Abstract: Staphylococcus aureus is a major pathogen both within hospitals and in the community. Methicillin, a beta-lactam antibiotic, acts by inhibiting penicillin-binding proteins (PBPs) that are involved in the synthesis of peptidoglycan, an essential mesh-like polymer that surrounds the cell. S. aureus can become resistant to methicillin and other beta-lactam antibiotics through the expression of a foreign PBP, PBP2a, that is resistant to the action of methicillin but which can perform the functions of the host PBPs. Methicillin-resistant S. aureus isolates are often resistant to other classes of antibiotics (through different mechanisms) making treatment options limited, and this has led to the search for new compounds active against these strains. An understanding of the mechanism of methicillin resistance has led to the discovery of accessory factors that influence the level and nature of methicillin resistance. Accessory factors, such as Fem factors, provide possible new targets, while compounds that modulate methicillin resistance such as epicatechin gallate, derived from green tea, and corilagin, provide possible lead compounds for development of inhibitors.

Abstract: Photodynamic therapy is a method for local destruction of tissue or organisms by generating toxic oxygen and other reactive species using light absorbed by an administered or an endogenously generated photosensitiser. It is a highly promising treatment for patients with cancer. More recently it has found increasing use as a method of therapy for non-cancerous illnesses. It depends on the exploitation of natural and vital reactions widespread in nature that have driven and preserved life on this planet. Following administration of a photosensitiser or its precursor there is an accumulation or retention in areas of cancer and disease relative to adjacent normal tissue. The photosensitiser is inactive until irradiated by light, following which cellular destruction occurs. The clear attraction of this method is the possibility of some targeting of the disease by drug and by the area irradiated. This explanation although oversimplified has been the reason for the scientific and clinical interest in photodynamic therapy. An understanding of evolutionary photobiology is enormously helpful to understand disease response and clinical outcomes.

Abstract: Inflammatory bowel disease (IBD) is a chronic relapsing inflammatory condition of the intestines that is clinically heterogenous. The cause(s) of IBD are currently unknown but the mechanisms of injury are immunological. Increasingly there is an emphasis on the study of the complex interactions at the interface of self and non-self--the gastrointestinal epithelial surface--in relationship to the pathogenesis of disease. There is mounting evidence that a lack of tolerance to the normal commensal flora of the intestine may underlie the disease pathogenesis. Several genetic loci that are markers of disease susceptibility have been identified. These loci map to areas of the genome that are concerned with antigen presentation or cytokine secretion and suggest a genetic heterogeneity that underlies the clinical differences. Overall a picture is emerging of defects in epithelial barrier function and, or immunoregulation leading to immune responses that are triggered or exaggerated by the antigenic components of the normal flora.

Abstract: Ever since the discovery of the ozone hole over the Antarctic and the recognition of the damaging effects of acid rain, the role of atmospheric aerosol particles in determining the chemical balance of the atmosphere has received much attention. Aerosol particles produced in combustion can also have a deleterious effect on human health. In this article we review the chemistry that can occur on aerosol particles, particularly on aqueous based aerosols in the troposphere. The sources, transformation and loss mechanisms of atmospheric aerosol will be discussed. In particular, we will focus on the role of chemical transformation on aerosol particles in promoting reactions that would otherwise be too slow in the homogeneous atmospheric gas phase. Heterogeneous reaction mechanisms of some key chemical reactions will be described. Recent observations of a high organic content of tropospheric aerosol particles will be described and a model of organic coated aerosols will be reviewed.

Abstract: Accumulative evidence suggests that resident γδ T cells in epithelia are biologically distinct from systemic γδ T cells in the circulation. Murine resident γδ T cells have innate immune characteris...

Abstract: The properties of a metal coordination complex are determined as much by the ligand set--the molecules and ions coordinated to the metal centre--as by the nature of the metal itself. The design and use of new ligands is consequently a major part of chemical research. This review considers the role of multifunctional ligands in three separate and distinct areas of chemistry. In homogeneous catalysis, the role of hybrid and hemilabile ligands is considered, and the introduction of functionalities designed to overcome problems of separation, either by tethering or solubilising, is discussed. In supramolecular chemistry, functionalities enabling the recognition and sensing of cations and anions are examined. In addition, ligands containing two or more faces are discussed for their role in metallodendrimer formation and self-assembly reactions, and the use of bifunctional ligands in crystal engineering is addressed. The application of metal complexes in medicine is examined by consideration of cis-platin and its derivatives as anti-tumour agents. Imaging agents are also discussed with the uses of gadolinium MRI contrast agents and gamma-emitting technetium complexes highlighted.

Abstract: Transport of alkali metals, particularly sodium and potassium, across cell membranes is an essential function performed by special proteins that enable cells to regulate inter- and extracellular io...

Abstract: A plethora of human pathogens are now resistant to all clinically significant antibiotics causing a crisis, in the treatment and management of infectious diseases, but also presenting a clear dange...

Abstract: The sensory organs--the eye, ear, and nose- are formed, in part, from ectodermal thickenings: placodes. Their development is distinct from that of other regions of the developing body and they are essential for the development of other structures. For example, the olfactory placode which gives rise to the nose is essential for the functional development of the reproductive organs and hence fertility. Recently much progress has been made in the understanding of placode development, at both a molecular and embryological level. This is important as abnormal development of placodes occurs in a number of human syndromes. Furthermore, knowledge of placode development will give insight into therapeutic strategies to prevent degenerative change such as deafness. This review highlights the current knowledge of placode development and the future challenges in unravelling the cascades of signalling interactions that control development of these unique structures.

Abstract: There are many diseases where the cause is unknown and this makes a specific treatment difficult. In many cases all that can be achieved is amelioration of the illness. Peptic ulcer disease was one such condition no more that 20 years ago. The management was drastic--either an operation or life-long medication in order to reduce the acid secreted by the stomach. However, the cause of this condition was discovered in 1983. Although initially sceptical, the medical fraternity now almost universally endorse Helicobacter pylori as the cause of the majority of stomach ulcers. Peptic ulcers can now be cured by antibiotics. This is a major shift in medical practice. Continued investigations on Helicobacter pylori are bringing to light other possible associations with disease as well as delineating plausible biological mechanisms for disease pathogenesis.

Abstract: This volume, in the main, covers a range of topics related to infectious disease caused by organisms which are, at present, or permanently, in the news. Many of these organisms are of substantial public concern, because of major health problems involving them. The article by Basset et al. (1), for example, reviews Helicobacter; who would have believed, 20 years ago, that gastric and duodenal ulcer and possibly gastric cancer, would be linked to the presence of a novel helical bacterium, in the stomach, and no doubt, even fewer would have anticipated the possible involvement of this organism in other diseases. The demonstrated involvement of Helicobacter has enabled clinicians, in some cases, to successfully use antimicrobials to alleviate these conditions. Basset and Holton review factors that influence the occurrence of inflammatory bowel disease, emphasising particularly immunological and bacteriological aspects (2); again, strikingly, there is some evidence for the involvement of Helicobacter spp in such d isorders, although the evidence is much less substantial. Hopefully, further studies will enable these painful and often intransigent disorders to be much more readily alleviated. The discovery of numerous natural antimicrobial agents, in the thirties, forties and fifties of the last century, and the synthesis of other antimicrobials, led many to believe that the days of lethal infectious diseases, especially those caused by bacteria, were almost over. Even in the earliest days after the discovery of antibiotics, however, resistance was noticed, and a major concern in recent years has been the evolution of numerous antibiotic-resistant organisms; with transferable resistance e.g. by plasmids, as a complication, and with resistance occurring against so many agents, the possible strategies available to the clinician have been greatly reduced. In a few cases, where resistance occurs towards all antibiotics useful against a particular organism, treatment with antibacterials is actually impossible. Stapleton and Taylor write here about antibiotic resistance (3), and their contribution is of considerable value, because their emphasis is on MRSA. MRSA (Methicillin-resistant Staphylococcus aur eus) had become one of the major bacterial problems of the last few years of the 20th century, and will no doubt continue to be a serious clinical problem in the early 21st century, because it is refractory to most, and sometimes all, of the chief agents generally useful against staphylococci. Stapleton and Taylor write cogently, not only about the nature of the resistance, but also about how it may be modulated (3); a number of agents appear able to reduce methicillin resistance of MRSA when they are administered with the antibiotic, and further studies on these agents may offer exciting possibilities for the future. The article of Waugh and Long is also on a "hot" topic in the infectious disease area, one which has become of critical importance because antibiotic resistance has become so widespread, namely on the search for new antibacterials (4). It is obvious from the account given, that there are several ways of approaching this problem. The major approach described in this article, namely gene and enzym e modification, with the use also of novel substrates, has already given some interesting and exciting results and there is clearly further substantial potential (4). The article by Warhurst (5) is in a similar area, in particular on resistance to antifolate drugs and how such resistance can be overcome by the use of novel compounds; what makes this article of even more interest, is that it relates to antimicrobial drug resistance in the malaria parasite. In 1940, D.D. Woods, having established the mode of action of sulphonamides, proposed that agents structurally resembling essential metabolites, should act as antimicrobials. Warhurst's demonstration (5), that we may be able, soon, to design agents which can fit into enzyme active sites, suggests that Woods' vision may soon become reality, and a plethora of new antimicrobials will become available. …

Abstract: The last century has seen a large development in diffraction techniques. The time-of-flight neutron diffraction method is now so advanced that it provides high precision results for position and th...

Abstract: Information on the first steps of the avian evolutionary history has dramatically increased during the last few years. The fossil record provides a general view of the morphological changes of the avian flight apparatus from nonvolant ancestors (non-avian theropod dinosaurs) to the first derived fliers of the Early Cretaceous. The Las Hoyas bird record includes three genera: Iberomesornis, Concornis and Eoalulavis. This fossil material has yielded information about the early avian evolutionary history. These Early Cretaceous birds (some 120 Myr old) had a wingbeat cycle and breathing devices similar to those of extant birds. The function of the rectricial fan was also similar. In the evolutionary transition from cursorial ancestors to derived fliers it is possible to verify a trend to increase lift. Primitive wing aspect ratio morphotypes were elliptical ones, other derived morphotypes appeared, for example, in the Neornithes (extant birds). Some primitive fliers, like the Las Hoyas genus Eoalulavis, had an alula (feathers attached to the first digit of the hand) similar to that of present day birds, indicating braking and manoeuvring skills similar to those of their extant relatives. Primitive avian life habits are poorly understood. Some evidence from the Las Hoyas bird record indicates that Early Cretaceous birds were present in the trophic chains.

Abstract: Ever since the discovery of the ozone hole over the Antarctic and the recognition of the damaging effects of acid rain, the role of atmospheric aerosol particles in determining the chemical balance of the atmosphere has received much attention. Aerosol particles produced in combustion can also have a deleterious effect on human health. In this article we review the chemistry that can occur on aerosol particles, particularly on aqueous based aerosols in the troposphere. The sources, transformation and loss mechanisms of atmospheric aerosol will be discussed. In particular, we will focus on the role of chemical transformation on aerosol particles in promoting reactions that would otherwise be too slow in the homogeneous atmospheric gas phase. Heterogeneous reaction mechanisms of some key chemical reactions will be described. Recent observations of a high organic content of tropospheric aerosol particles will be described and a model of organic coated aerosols will be reviewed.

Abstract: The direct measurement of intramolecular electron transfer through detection of the electromagnetic (EM) waveform that is emitted during this process is reviewed. The waveform is detected in the time-domain via free-space electrooptic sampling and then related to the dynamics of the charge transfer event. Electronmagnetic generation from two systems, Betaine-30 in chloroform and DMANS in toluene, are studied to illustrate this technique. A finite-difference time-domain calculation with a time-dependent polarization is used to model the EM generation and propagation through the solution. This method is very general since the movement of charge itself generates the EM waveform, and is sensitive to charge transfer occurring on a 0.1-10ps timescale. The potential for studying the primary steps of charge transfer in photosynthetic bacteria is also discussed. Keywords: measuring intramolecular change transfer Introduction Charge transfer is a ubiquitous phenomenon. Examples include photosynthesis, redox chemistry, corrosion, photography, xerography, respiration, and many other fundamental processes. Before reviewing research aspects of charge transfer, it is worth briefly reminding ourselves of the scope and magnitude of these processes that involve charge transfer. Photosynthesis represents the most important form of solar energy imaginable. It allows plants to generate their mass from building blocks of primarily C[O.sub.2] and [H.sub.2]O, and over several hundred million years has led to immense, yet finite, stores of energy as fossil fuels. In addition, [O.sub.2] is generated as a by product which is also quite beneficial. Redox chemistry and electrochemistry have tremendous industrial importance, from electroplating, to batteries, to extraction of metallic aluminum from aluminum oxide. For example, it is estimated that about 1.8% of the USA's industrial energy supply is directed toward production of metallic aluminum. (1) Corrosion represents an important example of redox chemistry. The corrosion and subsequent repair or replacement of structures that are underground andlor underwater is a costly enterprise, in terms of both money and manpower. In fact, it is estimated that the annual costs of metallic corrosion are about 4% of the gross domestic product (GDP) of industrialized nations (which amounted to roughly $300 billion in the USA in 1995). (2,3) Photography and xerography each permeate our everyday lives, and even if they do not seem as significant as photosynthesis and corrosion, they deserve continued attention. Finally, respiration, which in some sense is the inverse of photosynthesis, is of obvious importance for all plants and animals. Clearly, further understanding of charge transfer, especially at a very fundamental level, is a worthwhile endeavor. Background Broader issues aside, the remainder of this review will focus on basic research. There has been a particularly strong interest in photo-induced charge transfer, because spectroscopic investigations can monitor changes that occur due to electron transfer (ET), and the process can be initiated at a well defined instant. Also, extremely high temporal resolution can be obtained with modem lasers, on the order of 10 fs (1 fs = [10.sup.-15] S), which allows the dynamics accompanying ET to be monitored in addition to kinetics. That is, conformational changes of molecules or proteins in response to ET can be observed. A generic depiction of photoinduced ET is: DA[[right arrow].sup.hv] [D.sup.*] A[[right arrow].sup.E][[D.sup.+] [A.sup.-]][[right arrow].sup.separation] [D.sup.+] + [A.sup.-] (1) where D is the donor, A is the acceptor, and [D.sup.*] is the photoexcited donor, and the hope is that the charge will remain separated after excitation. The donor and acceptor can be individual molecules or ions, leading to intermolecular ET, or they can be separate chromophores within a large molecule, leading to intramolecular ET. …

Abstract: Every year there are 270 million clinical attacks of malaria and 2 million deaths, caused by the protozoan Plasmodium falciparum. Most of these cases occur in Africa. Chloroquine-resistance has led to reliance on anti-malarial antifolates, in particular the synergistic combination sulfadoxine/pyrimethamine (S/P) which targets enzymatic synthesis of folate co-factors through dihydropteroate synthase (DHPS) and dihydrofolate reductase (DHFR). Resistance to S/P is now increasing and replacement antimalarials are needed. Crystal structures are not yet available for these key enzymes in the folate pathway. This review focuses on the activity of drugs on DHFR in malaria parasites, attempts to interpret differences in activity of pyrimethamine and its related drugs, and to clarify how residue changes due to point mutations determine the development of resistance. In homology-modelled P. falciparum DHFR (PfDHFR), the typical structure of four alpha-helices, 8-stranded beta-sheet, four Loops and eight Turns is clearly seen. Long polar sequences specific for Plasmodium are inserted in Turns 1 and 2. Structures immediately concerned in drug binding are beta-A, L1, alpha-B, alpha-C, T-3, beta-E, alpha-F, and beta-F. The roles of several mutations associated with resistance are discussed. In view of sequence differences in turn 3 in PfDHFR and in the human enzyme, and the marked interaction with residues of T3 of the experimental flexible antifolate WR99210 effective in pyrimethamine and cycloguanil resistance, further drug development in this area is indicated.