Beyond Pseudo-natural Products: Sequential Ugi/Pictet-Spengler Reactions Leading to Steroidal Pyrazinoisoquinolines That Trigger Caspase-Independent Death in HepG2 Cells.

In this work, we describe how stereochemically complex polycyclic compounds can be generated by applying a synthetic sequence comprising an intramolecular Ugi reaction followed by a Pictet-Spengler cyclization on steroid-derived scaffolds. The resulting compounds, which combine a fragment derived from a natural product and a scaffold not found in nature. are both structurally distinct and globally similar to natural products at the same time, and interrogate an alternative region of the chemical space. One of the new compounds showed significant antiproliferative activity on HepG2 cells through a caspase-independent cell-death mechanism, an appealing feature when new antitumor compounds are searched.

Tracing molecular properties throughout evolution: A chemoinformatic approach.

Evolution of metabolism is a longstanding yet unresolved question, and several hypotheses were proposed to address this complex process from a Darwinian point of view. Modern statistical bioinformatic approaches targeted to the comparative analysis of genomes are being used to detect signatures of natural selection at the gene and population level, as an attempt to understand the origin of primordial metabolism and its expansion. These studies, however, are still mainly centered on genes and the proteins they encode, somehow neglecting the small organic chemicals that support life processes. In this work, we selected steroids as an ancient family of metabolites widely distributed in all eukaryotes and applied unsupervised machine learning techniques to reveal the traits that natural selection has imprinted on molecular properties throughout the evolutionary process. Our results clearly show that sterols, the primal steroids that first appeared, have more conserved properties and that, from then on, more complex compounds with increasingly diverse properties have emerged, suggesting that chemical diversification parallels the expansion of biological complexity. In a wider context, these findings highlight the worth of chemoinformatic approaches to a better understanding the evolution of metabolism.

Comparison of Two Detailed Models of Aedes aegypti Population Dynamics.

The success of control programs for mosquito borne diseases can be enhanced by crucial information provided by models of the mosquito populations. Models, however, can differ in their structure, complexity and biological assumptions, and these differences impact their predictions. Unfortunately, it is typically difficult to determine why two complex models make different predictions because we lack structured side-by-side comparisons of models using comparable parameterization. Here we present a detailed comparison of two complex, spatially-explicit, stochastic models of the population dynamics of Aedes aegypti, the main vector of dengue, yellow fever, chikungunya and Zika viruses. Both models describe the mosquito's biological and ecological characteristics, but differ in complexity and specific assumptions. We compare the predictions of these models in two selected climatic settings, a tropical and weakly seasonal climate in Iquitos, Peru, and a temperate and strongly seasonal climate in Buenos Aires, Argentina. Both models were calibrated to operate at identical average densities in unperturbed conditions in both settings, by adjusting parameters regulating densities in each model (number of larval development sites and amount of nutritional resources). We show that the models differ in their sensitivity to environmental conditions (temperature and rainfall), and trace differences to specific model assumptions. Temporal dynamics of the Ae. aegypti populations predicted by the two models differ more markedly under strongly seasonal Buenos Aires conditions. We use both models to simulate killing of larvae and/or adults with insecticides in selected areas. We show that predictions of population recovery by the models differ substantially, an effect likely related to model assumptions regarding larval development and (direct or delayed) density dependence. Our methodical comparison provides important guidance for model improvement by identifying key areas of Ae. aegypti ecology that substantially affect model predictions, and revealing the impact of model assumptions on population dynamics predictions in unperturbed and perturbed conditions.

Resistance and mutations of non-specificity in the field of anxiety-depressive disorders in Canadian medical journals, 1950-1990.

Pharmaceuticalisation is a complex phenomenon, co-constitutive of what scholars identify as a pharmaceutical regime, comprised of networks of actors, institutions and artefacts as well as cognitive structures that underlie the production, promotion and use of medications. The aim of this paper is to explore the linkages between different components of this pharmaceutical regime through the analysis of psychotropic drug advertising in Canadian medical journals between 1950 and 1990. Advertisements stand at the nexus of macro-level processes related to the development, regulation and marketing of new drug treatments and of micro-level processes related to the use of these drug treatments, both by clinicians and lay persons. We thus examine advertisements from the angle of the mental and classificatory universes to which doctors were exposed through direct-to-prescriber advertisement strategies implemented during this period. Furthermore, we explore to what extent the rationale behind advertisements was permeated by both scientific/professional and popular narratives of mind-body connections. This paper demonstrates that, although this period was marked by paradigm shifts in the classification of mental diseases, the development of modern psychopharmacology, and the questioning of the scientific legitimacy of psychiatry, advertisements unveil a remarkable continuity: that of the mass management of anxiety-depressive disorders by primary care physicians through psychotropic drugs. Also, despite the effective resistance to specificity as shown by the constant redefinitions of diagnostic categories and therapeutic indications, our analysis suggests that the language of specificity used in the promotion of new drugs and in the various narratives of mind-body connection may have been appealing to general practitioners. Finally, our study of the classes of psychoactive medications that have been in use for over half a century reveals a complex, non-linear dynamic of pharmaceuticalisation and de-pharmaceuticalisation.

Modeling dengue outbreaks.

We introduce a dengue model (SEIR) where the human individuals are treated on an individual basis (IBM) while the mosquito population, produced by an independent model, is treated by compartments (SEI). We study the spread of epidemics by the sole action of the mosquito. Exponential, deterministic and experimental distributions for the (human) exposed period are considered in two weather scenarios, one corresponding to temperate climate and the other to tropical climate. Virus circulation, final epidemic size and duration of outbreaks are considered showing that the results present little sensitivity to the statistics followed by the exposed period provided the median of the distributions are in coincidence. Only the time between an introduced (imported) case and the appearance of the first symptomatic secondary case is sensitive to this distribution. We finally show that the IBM model introduced is precisely a realization of a compartmental model, and that at least in this case, the choice between compartmental models or IBM is only a matter of convenience.

A stochastic spatial dynamical model for Aedes aegypti.

We develop a stochastic spatial model for Aedes aegypti populations based on the life cycle of the mosquito and its dispersal. Our validation corresponds to a monitoring study performed in Buenos Aires. Lacking information with regard to the number of breeding sites per block, the corresponding parameter (BS) was adjusted to the data. The model is able to produce numerical data in very good agreement with field results during most of the year, the exception being the fall season. Possible causes of the disagreement are discussed. We analyzed the mosquito dispersal as an advantageous strategy of persistence in the city and simulated the dispersal of females from a source to the surroundings along a 3-year period observing that several processes occur simultaneously: local extinctions, recolonization processes (resulting from flight and the oviposition performed by flyers), and colonization processes resulting from the persistence of eggs during the winter season. In view of this process, we suggest that eradication campaigns in temperate climates should be performed during the winter time for higher efficiency.

A stochastic population dynamics model for Aedes aegypti: formulation and application to a city with temperate climate.

Aedes aegypti is the main vector for dengue and urban yellow fever. It is extended around the world not only in the tropical regions but also beyond them, reaching temperate climates. Because of its importance as a vector of deadly diseases, the significance of its distribution in urban areas and the possibility of breeding in laboratory facilities, Aedes aegypti is one of the best-known mosquitoes. In this work the biology of Aedes aegypti is incorporated into the framework of a stochastic population dynamics model able to handle seasonal and total extinction as well as endemic situations. The model incorporates explicitly the dependence with temperature. The ecological parameters of the model are tuned to the present populations of Aedes aegypti in Buenos Aires city, which is at the border of the present day geographical distribution in South America. Temperature thresholds for the mosquito survival are computed as a function of average yearly temperature and seasonal variation as well as breeding site availability. The stochastic analysis suggests that the southern limit of Aedes aegypti distribution in South America is close to the 15 degrees C average yearly isotherm, which accounts for the historical and current distribution better than the traditional criterion of the winter (July) 10 degrees C isotherm.

[Suicide in Buenos Aires]. / Le suicide à Buenos Aires: la contribution des médecins à sa "thématisation" comme problème social.

Between 1880 and 1910, a new issue began to concern some in the Argentinean medical community: the increase in the suicide rate. The concept of suicide, till then considered to be an individual and private behaviour, changes noticeably. A group of institutions and discussions would increasingly focus as much on the causes of this apparent rise in the suicide rate as on how to reduce their number. Despite the variety of specialities and orientations of the Argentinean doctors (mental health specialists, psychiatrists, psychologists, criminologists and sociologists -before such terms were coined) who try to understand the rise in the number of suicides, there is a fundamental issue at the heart of their analyses: the deficient framework- perceived by them as non-existent-for the new behaviours disturbing the social order, or that the very least, the representaion of this order in the doctors' conceptual universe. Is this a social epidemic? An obsession? Or is it just a nutural mechanism of social selection? Around the complex, process of defining the suicide phenomenon as a social problem, medical discourse sheds light on the shaky ground at the limits between the scientific claim to objectivity for certain behaviours at the renewal of the concept of normalcy in modern societies.

Study of layer-by-layer self-assembled viscoelastic films on thickness-shear mode resonator surfaces.

We describe quartz crystal electroacoustic admittance studies in thickness shear mode resonators loaded with self-assembled multilayers composed of alternate layers of glucose oxidase (GOx) and poly(allylamine) covalently attached to [Os(bpy)2ClPyCOH]- , (PAH-Os), deposited on a 3-mercaptopropanesulfonic acid (MPS)-modified gold on the quartz crystal. The complex acoustic impedance parameters, R(S) and X(LS) of a lumped-element Butterworth-Van Dyke (BVD) resonator have been determined for organized thin films of different thickness obtained by varying the number of enzyme layers, n, in (PAH-Os)n(GOx)n structures. The ellipsometric film thickness and mass for dry enzyme multilayer films and films in contact with water were evaluated, and the average film density was estimated. By combination of the estimated film thickness and density, the expression for the surface mechanical impedance of the lumped-element modified resonator (Granstaff and Martin model), and the liquid density and viscosity, we simulate the layer-by-layer film growth on the basis of the measured electroacoustic impedance. The complex impedance X(LS) and R(S) increase with film thickness and the enzyme films can be regarded as acoustically thin in the reduced state for films thinner than 600 nm. We have also measured electroacoustic parameters for PAH-Os/GOx self-assembled multilayers under electrochemical perturbation in a buffer electrolytic solution. The electrostatically self-assembled multilayers behaved as lossy viscoelastic films at 10 MHz with G'f and G''f on the order of 10(6) Pa. The films became viscoelastic upon oxidation to Os(III), resulting in an increase of R(S) and X(LS) in the oxidized state with the number of (PAH-Os)(GOx) bilayers due to film swelling and an increase in the shear moduli during oxidation.