Showing papers by "University of East Anglia published in 1999"

Post-glacial re-colonization of European biota

Abstract: Population structure is the result of both present processes and past history. Molecular markers are proving of great value in describing the former, and it is important to similarly determine the latter in order to understand their respective contributions. The study of palaeo-climates has also advanced significantly, and in particular that of the Pleistocene ice ages, which modified species ranges considerably. The last ice age and rapid post-glacial colonization of Europe is summarized. Possible population genetic consequences of expansion northward from southern refugia, and those of remaining in these mountainous regions are discussed. A series of recent case studies are detailed where DNA sequence information has been used to describe species genetic variation and subdivision across Europe. These include a grasshopper, the hedgehog, oak trees, the common beech, the black alder, the brown bear, newts, shrews, water vole, silver fir and house mice. These molecular data confirm southern peninsulas of Europe as major ice age refugia, and in most cases demonstrate that genetically distinct taxa emerged from them. They can thus define genomic differences and so greatly augment previous fossil data. The refugial genomes contributed differently in various species to the re-colonization of Europe, with three broad patterns described as paradigms—«grasshopper», «hedgehog» and «bear». These different expansion patterns produced clusters of hybrid zones where they made contact, and it is argued that many species genomes may be further cryptically subdivided. A reduction in diversity from southern to northern Europe in the extent of allelic variation and species subdivision is seen; this is attributed to rapid expansion northward and the varied topography of southern refugia allowing populations to diverge through several ice ages. The differences in DNA sequence indicate that some species have been diverging in refugial regions for a few ice ages at most, whilst distinct lineages in other species suggest much more ancient separation.

Representing Twentieth-Century Space–Time Climate Variability. Part I: Development of a 1961–90 Mean Monthly Terrestrial Climatology

Abstract: The construction of a 0.5° lat × 0.5° long surface climatology of global land areas, excluding Antarctica, is described. The climatology represents the period 1961–90 and comprises a suite of nine variables: precipitation, wet-day frequency, mean temperature, diurnal temperature range, vapor pressure, sunshine, cloud cover, ground frost frequency, and wind speed. The climate surfaces have been constructed from a new dataset of station 1961–90 climatological normals, numbering between 19 800 (precipitation) and 3615 (wind speed). The station data were interpolated as a function of latitude, longitude, and elevation using thin-plate splines. The accuracy of the interpolations are assessed using cross validation and by comparison with other climatologies. This new climatology represents an advance over earlier published global terrestrial climatologies in that it is strictly constrained to the period 1961–90, describes an extended suite of surface climate variables, explicitly incorporates elevation...

Response Rate in Academic Studies-A Comparative Analysis:

Abstract: A study was conducted to explore what could and should be a reasonable response rate in academic studies. One hundred and forty-one papers which included 175 different studies were examined. They were published in the Academy of Management Journal, Human Relations, Journal of Applied Psychology, Organizational Behavior and Human Decision Processes, and Journal of International Business Studies in the years 1975, 1985, and 1995, covering about 200,000 respondents. The average response rate was 55.6 with a standard deviation of 19.7. Variations among the journals such as the year of publication and other variables were discussed. Most notable is the decline through the years (average 48.4, standard deviation of 20.1, in 1995), the lower level found in studies involving top management or organizational representatives (average 36.1, standard deviation of 13.3), and the predominance of North American studies. It is suggested that the average and standard deviation found in this study should be used as a norm ...

Missense mutations in the rod domain of the lamin A/C gene as causes of dilated cardiomyopathy and conduction-system disease.

Abstract: Background Inherited mutations cause approximately 35 percent of cases of dilated cardiomyopathy; however, few genes associated with this disease have been identified. Previously, we located a gene defect that was responsible for autosomal dominant dilated cardiomyopathy and conduction-system disease on chromosome 1p1–q21, where nuclear-envelope proteins lamin A and lamin C are encoded by the LMNA (lamin A/C) gene. Mutations in the head or tail domain of this gene cause Emery–Dreifuss muscular dystrophy, a childhood-onset disease characterized by joint contractures and in some cases by abnormalities of cardiac conduction during adulthood. Methods We evaluated 11 families with autosomal dominant dilated cardiomyopathy and conduction-system disease. Sequences of the lamin A/C exons were determined in probands from each family, and variants were confirmed by restriction-enzyme digestion. The genotypes of the family members were ascertained. Results Five novel missense mutations were identified: four in the α...

Consequences of the Allee effect for behaviour, ecology and conservation

Abstract: Warder C. Allee brought attention to the possibility of a positive relationship between aspects of fitness and population size 50 years ago. Until recently, however, this concept was generally regarded as an intriguing but relatively unimportant aspect of population ecology. Increasing appreciation that Allee effects must be incorporated into models of population dynamics and habitat use, together with recent interest in the implications of sociality for conservation, have shown that for ecology and conservation the consequences of the Allee effect are profound. The Allee effect can be regarded not only as a suite of problems associated with rarity, but also as the basis of animal sociality.

Social Vulnerability to Climate Change and the Architecture of Entitlements

Abstract: The objective of this paper is to outline a conceptual model of vulnerability to climate change as the first step in appraising and understanding the social and economic processes which facilitate and constrain adaptation. Vulnerability as defined here pertains to individuals and social groups. It is the state of individuals, of groups, of communities defined in terms of their ability to cope with and adapt to any external stress placed on their livelihoods and well-being. This proposed approach puts the social and economic well-being of society at the centre of the analysis, thereby reversing the central focus of approaches to climate impact assessment based on impacts on and the adaptability of natural resources or ecosystems and which only subsequently address consequences for human well-being. The vulnerability or security of any group is determined by the availability of resources and, crucially, by the entitlement of individuals and groups to call on these resources. This perspective extends the concept of entitlements developed within neo-classical and institutional economics. Within this conceptual framework, vulnerability can be seen as a socially-constructed phenomenon influenced by institutional and economic dynamics. The study develops proxy indicators of vulnerability related to the structure of economic relations and the entitlements which govern them, and shows how these can be applied to a District in coastal lowland Vietnam. This paper outlines the lessons of such an approach to social vulnerability for the assessment of climate change at the global scale. We argue that the socio-economic and biophysical processes that determine vulnerability are manifest at the local, national, regional and global level but that the state of vulnerability itself is associated with a specific population. Aggregation from one level to another is therefore not appropriate and global-scale analysis is meaningful only in so far as it deals with the vulnerability of the global community itself.

Climate change and world food security: a new assessment

Abstract: Building on previous work quantitative estimates of climate change impacts on global food production have been made for the UK Hadley Centre's HadCM2 greenhouse gas only ensemble experiment and the more recent HadCM3 experiment (Hulme et al., 1999). The consequences for world food prices and the number of people at risk of hunger as defined by the Food and Agriculture Organisation (FAO, 1988) have also been assessed. Climate change is expected to increase yields at high and mid-latitudes, and lead to decreases at lower latitudes. This pattern becomes more pronounced as time progresses. The food system may be expected to accommodate such regional variations at the global level, with production, prices and the risk of hunger being relatively unaffected by the additional stress of climate change. By the 2080s the additional number of people at risk of hunger due to climate change is about 80 million people (±10 million depending on which of the four HadCM2 ensemble members is selected). However, some regions (particularly the arid and sub-humid tropics) will be adversely affected. A particular example is Africa, which is expected to experience marked reductions in yield, decreases in production, and increases in the risk of hunger as a result of climate change. The continent can expect to have between 55 and 65 million extra people at risk of hunger by the 2080s under the HadCM2 climate scenario. Under the HadCM3 climate scenario the effect is even more severe, producing an estimated additional 70+ million people at risk of hunger in Africa.

Structural change in an exploited fish community: a consequence of differential fishing effects on species with contrasting life histories

Abstract: 1. An understanding of the links between life histories and responses to exploitation could provide the basis for predicting shifts in community structure by identifying susceptible species and linking life-history tactics with population dynamics. 2. We examined long-term trends in the abundance of species in the North Sea bottom-dwelling (demersal) fish community. Between 1925 & 1996 changes in species composition led to an increase in mean growth rate, while mean maximum size, age at maturity and size at maturity decreased. The demersal fish community was increasingly heavily fished during this period. 3. Trends in mean life-history characteristics of the community were linked to trends in abundance of component species. An approach based on phylogenetic comparisons was used to examine the differential effects of fishing on individual species with contrasting life histories. 4. Those species that decreased in abundance relative to their nearest relative, matured later at a greater size, grew more slowly towards a greater maximum size and had lower rates of potential population increase. The phylogenetically based analyses demonstrated that trends in community structure could be predicted from the differential responses of related species to fishing. 5. This is the first study to link exploitation responses of an entire community to the life histories of individual species. The results demonstrate that fishing has greater effects on slower growing, larger species with later maturity and lower rates of potential population increase. The comparative approach provides a basis for predicting structural change in other exploited communities.

Mechanisms for pro matrix metalloproteinase activation.

Abstract: The activation of pro matrix metalloproteinases (MMPs) by sequential proteolysis of the propeptide blocking the active site cleft is regarded as one of the key levels of regulation of these proteinases. Potential physiological mechanisms including cell-associated plasmin generation by urokinase-like plasminogen activator, or the action of cell surface MT1-MMPs appear to be involved in the initiation of cascades of pro MMP activation. Gelatinase A, collagenase 3 and gelatinase B may be activated by MT-MMP based mechanisms, as evidenced by both biochemical and cell based studies. Hence the regulation of MT-MMPs themselves becomes critical to the determination of MMP activity. This includes activation, assembly at the cell surfaces as TIMP-2 complexes and subsequent inactivation by proteolysis or TIMP inhibition.

Evidence that the extracytoplasmic function sigma factor sigmaE is required for normal cell wall structure in Streptomyces coelicolor A3(2).

Abstract: The sigE gene of Streptomyces coelicolor A3(2) encodes an RNA polymerase sigma factor belonging to the extracytoplasmic function (ECF) subfamily. Constructed sigE deletion and disruption mutants were more sensitive than the parent to muramidases such as hen egg white lysozyme and to the CwlA amidase from Bacillus subtilis. This correlated with an altered muropeptide profile, as determined by reverse-phase high-performance liquid chromatography analysis of lytic digests of purified peptidoglycan. The sigE mutants required high levels of magnesium for normal growth and sporulation, overproducing the antibiotic actino-rhodin and forming crenellated colonies in its absence. Together, these data suggest that sigE is required for normal cell wall structure. The role of s(E) was further investigated by analyzing the expression of hrdD, which is partially sigE dependent. The hrdD gene, which encodes the s(HrdD) subunit of RNA polymerase, is transcribed from two promoters, hrdDp1 and hrdDp2, both similar to promoters recognized by other ECF sigma factors. The activities of hrdDp1 and hrdDp2 were reduced 20- and 3-fold, respectively, in sigE mutants, although only hrdDp1 was recognized by Es(E) in vitro. Growth on media deficient in magnesium caused the induction of both hrdD promoters in a sigE-dependent manner

Climate change and future populations at risk of malaria

Abstract: Global estimates of the potential impact of climate change on malaria transmission were calculated based on future climate scenarios produced by the HadCM2 and the more recent HadCM3 global climate models developed by the UK Hadley Centre. This assessment uses an improved version of the MIASMA malaria model, which incorporates knowledge about the current distributions and characteristics of the main mosquito species of malaria. The greatest proportional changes in potential transmission are forecast to occur in temperate zones, in areas where vectors are present but it is currently too cold for transmission. Within the current vector distribution limits, only a limited expansion of areas suitable for malaria transmission is forecast, such areas include: central Asia, North America and northern Europe. On a global level, the numbers of additional people at risk of malaria in 2080 due to climate change is estimated to be 300 and 150 million for P. falciparum and P. vivax types of malaria, respectively, under the HadCM3 climate change scenario. Under the HadCM2 ensemble projections, estimates of additional people at risk in 2080 range from 260 to 320 million for P. falciparum and from 100 to 200 million for P. vivax. Climate change will have an important impact on the length of the transmission season in many areas, and this has implications for the burden of disease. Possible decreases in rainfall indicate some areas that currently experience year-round transmission may experience only seasonal transmission in the future. Estimates of future populations at risk of malaria differ significantly between regions and between climate scenarios.

Objective Climatology of Cyclones in the Mediterranean Region

Abstract: An objective cyclone detection and tracking analysis is performed over an 18-yr period, for the Mediterranean basin. The high-resolution (1.125° × 1.125° grid) European Centre for Medium-Range Weather Forecasts data used in this study proved to be particularly suitable for the detection and tracking techniques and to identify subsynoptic-scale Mediterranean lows, which have often been underestimated in previous studies. The major characteristics of Mediterranean cyclones are examined and compared with other Northern Hemisphere depressions. Both cyclogenesis and cyclolysis regions are identified in the domain of study. In addition, characteristics of Mediterranean depressions, such as cyclone duration and intensity, as well as their persistence throughout the year, are shown to be quite variable for different formation areas. Overall, the regions where cyclogenesis is mainly controlled by topography, like the Gulf of Genoa and south of the Atlas Mountains, seem to generally account for the most in...

Relative impacts of human-induced climate change and natural climate variability

Abstract: Assessments of the regional impacts of human-induced climate change on a wide range of social and environmental systems are fundamental for determining the appropriate policy responses to climate change1,2,3. Yet regional-scale impact assessments are fraught with difficulties, such as the uncertainties of regional climate-change prediction4, the specification of appropriate environmental-response models5, and the interpretation of impact results in the context of future socio-economic and technological change6. The effects of such confounding factors on estimates of climate-change impacts have only been poorly explored3,4,5,6,7. Here we use results from recent global climate simulations8 and two environmental response models9,10 to consider systematically the effects of natural climate variability (30-year timescales) and future climate-change uncertainties on river runoff and agricultural potential in Europe. We find that, for some regions, the impacts of human-induced climate change by 2050 will be undetectable relative to those due to natural multi-decadal climate variability. If misleading assessments of—and inappropriate adaptation strategies to—climate-change impacts are to be avoided, future studies should consider the impacts of natural multi-decadal climate variability alongside those of human-induced climate change.

A review of methods to calculate extreme wind speeds

Abstract: Methods to calculate extreme wind speeds are described and reviewed, including ‘classical’ methods based on the generalized extreme value (GEV) distribution and the generalized Pareto distribution (GPD), and approaches designed specifically to deal with short data sets. The emphasis is very much on the needs of users who seek an accurate method to derive extreme wind speeds but are not fully conversant with up-to-date developments in this complex subject area. First, ‘standard’ methods are reviewed: annual maxima, independent storms, r-largest extremes with the GEV distribution, and peak-over-threshold extremes with the GPD. Techniques for calculating the distribution parameters and quantiles are described. There follows a discussion of the factors which must be considered in order to fulfil the criterion that the data should be independent and identically distributed, and in order to minimize standard errors. It is commonplace in studies of extreme wind speeds that the time series available for analysis are very short. Finally, therefore, the paper deals with techniques applicable to data sets as short as two years, including simulation modelling and methods based on the parameters of the parent distribution.

Evaluation of the North Atlantic Oscillation as simulated by a coupled climate model

Abstract: The realism of the Hadley Centre’s coupled climate model (HadCM2) is evaluated in terms of its simulation of the winter North Atlantic Oscillation (NAO), a major natural mode of the Northern Hemisphere atmosphere that is currently the subject of considerable scientific interest. During 1400 y of a control integration with present-day radiative forcing levels, HadCM2 exhibits a realistic NAO associated with spatial patterns of sea level pressure, synoptic activity, temperature and precipitation anomalies that are very similar to those observed. Spatially, the main model deficiency is that the simulated NAO has a teleconnection with the North Pacific that is stronger than observed. In a temporal sense the simulation is compatible with the observations if the recent observed trend (from low values in the 1960s to high values in the early 1990s) in the winter NAO index (the pressure difference between Gibraltar and Iceland) is ignored. This recent trend is, however, outside the range of variability simulated by the control integration of HadCM2, implying that either the model is deficient or that external forcing is responsible for the variation. It is shown, by analysing two ensembles, each of four HadCM2 integrations that were forced with historic and possible future changes in greenhouse gas and sulphate aerosol concentrations, that a small part of the recent observed variation may be a result of anthropogenic forcing. If so, then the HadCM2 experiments indicate that the anthropogenic effect should reverse early next century, weakening the winter pressure gradient between Gibraltar and Iceland. Even combining this anthropogenic forcing and internal variability cannot explain all of the recent observed variations, indicating either some model deficiency or that some other external forcing is partly responsible.

Elasticity analysis as an important tool in evolutionary and population ecology

Abstract: Elasticity analysis estimates the proportional change in the population growth rate for a proportional change in a vital rate (i.e. survival, growth or reproduction). It can be used to pinpoint those parts of an organism's life history that should be the focus of management effort, or those that contribute most to fitness. Recent theoretical work has emphasized some limitations of the technique, has overcome other problems, and has shown that it is robust to some violations of its underlying assumptions. Thus, although care is needed, elasticity analysis is a simple first step in answering important questions in evolutionary and population ecology.

Resonance Energy Transfer

Abstract: 1. Resonance energy transfer in proteins introduction some basic considerations a short history of FRET determinations the components of the Foorster equation quantum yield determining spectral overlap steady state or time--resolved measurements? resonance energy transfer using intrinsic amino acids homotransfer between intrinsic probes heterotransfer the range of distances determined by resonance energy transfer precise location of resonance energy transfer probes properties of probes labeling specific residues in proteins resonance energy transfer experiments using lanthanide ions measurements in radially symmetrical systems comparison with crystallographic distances using resonance energy transfer to constrain molecular models resonance energy transfer with single fluorophores: new wave experiments intramolecular energy transfer in proteins bound to membranes green fluorescent protein resonance energy transfer and biosensors: a new and promising technique shortcomings the future of FRET summary dedication acknowledgements references. 2. Unified theory and radiative and raditionless energy transfer introduction background the basis of the unified theory spectral features refraction and dissipation dynamics of energy transfer between a pair of molecules in a dielectric medium conclusion appendix A: Heitler--MA method for analysis of the transition operator Appendix B: modified approach to the transition operator references. 3. Dynamics of radiative transport introduction overview of atomic and molecular radiative transport the Holstein--Biberman equation multiple scattering representation stochastic approach combined radiative and nonradiative transport conclusion appendix A: probablitity of emission of a photon between t + dt for an nth generation molecule appendix B: depolarization factor for radiative transferaccording to classical electrodynamics references. 4. Orientational aspects in pair energy transfer introduction Kappa--squared and probability, Kappa--squared and anisotropy notes on the effects of order and motion acknowledgements references. 5. Polarization in molecular complexes with incoherent energy transfer introduction interaction of light with single molecules or chromophores bichromophore molecular complexes trichromophore complexes multichromophore complexes with C3 symmetry conclusion appendix A appendix B appendix C appendix D references. 6. Theory of coupling in multichromophoric systems introduction reactant and product states: LMO model the origin of coupling matrix elements paradigmatic results coulombic coupling superexchange interpretation of steady state spectra calculation of couplings acknowledgements references. 7. Exciton annihilation in molecular aggregates introduction theory applications discussion acknowledgements references. 8. Energy transfer and localization: applications to photosynthetic systems introduction optical properties of dimers and aggregates energy and localization in antenna complexes and reaction centers acknowledgements references. 9.Excitation energy transfer in photosynthesis introduction the structure of light--harvesting complexes the mechanism of energy transfer and trapping in photosynthesis dynamics of excitation energy transfer conclusions acknowledgements references. 10. The Fenna--Matthews--Olson protein: a strongly coupled photosynthetic antenna introduction steady state spectroscopy FMO exciton simulations FMO primary processes epilog and future prospects acknowledgements references. 11. Use of a Monte carlo method in the problem of energy migration in molecular complexes introduction an illustration of Monte Carlo calculations in the problem of fluorescence decay energy transfer in CME: major algorithm applications of monte Carlo simulations conclusion acknowledgements references. Index

The Validity of Environmental Benefits Transfer: Further Empirical Testing

Abstract: This paper provides further empirical evidence of the validity of environmental benefits transfer based on CV studies by expanding the analysis to include control factors which have not been accounted for in previous studies. These factors refer to differences in respondent attitudes. Traditional population characteristics were taken into account, but these variables do not explain why respondents from the same socio-economic group may still hold different beliefs, norms or values and hence have different attitudes and consequently state different WTP amounts. The test results are mixed. The function transfer approach is valid in one case, but is rejected in the 3 other cases investigated in this paper. We provide further evidence that in the case of statistically valid benefits transfer, the function approach results in a more robust benefits transfer than the unit value approach. We also show that the equality of coefficient estimates is a necessary, but insufficient condition for valid benefit function transfer and discuss the implications for previous and future validity testing.

Institutions, climate change and cultural theory: towards a common analytical framework

Abstract: Institutions are the multitude of means for holding society together, for giving it a sense of purpose and for enabling it to adapt. Institutions help to define climate change both as a problem and a context, through such socialised devices as the use of scientific knowledge, culturally defined interpretation of scientific findings, and politically tolerable adaptation strategies. This paper briefly reviews the origins and current status of the ‘new’ institutional theories that have recently developed within the social sciences. The conclusion is that they are based on such contradictory interpretations of human behaviour that, although appealing, a complete synthesis will never be possible. In effect, there is a fundamental institutional ‘failure’ over the interpretation and resolution of climate change. Cultural theory helps to explain why this is the case by throwing light on the inherent contradictions that beset us all when confronted with global warming.

Inhibition of invasion and induction of apoptotic cell death of cancer cell lines by overexpression of TIMP-3

Abstract: Dysregulation of matrix degrading metalloproteinase enzymes (MMPs) leads to increased extracellular matrix turnover, a key event in the local invasion and metastasis of many tumours. The tissue inhibitors of metalloproteinases (TIMPs) limit the activity of MMPs, which suggests their use in gene therapy. We have previously shown that overexpression of TIMP-1, -2 or -3 inhibits vascular smooth muscle and melanoma cell invasion, while TIMP-3 uniquely promotes apoptosis. We have therefore sought to determine whether TIMP-3 can inhibit invasion and promote apoptosis in other cancer cell types. Adenoviral-mediated overexpression of TIMP-3 inhibited invasion of HeLa and HT1080 cells through artificial basement membrane to similar levels as that achieved by TIMP-1 and -2. However, TIMP-3 uniquely promoted cell cycle entry and subsequent death by apoptosis. Apoptosis was confirmed by morphological analysis, terminal dUTP nick end labelling (TUNEL) and flow cytometry. The apoptotic phenotype was mimicked by addition of exogenous recombinant TIMP-3 to uninfected cultures demonstrating that the death signal is initiated extracellularly and that a bystander effect exists. These results show that TIMP-3 inhibits invasion in vitro and promotes apoptosis in cancer cell type of differing origin. This clearly identifies the potential of TIMP-3 for gene therapy of multiple cancer types.

Matrix Metalloproteinase-9/Gelatinase B Is Required for Process Outgrowth by Oligodendrocytes

Abstract: Oligodendrocytes (OLs) extend processes to contact axons as a prerequisite step in myelin formation. As the OL processes migrate toward their axonal targets, they modify adhesion to their substrate, an event that may be regulated by matrix metalloproteinases (MMPs). In the mouse optic nerve, MMP-9/gelatinase B increases during myelin formation. Although tissue inhibitor of metalloproteinase (TIMP)-3 also increases in parallel, the developing optic nerve has focally active MMPs demonstrable by in situ zymography. The distribution of proteolytic activity is similar to that of myelin basic protein, a marker of myelin formation. OLs in culture secrete MMP-9 and express active cell-associated metalloproteinases at the growing tips of their processes. TIMP-1 and a function-perturbing anti-MMP-9 antibody attenuate outgrowth of processes by OLs, indicating a requirement for MMP-9 in process outgrowth. Process reformation is retarded significantly in OLs cultured from MMP-9 null mice, as compared with controls, providing genetic evidence that MMP-9 is necessary for process outgrowth. These data show that MMP-9 facilitates process outgrowth by OLs in vivo and in culture.

The Use of Indices to Identify Changes in Climatic Extremes

Abstract: Changes in the frequencies of extremes are investigated by a variety of methods using daily temperature data from the British Isles, and monthly 5° latitude x 5° longitude grid-box temperatures over the land and marine regions of the world. The 225 year long daily Central England Temperature record shows no significant increase in very warm days in recent years but there is a marked decrease in the frequency of very cold days. Thus the rise in temperature in the last two decades is principally associated with a reduction in very cold days. Temperatures on days with particular wind circulation or pressure pattern types over the British Isles show multidecadal variations. Analyses using monthly gridded temperature data around the world since 1951 indicate that the recent rise in global surface temperatures is accompanied both by reductions in the areas affected by extremely cool temperatures and by increases in the areas with extremely wann temperatures.

Fibrillin degradation by matrix metalloproteinases: implications for connective tissue remodelling

Abstract: Fibrillin is the principal structural component of the 10-12 nm diameter elastic microfibrils of the extracellular matrix. We have previously shown that both fibrillin molecules and assembled microfibrils are susceptible to degradation by serine proteases. In this study, we have investigated the potential catabolic effects of six matrix metalloproteinases (MMP-2, MMP-3, MMP-9, MMP-12, MMP-13 and MMP-14) on fibrillin molecules and on intact fibrillin-rich microfibrils isolated from ciliary zonules. Using newly synthesized recombinant fibrillin molecules, major cleavage sites within fibrillin-1 were identified. In particular, the six different MMPs generated a major degradation product of approximately 45 kDa from the N-terminal region of the molecule, whereas treatment of truncated, unprocessed and furin-processed C-termini also generated large degradation products. Introduction of a single ectopia lentis-causing amino acid substitution (E2447K; one-letter symbols for amino acids) in a calcium-binding epidermal growth factor-like domain, predicted to disrupt calcium binding, markedly altered the pattern of C-terminal fibrillin-1 degradation. However, the fragmentation pattern of a mutant fibrillin-1 with a comparable E-->K substitution in an upstream calcium-binding epidermal growth factor-like domain was indistinguishable from wild-type molecules. Ultrastructural examination highlighted that fibrillin-rich microfibrils isolated from ciliary zonules were grossly disrupted by MMPs. This is the first demonstration that fibrillin molecules and fibrillin-rich microfibrils are degraded by MMPs and that certain amino acid substitutions change the fragmentation patterns. These studies have important implications for physiological and pathological fibrillin catabolism and for loss of connective tissue elasticity in ageing and disease.