PubMed Health⌕ Search

Biomedical subjects

William R Taylor

Publications and source records attributed to William R Taylor.

At least 19 recordsLinked to original sources
PubMed2004

Toward the detection and validation of repeats in protein structure.

We present a method called DAVROS to detect, localize, and validate repeating motifs in protein structure allowing for insertions and deletions. DAVROS uses the score matrix from a structural alignment program (SAP) to search for repeating motifs using an algorithm based on concepts from signal processing and the statistical properties of the alignments. The method was tested against a nonredundant Protein Data Bank, and each chain was assigned a score. For the top 50 chains ranked by score, 70% contain repeating motifs detected without error. These represent 14 types of fold covering alpha, beta, and alphabeta protein classes. A second data set comprising protein chains in different sequence families for triosephosphate isomerase (TIM) barrel, leucine-rich repeat (LRR), trefoil, and alpha-alpha barrel folds was used to assess the ability of DAVROS to detect all motifs within a specific fold. For the second test set, the percentage of motifs detected was highest for the LRR chains (88.7%) and least for the TIM barrels (60%). This variability results from the regularity of the LRR motif compared to the alphabeta units of the TIM barrel, which generally have many more indels. These reduce the strength of the repeat signal in the SAP matrix, making repeat detection more difficult.

Amino Acid Motifs↗
PubMed2004

A structural pattern-based method for protein fold recognition.

A method (SPREK) was developed to evaluate the register of a sequence on a structure based on the matching of structural patterns against a library derived from the protein structure databank. The scores obtained were normalized against random background distributions derived from sequence shuffling and permutation methods. 'Random' structures were also used to evaluate the effectiveness of the method. These were generated by a simple random-walk and a more sophisticated structure prediction method that produced protein-like folds. For comparison with other methods, the performance of the method was assessed using collections of models including decoys and models from the CASP-5 exercise. The performance of SPREK on the decoy models was equivalent to (and sometimes better than) those obtained with more complex approaches. An exception was the two smallest proteins, for which SPREK did not perform well due to a lack of patterns. Using the best parameter combination from trials on decoy models, the CASP models of intermediate difficulty were evaluated by SPREK and the quality of the top scoring model was evaluated by its CASP ranking. Of the 14 targets in this class, half lie in the top 10% (out of around 140 models for each target). The two worst rankings resulted from the selection by our method of a well-packed model that was based on the wrong fold. Of the other poor rankings, one was the smallest protein and the others were the four largest (all over 250 residues).

Algorithms↗
PubMed2004

Consensus structural models for the amino terminal domain of the retrovirus restriction gene Fv1 and the murine leukaemia virus capsid proteins.

BACKGROUND: The mouse Fv1 (friend virus) susceptibility gene inhibits the development of the murine leukaemia virus (MLV) by interacting with its capsid (CA) protein. As no structures are available for these proteins we have constructed molecular models based on distant sequence similarity to other retroviral capsid proteins. RESULTS: Molecular models were constructed for the amino terminal domains of the probable capsid-like structure for the mouse Fv1 gene product and the capsid protein of the MLV. The models were based on sequence alignments with a variety of other retrovirus capsid proteins. As the sequence similarity of these proteins with MLV and especially Fv1 is very distant, a threading method was employed that incorporates predicted secondary structure and multiple sequence information. The resulting models were compared with equivalent models constructed using the sequences of the capsid proteins of known structure. CONCLUSIONS: These comparisons suggested that the MLV model should be accurate in the core but with significant uncertainty in the loop regions. The Fv1 model may have some additional errors in the core packing of its helices but the resulting model gave some support to the hypothesis that it adopts a capsid-like structure.

Amino Acid Sequence↗
PubMed2004

Distribution of bone mineral density with age and gender in the proximal tibia.

OBJECTIVE: To investigate both the age and gender related distributions of bone mineral density in the proximal tibia, specifically in aged patients. BACKGROUND: For surgeons to achieve stable long-term fixation of implants in the proximal tibia, the distribution of bone mineral density must first be known. The changes that occur due to age or gender can alter these distributions. METHODS: Quantitative computed tomography and indentation testing were used to investigate 40 human tibiae (27 female, 13 male, average age 63.3 years). RESULTS: A significant reduction in bone mineral density was found in female tibiae between the age groups of < 60 and > or =60. This difference was not found in the male groups and no other significant difference was found between consecutive age groups. A three-dimensional map of the bone mineral density of the proximal tibia is therefore presented for the groups female < 60, female > or =60 and male. Reduced bone mineral density was consistently found in the central regions, whilst the regions of highest bone quality varied from postero-lateral to postero-medial. CONCLUSIONS: Implant fixation for fracture treatment as well as joint replacement of the proximal tibia are now able to take the regions of both high and low bone mineral density into consideration in older patients and those suffering from osteoporosis. RELEVANCE: Knowledge regarding the regional distribution of bone mineral density in the proximal tibia is necessary in order to achieve stable primary and long-term fixation of implants. This manuscript documents the bone mineral density changes that occur with age and gender.

Absorptiometry, Photon↗
PubMed2004

Tibio-femoral loading during human gait and stair climbing.

Surgical intervention of the knee joint routinely endeavors to recreate a physiologically normal joint loading environment. The loading conditions resulting from osteotomies, fracture treatment, ligament replacements, and arthroplasties of the knee are considered to have an impact on the long term clinical outcome; however, knowledge regarding in vivo loading conditions is limited. Using a previously validated musculoskeletal lower limb model, we predicted the tibio-femoral joint contact forces that occur in the human knee during the common daily activities of walking and stair climbing. The average resultant peak force during walking was 3.1 times body weight (BW) across four total hip arthroplasty patients. Inter-individual variations proved larger than the variation of forces for each patient repeating the same task. Forces through the knee were considerably larger during stair climbing than during walking: the average resultant peak force during stair climbing was 5.4 BW although peaks of up to 6.2 BW were calculated for one particular patient. Average anteroposterior peak shear components of 0.6 BW were determined during walking and 1.3 BW during stair climbing. These results confirm both the joint contact forces reported in the literature and the importance of muscular activity in creating high forces across the joint. The magnitudes of these forces, specifically in shear, have implications for all forms of surgical intervention in the knee. The data demonstrate that high contact and shear forces are generated during weight bearing combined with knee flexion angles greater than approximately 15 degrees. Clinically, the conditions that produce these larger contact forces should be avoided during post-operative rehabilitation.

Biomechanical Phenomena↗
PubMed2004

Syringocephaly.

Syringomyelia is associated with Arnold-Chiari Type I malformations. Syringobulbia describes the phenomenon of syrinx extension into the brain stem. Syringocephaly is the further dissection of the fluid-filled cavity into the cerebral peduncles and cerebrum. In this case report, we describe a patient who presented with bulbar, sensory, motor, and coordination deficits both ipsilateral and contralateral to the lesion. This is most likely attributable to the wandering course the syrinx takes as it dissects through the spinal cord and into the internal capsule. This ill-defined syrinx disrupts various nuclei and fasciculi, both pre- and post-decussation, thus explaining the multiple deficits on each side. We initially treated this patient with a suboccipital craniectomy, C1 laminectomy, and duraplasty, which mildly improved his deficits. During follow-up, the patient was then found to have an exacerbation of his symptoms, at which time we performed a VP shunt revision (the patient had a history of hydrocephalus treated by a functioning VP shunt). Approximately 2 weeks after revision of the VP shunt, the patient had worsening of his symptoms, which we treated with a syringopleural shunt. This proved to be the most effective treatment with the greatest clinical improvement. Several months later, however, the patient died secondary to pulmonary disease exacerbated by VP shunt infection. In this paper, we also review the literature regarding the formation and treatment of syringocephaly, a rare and poorly understood entity.

Cerebellum↗
PubMed2004

Loss of CBP causes T cell lymphomagenesis in synergy with p27Kip1 insufficiency.

CBP can function as a tumor suppressor, but the mechanisms that govern oncogenesis in its absence are unknown. Here we show that CBP inactivation in mouse thymocytes leads to lymphoma. Although CBP has been implicated in the transactivation functions of p53, development of these tumors does not seem to involve loss of p53 activity. CBP-null tumors show reduced levels of p27Kip1 and increased levels of cyclin E and Skp2, two oncoproteins that can promote p27Kip1 proteolysis. Reduction of p27Kip1 by introduction of a p27Kip1-null allele into CBP knockout mice accelerates lymphomagenesis and seems to obviate the requirement for Skp2 and cyclin E upregulation. These data suggest that CBP loss mediates lymphomagenesis in cooperation with a mechanism that reduces p27Kip1 abundance.

Animals↗
PubMed2004

Stabilization of anterior cervical spine with bioabsorbable polymer in one- and two-level fusions.

OBJECTIVE: We present our experience using a bioabsorbable polymer in the surgical management of one- and two-level degenerative disc disease of the cervical spine with anterior cervical discectomy and fusion. Twenty-six patients were treated at the University of California, San Diego Medical Center or the Veterans Affairs Medical Center in San Diego, CA. All cases were performed under the direction of a single neurosurgeon (WRT). METHODS: A retrospective review of patients' charts and imaging was performed to determine outcomes after anterior cervical spine operations. Specifically, we looked at the need for additional surgery, local reaction to the bioabsorbable polymer, fusion rate, and complications. Procedures involved the C3-C4, C4-C5, C5-C6, and/or C6-C7 levels, and fibular allograft was used in all but one case. The anterior cervical discectomy and fusion procedures with internal fixation were performed in 26 patients between March 2000 and November 2001. The patients were followed for up to 2 years after surgery (average, 14 mo). RESULTS: Radiographic fusion was achieved in 25 (96.2%) of 26 patients. Only one instance of treatment failure was encountered that required additional surgery and the placement of a titanium plate. There were no clinical signs or symptoms of reaction to the bioabsorbable material. CONCLUSION: The rates of fusion after single-level anterior cervical discectomy and fusion with internal fixation using bioabsorbable polymer and screws in this study match those using metallic implants, as previously reported in the literature, and are superior to those achieved with noninstrumented fusions. Preliminary results suggest that this newly available technology for anterior fusion is as effective in single-level disease as traditional titanium plating systems. The bioabsorbable material seems to be tolerated well by patients. A larger, randomized, controlled study is necessary to bring the results to statistical significance.

Absorbable Implants↗
PubMed2004

Analyzing the G2/M checkpoint.

The G2 checkpoint prevents cells from entering mitosis when DNA is damaged, providing an opportunity for repair and stopping the proliferation of damaged cells. Because the G2 checkpoint helps to maintain genomic stability, it is an important focus in understanding the molecular causes of cancer. Many different methods have been used to investigate the G2 checkpoint and uncover some of the underlying mechanisms. Because cell-cycle controls are highly conserved, a remarkable synergy between the genetic power of model organisms and biochemical analyses is possible and has uncovered control mechanisms that operate in many diverse species, including humans. Cdc2, the cyclin-dependent kinase that normally drives cells into mitosis, is an important target of pathways that mediate rapid arrest in G2 in response to DNA damage. Additional pathways ensure that the arrest is stably maintained. When mammalian cells contain damaged DNA, the p53 tumor suppressor and the Rb family of transcriptional repressors work together to downregulate a large number of genes that encode proteins required for G2 and M. Elimination of these essential cell cycle proteins helps to keep the cells arrested in G2.

Animals↗
PubMed2004

FACS-based detection of phosphorylated histone H3 for the quantitation of mitotic cells.

The G2 checkpoint blocks cells from entering mitosis when DNA is damaged, and helps to protect the integrity of the genome. Tumor cells contain mutations that can inactivate checkpoints, and the inactivation of the G2 checkpoint can induce genomic instability and alter cellular responses to chemotherapeutic agents that damage DNA. The traditional method to assess whether the G2 checkpoint is normal is to microscopically count mitotic cells. A method using the fluorescence-activated cell scanner (FACS) is described, based on the presence of an intra-nuclear antigen present only in mitotic cells, detected using a specific, commercially available antibody. Cell staining and FACS analysis can be done in a single day, making this a rapid and reliable method to quantitate mitotic cells for various applications.

Fibrosarcoma↗
PubMed2004

Developmental hip dysplasia treated with total hip arthroplasty with a straight stem and a threaded cup.

BACKGROUND: Operative strategies to overcome the anatomical anomalies in patients with osteoarthritis secondary to developmental dysplasia of the hip remain controversial. The objective of this study was to determine the outcomes of total hip replacement with a grit-blasted cementless threaded cup and a cementless straight stem in patients with developmental dysplasia. METHODS: Ninety-three patients with developmental hip dysplasia who had been treated with a total of 121 cementless total hip arthroplasties were clinically assessed at a mean of 9.3 years. The acetabular reconstruction was done with a cementless threaded cup, which was medialized to ensure that at least one thread was anchored in the bone in order to achieve good primary stability. All radiographs were analyzed retrospectively. RESULTS: Kaplan-Meier survivorship analysis, with radiographic evidence of aseptic loosening as the end point, predicted a survival rate of 97.5% for the acetabular component and 100% for the femoral stem at 9.3 years. The average Harris hip score for the unrevised hips improved from 34.0 points preoperatively to 84.1 points at the latest follow-up evaluation. The average total volume of polyethylene wear at the time of final follow-up was 73.6 mm(3). CONCLUSIONS: These wear and loosening rates demonstrate that very good results were achieved in this relatively young patient population when the hip joint center had been properly restored, even when a small cup with a thin polyethylene liner had been used.

Adult↗
PubMed2003

The influence of alignment on the musculo-skeletal loading conditions at the knee.

BACKGROUND AND AIM: High tibial osteotomies attempt to recreate physiologically normal joint loading. Previous studies have discussed the influence of mal-alignment on the distribution of static loads to the medial and lateral compartments of the knee. The aim of this study was to determine the influence of mal-alignment on the tibio-femoral loading conditions during dynamic activities. MATERIAL AND METHODS: Using a musculo-skeletal model of the lower limb, which had been previously validated with in vivo data, in this study we modified the alignment of the knee in four patients, from a normal position to the extremes of 8 degrees valgus and 10 degrees varus mal-alignment. The resulting tibio-femoral joint contact forces were examined while patients were walking and stair climbing. RESULTS: Varying the mal-alignment resulted in a highly individual response in joint loads. Deviations from the normal alignment produced an increase in loading, with valgus generating a more rapid increase in loading than a varus deformity of the same amount. Varus deformities of 10 degrees resulted in increases in peak contact force from an average of 3.3-times bodyweight (BW) up to a peak of 7.4 BW (+45% to +114%) while patients were walking, whilst increases of 15% up to 35% were determined for stair climbing. Increases of up to 140% were calculated at 8 degrees valgus during walking and up to 53% for stair climbing. CONCLUSION: This study demonstrated a clear dependence of the individual joint loads on axial knee alignment. Based on the sensitivity of joint loading to valgus mal-alignment, more than 3 degrees of over-correction of a varus deformity to valgus should be carefully reconsidered.

Biomechanical Phenomena↗
PubMed2003

G2 arrest in response to topoisomerase II inhibitors: the role of p53.

We have previously found that the overexpression of p53 causes G(2) arrest and represses the synthesis of cyclin-dependent kinase 1 and cyclin B1, two proteins required for cells to traverse from G(2) into M. G(2) arrest occurs in response to DNA damage caused by a variety of agents and treatments. Here, we investigate the role of p53 in the G(2) arrest that occurs in response to the topoisomerase inhibitors etoposide and merbarone. In HT1080 cells expressing a dominant-negative form of p53, treatment with etoposide still caused G(2) arrest, but the arrest could be overcome by additional treatment with caffeine, which inhibits the damage-responsive kinases ataxia telangiectasia mutated (ATM) and atm and rad3-related (ATR). However, caffeine could not overcome etoposide-induced G(2) arrest in HT1080 cells with functional p53. We conclude that etoposide activates two pathways, one of which depends on p53 and the other of which is sensitive to caffeine, and that either pathway is sufficient to activate G(2) arrest. Etoposide inhibits topoisomerase II by trapping the enzyme in a complex with cleaved DNA. Inhibition of topoisomerase II with merbarone, which does not stabilize a cleavage complex, causes G(2) arrest by a checkpoint that monitors the decatenation of chromatin. We find that caffeine can abrogate merbarone-induced G(2) arrest even in cells with functional p53, indicating that p53 does not contribute to the decatenation-sensitive response. Thus, p53 has a differential role in effecting G(2) arrest in response to topoisomerase II inhibitors, depending upon the mechanisms of action of the inhibitors tested.

CDC2 Protein Kinase↗
PubMed2003

Modelling zinc-binding proteins with GADGET: genetic algorithm and distance geometry for exploring topology.

A novel combination of optimization methods (Genetic Algorithm with Distance Geometry) has been developed and shown to find near-optimal solutions to a set of imposed structural constraints. With this modelling tool (GADGET), the fold-space of a variety of small zinc-binding proteins was investigated under the constraints required to form a zinc-binding site (or pair of sites). Analysis of the results concentrated on the ring-finger domain as the "classic" zinc-finger domains were too constrained to provide much topological variety, whilst the TFIIH domain (which has large unstructured loops) did not behave well. The intermediate ring-finger domain, however, was found to adopt a variety of different folds, many of which had near-optimal scores under the fitness function employed in GADGET (forming good secondary structures and zinc-coordination). Although the native fold was dominant amongst the solutions, the discovery of good alternate folds shows that even the eight residues constrained to form two zinc-binding sites was not sufficient to uniquely determine the native fold. Despite this, the fold-space of 48 theoretically possible folds was greatly reduced with just six topologies found in significant numbers.

Algorithms↗
PubMed2003

Murine gammaherpesvirus-68 infects microglia and induces high levels of pro-inflammatory cytokine production.

Murine gammaherpesvirus-68 (MHV-68) has been established as a tractable model for the study of human herpesvirus infections. Recent associations between herpesvirus infections and inflammatory central nervous system (CNS) disorders, including multiple sclerosis (MS), have prompted us to investigate the susceptibility of cultured microglia and astrocytes to MHV-68 infection. In the present study, we demonstrate that MHV-68 can infect both cell types. Importantly, we show that MHV-68-infected microglia and astrocytes can produce pro-inflammatory cytokines. Such cytokine production may either contribute to protective host responses to viral challenges or could exacerbate damaging CNS inflammation.

Animals↗
PubMed2003

THA loading arising from increased femoral anteversion and offset may lead to critical cement stresses.

Aseptic loosening of artificial hip joints is believed to be influenced by the design and orientation of the implant. It is hypothesised that variations in implant anteversion and offset lead to changes in the loading of the proximal femur, causing critical conditions to both the bone and cement. The goal of this study was therefore to analyse the role of these parameters on loading, bone strains and cement stresses in total hip arthroplasty (THA). A validated musculo-skeletal model was used for the analysis of muscle and joint contact forces during walking and stair climbing. Two different anteversion angles (4 degrees vs. 24 degrees ) and prostheses offsets (standard vs. long) were analysed. The loads for each case were applied to a cemented THA finite element model. Generally, stair climbing caused higher bone strains and cement stresses (max. +25%) than walking. Variations in anteversion and offset caused changes in the loading environment, bone strain distribution and cement stresses. Compared to the standard THA configuration, cement stresses were raised by increasing anteversion (max. +52%), offset (max. +5%) and their combination (max. +67%). Femoral anteversion, offset and their combination may therefore lead to an increased risk of implant loosening. Analyses of implant survival should consider this as a limiting factor in THA longevity. In clinical practice, implant orientation, especially in regard to pre- and post-operative anteversion, should be considered to be more critical.

Arthroplasty, Replacement, Hip↗
PubMed2003

A knot or not a knot? SETting the record 'straight' on proteins.

A novel knot found in the SET domain is examined in the light of five recent crystal structures and their descriptions in the literature. Using the algorithm of Taylor it was established that the backbone chain does not form a true knot. However, only two crosslinks corresponding to hydrogen-bonds were needed to form a knotted structure. Such loosely knotted structures formed by hydrogen-bonded crosslinks were assessed as lying between covalent crosslinks (such as disulphide bonds) and threaded-loops which are formed by close (unbonded) contacts between different parts of the chain. The term pseudo-knot was introduced (from the RNA field) to distinguish hydrogen-bonded 'knots'.

Algorithms↗