New insights on surface-enhanced Raman scattering based on controlled aggregation and spectroscopic studies, DFT calculations and symmetry analysis for 3,6-bi-2-pyridyl-1,2,4,5-tetrazine adsorbed onto citrate-stabilized gold nanoparticles

Asystematic study on the surface-enhanced Raman scattering (SERS) for 3,6-bi-2-pyridyl-1,2,4,5-tetrazine (bptz) adsorbed onto citrate-modified gold nanoparticles (cit-AuNps) was carried out based on electronic and vibrational spectroscopy and density functional methods. The citrate/bptz exchange was carefully controlled by the stepwise addition of bptz to the cit-AuNps, inducing flocculation and leading to the rise of a characteristic plasmon coupling band in the visible region. Such stepwise procedure led to a uniform decrease of the citrate SERS signals and to the rise of characteristic peaks of bptz, consistent with surface binding via the N heterocyclic atoms. In contrast, single addition of a large amount of bptz promoted complete aggregation of the nanoparticles, leading to a strong enhancement of the SERS signals. In this case, from the distinct Raman profiles involved, the formation of a new SERS environment became apparent, conjugating the influence of the local hot spots and charge-transfer (CT) effects. The most strongly enhanced vibrations belong to a(1) and b(2) representations, and were interpreted in terms of the electromagnetic and the CT mechanisms: the latter involving significant contribution of vibronic coupling in the system. Copyright (C) 2010 John Wiley & Sons, Ltd.

Randomised controlled trials and 'unexpected' adverse events associated with newly released drugs : improvements in pharmacovigilance systems are necessary for real-time identification of patient safety risks

Adverse drug events are one of the major causes of morbidity in developed countries, yet the drugs involved in these events have been trialled and approved on the basis of randomised controlled trials (RCTs), regarded as the study design that will produce the best evidence.

Though the focus on adverse drug events has been primarily on processes and outcomes associated with the use of these approved drugs, attention needs to be directed to the way in which the RCT study design is structured. The implementation of controls to achieve internal validity in RCTs may be the very controls that reduce external validity, and contribute to the levels of adverse drug events associated with the release of a new drug to the wider patient population.

An examination of these controls, and the effects they can have on patient safety, underscore the importance of knowing about how the clinical trials of a drug are undertaken, rather than relying only on the recorded outcomes.

As the majority of new drugs are likely to be prescribed to older patients who have one or more comorbidities in addition to that targeted by a new drug, and as the RCTs of those drugs typically under-represent the elderly and exclude patients with multiple comorbidities, timely assessment of drug safety signals is essential.

It is unlikely that regulatory jurisdictions will undertake a reassessment of safety issues for drugs that are already approved. Instead, reliance has been placed on adverse drug event reporting systems. Such systems have a very low reporting rate, and most adverse drug events remain unreported, to the eventual cost to patients and healthcare systems.

This makes it essential for near real-time systems that can pick up safety signals as they occur, so that modifications to the product information (or removal of the drug) can be implemented.

Switchable biosensor controlled by biocatalytic process

The poly(dimethylamino methacrylate) (PDMAEMA) brush-modified indium tin oxide (ITO) electrode was used to test the switch properties of interfacial activity caused by bioelectrochemical signals. The swelling of the polymer brushes increased when the medium's pH changed from alkaline to acid after glucose was added to the system. A pH change generated in situ by means of biocatalytic reactions enabled bioelectrocatalytic interface's reversible activation. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Self-potential signals from an analog biogeobattery mode

A tank experiment was conducted to check if self-potential (SP) signals can be generated when buried organic matter is wire-connected to a near-surface, oxygen-rich, sediment layer. This experiment demonstrated that once wired, there was a flux of electrons (hence an electric current) between the lower and upper layers of the sandbox with the system responding as a large-scale microbial fuel cell (a type of bioelectrochemical system). An electric current was generated by this process in the wire and the SP method was used to monitor the associated electric potential distribution at the top of the tank.. The electric field was controlled by the flux of electrons through the wire, the oxidation of the organic matter, the reduction of oxygen used as a terminal electron acceptor, and the distribution of the DC resistivity in the tank. The current density through the wire was limited by the availability of oxygen and not by the oxidation of the organic matter. This laboratory experiment incorporated key elements of the biogeobattery observed in some organic-rich contaminant plumes. This analogy includes the generation of SP signals associated with a flux of electrons, the capacity of buried organic matter in sustaining anodic reactions, network resistance connecting terminal redox reactions spatially separated in space, and the existence of anodic secondary coupled reactions. A resistivity tomogram of the tank, after almost a year in operation, suggests that oxidative processes triggered by this geobattery can be imaged with this method to determine the radius of influence of the bioelectrochemical system.

Shoot meristem maintenance is controlled by a GRAS-gene mediated signal from differentiating cells

Plant shoot development depends on the perpetuation of a group of undifferentiated cells in the shoot apical meristem (SAM). In the Petunia mutant hairy meristem (ham), shoot meristems differentiate postembryonically as continuations of the subtending stem. HAM encodes a putative transcription factor of the GRAS family, which acts non-cell-autonomously from L3-derived tissue of lateral organ primordia and stem provasculature. HAM acts in parallel with TERMINATOR (PhWUSCHEL) and is required for continued cellular response to TERMINATOR and SHOOTMERISTEMLESS (PhSTM). This reveals a novel mechanism by which signals from differentiating tissues extrinsically control stem cell fate in the shoot apex.

Signals and Systems Students trainer.

Higher education students demand fast feedback about their assignments and the opportunity to repeat them in case they do in a wrong way. Here a computer based trainer for Signals and Systems students is presented. An application, that automatically generates and assesses thousands of numerically different versions of several Signals and Systems problems have been developed. This applet guides the students to find the solution and automatically assesses and grades the students proposed solution. The students can use the application to practice in solving several types of Signals and Systems basic problems. After selecting the problem type, the student introduces a seed and the application generates a numerical version of the selected problem. Then the application presents a sequence of questions that the students must solve and the application automatically assess their answers. After solving a given problem, the students can repeat the same numerical variation of the problem by introducing the same seed to the application. In this way, they can review their solution with the help of the hints given by the application for wrong solutions. This application can also be used as an automatic assessment tool by the instructor. When the assessment is made in a controlled environment (examination classroom or laboratory) the instructor can use the same seed for all students. Otherwise, different seeds can be assigned to different students and in this way they solve different numerical variation of the proposed problem, so cheating becomes an arduous task. Given a problem type, the mathematical or conceptual difficulty of the problem can vary depending on the numerical values of the parameters of the problem. The application permits to easily select groups of seeds that yield to numerical variations with similar mathematical or conceptual difficulty. This represents an advantage over a randomised task assignment where students are asked to solve tasks with different difficulty.

Circadian clock-controlled genes isolated from Neurospora crassa are late night- to early morning-specific

An endogenous circadian biological clock controls the temporal aspects of life in most organisms, including rhythmic control of genes involved in clock output pathways. In the fungus Neurospora crassa, one pathway known to be under control of the clock is asexual spore (conidia) development. To understand more fully the processes that are regulated by the N. crassa circadian clock, systematic screens were carried out for genes that oscillate at the transcriptional level. Time-of-day-specific cDNA libraries were generated and used in differential screens to identify six new clock-controlled genes (ccgs). Transcripts specific for each of the ccgs preferentially accumulate during the late night to early morning, although they vary with respect to steady-state mRNA levels and amplitude of the rhythm. Sequencing of the ends of the new ccg cDNAs revealed that ccg-12 is identical to N. crassa cmt encoding copper metallothionein, providing the suggestion that not all clock-regulated genes in N. crassa are specifically involved in the development of conidia. This was supported by finding that half of the new ccgs, including cmt(ccg-12), are not transcriptionally induced by developmental or light signals. These data suggest a major role for the clock in the regulation of biological processes distinct from development.

Identification of genes controlled by quorum sensing in Pseudomonas aeruginosa

Bacteria communicate with each other to coordinate expression of specific genes in a cell density-dependent fashion, a phenomenon called quorum sensing and response. Although we know that quorum sensing via acyl-homoserine lactone (HSL) signals controls expression of several virulence genes in the human pathogen Pseudomonas aeruginosa, the number and types of genes controlled by quorum sensing have not been studied systematically. We have constructed a library of random insertions in the chromosome of a P. aeruginosa acyl-HSL synthesis mutant by using a transposon containing a promoterless lacZ. This library was screened for acyl-HSL induction of lacZ. Thirty-nine quorum sensing-regulated genes were identified. The genes were organized into classes depending on the pattern of regulation. About half of the genes appear to be in seven operons, some seem organized in large patches on the genome. Many of the quorum sensing-regulated genes code for putative virulence factors or production of secondary metabolites. Many of the genes identified showed a high level of induction by acyl-HSL signaling.

Transduction of Basolateral-to-Apical Signals across Epithelial Cells: Ligand-stimulated Transcytosis of the Polymeric Immunoglobulin Receptor Requires Two Signals

Transcytosis of the polymeric immunoglobulin receptor (pIgR) is stimulated by binding of its ligand, dimeric IgA (dIgA). During this process, dIgA binding at the basolateral surface of the epithelial cell transmits a signal to the apical region of the cell, which in turn stimulates the transport of dIgA–pIgR complex from a postmicrotubule compartment to the apical surface. We have previously reported that the signal of stimulation was controlled by a protein-tyrosine kinase (PTK) activated upon dIgA binding. We now show that this signal of stimulation moves across the cell independently of pIgR movement or microtubules and acts through the tyrosine kinase activity by releasing Ca++ from inositol trisphosphate–sensitive intracellular stores. Surprisingly we have found that a second independent signal is required to achieve dIgA-stimulated transcytosis of pIgR. This second signal depends on dIgA binding to the pIgR solely at the basolateral surface and the ability of pIgR to dimerize. This enables pIgR molecules that have bound dIgA at the basolateral surface to respond to the signal of stimulation once they reach the postmicrotubule compartment. We propose that the use of two signals may be a general mechanism by which signaling receptors maintain specificity along their signaling and trafficking pathways.

Two-dimensional infrared spectroscopy of peptides by phase-controlled femtosecond vibrational photon echoes

Two-dimensional infrared spectra of peptides are introduced that are the direct analogues of two- and three-pulse multiple quantum NMR. Phase matching and heterodyning are used to isolate the phase and amplitudes of the electric fields of vibrational photon echoes as a function of multiple pulse delays. Structural information is made available on the time scale of a few picoseconds. Line narrowed spectra of acyl-proline-NH2 and cross peaks implying the coupling between its amide-I modes are obtained, as are the phases of the various contributions to the signals. Solvent-sensitive structural differences are seen for the dipeptide. The methods show great promise to measure structure changes in biology on a wide range of time scales.

Maternal effects and the evolution of aposematic signals

Aposematic signals that warn predators of the noxious qualities of prey gain their greatest selective advantage when predators have already experienced similar signals. Existing theory explains how such signals can spread through selective advantage after they are present at some critical frequency, but is unclear about how warning signals can be selectively advantageous when the trait is initially rare (i.e., when it first arises through mutation) and predators are naive. When aposematism is controlled by a maternal effect gene, the difficulty of initial rarity may be overcome. Unlike a zygotically expressed gene, a maternally expressed aposematism gene will be hidden from selection because it is not phenotypically expressed in the first individual with the mutation. Furthermore, the first individual carrying the new mutation will produce an entire family of aposematic offspring, thereby providing an immediate fitness advantage to this gene.

Control of somite patterning by signals from the lateral plate.

The body musculature of higher vertebrates is composed of the epaxial muscles, associated with the vertebral column, and of the hypaxial muscles of the limbs and ventro-lateral body wall. Both sets of muscles arise from different cell populations within the dermomyotomal component of the somite. Myogenesis first occurs in the medial somitic cells that will form the epaxial muscles and starts with a significant delay in cells derived from the lateral somitic moiety that migrate to yield the hypaxial muscles. The newly formed somite is mostly composed of unspecified cells, and the determination of somitic compartments toward specific lineages is controlled by environmental cues. In this report, we show that determinant signals for lateral somite specification are provided by the lateral plate. They result in a blockade of the myogenic program, which maintains the lateral somitic cells as undifferentiated muscle progenitors expressing the Pax-3 gene, and represses the activation of the MyoD family genes. In vivo, this mechanism could account for the delay observed in the onset of myogenesis between muscles of the epaxial and hypaxial domains.

Electrochemical Characterization of Shape-Controlled Pt Nanoparticles in Different Supporting Electrolytes

The voltammetric profile of preferentially shaped platinum nanoparticles has been used to analyze the different sites present on the surface. For the first time, this analysis has been made in NaOH solutions and revisited in sulfuric and perchloric acid media. The comparison with the voltammetric profiles of the model surfaces, that is, single-crystal electrodes, allows assigning the different signals appearing in the voltammograms of the nanoparticle to specific sites on the surface. A good correlation between the shape of the nanoparticle determined by TEM and the voltammetric profile is obtained. For the nanoparticles characterized in alkaline media, the adsorbed species on the surface have been characterized, and three major regions can be identified. Below 0.2 V, the major contribution is due to hydrogen adsorption, whereas above 0.6 V, adsorbed OH is the main species on the surface. Between those values, the signals are due to the competitive adsorption/desorption process of OH/H. New criteria for determining the active area in NaOH solutions has been proposed. In this medium, the total charge density measured between 0.06 and 0.90 V stands for 390 μC cm–2. The areas measured are in perfect agreement with those measured in acid media. Once the nanoparticles have been characterized, the behavior of the nanoparticles toward CO oxidation is analyzed and compared with that observed for single-crystal electrodes.

Classification of Biomedical Signals using the Dynamics of the False Nearest Neighbours (DFNN) Algorithm

* This study was supported in part by the Natural Sciences and Engineering Research Council of Canada, and by the Gastrointestinal Motility Laboratory (University of Alberta Hospitals) in Edmonton, Alberta, Canada.

Vibrational Feedback Training System for Use with SEMG Controlled Powered Prostheses

Loss of limb results in loss of function and a partial loss of freedom. A powered prosthetic device can partially assist an individual with everyday tasks and therefore return some level of independence. Powered upper limb prostheses are often controlled by the user generating surface electromyographic (SEMG) signals. The goal of this thesis is to develop a virtual environment in which a user can control a virtual hand to safely grasp representations of everyday objects using EMG signals from his/her forearm muscles, and experience visual and vibrotactile feedback relevant to the grasping force in the process. This can then be used to train potential wearers of real EMG controlled prostheses, with or without vibrotactile feedback. To test this system an experiment was designed and executed involving ten subjects, twelve objects, and three feedback conditions. The tested feedback conditions were visual, vibrotactile, and both visual and vibrotactile. In each experimental exercise the subject attempted to grasp a virtual object on the screen using the virtual hand controlled by EMG electrodes placed on his/her forearm. Two metrics were used: score, and time to task completion, where score measured grasp dexterity. It was hypothesized that with the introduction of vibrotactile feedback, dexterity, and therefore score, would improve and time to task completion would decrease. Results showed that time to task completion increased, and score did not improve with vibrotactile feedback. Details on the developed system, the experiment, and the results are presented in this thesis.