los actores involucrados, de su participación, opinión, estrategias y prioridades. La elaboración plan de desarrollo turístico participativo es el eje del presente proyecto que se pretende desarrollar en la comuna de Las Calles, pequeño destino turístico delas sierras de Córdoba. Ubicada en la región geográfica natural de traslasierras, departamento San Alberto, esta localidad se caracteriza por la abundancia de recursos paisajísticos autóctonos, la calidez de la gente, la presencia de varios micro emprendedores locales, la pasividad de su entorno a lo que se suma la disposición de los agentes públicos y privados por trabajar de manera conjunta en proyectos que apunten al desarrollo local y territorial. El objetivo del trabajo es establecer un plan de desarrollo de turismo rural, mediante la evaluación junto a los diferentes actores locales del potencial turístico del territorio, analizando las características, socioeconómicas, culturales y ambientales. La metodología contempla la realización de talleres participativos donde la comunidad elabora mapas de conocimiento y reconocimiento de su territorio y grupos de discusión que permiten explorar conocimientos, prácticas y opiniones orientados a seleccionar variables específicas que permitirán caracterizar la localidad. Se espera que este plan de desarrollo de turismo rural genere progreso en las economías regionales y con ello a una mejor calidad de vida para los actores directos e indirectos que se vinculan con esta actividad.Fil: Da Riva, Mariano Danilo. Universidad Nacional de Córdoba. Facultad de Ciencias Agropecuarias. Centro de Transferencia de Turismo Rural; Argentina.Fil: Pasquali, María Marcela. Universidad Nacional de Córdoba. Facultad de Ciencias Agropecuarias. Centro de Transferencia de Turismo Rural; Argentina.Fil: Manera, Gabriel Augusto. Universidad Nacional de Córdoba. Facultad de Ciencias Agropecuarias. Centro de Transferencia de Turismo Rural; Argentina.Fil: Carbelo, Leandro. Universidad Nacional de Córdoba. Facultad de Ciencias Agropecuarias. Centro de Transferencia de Turismo Rural; Argentina.Fil: Bino Raya, Rosanna E. Universidad Blas Pascal. Instituto de Investigaciones en Turismo; Argentina.Fil: Bino Raya, Rosanna E. Universidad Provincial de Córdoba; Argentina

Bayesian phylogeography of Crimean-Congo hemorrhagic fever virus in Europe

Crimean-Congo hemorrhagic fever (CCHF) is a zoonosis mainly transmitted by ticks that causes severe hemorrhagic fever and has a mortality rate of 5-60%. The first outbreak of CCHF occurred in the Crimean peninsula in 1944-45 and it has recently emerged in the Balkans and eastern Mediterranean. In order to reconstruct the origin and pathway of the worldwide dispersion of the virus at global and regional (eastern European) level, we investigated the phylogeography of the infection by analysing 121 publicly available CCHFV S gene sequences including two recently characterised Albanian isolates. The spatial and temporal phylogeny was reconstructed using a Bayesian Markov chain Monte Carlo approach, which estimated a mean evolutionary rate of 2.96 7 10-4 (95%HPD=1.6 and 4.7 7 10-4) substitutions/site/year for the analysed fragment. All of the isolates segregated into seven highly significant clades that correspond to the known geographical clades: in particular the two new isolates from northern Albania clustered significantly within the Europe 1 clade. Our phylogeographical reconstruction suggests that the global CCHFV clades originated about one thousand years ago from a common ancestor probably located in Africa. The virus then spread to Asia in the XV century and entered Europe on at least two occasions: the first in the early 1800s, when a still circulating but less or non-pathogenic virus emerged in Greece and Turkey, and the second in the early 1900s, when a pathogenic CCHFV strain began to spread in eastern Europe. The most probable location for the origin of this European clade 1 was Russia, but Turkey played a central role in spreading the virus throughout Europe. Given the close proximity of the infected areas, our data suggest that the movement of wild and domestic ungulates from endemic areas was probably the main cause of the dissemination of the virus in eastern Europe

Membrane transport of camptothecin: facilitation by human P-glycoprotein (ABCB1) and multidrug resistance protein 2 (ABCC2)

BACKGROUND: The purpose of the present study was to continue the investigation of the membrane transport mechanisms of 20-(S)-camptothecin (CPT) in order to understand the possible role of membrane transporters on its oral bioavailability and disposition. METHODS: The intestinal transport kinetics of CPT were characterized using Caco-2 cells, MDCKII wild-type cells and MDCKII cells transfected with human P-glycoprotein (PGP) (ABCB1) or human multidrug resistance protein 2 (MRP2) (ABCC2). The effects of drug concentration, inhibitors and temperature on CPT directional permeability were determined. RESULTS: The absorptive (apical to basolateral) and secretory (basolateral to apical) permeabilities of CPT were found to be saturable. Reduced secretory CPT permeabilities with decreasing temperatures suggests the involvement of an active, transporter-mediated secretory pathway. In the presence of etoposide, the CPT secretory permeability decreased 25.6%. However, inhibition was greater in the presence of PGP and of the breast cancer resistant protein inhibitor, GF120918 (52.5%). The involvement of additional secretory transporters was suggested since the basolateral to apical permeability of CPT was not further reduced in the presence of increasing concentrations of GF120918. To investigate the involvement of specific apically-located secretory membrane transporters, CPT transport studies were conducted using MDCKII/PGP cells and MDCKII/MRP2 cells. CPT carrier-mediated permeability was approximately twofold greater in MDCKII/PGP cells and MDCKII/MRP2 cells than in MDCKII/wild-type cells, while the apparent K(m )values were comparable in all three cell lines. The efflux ratio of CPT in MDCKII/PGP in the presence of 0.2 μM GF120918 was not completely reversed (3.36 to 1.49). However, the decrease in the efflux ratio of CPT in MDCKII/MRP2 cells (2.31 to 1.03) suggests that CPT efflux was completely inhibited by MK571, a potent inhibitor of the Multidrug Resistance Protein transporter family. CONCLUSIONS: The current results provide evidence that PGP and MRP2 mediate the secretory transport of CPT in vitro. However, the involvement of other transporters cannot be ruled out based on these studies. Since these transporters are expressed in the intestine, liver and kidney variations in their expression levels and/or regulation may be responsible for the erratic oral absorption and biliary excretion of CPT observed in human subjects

The Selectivity of Milking of Dunaliella salina

The process of the simultaneous production and extraction of carotenoids, milking, of Dunaliella salina was studied. We would like to know the selectivity of this process. Could all the carotenoids produced be extracted? And would it be possible to vary the profile of the produced carotenoids and, consequently, influence the type of carotenoids extracted? By using three different D. salina strains and three different stress conditions, we varied the profiles of the carotenoids produced. Between Dunaliella bardawil and D. salina 19/18, no remarkable differences were seen in the extraction profiles, although D. salina 19/18 seemed to be better extractable. D. salina 19/25 was not “milkable” at all. The milking process could only be called selective for secondary carotenoids in case gentle mixing was used. In aerated flat-panel photobioreactors, extraction was much better, but selectiveness decreased and also chlorophyll and primary carotenoids were extracted. This was possibly related to cell damage due to shear stress

Genetic mapping of semi-polar metabolites in pepper fruits (Capsicum sp.): towards unravelling the molecular regulation of flavonoid quantitative trait loci

Untargeted LCMS profiling of semi-polar metabolites followed by metabolite quantitative trait locus (mQTL) analysis was performed in ripe pepper fruits of 113 F2 plants derived from a cross between Capsicum annuum AC1979 (no. 19) and Capsicum chinense No. 4661 Selection (no. 18). The parental accessions were selected based on their variation in fruit morphological characteristics and fruit content of some target phytonutrients. Clear segregation of fruit colour and fruit metabolite profiles was observed in the F2 population. The F2 plants formed three clusters based on their metabolite profiles. Of the total of 542 metabolites, 52 could be annotated, including a range of flavonoids, such as flavone C-glycosides, flavonol O-glycosides and naringenin chalcone, as well as several phenylpropanoids, a capsaicin analogue, fatty acid derivatives and amino acid derivatives. Interval mapping revealed 279 mQTLs in total. Two mQTL hotspots were found on chromosome 9. These two chromosomal regions regulated the relative levels of 35 and 103 metabolites, respectively. Analysis also revealed an mQTL for a capsaicin analogue, located on chromosome 7. Confirmation of flavonoid mQTLs using a set of six flavonoid candidate gene markers and their corresponding expression data (expression QTLs) indicated the Ca-MYB12 transcription factor gene on chromosome 1 and the gene encoding flavone synthase (FS-2) on chromosome 6 as likely causative genes determining the variation in naringenin chalcone and flavone C-glycosides, respectively, in this population. The combination of large-scale metabolite profiling and QTL analysis provided valuable insight into the genomic regions and genes important for the production of (secondary) metabolites in pepper fruit. This will impact breeding strategies aimed at optimising the content of specific metabolites in pepper frui

Schedule-dependent cytotoxicity of SN-38 in p53 wild-type and mutant colon adenocarcinoma cell lines

In this study the effects of SN-38 on colon adenocarcinoma cell lines expressing wild-type p53 (LS174T) or mutant non-functional p53 (HT29) have been investigated. On exposure to SN-38, HT29 cells rapidly progressed through G1 and S and arrested in G2/M. Release and concomitant increase in apoptosis after 48 h was concentration- and time-dependent (P < 0.001), being more rapid at higher concentrations, but reaching plateau at 10 ng ml–1 with prolonged exposure. LS174T cells showed only a small increase in apoptosis, and only at high concentrations (50–100 ng ml–1). The main effect of SN-38 in LS174T cells was prolonged cell cycle arrest, which was independent of concentration. Arrest occurred in all phases of the cell cycle, with the distribution depending on concentration (P < 0.001) and not duration (P > 0.05). With increasing concentration, LS174T cells arrested in G2/M, S and G1. Cell cycle arrest was coincident with increased p53 expression in each phase of the cell cycle. Expression in G1 increased with time and concentration (P < 0.001, P = 0.01 respectively), whereas in S and G2/M p53 expression increased only with time (P < 0.001). Dose-dependent p53-associated G1 arrest, in the absence of DNA synthesis indicates an additional cytotoxic mechanism for SN-38, which requires higher concentrations than the S phase mechanism, and detection of which seems to involve p53. For incubations with the same ED (exposure × duration), apoptosis in HT29 cells was significantly higher for prolonged exposure to lower concentrations, whereas in LS174T cells there was a trend towards increased apoptosis with shorter exposures to higher concentrations, indicating a schedule effect of SN-38. Although expression of wild-type p53 leads to a more rapid induction of apoptosis, SN-38 cytotoxicity was generally greater in cells with mutant p53, as wild-type cells escaped apoptosis by p53 associated prolonged cell cycle arrest. Thus, pulsed schedules with higher doses may be more effective in cells expressing wild-type p53, whereas continued exposure with protracted schedules may be more active in cells expressing mutant p53. © 1999 Cancer Research Campaig

A phase I study with MAG-camptothecin intravenously administered weekly for 3 weeks in a 4-week cycle in adult patients with solid tumours

In MAG-camptothecin (MAG-CPT), the topoisomerase inhibitor camptothecin is linked to a water-soluble polymer. Preclinical experiments showed enhanced antitumour efficacy and limited toxicity compared to camptothecin alone. Prior phase I trials guided the regimen used in this study. The objectives were to determine the maximum tolerated dose, dose-limiting toxicities, safety profile, and pharmacokinetics of weekly MAG-CPT. Patients with solid tumours received MAG-CPT intravenously administered weekly for 3 weeks in 4-week cycles. At the starting dose level ( 80 mg m(-2) week(-1)), no dose-limiting toxicities occurred during the first cycle (n = 3). Subsequently, three patients were enrolled at the second dose level ( 120 mg m(-2) week(-1)). Two of three patients at the 80 mg m(-2) week(-1) cohort developed haemorrhagic cystitis ( grade 1/3 dysuria and grade 2/3 haematuria) during the second and third cycles. Next, the 80 mg m(-2) week(-1) cohort was enlarged to a total of six patients. One other patient at this dose level experienced grade 1 haematuria. At 120 mg m(-2) week(-1), grade 1 bladder toxicity occurred in two of three patients. Dose escalation was stopped at 120 mg m(-2) week(-1). Cumulative bladder toxicity was dose-limiting toxicity at 80 mg m(-2) week(-1). Pharmacokinetics revealed highly variable urinary camptothecin excretion, associated with bladder toxicity. Due to cumulative bladder toxicity, weekly MAG-CPT is not a suitable regimen for treatment of patients with solid tumours

Chemical Synthesis and Immunological Evaluation of Fragments of the Multiantennary Group-Specific Polysaccharide of Group B Streptococcus.

Group B Streptococcus (GBS) is a Gram-positive bacterium and the most common cause of neonatal blood and brain infections. At least 10 different serotypes exist, that are characterized by their different capsular polysaccharides. The Group B carbohydrate (GBC) is shared by all serotypes and therefore attractive be used in a glycoconjugate vaccine. The GBC is a highly complex multiantennary structure, composed of rhamnose rich oligosaccharides interspaced with glucitol phosphates. We here report the development of a convergent approach to assemble a pentamer, octamer, and tridecamer fragment of the termini of the antennae. Phosphoramidite chemistry was used to fuse the pentamer and octamer fragments to deliver the 13-mer GBC oligosaccharide. Nuclear magnetic resonance spectroscopy of the generated fragments confirmed the structures of the naturally occurring polysaccharide. The fragments were used to generate model glycoconjugate vaccine by coupling with CRM197. Immunization of mice delivered sera that was shown to be capable of recognizing different GBS strains. The antibodies raised using the 13-mer conjugate were shown to recognize the bacteria best and the serum raised against this GBC fragment-mediated opsonophagocytic killing best, but in a capsule dependent manner. Overall, the GBC 13-mer was identified to be a highly promising antigen for incorporation into future (multicomponent) anti-GBS vaccines.Bio-organic Synthesi