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L N Jones

Publications and source records attributed to L N Jones.

At least 19 recordsLinked to original sources
PubMed2005

Modelling of neutron survey instrument performance and experimental validation of those calculated response data.

Three moderator-type neutron survey instruments have been modelled for energy and angle dependence of the response, in greater detail than before. These response data have been verified by comparison with published experimental measurements and measurements made specifically for this project. Influences on the instrument response have also been investigated. These have included its mode-of-use and perturbations caused by variations in the instrument manufacture. The implications of these new response data have been assessed by an extensive programme of folding the responses with workplace energy distributions.

Computer Simulation↗
PubMed2004

Angle dependence of response characteristics of neutron survey instruments.

Neutron area survey instruments are designed to have an approximately isotropic response. In practice, the response cannot be perfectly isotropic for instruments that do not have spherical symmetry, and for all instruments it is modified by the inclusion of batteries, electronics, handles, etc. This affects the ability of the survey instrument to measure accurately an isotropic dose equivalent quantity. Measurements of the angle dependence of response for four of the most commonly used designs of survey instrument (Harwell 0949, Mark 7 NRM, NM2 and Studsvik 2202D) have been performed in a low-scatter room using radionuclide and monoenergetic neutron sources. The Monte Carlo code MCNP has been used to model the responses and to investigate their sensitivity to the polyethylene density, counting gas pressure and other manufacturing tolerances. Preliminary modelling results are presented here.

Environmental Exposure↗
PubMed2004

Practical implications of neutron survey instrument performance.

Improvements have been made to the Monte Carlo modelling used to calculate the response of the neutron survey instruments most commonly used in the UK, for neutron energies up to 20 MeV. The improved modelling of the devices includes the electronics and battery pack, allowing better calculations of both the energy and angle dependence of response. These data are used to calculate the response of the instruments in rotationally and fully isotropic, as well as unidirectional fields. Experimental measurements with radionuclide sources and monoenergetic neutron fields have been, and continue to be made, to test the calculated response characteristics. The enhancements to the calculations have involved simulation of the sensitivity of the response to variations in instrument manufacture, and will include the influence of the user and floor during measurements. The practical implications of the energy and angle dependence of response, variations in manufacture, and the influence of the user are assessed by folding the response characteristics with workplace energy and direction distributions.

Algorithms↗
PubMed2001

Effect of the proteasome inhibitor ALLnL on cisplatin sensitivity in human ovarian tumor cells.

Small molecules suppressing proteasome function inhibit the post-translational ubiquitination of selected proteins. Ubiquitin H2A is an example of an abundant chromatin-associated protein that is known to be ubiquitinated, which is important for several proteins involved in the repair of DNA damage. We therefore studied the effect of the proteasome inhibitor, N-acetyl leucyl-leucyl norlucinal (ALLnL), on cisplatin sensitivity in three human ovarian tumor cell lines. The proteasome inhibitor ALLnL was administered for 4 h before cells were subsequently exposed to cisplatin for 1 h. Our results showed that ALLnL, at its respective IC20 concentration, increased cellular sensitivity to cisplatin in an additive manner in human ovarian cancer A2780, A2780/CP70, and OVCAR3 cells. We also demonstrated that ALLnL caused a 50% increase in total cellular accumulation of cisplatin, and reduced the rate of cisplatin efflux by about 50%. In addition, DNA damage levels were increased after ALLnL treatment. By contrast, DNA repair was inhibited 2 to 3-fold in ALLnL-pretreated cells, as compared to the controls. Furthermore, our study showed that ALLnL deubiquitinated nucleosomal histone H2A in these cells in a concentration-dependent fashion, as assessed by Western blot analysis. These data suggest that sublethal levels of exposure to agents that inhibit proteasome function may alter the subcellular pharmacology of platinum in human ovarian carcinoma cells.

Antineoplastic Agents↗
PubMed2000

In vitro assembly and structure of trichocyte keratin intermediate filaments: a novel role for stabilization by disulfide bonding.

Intermediate filaments (IF) have been recognized as ubiquitous components of the cytoskeletons of eukaryotic cells for 25 yr. Historically, the first IF proteins to be characterized were those from wool in the 1960s, when they were defined as low sulfur keratins derived from "microfibrils." These proteins are now known as the type Ia/type IIa trichocyte keratins that constitute keratin IF of several hardened epithelial cell types. However, to date, of the entire class of >40 IF proteins, the trichocyte keratins remain the only ones for which efficient in vitro assembly remains unavailable. In this paper, we describe the assembly of expressed mouse type Ia and type IIa trichocyte keratins into IF in high yield. In cross-linking experiments, we document that the alignments of molecules within reduced trichocyte IF are the same as in type Ib/IIb cytokeratins. However, when oxidized in vitro, several intermolecular disulfide bonds form and the molecular alignments rearrange into the pattern shown earlier by x-ray diffraction analyses of intact wool. We suggest the realignments occur because the disulfide bonds confer substantially increased stability to trichocyte keratin IF. Our data suggest a novel role for disulfide bond cross linking in stabilization of these IF and the tissues containing them.

Amino Acid Sequence↗
PubMed1997

Intermediate filament structure: hard alpha-keratin.

Structurally there are four classes of intermediate filaments (IF) with distinct but closely related axial organisations. One of these, hard alpha-keratin IF, has been studied to clarify several apparently exceptional features which include the number of molecules in the IF cross-section and the mode by which the axial organisation of its constituent molecules is stabilised. Using the dark-field mode of the STEM at the Brookhaven National Laboratory (USA) mass measurements were obtained from unstained IF isolated from hair keratin. The data thus obtained show that the number of chains in cross-section is about 30 (+/-3: standard deviation) and is very similar to the numbers determined in previous STEM experiments for the dominant filament type in other classes of IF (about 32). Furthermore, re-analysis of the low-angle equatorial X-ray diffraction pattern reveals, in contrast to earlier work, solutions that are compatible with the number of chains in cross-section indicated by the STEM data. The absence of the head-to-tail overlap between parallel molecules characteristic of most of IF may be compensated in hard alpha-keratin by a network of intermolecular disulfide bonds. It is concluded that native IF of hard alpha-keratin and desmin/vimentin--and probably many other kinds of IF as well--contain about 32 chains in cross-section, and that the axial structures of these various kinds of IF differ in small but significant ways, while generally observing the same basic modes of aggregation.

Animals↗
PubMed1997

The role of 18-methyleicosanoic acid in the structure and formation of mammalian hair fibres.

Although branched chain fatty acids perform many functions in biological systems, the importance of the anteiso 18 methyleicosanoic acid (MEA) has only recently been recognized. In this first review on MEA its role and distribution is explored. MEA has been found in minor amounts in the fatty acid components of a wide range of biological materials, but the current interest results from it being the major covalently bound fatty acid in mammalian hair fibres, a finding which is unusual because protein-bound fatty acids are typically straight-chain, even-numbered acids (C14-C18). MEA is released by surface restricted reagents indicating that it is located exclusively in or on the surface of the cuticle cells, a conclusion that has been verified by analysis of isolated cuticle cells, X-ray photoelectron spectroscopy (XPS) and secondary-ion mass spectroscopy (SIMS) studies support these results in that they show the surface of the cuticle to be predominantly hydrocarbon. When either neutral hydroxylamine or acidic chlorine solutions are applied to hair and wool fibres fatty acids are liberated, indicating the presence of thioester bonds. Calculations, based on fatty acid and amino acid analysis, indicate that approximately one residue in 10 of the cuticular membrane protein is a fatty acid thioester of cysteine. Removal of this covalently linked fatty acid renders the fibre hydrophilic, thus offering a chemical explanation for many technological and cosmetic treatments of mammalian fibres. Examination of the fibre surface and that of isolated cuticle cells by transmission electron microscopy (TEM) confirms the presence of a thin non-staining continuous layer surrounding the cuticle cells. Alkaline treatments which remove the bound fatty acids were found to disrupt this layer. TEM examination of developing hair fibres has indicated that the fatty acid layer on the upper surface and scale edges of the cuticle cell differs from that of the underside of the cell. Similar structural studies of hair from patients with maple syrup urine disease (MSUD) support the findings that thioester-bound MEA is limited to the upper surface of fibre cuticle cells. The current model proposed for the boundary layer consists of crosslinked protein with surface thioester-linked fatty acids, forming a continuous hydrophobic layer on the upper surface and scale edges of the cells.

Animals↗
PubMed1996

Hair keratinization in health and disease.

The cells of the epidermis and its derivative, the hair follicle, undergo processes of terminal differentiation that involves the synthesis and assembly of classes of protein and enzymes to form the stratum corneum of the epidermis, and the hair fiber and its cuticle. Using genetic linkage and DNA sequencing methods, we now know that mutations in several genes encoding epidermal keratins or a transglutaminase enzyme cause ichthyosis-related diseases. Similar methods have now suggested that mutations in hair keratin genes underlie some cases of monilethrix, and a deficiency in a cuticle lipid metabolizing enzyme causes maple syrup urine disease. It is to be expected that further application of these methods will elucidate the molecular bases of other genetic hair diseases.

Animals↗
PubMed1996

Hairs from patients with maple syrup urine disease show a structural defect in the fiber cuticle.

Models for the surface of cuticle cells in hair fibers consist of a monolayer of fatty acids covalently bound to the underlying protein membrane by thioester linkages. The most prominent of these fatty acids is 18-methyleicosanoic acid (C21a), the synthesis of which requires the oxidative decarboxylation of isoleucine. Maple syrup urine disease (MSUD) is caused by an inherited deficiency in the enzyme branched chain 2-oxo acid dehydrogenase, which leads to the accumulation of branched chain alpha-keto-acids derived from the amino acids, leucine, isoleucine, and valine. Transmission electron microscopy studies of developing hair fibers show a structural defect in the fiber shaft in hair from patients with MSUD. This defect is confined to the cuticle of the fiber, where the cuticle membrane directly apposes the intercellular material. Thus, the defect indicates that C21a is located exclusively on the upper surface of fiber cuticle cells. Lipid analysis of MSUD hairs has demonstrated significant changes in the relative abundance of the covalently bound fatty acids and an almost complete absence of C21a, whereas there was little difference in the amino acid composition compared with normal hair. These results provide further evidence for the existence of the surface lipid monolayer and its crucial role in cellular adhesion.

Amino Acids↗
PubMed1996

Locations of synthesis of hair structural proteins in human anagen follicles.

Live tissue containing cells of the presumptive hair shaft (PHS), was obtained by microdissection of human anagen hair follicles. Whole PHS, as well as PHS further dissected into three levels of hair development, were subsequently used in protein solubilization procedures. Single- and two-dimensional polyacrylamide gel electrophoresis (PAGE) of radiolabelled extracts, with fluorography, enabled comparison of hair and PHS keratin proteins. Fluorographs demonstrated the major classes of protein comprising the intermediate filaments (IF) and matrix of hair keratins. In addition, extracts from various levels of PHS tissue have provided direct evidence for the locations of synthesis of these protein moieties. Thus, IF and matrix proteins are synthesized sequentially in PHS. A previously unobserved polypeptide component, not present in hair extracts, has been identified and found to vary in relative proportions when compared with the major IF and matrix protein classes as PHS cells differentiate to form hair. In the absence of reliable methods for extraction of human hair, PHS provides an alternative source of material, despite the extra burden of follicle collection and specimen preparation. The procedures described provide a new basis for studying human hair defects and are potentially useful for comparing human hair proteins in a variety of situations.

Electrophoresis, Polyacrylamide Gel↗
PubMed1996

Investigation of structural proteins in human hair defects using anagen follicles.

An alternative to using hair specimens for the study of inherited hair shaft defects has been to explore protein compositions in the context of hair formation. Hair follicles were obtained from patients with a hair disorder and the presumptive hair shaft (PHS) separated by microdissection for protein solubilization and electrophoretic experiments aimed at providing a new basis to help explain the mechanism of hair shaft defects. Two-dimensional electrophoresis (fluorographs) of labelled extracts was used to examine the major hair structural proteins and other polypeptide(s) found associated with PHS extracts in normal and aberrant specimens. Changes in either the intermediate filaments (IFs) or matrix polypeptides were not normally found in defective PHS specimens. The polypeptides showing greatest variation were associated with a PHS-specific component which was recently found in normal specimens. The variation in this polypeptide was manifested as multiple spots of different molecular weights. An investigation of the role of PHS-associated polypeptides as a likely part of the hair cross-linking mechanisms, involved examination of a PHS extract from a Menkes' patient. The observations suggest that formation of hair fibre shaft defects may be related to the status of PHS-associated polypeptides which could in turn be influenced by the presence of copper in the hair follicle.

Electrophoresis, Polyacrylamide Gel↗
PubMed1994

Formation of surface membranes in developing mammalian hair fibres.

Mammalian hair fibres result from complex mechanisms involving synthesis, assembly and stabilisation of keratin proteins in the follicle. The developing hair shaft consists of outer cuticle cells surrounding cortical and medullary (optional) cell types. Presumptive fibre cuticle (FC) is contained by the inner root sheath (IRS) consisting of IRS cuticle, Huxley and Henle cells which are in turn enclosed in an outer root sheath (ORS) of epidermal-like cells. In the current structural studies we have used energy filtered transmission electron microscopy (Zeiss 902A) on Merino sheep skin biopsies to examine the fine sequence of morphological changes involved in forming the fibre surface membrane and the associated underlying structural bands comprising the a-layer and exocuticle. Prior to the development of the exocuticle, FC cells demonstrate a typical plasma-membrane apposed to IRS cuticle plasma-membranes separated by an intercellular space. The formation of exocuticular lamellae is followed by degradation of the residual FC surface membrane and the appearance of intercellular laminae demonstrating a stained central band. As maturation continues cleavage between IRS cuticle and FC occurs along this central band liberating hair into the pilary canal. The mature surface consists of keratinized cells containing a well developed exocuticle and a-layer coated with paired lamina (presumably two lipid containing bilayers) of material approximately 10-12 nm thick derived from the intercellular laminae. The current observations show FC surface formation is similar to processes occurring in epidermal stratum corneum and that the cuticle surface membrane of mammalian fibres is not derived from a modified plasma-membrane as previously documented.

Animals↗
PubMed1990

Are hypertension or cardiac embolism likely causes of lacunar infarction?

We tested the hypothesis that hypertension is more common and cardiac embolism less common in patients with lacunar infarction than in patients with other types of cerebral infarction. We studied risk factor profiles in a series of 102 consecutive patients with a lacunar infarct and 202 consecutive patients with a carotid artery-distribution infarct involving the cortex registered in the Oxfordshire Community Stroke Project, a community-based study of first-ever stroke. The two groups did not differ in the prevalence of prestroke hypertension (defined in a number of ways) or in the prevalence of markers of sustained hypertension. The presence of atrial fibrillation and a history of myocardial infarction, particularly during the 6 weeks before the stroke, were significantly more common in the group with carotid-distribution infarcts involving the cortex. There was no significant difference in the prevalence of other accepted risk factors for ischemic stroke, including previous transient ischemic attack, cervical bruit, diabetes mellitus, peripheral vascular disease, or cigarette smoking. Our results suggest that hypertension is no more important in the development of lacunar infarction than it is in the development of other types of ischemic stroke that are presumed to be due to atherosclerotic thromboembolism in a major cerebral artery. Our data support the autopsy evidence that cardioembolic occlusion is an unusual cause of lacunar infarction.

Aged↗
PubMed1989

Predisposing factors for cerebral infarction: the Oxfordshire community stroke project.

The frequency of known causative factors of cerebral infarction was studied in 244 cases of first ever stroke due to cerebral infarction proved by computed tomography or at necropsy who were registered in the first two years of a prospective community based study. Risk factors for cerebral infarction were present in 196 (80%) cases; hypertension in 126 (52%); ischaemic heart disease in 92 (38%); peripheral vascular disease in 60 (25%); a cardiac lesion that was a major potential source of embolism to the brain in 50 (20%); transient ischaemic attacks in 35 (14%); cervical arterial bruit in 33 (14%); and diabetes mellitus in 24 (10%). Thirty one patients (13%) were in atrial fibrillation. Of the 48 patients who were free of risk factors or a major potential cardiac source of embolism at the time of the stroke, 18 were found to have hypertension after the stroke and 10 to have non-atheromatous non-embolic conditions (migrainous cerebral infarction (three), arteritis (two), inflammatory bowel disease (one), arterial trauma (one), autoimmune disease (one), carcinoma of the thyroid (one), and major operation (one). In 20 patients no causative factors could be identified. In this unselected series of patients with first ever stroke due to cerebral infarction most of the strokes were presumed to be due to either atheromatous arterial disease or embolism from the heart, and only 4% (95% confidence interval 2 to 7%) were probably due to non-atheromatous non-embolic causes. This has implications for research into strokes and allocation of public health expenditure.

Aged↗
PubMed1988

Cooperative study on the value of long term anticoagulation in patients with stroke and non-rheumatic atrial fibrillation.

The benefits of long term anticoagulant treatment of patients with non-rheumatic atrial fibrillation and cerebral infarction were studied by comparing two series of patients with stroke from centres with different policies on anticoagulant treatment. The long term prognosis of 50 patients from the Oxfordshire community stroke project, who did not receive anticoagulants, was compared with that of 70 similar patients from Maastricht, who were treated with anticoagulants. After a mean follow up of 27 months there was no significant difference in either the rate of survival or the rate of recurrent stroke between the two groups. These data suggest that any benefit of anticoagulation is modest. A large randomised trial is planned to establish whether long term anticoagulant treatment is of value and, if so, to what extent.

Aged↗