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C Watts

Publications and source records attributed to C Watts.

At least 37 records · Page 2Linked to original sources
PubMed2001

Bm-CPI-2, a cystatin homolog secreted by the filarial parasite Brugia malayi, inhibits class II MHC-restricted antigen processing.

While interference with the class I MHC pathway by pathogen-encoded gene products, especially those of viruses, has been well documented, few examples of specific interference with the MHC class II pathway have been reported. Potential targets for such interference are the proteases that remove the invariant chain chaperone and generate antigenic peptides. Indeed, recent studies indicate that immature dendritic cells express cystatin C to modulate cysteine protease activity and the expression of class II MHC molecules [1]. Here, we show that Bm-CPI-2, a recently discovered cystatin homolog produced by the filarial nematode parasite Brugia malayi (W. F. Gregory et al., submitted), inhibits multiple cysteine protease activities found in the endosomes/lysosomes of human B lymphocyte lines. CPI-2 blocked the hydrolysis of synthetic substrates favored by two different families of lysosomal cysteine proteases and blocked the in vitro processing of the tetanus toxin antigen by purified lysosome fractions. Moreover, CPI-2 substantially inhibited the presentation of selected T cell epitopes from tetanus toxin by living antigen-presenting cells. Our studies provide the first example of a product from a eukaryotic parasite that can directly interfere with antigen presentation, which, in turn, may suggest how filarial parasites might inactivate the host immune response to a helminth invader.

Animals↗
PubMed2001

Antigen processing in the endocytic compartment.

Proteolysis generates the peptides that bind to class II MHC molecules and, by destruction of the invariant chain, prepares the class II MHC molecule for capture of those peptides. A clearer picture is emerging of the proteases, protease inhibitors and other factors that together control the environment for class II MHC peptide loading. However, the details of invariant-chain processing and antigen processing may differ depending on the allele of class II and the antigen substrate under consideration.

Animals↗
PubMed2001

Opportunities for public health genetics trainees: results of an employer/workplace survey.

OBJECTIVE: To conduct the first employer/workplace survey identifying employment opportunities for graduates of programs with training in public health genetics in the USA, and to determine whether employment opportunities will increase in coming years. METHODS: Six public health genetics training competencies were developed. A survey about workplace and employment opportunities was then conducted with mailings to (1) departments in schools of public health and departments of preventive medicine, (2) local and regional public health officials, (3) insurance companies and health management organizations (HMOs), and (4) biotechnology and pharmaceutical companies. RESULTS: A total of 196 surveys were returned among 1,464 that were mailed. Response rates varied from 5.8 to 46.5% among the target groups. The percent of responding organizations currently employing individuals with skills in genetics ranged from 20 to 62%. The percent currently employing individuals with skills in public health ranged from 39 to 96%. Training opportunities such as internships or practicum experiences are reported for one-third of respondents. For all of the competencies, approximately half of survey respondents who rated the competency important or very important already employ individuals with public health genetics skills. Similarly, at least a quarter of survey respondents who rated the competency important or very important plan to hire individuals with that skill in the next 5 years. Overall, approximately 40% of those surveyed are planning to hire individuals with competencies in public health genetics in the next 5 years. CONCLUSION: Employment opportunities already exist and new positions are becoming available in schools of public health and departments of preventive medicine, departments of public health, insurance companies and HMOs for professionals with public health genetics training. Based on our survey findings, skills and training in public health genetics are important in the workplace.

Journal Article↗
PubMed2000

Rac is required for constitutive macropinocytosis by dendritic cells but does not control its downregulation.

BACKGROUND: Dendritic cells use constitutive macropinocytosis to capture exogenous antigens for presentation on MHC molecules. Upon exposure to inflammatory stimuli or bacterial products such as lipopolysaccharide (LPS), macropinocytosis is dramatically downregulated as part of a developmental programme leading to dendritic cell maturation, migration and activation of T cells. It is not known, however, how macropinocytosis is sustained in dendritic cells in the absence of exogenous stimuli, nor how it is downregulated upon maturation. We have tested the possibility that one or more members of the Rho family of GTPases are involved in and control pinocytosis in dendritic cells. RESULTS: We established dendritic cell populations that show constitutive macropinocytosis that was downregulated by LPS treatment. Microinjection of immature cells with dominant-negative Rac (N17Rac1) or treatment with Clostridium difficile toxin B, the phosphoinositide 3-kinase (PI3-K) inhibitor wortmannin, or LPS all inhibited the formation of macropinosomes but, surprisingly, did not eliminate membrane ruffling. Microinjection of N17Cdc42 or the Rho inhibitor C3 transferase eliminated actin plaques/podosomes and actin cables, respectively, but had little effect on the formation of macropinosomes. Surprisingly, dendritic cells matured with LPS had equivalent or even somewhat higher levels of active Rac than immature cells. Moreover, microinjection of a constitutively active form of Rac (V12Rac1) into mature dendritic cells did not reactivate macropinocytosis. CONCLUSIONS: Rac has an important role in the constitutive formation of macropinosomes in dendritic cells but may be required downstream of membrane ruffling. Furthermore, regulation of Rac activity does not appear to be the control point in the physiological downregulation of dendritic cell pinocytosis. Instead, one or more downstream effectors may be modulated to allow Rac to continue to regulate other cellular functions.

Animals↗
PubMed2000

Riverine inputs of major ions and trace elements to the tidal reaches of the River Tweed, UK.

This paper examines spatial and temporal variability in freshwater inputs of trace elements and major ions to the tidal reaches of the River Tweed. The relationships between concentrations of major ions and trace elements (in dissolved and acid-available particulate forms) and flow are examined, and a simple two-component endmember mixing analysis performed to link river water chemistry to catchment sources, and to identify whether within-river processes modify concentrations to produce non-conservative behaviour. The results indicate that most dissolved major ions and trace elements behave conservatively in the lower reaches of the River Tweed, the variability in concentrations being dominated by hydrology and the existence of different high-flow and low-flow endmember runoff chemistries. This suggests that the variability in concentration of most dissolved trace elements and major ions in the lower Tweed can be modelled using simple mixing relationships. However, the relationships between pH, Ca, Mg and Gran alkalinity show pronounced non-conservative behaviour, indicating the importance of understanding within-river process for modelling these determinants. The non-conservative behaviour identified is related to biological controls and the resultant diurnal variations in pH which promote daytime removal of Ca from solution by precipitation of calcium carbonate (and corresponding removal of Mg by co-precipitation) during extreme low-flow conditions and algal blooms during the summer.

Eutrophication↗
PubMed2000

The structures of the H(C) fragment of tetanus toxin with carbohydrate subunit complexes provide insight into ganglioside binding.

The entry of tetanus neurotoxin into neuronal cells proceeds through the initial binding of the toxin to gangliosides on the cell surface. The carboxyl-terminal fragment of the heavy chain of tetanus neurotoxin contains the ganglioside-binding site, which has not yet been fully characterized. The crystal structures of native H(C) and of H(C) soaked with carbohydrates reveal a number of binding sites and provide insight into the possible mode of ganglioside binding.

Acetylgalactosamine↗
PubMed2000

Embryonic donor age and dissection influences striatal graft development and functional integration in a rodent model of Huntington's disease.

The method of embryonic dissection and the age of the donor material remain areas of controversy in the preparation of striatal tissue for intrastriatal implantation. This study explores the relationship between these two parameters with respect to the morphology, function, and physiological integration of the resultant grafts. Tissue derived from embryos of 14 and 16 days of gestation (CRL 10-11 and 14-15 mm, respectively) was prepared as whole, lateral, and medial ganglionic eminence suspensions (WGE, LGE, and MGE, respectively). The embryonic material was implanted into the excitotoxically lesioned striatum of host rats. Grafts derived from E14 LGE attenuated drug-induced rotational bias whereas grafts from E14 MGE ameliorated contralateral deficits in paw reaching. Six months after grafting retrograde tracing of graft projections to the globus pallidus was performed followed by electrical excitation of cortical afferent fibers. Grafts derived from E14 WGE had the largest volume of striatum-like tissue and more striatal neurons compared to LGE from the same donor age. These results suggest that MGE tissue as well as LGE plays a role in the structural and functional integration of striatal grafts.

Acetylcholinesterase↗
PubMed2000

Ethical and methodological issues in conducting research on gender-based violence in Southern Africa.

International experience of carrying out research on violence against women among women who may have experienced such violence and among men who may have been violent has raised a number of ethical issues, which appear in sharp focus. This paper is based on the collective experiences derived from involvement in three large gender-based violence surveys in South Africa and one in Zimbabwe. These are broadly concerned with the safety of researchers and research subjects from violence arising because of the research project, risks of traumatisation of both respondents and researchers as violent experiences are recounted; impact of work on violence as an issue in researchers' own relationships; risks of under-reporting the extent of violence experienced or perpetrated; and the need for research efforts to be followed up in ways beneficial to women experiencing violence, such as increased support, public information, and law and policy changes. This paper discusses how these issues have pertained and been addressed in research on gender-based violence in Southern Africa and consider lessons for this and other sensitive areas of reproductive and sexual health research.

Battered Women↗
PubMed2000

Control of antigen presentation by a single protease cleavage site.

Protein antigens require limited proteolytic processing to generate peptides for binding to class II MHC molecules, but the proteases and processing sites involved are largely unknown. Here we analyze the effect of eliminating the three major asparagine endopeptidase (AEP)-processing sites in the microbial antigen tetanus toxin C fragment. The mutant antigen is highly resistant to proteolysis by AEP and crude lysosomal extracts and is dramatically impaired in its ability to be processed and presented to T cells. Remarkably, processing at a single asparagine residue (1219) is obligatory for optimal presentation of many T cell epitopes in this antigen. These studies demonstrate that cleavage at a single processing site can be crucial for effective antigen presentation.

Amino Acid Sequence↗
PubMed2000

Antigen traffic pathways in dendritic cells.

Dendritic cells (DC) are now believed to be the principal initiators of T cell-mediated immune responses. Their location in body tissues, migratory behaviour in response to inflammatory stimuli, endocytic properties, expression of MHC molecules and key T cell stimulatory molecules and many other attributes place these remarkable cells in a unique and influential position in the immune system. Progress in DC culture methods has recently allowed in-depth studies on the cell biological features that enable them to fulfill their crucial role in the immune response.

Animals↗
PubMed2000

Functional corticospinal projections are established prenatally in the human foetus permitting involvement in the development of spinal motor centres.

From studies of subhuman primates it has been assumed that functional corticospinal innervation occurs post-natally in man. We report a post-mortem morphological study of human spinal cord, and neurophysiological and behavioural studies in preterm and term neonates and infants. From morphological studies it was demonstrated that corticospinal axons reach the lower cervical spinal cord by 24 weeks post-conceptional age (PCA) at the latest. Following a waiting period of up to a few weeks, it appears they progressively innervate the grey matter such that there is extensive innervation of spinal neurons, including motor neurons, prior to birth. Functional monosynaptic corticomotoneuronal projections were demonstrated neurophysiologically from term, but are also likely to be present from as early as 26 weeks PCA. At term, direct corticospinal projections to Group Ia inhibitory interneurons were also confirmed. Independent finger movements developed much later, between 6 and 12 months post-natally. These data do not support the proposal that in man, establishment of functional corticomotoneuronal projections occurs immediately prior to and provides the capacity for the expression of fine finger movement control. We propose instead that such early corticospinal innervation occurs to permit cortical involvement in activity dependent maturation of spinal motor centres during a critical period of perinatal development. Spastic cerebral palsy from perinatal damage to the corticospinal pathway secondarily involves disrupted development of spinal motor centres. Corticospinal axons retain a high degree of plasticity during axon growth and synaptic development. The possibility therefore exists to promote regeneration of disrupted corticospinal projections during the perinatal period with the double benefit of restoring corticospinal connectivity and normal development of spinal motor centres.

Autopsy↗
PubMed2000

Clathrin-coated lattices and buds on MHC class II compartments do not selectively recruit mature MHC-II.

Newly synthesized major histocompatibility complex class II molecules (MHC-II) are transported to MHC-II-containing endosomal and lysosomal compartments (MIICs) for the degradation of associated invariant chain and peptide loading. Subsequently MHC-II is transported to the plasma membrane, in part through direct fusion of MIICs with the plasma membrane. In search of potential alternative pathway(s) we studied the 3-dimensional structure of MIICs and the subcellular distribution of MHC-II by immuno electronmicroscopy on whole-mount preparations and cryosections of Mel JuSo cells. Intracellular MHC-II and invariant chain mainly localized to lamp-1 positive compartments suggesting that the majority of MHC-II exits the endocytic tract at lysosomes. Clathrin-coated lattices and buds were found to be associated with these organelles, but MHC-II was not found to be enriched in the clathrin-coated domains. Moreover, leupeptin, a drug that interferes with Ii-processing and delays delivery of newly synthesized MHC-II to the plasma membrane, was not found to decrease the relative amount of MHC-II in clathrin-coated areas. Together these data indicate clathrin-mediated exit site(s) from lysosomes but suggest that they do not selectively recruit mature MHC-II, consistent with the notion that transport to the plasma membrane occurs independently of the cytoplasmic domains of the MHC-II (&agr;) and (beta) chains.

Antigens, Differentiation, B-Lymphocyte↗
PubMed2000

Patients readmitted to ICUs* : a systematic review of risk factors and outcomes.

STUDY OBJECTIVE: To evaluate the causes, risk factors, and mortality rates associated with unexpected readmission to medical and surgical ICUs. DATA SOURCES: MEDLINE citation review of primary articles focusing on ICU readmission or ICU outcomes from January 1966 to June 1999, and contact with authors of primary studies. STUDY SELECTION: Eight primary studies of ICU readmission and eight multi-institutional ICU outcome studies that reported ICU readmission rates were included. DATA EXTRACTION: We abstracted data on the methodology and design of the primary studies, overall rates, causes, predictors, outcomes, and measures of quality of care associated with ICU readmission. DATA SYNTHESIS: The average ICU readmission rate of 7% (range, 4 to 14%) has remained relatively unchanged in both North America and Europe. Respiratory and cardiac conditions were the most common (30 to 70%) precipitating cause of ICU readmission. Patients readmitted to ICUs had average hospital stays at least twice as long as nonreadmitted patients. Hospital death rates were 2- to 10-times higher for readmitted patients than for those who survived an ICU admission and were never readmitted. Predictors of ICU readmission have been neither well studied nor reproducible. Unstable vital signs, especially respiratory and heart rate abnormalities, and the presence of poor pulmonary function at time of ICU discharge appear to be the most consistent predictors of ICU readmission. There were no consistent data supporting the use of readmission rates as a measure of quality of care. CONCLUSIONS: ICU readmission is associated with dramatically higher hospital mortality. Unstable vital signs at the time of ICU discharge are the most consistent predictor of ICU readmission. Further studies focusing on processes of ICU and hospital care are needed to determine if ICU readmission rates are a measure of quality of care.

Europe↗