Neurotrophin action on a rapid timescale

Mechanisms underlying the fast action of neurotrophins include intracellular Ca(2+) signaling, neuronal excitation, augmentation of synaptic excitation by modulation of N-methyl-d-aspartate receptor activity and control of synaptic inhibition through the regulation of the K(+)-Cl(-) cotransporter KCC2. The fastest action of brain-derived neurotrophic factor and neurotrophin-4/5 occurs within milliseconds, and involves activation of TrkB and the opening of the Na(+) channel Na(v)1.9. Through these rapid actions, neurotrophins shape neuronal activity, modulate synaptic transmission and produce instructive signals for the induction of long-term changes in the efficacy of synaptic transmission.     

Is there a general paradigm of cyclic AMP action in eukaryotes?

Summary The cyclic AMP control system in eukaryotes has been highly conserved evolutionarily in four of its central properties. Such conservation suggests conservation of the regulatory function of cyclic AMP. Conservation is seen in the properties of adenylate cyclase, cyclic AMP-dependent protein kinase and, among diverse lower eukaryotes, the control of endogenous cyclic AMP levels. A conserved regulatory response to cyclic AMP is the stimulation of glycolysis and inhibition of gluconeogenesis. The control of glycolysis and gluconeogenesis is proposed to be evidence of general pattern of cyclic AMP action in many lower and higher eukaryotic cells.     

Estrogen: mechanisms for a rapid action in CA1 hippocampal neurons.

Estrogen modulates a variety of functions, most of which can be explained by the classical genomic mechanism of action. However, a number of estrogen's actions appear to be incompatible with this mechanism and fall into the category of nongenomic. In the hippocampus, application of 17beta-estradiol rapidly enhances the amplitude of kainate-induced currents of CA1 neurons. The potentiation resulted from a cyclic adenosine monophosphate-dependent phosphorylation process rather than a direct allosteric modulation of AMPA/kainate receptors. To initiate this potentiation, estrogen is required on both sides of the plasma membrane. Extracellularly, estrogen appears to activate a G-protein-coupled receptor, whereas the intracellular action of estrogen appears to be a modulation of the balance between phosphorylation and dephosphorylation. The binding sites responsible for the potentiation are genetically or pharmacologically distinct from both estrogen receptors alpha and beta. These findings provide support for the concept of a novel mechanism of action for estrogen.     

Action anticipation in human infants reveals assumptions about anteroposterior body-structure and action

Animal actions are almost universally constrained by the bilateral body-plan. For example, the direction of travel tends to be constrained by the orientation of the animal''s anteroposterior axis. Hence, an animal''s behaviour can reliably guide the identification of its front and back, and its orientation can reliably guide action prediction. We examine the hypothesis that the evolutionarily ancient relation between anteroposterior body-structure and behaviour guides our cognitive processing of agents and their actions. In a series of studies, we demonstrate that, after limited exposure, human infants as young as six months of age spontaneously encode a novel agent as having a certain axial direction with respect to its actions and rely on it when anticipating the agent''s further behaviour. We found that such encoding is restricted to objects exhibiting cues of agency and does not depend on generalization from features of familiar animals. Our research offers a new tool for investigating the perception of animate agency and supports the proposal that the underlying cognitive mechanisms have been shaped by basic biological adaptations in humans.     

Process analytics 4.0: A paradigm shift in rapid analytics for biologics development

Analytical testing of product quality attributes and process parameters during the biologics development (Process analytics) has been challenging due to the rapid growth of biomolecules with complex modalities to support unmet therapeutic needs. Thus, the expansion of the process analytics tool box for rapid analytics with the deployment of cutting-edge technologies and cyber-physical systems is a necessity. We introduce the term, Process Analytics 4.0; which entails not only technology aspects such as process analytical technology (PAT), assay automation, and high-throughput analytics, but also cyber-physical systems that enable data management, visualization, augmented reality, and internet of things (IoT) infrastructure for real time analytics in process development environment. This review is exclusively focused on dissecting high-level features of PAT, automation, and data management with some insights into the business aspects of implementing during process analytical testing in biologics process development. Significant technological and business advantages can be gained with the implementation of digitalization, automation, and real time testing. A systematic development and employment of PAT in process development workflows enable real time analytics for better process understanding, agility, and sustainability. Robotics and liquid handling workstations allow rapid assay and sample preparation automation to facilitate high-throughput testing of attributes and molecular properties which are otherwise challenging to monitor with PAT tools due to technological and business constraints. Cyber-physical systems for data management, visualization, and repository must be established as part of Process Analytics 4.0 framework. Furthermore, we review some of the challenges in implementing these technologies based on our expertise in process analytics for biopharmaceutical drug substance development.     

Vector field approximation: a computational paradigm for motor control and learning

Recent experiments in the spinalized frog (Bizzi et al. 1991) have shown that focal microstimulation of a site in the premotor layers in the lumbar grey matter of the spinal cord results in a field of forces acting on the frog's ankle and converging to a single equilibrium position. These experiments suggested that the neural circuits in the spinal cord are organized in a set of control modules that store a few limb postures in the form of convergent force fields acting on the limb's end-point. Here, we investigate how such postural modules can be combined by the central nervous system for generating and representing a wider repertoire of control patterns. Our work is related to some recent investigations by Poggio and Girosi (1990a, b) who have proposed to represent the task of learning scalar maps as a problem of surface approximation. Consistent both with this view and with our experimental findings in the spinal frog, we regard the issue of generating motor repertoires as a problem of vector-field approximation. To this end, we characterize the output of a control module as a basis field (Mussa-Ivaldi 1992), that is as the vectorial equivalent of a basis function. Our theoretical findings indicate that by combining basis fields, the central nervous system may achieve a number of goals such as (1) the generation of a wide repertoire of control patterns and (2) the representation of these control patterns with a set of coefficients that are invariant under coordinate transformations.     

Auditory event-related potentials from a single-stimulus paradigm during rapid eye movement sleep

Sleep and Biological Rhythms - Auditory evoked potentials to a 2000-Hz pure tone were recorded in wakefulness and in rapid eye movement (REM) sleep. A late positive wave with a maximal amplitude...     

The Shigella virulence gene regulatory cascade: a paradigm of bacterial gene control mechanisms

Shigella flexneri is the causative agent of bacillary dysentery and is a facultative intracellular pathogen. Its virulence regulon is subject to tight control by several mechanisms involving the products of over 20 genes and an array of environmental signals. The regulon is carried on a plasmid that is prone to instability and to integration into the chromosome, with associated silencing of the virulence genes. Closely related regulons are found in other species of Shigella and in enteroinvasive Escherichia coli . A wealth of detailed information is now available on the Shigella virulence gene control circuits, and it is becoming clear that these share many features with regulatory systems found in other bacterial pathogens. All of this makes the S. flexneri virulence gene control system a very attractive topic for those interested in the nature of gene regulatory networks in bacteria.     

B-cell epitope prediction for peptide-based vaccine design: towards a paradigm of biological outcomes for global health

Global health must address a rapidly evolving burden of disease, hence the urgent need for versatile generic technologies exemplified by peptide-based vaccines. B-cell epitope prediction is crucial for designing such vaccines; yet this approach has thus far been largely unsuccessful, prompting further inquiry into the underlying reasons for its apparent inadequacy. Two major obstacles to the development of B-cell epitope prediction for peptide-based vaccine design are (1) the prevailing binary classification paradigm, which mandates the problematic dichotomization of continuous outcome variables, and (2) failure to explicitly model biological consequences of immunization that are relevant to practical considerations of safety and efficacy. The first obstacle is eliminated by redefining the predictive task as quantitative estimation of empirically observable biological effects of antibody-antigen binding, such that prediction is benchmarked using measures of correlation between continuous rather than dichotomous variables; but this alternative approach by itself fails to address the second obstacle even if benchmark data are selected to exclusively reflect functionally relevant cross-reactivity of antipeptide antibodies with protein antigens (as evidenced by antibody-modulated protein biological activity), particularly where only antibody-antigen binding is actually predicted as a surrogate for its biological effects. To overcome the second obstacle, the prerequisite is deliberate effort to predict, a priori, biological outcomes that are of immediate practical significance from the perspective of vaccination. This demands a much broader and deeper systems view of immunobiology than has hitherto been invoked for B-cell epitope prediction. Such a view would facilitate comprehension of many crucial yet largely neglected aspects of the vaccine-design problem. Of these, immunodominance among B-cell epitopes is a central unifying theme that subsumes immune phenomena of tolerance, imprinting and refocusing; but it is meaningful for vaccine design only in the light of disease-specific pathophysiology, which for infectious processes is complicated by host-pathogen coevolution. To better support peptide-based vaccine design, B-cell epitope prediction would entail individualized quantitative estimation of biological outcomes relevant to safety and efficacy. Passive-immunization experiments could serve as an important initial proving ground for B-cell epitope prediction en route to vaccine-design applications, by restricting biological complexity to render epitope-prediction problems more computationally tractable.      

Proteomics: a paradigm shift

Proteome--the protein complement of a genome--has become the protein renaissance and a key research tool in the post-genomic era. The basic technology involves the routine usage of gel electrophoresis and spectrometry procedures for deciphering the primary protein sequence/structure as well as knowing certain unique post-translational modifications that a particular protein has undergone to perform a specific function in the cell. However, the recent advancements in protein analysis have ushered this science to provide deeper, bigger and more valuable perspectives regarding performance of subtle protein-protein interactions. Applications of this branch of molecular biology are as vast as the subject is and include clinical diagnostics, pharmaceutical and biotechnological industries. The 21st century hails the use of products, procedures and advancements of this science as finer touches required for the grooming of fast-paced technology.     

A control theoretic paradigm for cell signaling networks: a simple complexity for a sensitive robustness

The fields of molecular biology and cell biology are being flooded with complex genomic and proteomic datasets of large dimensions. We now recognize that each molecule in the cell and tissue can no longer be viewed as an isolated entity. Instead, each molecule must be considered as one member of an interacting network. Consequently, there is an urgent need for mathematical models to understand the behavior of cell signaling networks in health and in disease.     

Electrochemical biofilm control: mechanism of action

Although it has been previously demonstrated that an electrical current can be used to control biofilm growth on metal surfaces, the literature results are conflicting and there is no accepted mechanism of action. One of the suggested mechanisms is the production of hydrogen peroxide (H(2)O(2)) on metal surfaces. However, there are literature studies in which H(2)O(2) could not be detected in the bulk solution. This is most likely because H(2)O(2) was produced at a low concentration near the surface and could not be detected in the bulk solution. The goals of this research were (1) to develop a well-controlled system to explain the mechanism of action of the bioelectrochemical effect on 316L stainless steel (SS) surfaces and (2) to test whether the produced H(2)O(2) can reduce cell growth on metal surfaces. It was found that H(2)O(2) was produced near 316L SS surfaces when a negative potential was applied. The H(2)O(2) concentration increased towards the surface, while the dissolved oxygen decreased when the SS surface was polarized to?-600 mV(Ag/AgCl). When polarized and non-polarized surfaces with identical Pseudomonas aeruginosa PAO1 biofilms were continuously fed with air-saturated growth medium, the polarized surfaces showed minimal biofilm growth while there was significant biofilm growth on the non-polarized surfaces. Although there was no detectable H(2)O(2) in the bulk solution, it was found that the surface concentration of H(2)O(2) was able to prevent biofilm growth.     

Caribbean ciguatera: a changing paradigm

Analyses of ciguatoxicity in the great barracuda Sphyraena barracuda and quantity of toxic benthic dinoflagellates on coastal reefs (correlated with the number of cases of human ciguatera intoxications in Puerto Rico) were used to construct a model formulated on data obtained during the period of 1985-1988. The validity of the proposed model has been questioned by recent data obtained during the period of 1990-2000. Barracuda ciguatoxicity no longer showed a prominent seasonality while the fraction of randomly caught barracuda that were ciguatoxic significantly increased during this period. These two changes, accompanied by the discovery that ciguatoxic fish contained a variety of multiple toxins, appear to be correlated with the steadily increasing periods of elevated sea surface temperatures in this region.