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K Taylor

Publications and source records attributed to K Taylor.

At least 19 recordsLinked to original sources
PubMed2025

Identification and Validation of Novel Combinatorial Genetic Risk Factors for Endometriosis across Multiple UK and US Patient Cohorts.

BACKGROUND: Endometriosis affects about 10% of women usually of reproductive age. It often has severe negative impacts on patients' quality of life, but the average time to a definitive diagnosis remains 7-9 years, and there are few effective therapeutic options. Relatively little is known about the genetic drivers of the disease even though its heritability is fairly high. A recent large genome wide association study (GWAS) meta-analysis identified 42 genomic loci associated with risk of endometriosis, but together these explain only 5% of disease variance. METHODS: We used the PrecisionLife&#xae; combinatorial analytics platform to identify multi-SNP disease signatures significantly associated with endometriosis in a white European UK Biobank (UKB) cohort. We assessed the reproducibility of these multi-SNP disease signatures as well as 35 of the 42 meta-GWAS SNPs in a multi-ancestry American endometriosis cohort from All of Us (AoU) after controlling for population structure. RESULTS: We identified 1,709 disease signatures, comprising 2,957 unique SNPs in combinations of 2-5 SNPs, that were associated with increased prevalence of endometriosis in UKB. Pathways enriched in the disease signatures included cell adhesion, proliferation and migration, cytoskeleton remodeling, angiogenesis as well as biological processes involved in fibrosis and neuropathic pain.We observed a significant enrichment of these signatures (58-88%, p<0.04) that are also positively associated with endometriosis in the AoU cohort, including one 2-SNP signature that is individually significant. Reproducibility rates were greatest for higher frequency signatures, ranging from 80-88% for signatures with greater than 9% frequency (p<0.01) in AoU. Encouragingly, the disease signatures also show high reproducibility rates in non-white European AoU sub-cohorts (66-76%, p<0.04 for signatures with greater than 4% frequency).A total of 195 unique SNPs mapping to 98 genes were identified in the high frequency reproducing signatures (>9%). Of these, 7 genes were previously identified in the endometriosis meta-GWAS study and 16 genes have a previous association with endometriosis. 75 novel genes were identified in this study.We characterized 9 novel genes that occur at the highest frequency in reproducing signatures and that do not contain any SNPs linked to known GWAS genes, providing new evidence for links between endometriosis and autophagy and macrophage biology. Reproducibility rates, ranging between 73% to 85%. are especially strong for the signatures that contain these 9 genes independently of any SNPs mapping to the meta-GWAS genes. CONCLUSION: Although using much smaller, less well-characterized datasets than the previous whole genome meta-GWAS study, combinatorial analysis has provided important new insights into the genetics and biology of endometriosis including reproducible biologically relevant genes that are overlooked by GWAS approaches.The 75 novel gene associations provide new insights and routes for study of the disease and potential new therapies. Several of the novel genes identified are credible targets for drug discovery, repurposing and/or repositioning. Using the disease signatures identified as genetic biomarkers in trials of candidates drugs targeting specific mechanisms will enable precision medicine-based approaches. We hope this will encourage new targeted therapy discovery efforts.

Endometriosis↗
PubMed2025

Reproducibility of genetic risk factors identified for long COVID using combinatorial analysis across US and UK patient cohorts with diverse ancestries.

BACKGROUND: Long COVID is a major public health burden causing a diverse array of debilitating symptoms in tens of millions of patients globally. In spite of this overwhelming disease prevalence, staggering cost, severe impact on patients' lives and intense global research efforts, study of the disease has proved challenging due to its complexity. Genome-wide association studies (GWAS) have identified only four loci potentially associated with the disease, although these results did not statistically replicate between studies. A previous combinatorial analysis study identified a total of 73 genes that were highly associated with two long COVID cohorts in the predominantly (>&#x2009;91%) white European ancestry Sano GOLD population, and we sought to reproduce these findings in the independent and ancestrally more diverse All of Us (AoU) population. METHODS: We assessed the reproducibility of the 5343 long COVID disease signatures from the original study in the AoU population. Because the very small population sizes provide very limited power to replicate findings, we initially tested whether we observed a statistically significant enrichment of the Sano GOLD disease signatures that are also positively correlated with long COVID in the AoU cohort after controlling for population substructure. RESULTS: For the Sano GOLD disease signatures that have a case frequency greater than 5% in AoU, we consistently observed a significant enrichment (77-83%, p&#x2009;<&#x2009;0.01) of signatures that are also positively associated with long COVID in the AoU cohort. These encompassed 92% of the genes identified in the original study. At least five of the disease signatures found in Sano GOLD were also shown to be individually significantly associated with increased long COVID prevalence in the AoU population. Rates of signature reproducibility are strongest among self-identified white patients, but we also observe significant enrichment of reproducing disease associations in self-identified black/African-American and Hispanic/Latino cohorts. Signatures associated with 11 out of the 13 drug repurposing candidates identified in the original Sano GOLD study were reproduced in this study. CONCLUSION: These results demonstrate the reproducibility of long COVID disease signal found by combinatorial analysis, broadly validating the results of the original analysis. They provide compelling evidence for a much broader array of genetic associations with long COVID than previously identified through traditional GWAS studies. This strongly supports the hypothesis that genetic factors play a critical role in determining an individual's susceptibility to long COVID following recovery from acute SARS-CoV-2 infection. It also lends weight to the drug repurposing candidates identified in the original analysis. Together these results may help to stimulate much needed new precision medicine approaches to more effectively diagnose and treat the disease. This is also the first reproduction of long COVID genetic associations across multiple populations with substantially different ancestry distributions. Given the high reproducibility rate across diverse populations, these findings may have broader clinical application and promote better health equity. We hope that this will provide confidence to explore some of these mechanisms and drug targets and help advance research into novel ways to diagnose the disease and accelerate the discovery and selection of better therapeutic options, both in the form of newly discovered drugs and/or the immediate prioritization of coordinated investigations into the efficacy of repurposed drug candidates.

Humans↗
PubMed1992

Malarial toxic antigens synergistically enhance insulin signalling.

Hypoglycaemia is a major complication of severe malaria [(1990) Trans. Roy. Soc. Trop. Med. 84 (suppl. 2) 1-65], especially cerebral malaria, in which it is associated with increased mortality [(1990) Lancet 336, 1039-1043; (1989) Quart. J. Med. (New series) 71, 441-459]; however, the mechanisms responsible have not been fully explained. Preparations containing toxic malaria antigens (TMA) released by blood stage Plasmodium yoelii malaria parasites have been shown to induce hypoglycaemia in mice lasting at least 8 h [(1992) Clin. Exp. Immunol. (in press)]. Here we report that TMAs can act synergistically with insulin in both stimulating lipogenesis and inhibiting lipolysis in rat adipocytes in vitro, and, furthermore, that they act synergistically with insulin in the induction of hypoglycaemia in vivo.

Adipose Tissue↗
PubMed1992

Stability of coliphage lambda DNA replication initiator, the lambda O protein.

The initiator of coliphage lambda DNA replication, lambda O protein, may be detected among other 35S-labeled phage and bacterial proteins by a method based on immunoprecipitation. This method makes it possible to study lambda O proteolytic degradation in lambda plasmid-harboring or lambda phage-infected cells; it avoids ultraviolet (u.v.)-irradiation of bacteria, used for depression of host protein synthesis, prior to lambda phage infection. We confirm the rapid decay of lambda O protein (half-time of 80 s), but we demonstrate the existence of a stable lambda O fraction. In the standard five minute pulse-chase experiments, 20% of synthesized lambda O is stable. The extension of the [35S]methionine pulse, possible in lambda plasmid-harboring cells, leads to a linear increase of this fraction, as if a part of the synthesized lambda O was constantly made resistant to proteolysis. Less than 5% of lambda O protein synthesized during one minute is transformed into a stable form. We presume that the stable lambda O is identical with lambda O present in the normal replication complex and thus protected from proteases. We cannot find any stable lambda O in Escherichia coli recA+ cells that were irradiated with u.v. light prior to lambda phage infection, but their recA- counterparts behave normally, suggesting that recA function interferes in the assembly of a normal replication complex in u.v.-irradiated bacteria. The stable lambda O found in lambda plasmid-harboring, amino acid-starved relA cells is responsible for the lambda O-dependent lambda plasmid replication that occurs in this system in the absence of lambda O synthesis. The existence of stable lambda O raises doubt concerning its role as the limiting initiator protein in the control of replication. Another significance of lambda O rapid degradation is proposed.

Bacteriophage lambda↗
PubMed1992

Inheritance of the replication complex by one of two daughter copies during lambda plasmid replication in Escherichia coli.

Direct measurement of DNA synthesis confirmed that lambda plasmid replication proceeds for several hours in an amino acid-starved relA mutant of Escherichia coli, leading to plasmid amplification; this replication is lambda cro-independent, but requires the function of lambda O initiator in the absence of its synthesis. This suggests that after the assembly of the replication complex (RC) at ori lambda the lambda O protein remains in this structure and the affinity of lambda O to ori lambda is alleviated in the assembled RC allowing its movement along the DNA. During amino acid starvation the lambda plasmid DNA synthesis per bacterial mass occurs at a constant level, as would be expected if the number of functioning RCs remained constant. This favors the idea that under these conditions the next replication round operates due to the activity of the RC inherited from the preceding round. Density shift experiments reveal indeed that, from two daughter plasmid copies synthesized after the onset of amino acid starvation only one is able to enter into the next round of replication. We infer that this is the plasmid copy that inherits the lambda O-enclosing RC from the previous replication round. Moreover, the same results of density shift experiments were obtained for plasmids synthesized before the onset of amino acid starvation. Therefore, we presume that in lambda plasmid-harboring bacteria growing in nutrient medium, every second plasmid circle bears an RC that originates from the preceding round of replication. This structure has to be assembled de novo only on the daughter plasmid copy that does not inherit the parental RC. In the absence of lambda O initiator synthesis in amino acid-starved relA cells this process cannot occur, leaving as the only replication pathway that driven by the parental RC. Our results are discussed in relation to the model of regulation of lambda plasmid replication.

Bacteriophage lambda↗
PubMed1992

Proof of differentiative mode of action of all-trans retinoic acid in acute promyelocytic leukemia using X-linked clonal analysis.

Using X-linked clonal analysis, mechanism of action of all-trans retinoic acid (ATRA) was sought in a 16-year-old female with relapsed clonally evolved acute promyelocytic leukemia (APL), who achieved complete remission. On ATRA, metamorphosis of peripheral blood leukemic promyelocytes to mature neutrophils was observed, despite the persistence of t(15;17) in 100% of bone marrow metaphases. DNA was extracted from fractionated serial blood specimens, collected at diagnosis, in first complete remission (CR), relapse, and during ATRA treatment. Using a phosphoglycerokinase (PGK) probe, the patient was heterozygous for both Bgl I and Bst XI PGK polymorphisms. Methylation analysis showed monoclonal leukemic promyelocytes with a polyclonal first CR achieved by standard chemotherapy. Subsequent examination, in relapse, of granulocytes appearing during ATRA treatment showed these to be monoclonal, proving these were derived from the neoplastic clone. The X-linked clonal analysis methodology has provided in vivo evidence of cellular differentiation as the mechanism of action of ATRA. Parallel studies of cytogenetic and clonal analysis showed a regression of the t(15;17) cytogenetic abnormality and return of a polyclonal PGK methylation pattern in 5 weeks, indicating a repopulation of marrow by normal stem cells. As standard cytogenetic techniques are inappropriate for nondividing cells, X-linked clonal analysis provides a marker system to allow insight into mechanism of drug action in malignant hematologic disease.

Adolescent↗
PubMed1992

Surface-exposed proteins of 3T3-L1 adipocytes: identification of phosphorylated, insulin-translocated, and recycling proteins.

Twenty-seven adipocyte-specific, cell surface-exposed proteins were detected by derivatizing undifferentiated and differentiated 3T3-L1 cells with membrane impermeant sulfosuccinimidyl 2-(biotinamido)ethyl-1,3-dithiopropionate at 0 degrees C. Biotinylated proteins were adsorbed onto streptavidin-agarose, resolved on two-dimensional polyacrylamide gels, and detected by autoradiography or silver staining. Of the surface-exposed proteins specific to adipocytes, three were phosphorylated and seven were glycoproteins that bound to wheat germ agglutinin and eluted with N-acetylglucosamine. Eleven of the adipocyte-specific proteins were bound to streptavidin-agarose after the cells were biotinylated at 20 degrees C and then stripped with glutathione at 0 degrees C to isolate plasma membrane proteins that localize to recycling endosomes as well as the cell surface. When insulin-deprived cells were acutely treated with insulin, only a few proteins, including one protein tentatively identified as the GLUT4 glucose transporter, were found to increase in concentration at the cell surface. These latter results imply that up-regulation of glucose transport by the translocation of GLUT4 to the cell surface in response to insulin occurs by exocytic fusion of an intracellular compartment having a limited number of proteins.

Adipose Tissue↗
PubMed1992

Segregation of the growth slowing effects of valproic acid from phenytoin and carbamazepine on lymphoid tumor cells.

One human and six murine tumor cell lines of lymphoid origin were assessed for growth in the presence of three commonly used antiepileptic drugs (AEDs). All seven lines were sensitive to the growth slowing effects of phenytoin (PHT) and carbamazepine (CBZ). Six lines showed a similar effect when exposed to valproic acid (VPA), while one murine B cell line was resistant to inhibition of growth by VPA.

Carbamazepine↗
PubMed1992

Cytogenetic effects of singlet oxygen.

Singlet oxygen was generated in the gas phase at atmospheric pressure by the method of heterogeneous photosensitization. In vitro exposure of human lung WI-38 fibroblasts to gas-phase singlet oxygen resulted in sister chromatid exchange.

Cell Line↗
PubMed1992

Kallmann syndrome due to a translocation resulting in an X/Y fusion gene.

The X-linked Kallmann syndrome gene was recently cloned and homologous sequences of unknown functional significance identified on the Y chromosome. We now describe a patient with Kallmann syndrome carrying an X;Y translocation resulting from abnormal pairing and precise recombination between the X-linked Kallmann syndrome gene and its homologue on the Y. The translocation created a recombinant, non-functional Kallmann syndrome gene identical to the normal X-linked gene with the exception of the 3' end which is derived from the Y. Our findings indicate that the 3' portion of the Kallmann syndrome gene is essential for its function and cannot be substituted by the Y-derived homologous region, although a 'position' effect remains a formal possibility.

Amino Acid Sequence↗
PubMed1992

Effect of electrically induced muscle contractions on posttraumatic edema formation in frog hind limbs.

We tested the hypothesis that repeated muscle contractions induced by high voltage pulsed current (HVPC) would limit volume increases in traumatized frog hind limbs. Twelve frogs were anesthetized, and both hind limbs of each frog were traumatized by impact. Limb volumes were measured via water displacement over a 24-hour period. Four 30-minute treatments of continuous 1-pulse per second HVPC were applied to one limb selected randomly. Stimulation produced muscle contractions that resulted in minimal joint movements. Volume changes from pretrauma limb volumes (in milliliters per kilogram) were analyzed by an analysis of variance for repeated measures. Our hypothesis was rejected (ie, repeated muscle contractions, as induced in this study, did not limit posttraumatic edema formation in frogs). Further investigation of the relative influences of limb position and varying pulse rates, pulse durations, and intensities of HVPC on edema formation may provide valuable insights on effective treatment of edema in humans.

Animals↗
PubMed1992

Phospholipid-containing toxic malaria antigens induce hypoglycaemia.

Hypoglycaemia is associated with severe malaria and is an important prognostic indicator. Molecules liberated during overnight incubation of erythrocytes infected with Plasmodium yoelii induce marked hypoglycaemia in normal mice, with a delayed time course compared with insulin; some, though weaker, activity could also be obtained by overnight incubation of uninfected erythrocytes. The active component shares many properties with the phospholipid-containing molecules which we have previously shown to be toxic and to induce the release of tumour necrosis factor (TNF) from macrophages. However a MoAb which neutralizes the cytotoxicity of tumour necrosis factor in vitro did not prevent this induction of hypoglycaemia, whereas antiserum against the toxic antigens did, as did immunization of normal (but not the immunoglobulin-deficient SCID) mice with the same material. Furthermore, normal mice injected with the antigens after immunization with phosphatidyl inositol or inositol monophosphate did not develop hypoglycaemia; the latter compound was also inhibitory when mixed with the antigens before injection. These compounds were previously shown to block the induction of TNF by the antigens and to induce the production of inhibitory antibodies. The role of these molecules in the etiology of the hypoglycaemia of malaria is discussed.

Animals↗
PubMed1992

Monoclonal large granular lymphocyte proliferation in SLE with HTLV-I seroreactivity.

A 60-year-old part Aboriginal woman was observed to develop severe neutropenia and a large granular lymphocyte (LGL) proliferation five years after the diagnosis of systemic lupus erythematosus (SLE). Monoclonality of the CD3+, CD4-, CD8+ LGL population was confirmed using the novel approach of X-linked restriction fragment length polymorphism (RFLP) analysis. Indeterminate HTLV-I serology was present. The patient responded to steroid therapy. LGL proliferation in the setting of SLE and the use of X-linked RFLP analysis to define LGL clonality have not previously been reported.

Antibodies, Monoclonal↗
PubMed1992

Ferrocenopapain, an organometallic protein formed by site-specific inactivation of papain using chloroacetylferrocene.

Papain is rapidly, specifically and irreversibly inactivated by chloroacetylferrocene in a time-dependent, two-stage process which involves initial, physical complexation between the enzyme and the organometallic reagent followed by chemical reaction. The kinetics of the process show saturation kinetics with respect to inactivator concentration. The modification occurs with a 1:1 stoichiometry and the degree of loss of enzymatic activity is directly reflected in the loss of thiol groups in the active-site that are accessible to Ellman's reagent. The modification is faster at higher pH. The ferrocenium ion of the modified papain can be generated at low pH by anaerobic treatment with ferric nitrate and shows a 180 percent increased lifetime at pH 3.3 compared to the acetylferrocenium ion under identical conditions. The spectral properties of the ferrocenopapain indicate that the ferrocene is in an unusual environment at the protein active-site and the implications of this are discussed.

Cysteine↗
PubMed1992

All-trans retinoic acid in the treatment of acute promyelocytic leukaemia.

All-trans-retinoic acid (ATRA) is known to induce differentiation of promyelocytes in vitro and also to induce remission of acute promyelocytic leukaemia in vivo. We treated 11 patients with poor prognosis acute promyelocytic leukaemia (APL) with ATRA and obtained seven complete and one partial remission. Remissions took one to three months to achieve and were associated with adverse effects including dry skin and bone pain. In eight patients the white cell count rose above 20 x 10(9)/L within the first ten days of retinoic acid treatment and this was associated with the development of pulmonary leukostasis in three patients which was fatal in one. Another two patients died of intracranial haemorrhage also within the first ten days. ATRA is a promising new agent in the induction therapy of this particular category of acute leukaemia.

Adult↗
PubMed1979

The fate of phage lambda DNA in lambda-infected minicells.

The fate of phage lambda DNA in lambda-infected Escherichia coli minicells harboring the plasmid ColE1, and in plasmid-free minicells, were studied. Binding of lambda DNA to the minicell membrane, and formation of the supercoiled covalently-closed circular structure has been demonstrated. Phage infection abolishes plasmid DNA synthesis. Only a very slight, non-replicative lambda DNA synthesis occurs, soon after infection. This synthesis is associated with fragments of lambda DNA arising during, or soon after its penetration.

Bacteriophage lambda↗