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Biomedical subjects

J C Knight

Publications and source records attributed to J C Knight.

At least 37 records · Page 2Linked to original sources
PubMed2002

Experimental evidence for supercontinuum generation by fission of higher-order solitons in photonic fibers.

We report on an experimental study of supercontinuum generation in photonic crystal fibers with low-intensity femtosecond pulses, which provides evidence for a novel spectral broadening mechanism. The observed results agree with our theoretical calculations carried out without making the slowly varying envelope approximation. Peculiarities of the measured spectra and their theoretical explanation demonstrate that the reason for the white-light generation in photonic crystal fibers is fission of higher-order solitons into redshifted fundamental solitons and blueshifted nonsolitonic radiation.

Journal Article↗
PubMed2000

Alastrim smallpox variola minor virus genome DNA sequences.

Alastrim variola minor virus, which causes mild smallpox, was first recognized in Florida and South America in the late 19th century. Genome linear double-stranded DNA sequences (186,986 bp) of the alastrim virus Garcia-1966, a laboratory reference strain from an outbreak associated with 0.8% case fatalities in Brazil in 1966, were determined except for a 530-bp fragment of hairpin-loop sequences at each terminus. The DNA sequences (EMBL Accession No. Y16780) showed 206 potential open reading frames for proteins containing >/=60 amino acids. The amino acid sequences of the putative proteins were compared with those reported for vaccinia virus strain Copenhagen and the Asian variola major strains India-1967 and Bangladesh-1975. About one-third of the alastrim viral proteins were 100% identical to correlates in the variola major strains and the remainder were >/=95% identical. Compared with variola major virus DNA, alastrim virus DNA has additional segments of 898 and 627 bp, respectively, within the left and right terminal regions. The former segment aligns well with sequences in other orthopoxviruses, particularly cowpox and vaccinia viruses, and the latter is apparently alastrim-specific.

3-Hydroxysteroid Dehydrogenases↗
PubMed2000

Antineoplastic agents 430. Isolation and structure of cribrostatins 3, 4, and 5 from the republic of maldives cribrochalina species.

Continued investigation of cancer-cell growth-inhibitory constituents of the blue marine sponge Cribrochalina sp. has led to discovery of cribrostatins 3 (4a), 4 (5), and 5 (4b) in 10(-5) to 10(-7) % of the wet weight. The structure of cribrostatin 3 (4a) was determined by results of high field (500 MHz) (1)H and (13)C NMR and HRMS interpretations. The same general approach to the structures of cribrostatins 4 (5) and 5 (4b) was completed by X-ray crystal structure determinations. Cribrostatins 3, 4, and 5 provided significant cancer cell line inhibitory activities. Cribrostatins 1 and 2(2) and the newly isolated cribrostatins 3-5 displayed antibacterial and/or antifungal activities.

Animals↗
PubMed2000

Assessing smoking prevalence amongst school children in a health board region.

The objective of the study was to provide baseline data for Tayside in 1995 on the prevalence of smoking cigarettes in school children, aged 11 to 15 years. The design was a cross-sectional survey of 4675 children, obtained using a random cluster sample of 79 schools, stratified by school year and deprivation category. The main outcomes measures using a structured questionnaire, were the prevalence and level of smoking, by age and gender. The prevalence rate of regular smoking was 9% (95% CI 8.2%-9.8%). The rate rises appreciably for boys between 13 and 14 years and for girls between 12 and 13 years. Source of cigarettes was also an outcome measure, most cigarettes were obtained from small shops. Health Boards require a standard method for collecting regional baseline data on the prevalence of smoking among children both for evaluation of targeted health promotion initiatives by age and gender and also for comparison of regional smoking prevalence with national targets.

Adolescent↗
PubMed1999

SSX and the synovial-sarcoma-specific chimaeric protein SYT-SSX co-localize with the human Polycomb group complex.

Chromosome translocation t(X;18)(p11.2;q11.2) is unique to synovial sarcomas and results in an 'in frame' fusion of the SYT gene with the SSX1 or closely-related SSX2 gene. Wild-type SYT and SSX proteins, and the SYT-SSX chimaeric proteins, can modulate transcription in gene reporter assays. To help elucidate the role of these proteins in cell function and neoplasia we have performed immunolabelling experiments to determine their subcellular localization in three cell types. Transient expression of epitope-tagged proteins produced distinctive nuclear staining patterns. The punctate staining of SYT and SYT-SSX proteins showed some similarities. We immunolabelled a series of endogenous nuclear antigens and excluded the SYT and SYT-SSX focal staining from association with these domains (e.g. sites of active transcription, snRNPs). In further experiments we immunolabelled the Polycomb group (PcG) proteins RING1 or BMI-1 and showed that SSX and SYT-SSX proteins, but not SYT, co-localized with these markers. Consistent with this we show that SSX and SYT-SSX associate with chromatin, and also associate with condensed chromatin at metaphase. Noteably, SSX produced a dense signal over the surface of metaphase chromosomes whereas SYT-SSX produced discrete focal staining. Our data indicate that SSX and SYT-SSX proteins are recruited to nuclear domains occupied by PcG complexes, and this provides us with a new insight into the possible function of wild-type SSX and the mechanism by which the aberrant SYT-SSX protein might disrupt fundamental mechanisms controlling cell division and cell fate.

Animals↗
PubMed1999

A polymorphism that affects OCT-1 binding to the TNF promoter region is associated with severe malaria.

Genetic variation in cytokine promoter regions is postulated to influence susceptibility to infection, but the molecular mechanisms by which such polymorphisms might affect gene regulation are unknown. Through systematic DNA footprinting of the TNF (encoding tumour necrosis factor, TNF) promoter region, we have identified a single nucleotide polymorphism (SNP) that causes the helix-turn-helix transcription factor OCT-1 to bind to a novel region of complex protein-DNA interactions and alters gene expression in human monocytes. The OCT-1-binding genotype, found in approximately 5% of Africans, is associated with fourfold increased susceptibility to cerebral malaria in large case-control studies of West African and East African populations, after correction for other known TNF polymorphisms and linked HLA alleles.

Animals↗
PubMed1999

Severe malarial anemia and cerebral malaria are associated with different tumor necrosis factor promoter alleles.

Experimental evidence implicates tumor necrosis factor (TNF) in the pathogenesis of malarial anemia, but there are few data relating to this hypothesis. This study found that severely anemic children with Plasmodium falciparum infection have low plasma TNF levels, in contrast to the high levels found in cerebral malaria. A previous case-control study in The Gambia found cerebral malaria, but not severe malarial anemia, was associated with the TNF-308 A allele. This study found that in the same population, severe malarial anemia was associated with the TNF-238 A allele, with an odds ratio of 2.5 (P<.001) after stratification for HLA type. These findings suggest that severe malarial anemia and cerebral malaria are influenced by separate genetic factors situated near the TNF gene.

Alleles↗
PubMed1998

A KRAB-related domain and a novel transcription repression domain in proteins encoded by SSX genes that are disrupted in human sarcomas.

SSX genes show extensive nucleotide sequence conservation but little is known of their function. Disruption of SSX1 or SSX2, by chromosome translocation and 'in-frame' fusion to SYT, is a consistent feature of synovial sarcomas. The resulting SYT-SSX1/SSX2 proteins are activators of transcription; transactivation function is located in SYT. Unrearranged SSX1 can repress transcription, and this has been attributed to a putative Krüppel associated box (KRAB) repression domain at the N-terminus. Here we isolated SSX-KRAB domains to specifically measure repression activity, using a previously characterized KOX1-KRAB domain as a control. In our repressor assay SSX1- and SSX2-KRAB domains down-modulated the transactivation of a reporter gene by threefold, compared with 83-fold repression achieved by KOX1-KRAB in the assay. Yeast two-hybrid analysis showed that SSX1-KRAB, unlike KOX1-KRAB, fails to interact with the KRAB co-repressor TIF1beta. These results raise questions about the evolutionary and functional relationship of SSX-KRAB and typical KRAB domains of Krüppel zinc finger genes. We found that full-length SSX1 showed potent (74-fold) repression in our repressor assay, indicating the existence of a repression domain distinct from SSX-KRAB. By assaying deletion constructs of SSX1 we localized repression activity to 33 amino acids at the C-terminus. This novel domain is conserved between SSX family members, and, unlike the KRAB-related domain, is retained on fusion with SYT. This has important implications in understanding the mechanism by which the SYT-SSX fusion protein could contribute to neoplasia.

Amino Acid Sequence↗
PubMed1998

Complex NF-kappaB interactions at the distal tumor necrosis factor promoter region in human monocytes.

We describe a dense cluster of DNA-protein interactions located 600 nucleotides upstream of the transcriptional start site of the human tumor necrosis factor (TNF) gene. This area was identified as being of potential importance for lipopolysaccharide-inducible TNF expression in the human monocyte cell line Mono Mac 6, based on reporter gene analysis of point mutations at a number of nuclear factor kappaB (NF-kappaB)-like motifs within the human TNF promoter region. The area contains two NF-kappaB sites, which are here shown by DNase I and methylation interference footprinting to flank a novel binding site. UV cross-linking studies reveal that the novel site can also bind NF-kappaB as well as an unknown protein(s) of approximately 40 kDa. We show that these three adjacent kappaB-binding sites differ markedly in their relative affinities for p50/p50, p65/p65, and p65/p50, yet this 39-nucleotide segment of DNA appears capable of binding up to three NF-kappaB heterodimers simultaneously. Reporter gene studies indicate that each element of the cluster contributes to lipopolysaccharide-induced transcriptional activation in Mono Mac 6 cells. These findings suggest that NF-kappaB acts in a complex manner to activate TNF transcription in human monocytes.

Base Sequence↗
PubMed1998

A third distinct tumor necrosis factor receptor of orthopoxviruses.

Cowpox virus Brighton red strain (CPV) contains a gene, crmD, which encodes a 320-aa tumor necrosis factor receptor (TNFR) of 44% and 22% identity, respectively, to the CPV TNFR-like proteins, cytokine response modifiers (crm) CrmB and CrmC. The crmD gene was interrupted in three other cowpox strains examined and absent in various other orthopoxviruses; however, four strains of ectromelia virus (ECT) examined contained an intact crmD (97% identity to CPV crmD) and lacked cognates of crmB and crmC. The protein, CrmD, contains a transport signal; a 151-aa cysteine-rich region with 21 cysteines that align with human TNFRII ligand-binding region cysteines; and C-terminal region sequences that are highly diverged from cellular TNFR C-terminal region sequences involved in signal transduction. Bacterial maltose-binding proteins containing the CPV or ECT CrmD cysteine-rich region bound TNF and lymphotoxin-alpha (LTalpha) and blocked their in vitro cytolytic activity. Secreted viral CrmD bound TNF and LTalpha and was detectable after the early stage of replication, using nonreducing conditions, as 60- to 70-kDa predominant and 90- to 250-kDa minor disulfide-linked complexes that were able to be reduced to a 46-kDa form and deglycosylated to a 38-kDa protein. Cells infected with CPV produced extremely low amounts of CrmD compared with ECT. Possessing up to three TNFRs, including CrmD, which is secreted as disulfide-linked complexes in varied amounts by CPV and ECT, likely enhances the dynamics of the immune modulating mechanisms of orthopoxviruses.

Amino Acid Sequence↗
PubMed1997

The malarial fever response--pathogenesis, polymorphism and prospects for intervention.

It is estimated that over 200 million people each year suffer debilitating attacks of malarial fever, and roughly 2 million of these episodes are fatal. The fever is caused by tumour necrosis factor (TNF) and other pyrogenic cytokines that are released by the host immune system response to products of schizont rupture. TNF has anti-parasitic properties but excessive TNF production is thought to play an important role in the pathogenesis of cerebral malaria. This review summarizes recent attempts to achieve molecular characterization of the parasite components that stimulate the host TNF response, and to define the host and parasite factors that affect the level of TNF production. Of particular interest are host polymorphisms that may regulate TNF gene expression, and naturally acquired antibodies that prevent the parasite from inducing TNF, both of which correlate with the clinical severity of infection. Our understanding of these processes, which are potentially of considerable therapeutic relevance, remains very limited at both the molecular and the epidemiological level.

Child↗
PubMed1996

Terminal region sequence variations in variola virus DNA.

Genome DNA terminal region sequences were determined for a Brazilian alastrim variola minor virus strain Garcia-1966 that was associated with an 0.8% case-fatality rate and African smallpox strains Congo-1970 and Somalia-1977 associated with variola major (9.6%) and minor (0.4%) mortality rates, respectively. A base sequence identity of > or = 98.8% was determined after aligning 30 kb of the left- or right-end region sequences with cognate sequences previously determined for Asian variola major strains India-1967 (31% death rate) and Bangladesh-1975 (18.5% death rate). The deduced amino acid sequences of putative proteins of > or = 65 amino acids also showed relatively high identity, although the Asian and African viruses were clearly more related to each other than to alastrim virus. Alastrim virus contained only 10 of 70 proteins that were 100% identical to homologs in Asian strains, and 7 alastrim-specific proteins were noted.

Africa↗
PubMed1995

Topography of variola smallpox virus inverted terminal repeats.

We examined the nucleotide sequences of the inverted terminal repeat (ITR) regions adjacent to the covalently closed hairpin end sequences of three variola major and four minor strains from smallpox outbreaks in Europe, Asia, Africa, and South America. The ITR regions ranged in size from 581 to 1051 base pairs (bp) and contained no apparent open reading frames. Two nonrepetitive sequence elements, NR1 and NR2, were conserved and resembled nonrepetitive elements in the ITRs of other orthopoxviruses. Depending on strain, the terminally positioned NR1 and the more internal NR2 flanked a direct repeat region containing from none to four copies of a 69-bp sequence and one copy of a 54-bp related sequence partial repeat. A distinctive pattern of ITR topography of NR1 and NR2 flanking a single copy of the 69-bp unit characterized each of three examined alastrim variola minor strains. A nonalastrim African minor strain from the last natural case of smallpox in Somalia in 1977 showed the largest ITR region of the examined viruses because of a second direct repeat cluster following NR2.

Africa↗
PubMed1995

Translocation t(12;16)(q13;p11) in myxoid liposarcoma and round cell liposarcoma: molecular and cytogenetic analysis.

Translocation t(12;16)(q13;p11) is regarded as a diagnostic marker for myxoid liposarcoma. Cytogenetic data on round cell liposarcomas and combined myxoid and round cell tumors is scarce, and the genetic basis of progression of myxoid tumors to high grade, round cell lesions is unknown. We have accumulated six round cell, four combined myxoid and round cell, and three myxoid liposarcomas for analysis. t(12;16)(q13;p11) was present in three round cell lesions and was detectable in all of the tumors by DNA analysis. In each tumor type, the CHOP gene in 12q13 was rearranged and fused to the TLS gene in 16p11. A variant TLS-CHOP RNA transcript was detected by polymerase chain reaction but did not correlate with clinicopathological data. No distinguishing cytogenetic or molecular markers for round cell or mixed lesions were found. The histogenic and genetic relatedness of myxoid and round cell liposarcomas is apparent from these data.

Adult↗
PubMed1995

Software safety in medical applications.

The use of software in safety-critical medical applications permits sophisticated functionality that would otherwise not be achievable. However, it is very difficult to ensure that software in these systems is dependable. In particular all software development techniques have limitations, and none can provide any guarantee of overall software dependability. Given this shortcoming, the approach that we have taken is to develop techniques that emphasize the verification of properties that are important to overall software dependability. In this paper we describe two techniques that support the implementation and verification of dependable software for an experimental neurosurgical device and safety-critical applications in general. The first technique involves the assurance of critical safety properties by a relatively simple software component known as a safety kernel. Situated between the application software and the application devices, the safety kernel enforces rules that govern the safe operation of the devices. The simplicity of the safety kernel facilitates its implementation and verification. In most cases, it is not possible to rely on testing to provide the necessary verification of the software in a safety-critical application. However, testing can play an appropriate and vital role in the demonstration of safety properties. The second technique takes this approach, utilizing automated testing and selected test cases to demonstrate useful system properties.

Neurosurgery↗