Constitutive activity and inverse agonism at the alpha1adrenoceptors.

Mutations of G protein-coupled receptors (GPCR) can increase their constitutive (agonist-independent) activity. Some of these mutations have been artificially introduced by site-directed mutagenesis, others occur spontaneously in human diseases. The alpha(1B)adrenoceptor was the first GPCR in which point mutations were shown to trigger receptor activation. This article briefly summarizes some of the findings reported in the last several years on constitutive activity of the alpha(1)adrenoceptor subtypes, the location where mutations have been found in the receptors, the spontaneous activity of native receptors in recombinant as well as physiological systems. In addition, it will highlight how the analysis of the pharmacological and molecular properties of the constitutively active adrenoceptor mutants provided an important contribution to our understanding of the molecular mechanisms underlying the mechanism of receptor activation and inverse agonism.

Homeodomain binding motifs modulate the probability of odorant receptor gene choice in transgenic mice.

Odorant receptor (OR) genes constitute with 1200 members the largest gene family in the mouse genome. A mature olfactory sensory neuron (OSN) is thought to express just one OR gene, and from one allele. The cell bodies of OSNs that express a given OR gene display a mosaic pattern within a particular region of the main olfactory epithelium. The mechanisms and cis-acting DNA elements that regulate the expression of one OR gene per OSN - OR gene choice - remain poorly understood. Here, we describe a reporter assay to identify minimal promoters for OR genes in transgenic mice, which are produced by the conventional method of pronuclear injection of DNA. The promoter transgenes are devoid of an OR coding sequence, and instead drive expression of the axonal marker tau-β-galactosidase. For four mouse OR genes (M71, M72, MOR23, and P3) and one human OR gene (hM72), a mosaic, OSN-specific pattern of reporter expression can be obtained in transgenic mice with contiguous DNA segments of only ~300 bp that are centered around the transcription start site (TSS). The ~150bp region upstream of the TSS contains three conserved sequence motifs, including homeodomain (HD) binding sites. Such HD binding sites are also present in the H and P elements, DNA sequences that are known to strongly influence OR gene expression. When a 19mer encompassing a HD binding site from the P element is multimerized nine times and added upstream of a MOR23 minigene that contains the MOR23 coding region, we observe a dramatic increase in the number of transgene-expressing founders and lines and in the number of labeled OSNs. By contrast, a nine times multimerized 19mer with a mutant HD binding site does not have these effects. We hypothesize that HD binding sites in the H and P elements and in OR promoters modulate the probability of OR gene choice.

Free inertial processes driven by Gaussian noise: Probability distributions, anomalous diffusion and fractal behavior

We study the motion of an unbound particle under the influence of a random force modeled as Gaussian colored noise with an arbitrary correlation function. We derive exact equations for the joint and marginal probability density functions and find the associated solutions. We analyze in detail anomalous diffusion behaviors along with the fractal structure of the trajectories of the particle and explore possible connections between dynamical exponents of the variance and the fractal dimension of the trajectories.

Generalized Langevin equations: Anomalous diffusion and probability distributions

We study the motion of a particle governed by a generalized Langevin equation. We show that, when no fluctuation-dissipation relation holds, the long-time behavior of the particle may be from stationary to superdiffusive, along with subdiffusive and diffusive. When the random force is Gaussian, we derive the exact equations for the joint and marginal probability density functions for the position and velocity of the particle and find their solutions.

The mean-variance model from the inverse of the variance-covariance matrix

En este artículo, a partir de la inversa de la matriz de varianzas y covarianzas se obtiene el modelo Esperanza-Varianza de Markowitz siguiendo un camino más corto y matemáticamente riguroso. También se obtiene la ecuación de equilibrio del CAPM de Sharpe.

Inverse metamorphic zonation in very low-grade Tibetan zone series of SE Zanskar and its tectonic consequences (NW India, Himalaya)

The metamorphism of the carbonate rocks of the SE Zanskar Tibetan zone has been studied by `'illite crystallinity'' and calcite-dolomite thermometry. The epizonal Zangla unit overlies the anchizonal Chumik unit. This discontinuous inverse zonation demonstrates a late to post-metamorphic thrust of the first unit over the second. The studied area underwent a complex tectonic history: - The tectonic units were stacked from the NE to the SW, generating recumbent folds, NE dipping thrusts and the regional metamorphism. The compressive movements were active under lower temperature conditions, resulting in late thrusts that disturbed the metamorphic zonation. The discontinuous inverse metamorphic zonation dates from this phase. - A NE vergent backfolding phase occurred at lower temperature conditions. It caused the uplift of more metamorphic levels. - A late extensional phase is revealed by the presence of NE dipping low angle normal faults, and a major high angle fault, the Sarchu fault. The low angle normal faults locally run along earlier thrusts (composite tectonic contacts). Their throw has been sufficient to reset a normal stratigraphic superposition (young layers overlying old ones), but insufficient to erase the inverse metamorphic relationship. However, the combined action of backfolding and normal faulting can locally lessen, or even cancel, the inverse metamorphic superposition. After deduction of the normal fault translation, the vertical component of the original thrust displacement through stratigraphy is 400 m, which is a value far too low to explain the temperature difference between the two units. The horizontal component of displacement is therefore far more important than the vertical one. The regional distribution of metamorphism within the Zangla unit points out to an anchizonal front and an epizonal inner part. This fact is in agreement with nappe tectonics.

Letter to the Editor : on the value of probability for evaluating results of comparative pattern analyses

This letter to the Editor comments on the article Practical relevance of pattern uniqueness in forensic science by P.T. Jayaprakash (Forensic Science International, in press).

Variation in forest fire ignition probability in Finland

Abstract

New reference tables and user-friendly Internet application for predicted heart weights.

BACKGROUND: Knowledge of normal heart weight ranges is important information for pathologists. Comparing the measured heart weight to reference values is one of the key elements used to determine if the heart is pathological, as heart weight increases in many cardiac pathologies. The current reference tables are old and in need of an update. AIMS: The purposes of this study are to establish new reference tables for normal heart weights in the local population and to determine the best predictive factor for normal heart weight. We also aim to provide technical support to calculate the predictive normal heart weight. METHODS: The reference values are based on retrospective analysis of adult Caucasian autopsy cases without any obvious pathology that were collected at the University Centre of Legal Medicine in Lausanne from 2007 to 2011. We selected 288 cases. The mean age was 39.2 years. There were 118 men and 170 women. Regression analyses were performed to assess the relationship of heart weight to body weight, body height, body mass index (BMI) and body surface area (BSA). RESULTS: The heart weight increased along with an increase in all the parameters studied. The mean heart weight was greater in men than in women at a similar body weight. BSA was determined to be the best predictor for normal heart weight. New reference tables for predicted heart weights are presented as a web application that enable the comparison of heart weights observed at autopsy with the reference values. CONCLUSIONS: The reference tables for heart weight and other organs should be systematically updated and adapted for the local population. Web access and smartphone applications for the predicted heart weight represent important investigational tools.