Differential scanning calorimetry in life science: thermodynamics, stability, molecular recognition and application in drug design

All biological phenomena depend on molecular recognition, which is either intermolecular like in ligand binding to a macromolecule or intramolecular like in protein folding. As a result, understanding the relationship between the structure of proteins and the energetics of their stability and binding with others (bio)molecules is a very interesting point in biochemistry and biotechnology. It is essential to the engineering of stable proteins and to the structure-based design of pharmaceutical ligands. The parameter generally used to characterize the stability of a system (the folded and unfolded state of the protein for example) is the equilibrium constant (K) or the free energy (deltaG(o)), which is the sum of enthalpic (deltaH(o)) and entropic (deltaS(o)) terms. These parameters are temperature dependent through the heat capacity change (deltaCp). The thermodynamic parameters deltaH(o) and deltaCp can be derived from spectroscopic experiments, using the van't Hoff method, or measured directly using calorimetry. Along with isothermal titration calorimetry (ITC), differential scanning calorimetry (DSC) is a powerful method, less described than ITC, for measuring directly the thermodynamic parameters which characterize biomolecules. In this article, we summarize the principal thermodynamics parameters, describe the DSC approach and review some systems to which it has been applied. DSC is much used for the study of the stability and the folding of biomolecules, but it can also be applied in order to understand biomolecular interactions and can thus be an interesting technique in the process of drug design.

[Book review] Rights of the Accused, Crime Control and Protection of Victims

Review of: Rights of the Accused, Crime Control and Protection of Victims. Edited by Eliahu Harnon & Alex Stein. A special volume of the Israel Law Review, Vol. 31, Nos. 1-3, Winter-Summer 1997. Published by the Faculty of Law, Hebrew University, Jerusalem.

Moment decay rates of solutions of stochastic differential equations

The objective of this paper is to investigate the p-ίh moment asymptotic stability decay rates for certain finite-dimensional Itό stochastic differential equations. Motivated by some practical examples, the point of our analysis is a special consideration of general decay speeds, which contain as a special case the usual exponential or polynomial type one, to meet various situations. Sufficient conditions for stochastic differential equations (with variable delays or not) are obtained to ensure their asymptotic properties. Several examples are studied to illustrate our theory.

Differential amplifier with improved gain-accuracy and linearity

A novel circuit design technique is presented which improves gain-accuracy and linearity in differential amplifiers. The technique employs negative impedance compensation and results demonstrate a significant performance improvement in precision, lowering sensitivity, and wide dynamic range. A theoretical underpinning is given together with the results of a demonstrator differential input/output amplifier with gain of 12 dB. The simulation results show that, with the novel method, both the gain-accuracy and linearity can be improved greatly. Especially, the linearity improvement in IMD can get to more than 23 dB with a required gain.

Assessment of the origin and stability of Nifedipine polymorph IV by differential scanning calorimetry (DSC)

Purpose. To examine the thermal transition(s) between different polymorphic forms of Nifedipine and to define experimental conditions that lead to the generation of polymorph IV. Methods. Experiments were performed using a DSC 823e (Mettler Toledo). Nifedipine exists in four polymorphic forms, as well as an amorphous state. Examination of Nifedipine was conducted using the following method(s): cycle 1: 25ºC to 190ºC, 190ºC to 25ºC (formation of amorphous Nifedipine); cycle 2: 25ºC to X (60,70,80...150ºC), X to 25ºC; cycle 3: 25ºC to 190ºC and holding isothermally for 5 min between cycles (heating/cooling rate of 10ºC/min). Results. The amorphous state Nifedipine can sustain heating up to 90ºC without significant changes in its composition. Cycle 2 of amorphous material heated up to 90ºC shows only the glass transition at ~44ºC. In cycle 3 of the same material, a glass transition has been recorded at ~44ºC, followed by two exotherms (~100 and ~115ºC (crystallisation of polymorph III and II, respectively) and an endotherm (169ºC (melting of polymorphs I/II)). Samples that have been heated to temperatures between 100ºC and 120ºC in the second cycle showed a glass transition at ~44ºC and an additional exotherm at ~95ºC (crystallisation of polymorph III) on cooling a exotherm was observed at ~40ºC (crystallisation of polymorph IV). The same material showed no glass transition in cycle 3 but an endotherm at around 62ºC (melting of polymorph IV) an exotherm (~98ºC) and an endotherm (169ºC) melting of polymorph I/II. Heating the sample to a temperatures greater than 130ºC in cycle two results in a glass transition at ~44ºC, and two exotherms at ~102 and 125ºC (crystallisation of polymorphs III and I, respectively). Conclusions. DSC data suggests that polymorph IV can only be produced from amorphous or polymorph III samples. The presence of polymorph I or II drives the conversion of the less stable polymorphic form IV into the most stable form, I. Although form IV of Nifedipine can easily be created, following defined experimental conditions, it may only coexist with amorphous or polymorph III states. When polymorphs I and II are present in the sample polymorph IV cannot be etected.

Differential cytotoxic and prooxidnant activity of knipholone and knipholone anthrone

Knipholone (KP) and knipholone anthrone (KA) are natural 4-phenylanthraquinone structural analogues with established differential biological effects including in vitro antioxidant [1] and antimicrobial properties [2]. The present study was designed to investigate the comparative in vitro cytotoxic activity and the possible mechanism of action of these two compounds. We demonstrated that KA is by order of magnitude more cytotoxic to mammalian cells than KP. In parallel with the demonstrated cytotoxic effect, KA but not KP induces prooxidative DNA damage in the presence of copper ions. In order to establish the possible involvement of reactive oxygen species in the KA-mediated prooxidative effect, we investigated the protective effect of several metal chelators and reactive oxygen species scavengers. Our data suggest that reactive oxygen species such as hydrogen peroxide are involved and a good correlation between prooxidative action, antioxidant effect and cytotoxicity is established for these two structural analogues. The chemistry, pharmacology and potential medicinal/toxicological potential of these compounds are discussed.

Assessment of the degradation of Aspirin by Differential Scanning Calorimetry (DSC)

Purpose. To study thermal stability of Aspirin and define thermal events that are associated with the thermal degradation of aspirin. Methods. Experiments were performed using a DSC 823e (Mettler Toledo, Swiss). Aspirin is prone to thermal degradation upon exposure to high temperatures. The melting point of aspirin is 140.1±0.4ºC (DSC). Aspirin has been examined by heating samples to 120ºC, 155ºC and 185ºC with subsequent cooling to -55ºC and a final heating to 155ºC. Although different heating and cooling ranges have been used, only results obtained at a rate of 10ºC/min will be presented. All runs where conducted in hermetically sealed pans. Results. Upon heating the sample to 120ºC no significant thermal event can be detected. After cooling the sample and reheating a glass transition can be observed at ~-8ºC, followed by the melting of aspirin at ~139ºC. By heating the sample to 155ºC melting of aspirin has been detected at ~139ºC. On cooling and subsequent heating a glass transition occurs at ~-32ºC, together with a broad crystallisation (onset at ~38ºC and peak maximum at ~57ºC) followed by a broad melting with an onset at 94ºC and peak maximum at ~112ºC. Finally, by heating the sample to 185ºC melting at ~ 139ºC was observed, and upon cooling and reheating a glass transition was detected at ~-26ºC and no further events could be recorded. Conclusions. This research demonstrates that the degradation steps of Aspirin depend on the thermal treatment. The main degradation products of different thermal treatments are currently unknown it is clear that acetic acid, which is one of the degradation products, acts as an antiplasticiser by lowering the glass transition temperature. In addition, due to the presence of the degradation products in liquid form (observed by hot stage microscopy), Aspirin is still present in the sample and recrystallises during the second heating step and melts at much lower temperatures.

Occupational health regulations and health workers: protection or vulnerability?

Several trade agreements include occupational health and safety regulations but there are many barriers to implementation. Mechanisms for sanctions are often weak but the lack of political will is the biggest barrier.

Communication system model for information rate evaluation of differential detection over time-varying channels

A communication system model for mutual information performance analysis of multiple-symbol differential M-phase shift keying over time-correlated, time-varying flat-fading communication channels is developed. This model is a finite-state Markov (FSM) equivalent channel representing the cascade of the differential encoder, FSM channel model and differential decoder. A state-space approach is used to model channel phase time correlations. The equivalent model falls in a class that facilitates the use of the forward backward algorithm, enabling the important information theoretic results to be evaluated. Using such a model, one is able to calculate mutual information for differential detection over time-varying fading channels with an essentially finite time set of correlations, including the Clarke fading channel. Using the equivalent channel, it is proved and corroborated by simulations that multiple-symbol differential detection preserves the channel information capacity when the observation interval approaches infinity.

Mutual information performance of differential MPSK detection over time-varying channels

This paper provides mutual information performance analysis of multiple-symbol differential WSK (M-phase shift keying) over time-correlated, time-varying flat-fading communication channels. A state space approach is used to model time correlation of time varying channel phase. This approach captures the dynamics of time correlated, time-varying channels and enables exploitation of the forward-backward algorithm for mutual information performance analysis. It is shown that the differential decoding implicitly uses a sequence of innovations of the channel process time correlation and this sequence is essentially uncorrelated. It enables utilization of multiple-symbol differential detection, as a form of block-by-block maximum likelihood sequence detection for capacity achieving mutual information performance. It is shown that multiple-symbol differential ML detection of BPSK and QPSK practically achieves the channel information capacity with observation times only on the order of a few symbol intervals

Design of differential amplifier with negative impedance compensation

Design of differential amplifier with high gain accuracy and high linearity is presented in the paper. The amplifier design is based on the negative impedance compensation technique reported by the authors in [1]. A negative impedance with high precision, low sensitivity, wide input signal range and simple structure is used for the compensation of differential amplifier. Analysis and simulation results show that gain accuracy and linearity can be improved significantly with the negative impedance compensation

Use of Continuous Plankton Recorder information in support of marine management: applications in fisheries, environmental protection, and in the study of ecosystem response to environmental change

The Continuous Plankton Recorder (CPR) survey was conceived from the outset as a programme of applied research designed to assist the fishing industry. Its survival and continuing vigour after 70 years is a testament to its utility, which has been achieved in spite of great changes in our understanding of the marine environment and in our concerns over how to manage it. The CPR has been superseded in several respects by other technologies, such as acoustics and remote sensing, but it continues to provide unrivalled seasonal and geographic information about a wide range of zooplankton and phytoplankton taxa. The value of this coverage increases with time and provides the basis for placing recent observations into the context of long-term, large-scale variability and thus suggesting what the causes are likely to be. Information from the CPR is used extensively in judging environmental impacts and producing quality status reports (QSR); it has shown the distributions of fish stocks, which had not previously been exploited; it has pointed to the extent of ungrazed phytoplankton production in the North Atlantic, which was a vital element in establishing the importance of carbon sequestration by phytoplankton. The CPR continues to be the principal source of large-scale, long-term information about the plankton ecosystem of the North Atlantic. It has recently provided extensive information about the biodiversity of the plankton and about the distribution of introduced species. It serves as a valuable example for the design of future monitoring of the marine environment and it has been essential to the design and implementation of most North Atlantic plankton research.

Characterisation of European Marine Sites: Mersey Estuary Special Protection Area. Occasional Publication of the Marine Biological Association 18

This report provides an overview of water and sediment quality within the Mersey Estuary European Marine Site (EMS) and examines evidence for their influence on bioloigcal condition. It has not been possible to determine adequately whether prevailing conditions in the Mersey impact on the interest features of the site as studies which address this issue have not been carried out. It is only possible to review the current level of knowledge regarding the biological and chemical status for the estuary, and extrapolate risks to the bird population. Often information relates to sites outside the EMS; where this is the case the authors have tried to appraise the general status of the estuary, based on best available knowledge.