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PubMed2002

Place makes the poison: Wesolowski Award Lecture - 1999.

Paracelsus, the Renaissance figure often called the father of toxicology, is given that credit partly for being the first to note that "the dose makes the poison." Modern understanding of the importance of personal exposure in determining dose, however, indicates that to a large extent as well, "place makes the poison." The relative proximity of a pollution source to people has just as big an impact on its importance as a hazard as does the relative toxicity (including chemical nature and size distribution) of its emissions. The exposure effectiveness (or intake fraction) of common air pollution sources, for example, varies over nearly four orders of magnitude. A place-makes-the-poison perspective not only identifies new relationships and priorities among known sources, but also reveals an entirely new landscape of sources and potential control measures. It, thus, has profound economic and policy implications, which will be examined in the context of particle air pollution in different parts of the world.

Air Pollutants↗
PubMed1998

Genes for all metals--a bacterial view of the periodic table. The 1996 Thom Award Lecture.

Bacterial chromosomes have genes for transport proteins for inorganic nutrient cations and oxyanions, such as NH4+, K+, Mg2+, Co2+, Fe3+, Mn2+, Zn2+ and other trace cations, and PO4(3-), SO4(2-) and less abundant oxyanions. Together these account for perhaps a few hundred genes in many bacteria. Bacterial plasmids encode resistance systems for toxic metal and metalloid ions including Ag+, AsO2-, AsO4(3-), Cd2+, Co2+, CrO4(2-), Cu2+, Hg2+, Ni2+, Pb2+, TeO3(2-), Tl+ and Zn2+. Most resistance systems function by energy-dependent efflux of toxic ions. A few involve enzymatic (mostly redox) transformations. Some of the efflux resistance systems are ATPases and others are chemiosmotic ion/proton exchangers. The Cd(2+)-resistance cation pump of Gram-positive bacteria is membrane P-type ATPase, which has been labeled with 32P from [gamma-32P]ATP and drives ATP-dependent Cd2+ (and Zn2+) transport by membrane vesicles. The genes defective in the human hereditary diseases of copper metabolism, Menkes syndrome and Wilson's disease, encode P-type ATPases that are similar to bacterial cadmium ATPases. The arsenic resistance system transports arsenite [As(III)], alternatively with the ArsB polypeptide functioning as a chemiosmotic efflux transporter or with two polypeptides, ArsB and ArsA, functioning as an ATPase. The third protein of the arsenic resistance system is an enzyme that reduces intracellular arsenate [As(V)] to arsenite [As(III)], the substrate of the efflux system. In Gram-negative cells, a three polypeptide complex functions as a chemiosmotic cation/protein exchanger to efflux Cd2+, Zn2+ and Co2+. This pump consists of an inner membrane (CzcA), an outer membrane (CzcC) and a membrane-spanning (CzcB) protein that function together.

Adenosine Triphosphatases↗
PubMed1997

The Charlotte Friend Memorial Lecture. The role of hematopoietic growth factors in the development and suppression of myeloid leukemias.

The transformation of normal hematopoietic cells to leukemic cells requires cells to acquire two intrinsic changes. These are the acquisition by some method of autocrine growth stimulation and a perturbation of differentiation commitment leading to abnormal levels of self-generation. Hematopoietic regulator action can be involved to produce or facilitate both these changes but the same regulators can also suppress some leukemic populations by enforced differentiation commitment.

Animals↗
PubMed2001

What's new in the cerebral microcirculation? Landis Award lecture.

The first part of this paper focuses on unusual aspects of the cerebral circulation. Cerebral vessels have less smooth muscle and adventitia than other vessels, and the endothelial blood-brain barrier is unique. Because the wall of the arteries is thin, one might expect that the vessels are especially vulnerable to rupture. Pressure in intracranial arteries, however, is lower than in other arteries, because resistance of larger cerebral arteries is remarkably high. The low pressure in cerebral arteries presumably protects against rupture of the vessels. The second part of the paper summarizes some new insights into regulation of cerebral circulation. One concept is that "breakthrough" of autoregulation, with dilatation of cerebral vessels at high levels of pressure, is an active process, rather than a passive phenomenon. This conclusion is based on the finding that inhibitors of calcium-dependent potassium channels greatly attenuate the cerebral vasodilator response during acute hypertension. The third part of the paper focuses on effects of gene transfer to cerebral blood vessels. Gene transfer to intracranial and extracranial vessels is feasible and vasomotor function can be altered. Gene transfer has proven to be useful to study vascular biology, and we are optimistic that the approach will ultimately lead to gene therapy.

Animals↗
PubMed2004

Introductory lecture: from biomolecules to biodiagnostics: spectroscopy does it all.

Optical spectroscopy and imaging have been used in medicine since medicine was first practised. However, the more sophisticated instrumental methods now under development have made little impact on clinical medicine. In this paper a brief overview of the development of optical diagnostics is presented, highlighted by some successful pre-clinical applications. The reasons for the slow penetration of optical diagnostics into clinical practice are discussed.

Diagnosis↗
PubMed2006

Spiers Memorial Lecture. Molecular mechanics and molecular electronics.

We describe our research into building integrated molecular electronics circuitry for a diverse set of functions, and with a focus on the fundamental scientific issues that surround this project. In particular, we discuss experiments aimed at understanding the function of bistable rotaxane molecular electronic switches by correlating the switching kinetics and ground state thermodynamic properties of those switches in various environments, ranging from the solution phase to a Langmuir monolayer of the switching molecules sandwiched between two electrodes. We discuss various devices, low bit-density memory circuits, and ultra-high density memory circuits that utilize the electrochemical switching characteristics of these molecules in conjunction with novel patterning methods. We also discuss interconnect schemes that are capable of bridging the micrometre to submicrometre length scales of conventional patterning approaches to the near-molecular length scales of the ultra-dense memory circuits. Finally, we discuss some of the challenges associated with fabricated ultra-dense molecular electronic integrated circuits.

Computers, Molecular↗
PubMed1996

Overview lecture. Hydration processes in biological and macromolecular systems.

I discuss several themes arising from the papers presented at this Faraday Discussion that are, in my view, particularly interesting and/or important. With respect to model systems, recent progress in understanding structural aspects of the hydrophobic interaction, and of through-solvent interactions in general, is highlighted, together with the need to continue to develop more sophisticated (theoretical and computational) interpretational techniques if we are to exploit to the full the power of present-day experimental techniques. The current state of our knowledge of hydration effects on the structure and dynamics of biomolecules is discussed, and the importance of being able to see how molecular-level structural effects control behaviour at the important mesoscopic level is underlined. Issues relating to recent progress in characterising solvent effects in more complex systems and processes, including those of industrial interest, are raised, and the necessity of using a range of appropriate experimental techniques when tackling such complex problems is stressed. Progress since the 1975 Royal Society Discussion is highlighted, and interesting issues ripe for fruitful discussion at this meeting are raised. A strong case can now be made that our under-standing of both the structure and dynamics of water as a function of its local environment is now sufficiently good to enable us to use water as a probe of complex system behaviour, rather than, as heretofore, an objects of study in itself.

Animals↗
PubMed2001

Structure and assembly of the spliceosomal snRNPs. Novartis Medal Lecture.

The spliceosome is a macromolecular machine that carries out the excision of introns from eukaryotic pre-mRNAs and splicing together of exons. Four large RNA-protein complexes, called the U1, U2, U4/U6 and U5 small nuclear ribonucleoprotein particles (snRNPs), and some non-snRNP proteins assemble around three short conserved sequences within the intron in an ordered manner to form the active spliceosome. We aim to provide insight into the molecular details of the mechanism of pre-mRNA splicing through crystallographic studies of the snRNPs. We have solved the X-ray crystal structure of some snRNP proteins as part of either protein-protein complexes or RNA-protein complexes. These structures have provided an important insight into the overall architecture of the U1 and U2 snRNPs and the mechanisms of RNA-protein and protein-protein recognition.

Base Sequence↗
PubMed2001

Society and the human genome. Sir Frederick Gowland Hopkins Memorial Lecture.

In June 2000, the draft sequence of the human genome was announced. It is, and will be for some years, incomplete, but the vast majority is now available. Currently about a third is finished (including two complete chromosomes); the rest has good coverage, but not long-range continuity. First-pass analysis indicates, among other things, fewer genes than expected: about 40000 now looks a likely number. This uncertainty illustrates the difficulty of interpretation: the sequence is not an end in itself, but a resource to be continually reanalysed as our biological understanding increases. That is the scientific reason for releasing it promptly, fully and freely. The social reasons for doing so are even more compelling.

Databases as Topic↗
PubMed2001

Enzymes: nature's nanomachines. Royal Irish Academy Medal Lecture.

The development of enzyme kinetics, protein crystallography and NMR studies allows enzyme-catalysed reactions to be described in terms of mechanistic chemistry, albeit applied to relatively enormous molecules. These nanomachines, which so inspired Drexler's "Engines of Creation," have been working in biological systems for over three billion years and represent a useful knowledge base for our further understanding of mechanistic biology. They also provide a tantalizing glimpse into what may be the basis for novel technologies with industrial applications for the twenty-first century.

Animals↗