Synthesis and multi-target biological profiling of a novel family of rhein derivatives as disease-modifying anti-Alzheimer agents

We have synthesized a family of rheinhuprine hybrids to hit several key targets for Alzheimer"s disease. Biological screening performed in vitro and in Escherichia coli cells has shown that these hybrids exhibit potent inhibitory activities against human acetylcholinesterase butyrylcholinesterase, and BACE-1, dual Aβ42 and tau anti-aggregating activity, and brain permeability. Ex vivo studies with the leads (+)- and ()-7e in brain slices of C57bl6 mice have revealed that they efficiently protect against the Aβ-induced synaptic dysfunction , preventing the loss of synaptic proteins and/or have a positive effect on the induction of long term potentiation. In vivo studies in APP-PS1 transgenic mice treated i.p. for 4 weeks with (+)- and ()-7e have shown a central soluble Aβ lowering effect, accompanied by an increase in the levels of mature amyloid precursor protein (APP). Thus, (+)- and ()-7e emerge as very promising disease-modifying anti-Alzheimer drug candidates.

Synthesis and multi-target biological profiling of a novel family of rhein derivatives as disease-modifying anti-Alzheimer agents

We have synthesized a family of rheinhuprine hybrids to hit several key targets for Alzheimer"s disease. Biological screening performed in vitro and in Escherichia coli cells has shown that these hybrids exhibit potent inhibitory activities against human acetylcholinesterase butyrylcholinesterase, and BACE-1, dual Aβ42 and tau anti-aggregating activity, and brain permeability. Ex vivo studies with the leads (+)- and ()-7e in brain slices of C57bl6 mice have revealed that they efficiently protect against the Aβ-induced synaptic dysfunction , preventing the loss of synaptic proteins and/or have a positive effect on the induction of long term potentiation. In vivo studies in APP-PS1 transgenic mice treated i.p. for 4 weeks with (+)- and ()-7e have shown a central soluble Aβ lowering effect, accompanied by an increase in the levels of mature amyloid precursor protein (APP). Thus, (+)- and ()-7e emerge as very promising disease-modifying anti-Alzheimer drug candidates.

Novel synthesis of arylethynyl heterocyles

A new and easy synthesis of 2-arylethynyl-indole and 2-arylethynyl-pyrrole is described. N-deprotection and subsequent base-catalyzed elimination of N-tosylheteroaryl benzyl ketones are the key steps of the process.

Novel synthesis of arylethynyl heterocyles

A new and easy synthesis of 2-arylethynyl-indole and 2-arylethynyl-pyrrole is described. N-deprotection and subsequent base-catalyzed elimination of N-tosylheteroaryl benzyl ketones are the key steps of the process.

A novel source for miR-21 expression through the alternative polyadenylation of VMP1 gene transcripts

miR-21 is the most commonly over-expressed microRNA (miRNA) in cancer and a proven oncogene. Hsa-miR-21 is located on chromosome 17q23.2, immediately downstream of the vacuole membrane protein-1 (VMP1) gene, also known as TMEM49. VMP1 transcripts initiate ∼130 kb upstream of miR-21, are spliced, and polyadenylated only a few hundred base pairs upstream of the miR-21 hairpin. On the other hand, primary miR-21 transcripts (pri-miR-21) originate within the last introns of VMP1, but bypass VMP1 polyadenylation signals to include the miR-21 hairpin. Here, we report that VMP1 transcripts can also bypass these polyadenylation signals to include miR-21, thus providing a novel and independently regulated source of miR-21, termed VMP1–miR-21. Northern blotting, gene-specific RT-PCR, RNA pull-down and DNA branching assays support that VMP1–miR-21 is expressed at significant levels in a number of cancer cell lines and that it is processed by the Microprocessor complex to produce mature miR-21. VMP1 and pri-miR-21 are induced by common stimuli, such as phorbol-12-myristate-13-acetate (PMA) and androgens, but show differential responses to some stimuli such as epigenetic modifying agents. Collectively, these results indicate that miR-21 is a unique miRNA capable of being regulated by alternative polyadenylation and two independent gene promoters.

The UlaG protein familly defines novel structural and functional motifs grafted on an ancient RNase fold

Background: Bacterial populations are highly successful at colonizing new habitats and adapting to changing environmental conditions, partly due to their capacity to evolve novel virulence and metabolic pathways in response to stress conditions and to shuffle them by horizontal gene transfer (HGT). A common theme in the evolution of new functions consists of gene duplication followed by functional divergence. UlaG, a unique manganese-dependent metallo-b-lactamase (MBL) enzyme involved in L-ascorbate metabolism by commensal and symbiotic enterobacteria, provides a model for the study of the emergence of new catalytic activities from the modification of an ancient fold. Furthermore, UlaG is the founding member of the so-called UlaG-like (UlaGL) protein family, a recently established and poorly characterized family comprising divalent (and perhaps trivalent)metal-binding MBLs that catalyze transformations on phosphorylated sugars and nucleotides. Results: Here we combined protein structure-guided and sequence-only molecular phylogenetic analyses to dissect the molecular evolution of UlaG and to study its phylogenomic distribution, its relatedness with present-day UlaGL protein sequences and functional conservation. Phylogenetic analyses indicate that UlaGL sequences are present in Bacteria and Archaea, with bona fide orthologs found mainly in mammalian and plant-associated Gramnegative and Gram-positive bacteria. The incongruence between the UlaGL tree and known species trees indicates exchange by HGT and suggests that the UlaGL-encoding genes provided a growth advantage under changing conditions. Our search for more distantly related protein sequences aided by structural homology has uncovered that UlaGL sequences have a common evolutionary origin with present-day RNA processing and metabolizing MBL enzymes widespread in Bacteria, Archaea, and Eukarya. This observation suggests an ancient origin for the UlaGL family within the broader trunk of the MBL superfamily by duplication, neofunctionalization and fixation. Conclusions: Our results suggest that the forerunner of UlaG was present as an RNA metabolizing enzyme in the last common ancestor, and that the modern descendants of that ancestral gene have a wide phylogenetic distribution and functional roles. We propose that the UlaGL family evolved new metabolic roles among bacterial and possibly archeal phyla in the setting of a close association with metazoans, such as in the mammalian gastrointestinal tract or in animal and plant pathogens, as well as in environmental settings. Accordingly, the major evolutionary forces shaping the UlaGL family include vertical inheritance and lineage-specific duplication and acquisition of novel metabolic functions, followed by HGT and numerous lineage-specific gene loss events.

Hepatocyte nuclear factor-4 alpha regulates the human apolipoprotein AV gene: Identification of a novel response element and involvement in the control by peroxisome proliferator-activated receptor-gamma coactivator-1 alpha, AMP-activated protein kinase, and mitogen-activated protein kinase pathway

The recently discovered apolipoprotein AV (apoAV) gene has been reported to be a key player in modulating plasma triglyceride levels. Here we identify the hepatocyte nuclear factor-4 (HNF-4 ) as a novel regulator of human apoAV gene. Inhibition of HNF-4 expression by small interfering RNA resulted in down-regulation of apoAV. Deletion, mutagenesis, and binding assays revealed that HNF-4 directly regulates human apoAV promoter through DR1 [a direct repeat separated by one nucleotide (nt)], and via a novel element for HNF-4 consisting of an inverted repeat separated by 8 nt (IR8). In addition, we show that the coactivator peroxisome proliferator-activated receptor- coactivator-1 was capable of stimulating the HNF-4 -dependent transactivation of apoAV promoter. Furthermore, analyses in human hepatic cells demonstrated that AMP-activated protein kinase (AMPK) and the MAPK signaling pathway regulate human apoAV expression and suggested that this regulation may be mediated, at least in part, by changes in HNF-4 . Intriguingly, EMSAs and mice with a liver-specific disruption of the HNF-4 gene revealed a species-distinct regulation of apoAV by HNF-4 , which resembles that of a subset of HNF-4 target genes. Taken together, our data provide new insights into the binding properties and the modulation of HNF-4 and underscore the role of HNF-4 in regulating triglyceride metabolism.

Behind and beyond of the cyborgs and robots ideas and realities: some techno-scientific and philosophical hints

We are progressively immersed in technology to such extend that in our everyday life we are and we do what technology allows us to be and to do. In this process, cyborgs and robots constitute elements that we analyze from a number of techno scientific and philosophical approaches. Additionally, we propose that a new concept: GEH (Genetic Engineered Human) as a new potential social imaginary element, which would be the human being improved by the broad-sense genetics engineer (that is, changing many genes by genetics engineer, modifications in the genome, cloning, and so on). If our aspirations as humans pass through technology and in particular for cyborgs, robots and GEH, the bidirectional links between these theoretical or real entities and our personal identities will be the more and more substantial in our society.

Evaluación de la formación del profesorado universitario novel

Durante el curso académico 2001-2002 se desarrolló en la Universidad de Barcelona el Curso de Postgrado 'Innovación en la Docencia Universitaria' dirigido al profesorado novel de la misma. Finalizado el programa se hacía imprescindible conocer su contribución a la mejora de la docencia del profesorado debutante. A través de este estudio se pretende, por tanto, identificar y valorar los cambios, transformaciones y mejoras acaecidas en la práctica docente del profesorado novel como consecuencia de su participación en el Postgrado. El presente trabajo recoge estos aspectos articulados en una evaluación diferida del impacto del Curso de Postgrado. El enfoque metodológico usado ha sido cualitativo-fenomenológico En lo que se refiere a los criterios de evaluación, dos han sido los utilizados en este estudio: la utilidad percibida por el profesorado y la transferibilidad del conocimiento elaborado en el curso.

The awr gene family encodes a novel class of Ralstonia solanacearum type III effectors displaying virulence and avirulence activities

We present here the characterization of a new gene family, awr, found in all sequenced Ralstonia solanacearum strains and in other bacterial pathogens. We demonstrate that the five paralogues in strain GMI1000 encode type III-secreted effectors and that deletion of all awr genes severely impairs its capacity to multiply in natural host plants. Complementation studies show that the AWR (alanine-tryptophanarginine tryad) effectors display some functional redundancy, although AWR2 is the major contributor to virulence. In contrast, the strain devoid of all awr genes (¿awr1-5) exhibits enhanced pathogenicity on Arabidopsis plants. A gain-of-function approach expressing AWR in Pseudomonas syringae pv. tomato DC3000 proves that this is likely due to effector recognition, because AWR5 and AWR4 restrict growth of this bacterium in Arabidopsis. Transient overexpression of AWR in nonhost tobacco species caused macroscopic cell death to varying extents, which, in the case of AWR5, shows characteristics of a typical hypersensitive response. Our work demonstrates that AWR, which show no similarity to any protein with known function, can specify either virulence or avirulence in the interaction of R. solanacearum with its plant hosts.

A novel approach to analysing the regimes of temporary streams in relation to their controls on the composition and structure of aquatic biota

Temporary streams are those water courses that undergo the recurrent cessation of flow or the complete drying of their channel. The structure and composition of biological communities in temporary stream reaches are strongly dependent on the temporal changes of the aquatic habitats determined by the hydrological conditions. Therefore, the structural and functional characteristics of aquatic fauna to assess the ecological quality of a temporary stream reach cannot be used without taking into account the controls imposed by the hydrological regime. This paper develops methods for analysing temporary streams' aquatic regimes, based on the definition of six aquatic states that summarize the transient sets of mesohabitats occurring on a given reach at a particular moment, depending on the hydrological conditions: Hyperrheic, Eurheic, Oligorheic, Arheic, Hyporheic and Edaphic. When the hydrological conditions lead to a change in the aquatic state, the structure and composition of the aquatic community changes according to the new set of available habitats. We used the water discharge records from gauging stations or simulations with rainfall-runoff models to infer the temporal patterns of occurrence of these states in the Aquatic States Frequency Graph we developed. The visual analysis of this graph is complemented by the development of two metrics which describe the permanence of flow and the seasonal predictability of zero flow periods. Finally, a classification of temporary streams in four aquatic regimes in terms of their influence over the development of aquatic life is updated from the existing classifications, with stream aquatic regimes defined as Permanent, Temporary-pools, Temporary-dry and Episodic. While aquatic regimes describe the long-term overall variability of the hydrological conditions of the river section and have been used for many years by hydrologists and ecologists, aquatic states describe the availability of mesohabitats in given periods that determine the presence of different biotic assemblages. This novel concept links hydrological and ecological conditions in a unique way. All these methods were implemented with data from eight temporary streams around the Mediterranean within the MIRAGE project. Their application was a precondition to assessing the ecological quality of these streams.

Erwinia amylovora Novel Plasmid pEI70: Complete Sequence, Biogeography, and Role in Aggressiveness in the Fire Blight Phytopathogen

Comparative genomics of several strains of Erwinia amylovora, a plant pathogenic bacterium causal agent of fire blight disease, revealed that its diversity is primarily attributable to the flexible genome comprised of plasmids. We recently identified and sequenced in full a novel 65.8 kb plasmid, called pEI70. Annotation revealed a lack of known virulence-related genes, but found evidence for a unique integrative conjugative element related to that of other plant and human pathogens. Comparative analyses using BLASTN showed that pEI70 is almost entirely included in plasmid pEB102 from E. billingiae, an epiphytic Erwinia of pome fruits, with sequence identities superior to 98%. A duplex PCR assay was developed to survey the prevalence of plasmid pEI70 and also that of pEA29, which had previously been described in several E. amylovora strains. Plasmid pEI70 was found widely dispersed across Europe with frequencies of 5–92%, but it was absent in E. amylovora analyzed populations from outside of Europe. Restriction analysis and hybridization demonstrated that this plasmid was identical in at least 13 strains. Curing E. amylovora strains of pEI70 reduced their aggressiveness on pear, and introducing pEI70 into low-aggressiveness strains lacking this plasmid increased symptoms development in this host. Discovery of this novel plasmid offers new insights into the biogeography, evolution and virulence determinants in E. amylovora

Classical references and their significance in The Magic Mountain by Thomas Mann

Although Thomas Mann’s novel The Magic Mountain has been the object of innumerable studies, this paper suggests that so far none of these has given truly close attention to the significance of the classical references in this novel with regard to the search for a true humanism. This is probably owing to the generally held belief that the influence of the classical tradition is relatively inconsequential in relation to the ample conjunction of philosophical ideas on which the novel is based. This article takes a differing view and, through a close analysis and comment of the explicit and implicit classical notions in the text, concludes that these ideas are also a valuable key to a greater comprehension of the ideological design of the main character, Hans Castorp, and to a certain degree they also help to continue to reflect on the most enigmatic and controversial episode of the novel: the young protagonist’s descent to the plain from the magical mountain (Zauberberg) in order to take part in the great tragedy of World War I, alien as is any war to the prevalent but ultimately futile desire that love (Liebe) should in the end prevail in the life of humans.

Establishing Zebrafish as a Novel Exercise Model: Swimming Economy, Swimming-enhanced Growth and Muscle Growth Marker Gene Expression

Zebrafish has been largely accepted as a vertebrate multidisciplinary model but its usefulness as a model for exercise physiology has been hampered by the scarce knowledge on its swimming economy, optimal swimming speeds and cost of transport. Therefore, we have performed individual and group-wise swimming experiments to quantify swimming economy and to demonstrate the exercise effects on growth in adult zebrafish.