Neuron firing in driven nonlinear integrate-and-fire models

Statistical properties of neuron firing are studied in the framework of a nonlinear leaky integrate-and-fire model that is driven by a slow periodic subthreshold signal. The firing events are characterized by first passage time densities. The experimentally better accessible interspike interval density generally depends on the sojourn times in a refractory state of the neuron. This aspect is not part of the integrate-and-fire model and must be modelled additionally. For a large class of refractory dynamics, a general expression for the interspike interval density is given and further evaluated for the two cases with an instantaneous resetting (i.e. no refractory state) and a refractory state possessing a deterministic lifetime. First passage time densities and interspike interval densities following from the proposed theory compare favorably with precise numerical simulations.     

Fingerprint formation

Fingerprints (epidermal ridges) have been used as a means of identifications for more than 2000 years. They have also been extensively studied scientifically by anthropologists and biologists. However, despite all the empirical and experimental knowledge, no widely accepted explanation for the development of epidermal ridges on fingers, palms and soles has yet emerged. In this article we argue that fingerprint patterns are created as the result of a buckling instability in the basal cell layer of the fetal epidermis. Analysis of the well-known von Karman equations informs us that the buckling direction is perpendicular to the direction of greatest stress in the basal layer. We propose that this stress is induced by resistance of furrows and creases to the differential growth of the basal layer and regression of the volar pads during the time of ridge formation. These ideas have been tested by computer experiments. The results are in close harmony with observations. Specifically, they are consistent with the well-known observation that the pattern type is related to the geometry of the fingertip surface when fingerprint patterns are formed.     

Structure based drug design and in vitro metabolism study: Discovery of N-(4-methylthiophenyl)-N,2-dimethyl-cyclopenta[d]pyrimidine as a potent microtubule targeting agent

We report a series of tubulin targeting agents, some of which demonstrate potent antiproliferative activities. These analogs were designed to optimize the antiproliferative activity of 1 by varying the heteroatom substituent at the 4′-position, the basicity of the 4-position amino moiety, and conformational restriction. The potential metabolites of the active compounds were also synthesized. Some compounds demonstrated single digit nanomolar IC₅₀ values for antiproliferative effects in MDA-MB-435 melanoma cells. Particularly, the S-methyl analog 3 was more potent than 1 in MDA-MB-435 cells (IC₅₀?=?4.6?nM). Incubation of 3 with human liver microsomes showed that the primary metabolite of the S-methyl moiety of 3 was the methyl sulfinyl group, as in analog 5. This metabolite was equipotent with the lead compound 1 in MDA-MB-435 cells (IC₅₀?=?7.9?nM). Molecular modeling and electrostatic surface area were determined to explain the activities of the analogs. Most of the potent compounds overcome multiple mechanisms of drug resistance and compound 3 emerged as the lead compound for further SAR and preclinical development.     

Design,synthesis, and structure–activity relationships of pyrimido[4,5-b]indole-4-amines as microtubule depolymerizing agents that are effective against multidrug resistant cells

To identify the structural features of 9H-pyrimido[4,5-b]indoles as microtubule depolymerizers, pyrimido[4,5-b]indoles 2–8 with varied substituents at the 2-, 4- and 5-positions were designed and synthesized. Nucleophilic displacement of 2,5-substituted-4-chloro-pyrimido[4,5-b]indoles with appropriate arylamines was the final step employed in the synthesis of target compounds 2–8. Compounds 2 and 6 had two-digit nanomolar potency (IC₅₀) against MDA-MB-435, SK-OV-3 and HeLa cancer cells in vitro. Compounds 2 and 6 also depolymerized microtubules comparable to the lead compound 1. Compounds 2, 3, 6 and 8 were effective in cells expressing P-glycoprotein or the βIII isotype of tubulin, mechanisms that are associated with clinical drug resistance to microtubule targeting drugs. Proton NMR and molecular modeling studies were employed to identify the structural basis for the microtubule depolymerizing activity of pyrimido[4,5-b]indoles.     

High risk water pollution hazards affecting Aveiro coastal lagoon (Portugal) – A habitat risk assessment using InVEST

Anthropogenic pressures put at jeopardy ecosystem services (ES) provided by natural habitats. Ecosystem Based Management (EBM) approaches can support policymakers dealing with physical, chemical, and biological stresses caused by high-risk water pollution (HRWP) and sudden-accidental pollution (SAP). The objective of this study is to evaluate how alarming HRWP pressures might become in fragile marine, coastal, estuarine, and freshwater socio-ecological systems (MCEF-SES) surrounded by heavily industrialized and urbanized areas. To this end a spatially explicit analysis, using the InVEST-Habitat Risk Assessment (InVEST-HRA) model in combination with expert judgement from researchers from various fields, is performed. An application is provided for the case of the Ria de Aveiro (RdA) coastal lagoon in Portugal. Results show high spatial variance of HRWP hazards across RdA, with one major multi-layer risk hotspot at the center of the research area and a second patch of multiple risk hotspots towards the North of RdA. Salines emerge as the most threatened habitat followed by Intertidal flats and Saltmarshes. The most significant water pollution risk sources contributing to Salines cumulative risk are Fossil fuel processing, storage and sale units, Industrial units, Aquaculture, and the Marinas. Industries involving dangerous substances in the region threaten primarily Watercourses. This study confirms the InVEST-HRA model in combination with expert judgement is a transparent and easily replicable approach to build ES-based knowledge about habitat risks threatening MCEF-SES in a Natura 2000 site heavily pressured by HRWP hazards. After further valuation analysis, pondering gains and losses from regional development and environmental protection, this knowledge can support the planning and management of coastal areas and the prioritization of pollution abatement interventions. In particular, by estimating the loss that HRWP causes in the value of ecosystem services, defining HRWP abatement policies, assessing the effectiveness, costs and benefits of those abatement policies and, ultimately, evaluating the results for the well-being of local communities through global efficiency analysis, cost-benefit analysis or cost-effectiveness analysis. Hence, it bridges the gap between an informed EBM and the development policies of fragile regions.