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At least 1,135 records · Page 63Linked to original sources
PubMed2003

Design of artificial nucleobases for the recognition of the AT inversion by triple-helix forming oligonucleotides: a structure-stability relationship study and neighbour bases effect.

We report herein on the synthesis, the incorporation into triplex forming oligonucleotides (TFO) and the recognition properties of a series of synthetic nucleosides designed for the specific recognition of an inverted A x T base pair in a pyrimidine triple helix motif. These analogues were designed on the basis of the results obtained with our previously reported compounds S and B(t), in order to define a structure-stability relationship. We report also on the chemical nature effect of the bases flanking S in the case of S-containing TFOs, in order to get further informations about the recognition process within the A x TxS triplet. This study establishes guidelines for the conception of more potent analogues for the recognition of both A x T and G x C inverted base pairs.

Adenine↗
PubMed2001

Crystal structure of Streptococcus mutans pyrophosphatase: a new fold for an old mechanism.

BACKGROUND: Streptococcus mutans pyrophosphatase (Sm-PPase) is a member of a relatively uncommon but widely dispersed sequence family (family II) of inorganic pyrophosphatases. A structure will answer two main questions: is it structurally similar to the family I PPases, and is the mechanism similar? RESULTS: The first family II PPase structure, that of homodimeric Sm-PPase complexed with metal and sulfate ions, has been solved by X-ray crystallography at 2.2 A resolution. The tertiary fold of Sm-PPase consists of a 189 residue alpha/beta N-terminal domain and a 114 residue mixed beta sheet C-terminal domain and bears no resemblance to family I PPase, even though the arrangement of active site ligands and the residues that bind them shows significant similarity. The preference for Mn2+ over Mg2+ in family II PPases is explained by the histidine ligands and bidentate carboxylate coordination. The active site is located at the domain interface. The C-terminal domain is hinged to the N-terminal domain and exists in both closed and open conformations. CONCLUSIONS: The active site similiarities, including a water coordinated to two metal ions, suggest that the family II PPase mechanism is "analogous" (not "homologous") to that of family I PPases. This is a remarkable example of convergent evolution. The large change in C-terminal conformation suggests that domain closure might be the mechanism by which Sm-PPase achieves specificity for pyrophosphate over other polyphosphates.

Binding Sites↗
PubMed2002

Evidence of intradomain and interdomain flexibility in an OmpR/PhoB homolog from Thermotoga maritima.

Two-component systems, the predominant signal transduction strategy used by prokaryotes, involve phosphorelay from a sensor histidine kinase (HK) to an intracellular response regulator protein (RR) that typically acts as a transcription regulator. RRs are modular proteins, usually composed of a conserved regulatory domain, which functions as a phosphorylation-activated switch, and an attached DNA binding effector domain. The crystal structure of a Thermotoga maritima transcription factor, DrrD, has been determined at 1.5 A resolution, providing the first structural information for a full-length member of the OmpR/PhoB subfamily of RRs. A small interdomain interface occurs between alpha 5 of the regulatory domain and an antiparallel sheet of the effector domain. The lack of an extensive interface in the unphosphorylated protein distinguishes DrrD from other structurally characterized multidomain RRs and suggests a different mode of interdomain regulation.

Amino Acid Sequence↗
PubMed2002

Continuum secondary structure captures protein flexibility.

The DSSP program assigns protein secondary structure to one of eight states. This discrete assignment cannot describe the continuum of thermal fluctuations. Hence, a continuous assignment is proposed. Technically, the continuum results from averaging over ten discrete DSSP assignments with different hydrogen bond thresholds. The final continuous assignment for a single NMR model successfully reflected the structural variations observed between all NMR models in the ensemble. The structural variations between NMR models were verified to correlate with thermal motion; these variations were captured by the continuous assignments. Because the continuous assignment reproduces the structural variation between many NMR models from one single model, functionally important variation can be extracted from a single X-ray structure. Thus, continuous assignments of secondary structure may affect future protein structure analysis, comparison, and prediction.

Computer Systems↗
PubMed2003

Young's modulus varies with differential orientation of keratin in feathers.

Feathers are composed of a structure that, whilst being very light, is able to withstand the large aerodynamic forces exerted upon them during flight. To explore the contribution of molecular orientation to feather keratin mechanical properties, we have examined the nanoscopic organisation of the keratin molecules by X-ray diffraction techniques and have confirmed a link between this and the Young's modulus of the feather rachis. Our results indicate that along the rachis length, from calamus to tip, the keratin molecules become more aligned than at the calamus before returning to a state of higher mis-orientation towards the tip of the rachis. We have also confirmed the general trend of increasing Young's modulus with distance along the rachis. Furthermore, we report a distinct difference in the patterns of orientation of beta-keratin in the feathers of flying and flightless birds. The trend for increased modulus along the feathers of volant birds is absent in the flightless ostrich.

Animals↗
PubMedDate not supplied

Comparative effectiveness of intravascular stents in resisting arterial vasoconstriction: evaluation with use of intact elastic (rabbit aorta) and muscular (dog carotid) arteries in an ex vivo model.

PURPOSE: The ability of three different intravascular stents (Gianturco-Roubin, Palmaz-Schatz, and CV Rad), and two different metals (stainless steel and tantalum) to resist vasoconstriction was evaluated in an intact artery ex vivo model. MATERIALS AND METHODS: Stents were deployed in 21 rabbit thoracic aortae and five dog carotid arteries, which were constricted with phenylephrine and serotonin, respectively. Vasoconstriction was measured with the use of high-frequency ultrasonic imaging. RESULTS: The maximal vasoconstriction of the control segment was 37.7% +/- 2.6 with rabbit aortae and 36.3% +/- 4.1 with dog carotid arteries, while the average maximal constriction for all segments in which stents were placed was 5.7% +/- 1.1 (P < .01). The maximal constriction of the Gianturco-Roubin stainless steel stent was 9.4% +/- 2.7 versus 7.9% +/- 1.6 with the tantalum version (P = .65). Both designs showed somewhat greater constriction compared with either the Palmaz-Schatz (3.3% +/- 0.9) or the CV Rad (1.4% +/- 1.1) stents. CONCLUSIONS: Although all of the stents tested substantially resist arterial vasoconstrictive forces, the Palmaz-Schatz and CV Rad stents resist vasoconstriction to a greater degree than the Gianturco-Roubin stents. Tantalum and stainless steel stents of the same design (Gianturco-Roubin) appear similar in their ability to resist vasoconstrictive forces.

Animals↗
PubMedDate not supplied

Esophageal stent with antireflux valve for tumors involving the cardia: work in progress.

PURPOSE: To describe an esophageal stent with a polyester mesh cover and an antireflux valve, and to assess its efficacy in the treatment of patients with inoperable tumors of the gastric cardia. MATERIALS AND METHODS: Thirteen patients with adenocarcinoma of the cardia, two patients with squamous cell carcinoma, and three patients with recurrent carcinoma of the gastric fundus after surgery were treated by placement of an esophageal stent with an antireflux valve. The spiral Z stent has a porous, polyester mesh cover and an antireflux sleeve made of pliable polyurethane at its lower end. RESULTS: Placement of the stent was successful in all patients, and their dysphagia disappeared or significantly improved. All were able to swallow solid food, and no patient reported significant reflux or "gas bloat" syndrome prior to death or the end of follow-up. Two patients only complained of minor heartburn. Follow-up barium swallow studies showed the absence of significant gastroesophageal reflux in all patients. No stent migration occurred. CONCLUSION: The esophageal stent with antireflux valve has been effective in the treatment of malignant obstruction of the cardia and allowed good esophageal passage without migration and major gastroesophageal reflux.

Adenocarcinoma↗
PubMedDate not supplied

Early subclinical limited axial and large joint flexibility in type 1 diabetes mellitus adolescents.

OBJECTIVE: The objective of this study was to compare the axial and large joint mobility in adolescents with and without type 1 diabetes mellitus (DM1). PATIENT AND METHODS: To check this relationship, 72 DM1 adolescents aged 9-20 years were admitted into the trial and compared with 46 healthy control subjects aged 10-18 years. The youths were compared with regard to anthropometrics (age, proportion female/male, weight, height, and BMI) data. The years from DM1 diagnosis and HbA(1c) (index) were 4.9 +/- 3.6 years and 1.40 +/- 0.39%, respectively. The values of the tests of flexibility of the movements of cervical joint, the abduction of scapular, wrist and back-lumbar joints and abduction of lame-femoral were obtained through the Fleximeter. RESULTS: The DM1 patients and controls did not differ regarding age (DM1 median 16, range 9-20 years vs. controls 16, range 10-18 years) and BMI (DM1 mean+/-S.D. 21.49 +/- 3.69 kg/m(2) vs. controls 20.76 +/- 2.81 kg/m(2)). The scapular, back-lumbar, and lame-femoral flexibility were, respectively, significantly lower (P < .001) in DM1 adolescents (175 +/- 8 degrees , 107 +/- 4 degrees , 66 +/- 10 degrees) compared with controls (189 +/- 13, 116 +/- 14, 76 +/- 12), but the cervical joint mobility was the same in both groups (DM1: 98 +/- l2 degrees vs. control: 101 +/- 13 degrees). CONCLUSION: Thus, the results of our study show a subclinical limited axial and large joint mobility in DM1 adolescents. Future prospective studies are needed to ascertain whether the joint limitations found in these DM1 adolescents will persist into adulthood and play a role in the development of other diabetic complications.

Adolescent↗
PubMed1994

Clinical, biochemical and imaging methods of assessing osteoarthritis and clinical trials with agents claiming 'chondromodulating' activity.

This paper reviews, in a first part, methods used for the clinical assessment of osteoarthritis (OA) with special reference, in a second part, to trials of drugs claimed to be chondromodulating agents. The agents examined include glycosaminoglycan-peptide complex (GP-C, Rumalon) and glycosaminoglycan-polysulfate (GAGPS, Arteparon), which both showed some beneficial clinical response. However, their effect on cartilage still remains controversial. The development of a functional hip and knee OA index in clinical assessment and the role of imaging methods and biochemical markers are discussed. In future clinical trials only validated OA indices such as the Lequesne or WOMAC index and the newly established ILAR guidelines for classifying and testing drugs in OA will be accepted for registration purposes. Imaging methods including magnetic resonance imaging (MRI) offer the capacity to provide more precise information concerning cartilage destruction in OA joints. In addition, the biochemical assessment of proteoglycan fragments, bone sialoprotein (BSP), cartilage oligometric matrix protein (COMP) and the balance between stromelysin and its inhibitor (TIMP) in synovial fluid would appear to offer potential applications for the determination of joint tissue damage in the early and later stages of OA. However, these biochemical markers have yet to be validated. It is clear that in the 1990s, for a drug to be designated as disease modifying in OA, it will require a more rigorous evaluation than was hitherto required.

Analgesics↗
PubMedDate not supplied

The severe flexible flatfoot: a combined reconstructive procedure with rerouting of the tibialis anterior tendon.

A combined procedure is described that addresses all the components at fault in the severely flexible flatfoot deformity in children. The Evans calcaneal distraction wedge osteotomy will lengthen the lateral column, correcting the heel valgus and forefoot abduction. A naviculo--first cuneiform wedge resection (medial and plantar) and fusion will shorten and reshape the collapsed medial arch. This is augmented by reconstruction and plication of the lengthened plantar ligaments, with plantar rerouting of the tibialis anterior tendon to act as a strong plantar ligament. In addition, shifting the tibialis anterior's pull proximally acts as a sling to the talar head. Z plasty of the tight tendo Achillis is always needed. Nineteen feet in 11 patients were the subject of this study. The period of follow-up ranged from 8 to 42 months. The results were assessed according to the relief of foot strain and calf pains, improvement in shoewear, general activity, and foot shape. To evaluate foot shape, reconstruction of the medial arch and heel posture were assessed. The children and parents were satisfied with the final results in 17 feet (89.5%). Improvement of the radiological measurements was evident and was statistically significant.

Adolescent↗
PubMed1995

State-of-the-art flexible hysteroscopy for office gynecologic evaluation.

STUDY OBJECTIVE: To evaluate office flexible hysteroscopy without anesthesia with regard to pain, inconvenience and cost. DESIGN: A survey of patients to evaluate the level of pain they experienced during office hysteroscopy, and a comparison of costs for these procedures with those of hospital dilatation and curettage. SETTING: Office-based hysteroscopy suite in the outpatient building of a tertiary institution. PATIENTS: Women referred to this institution for gynecologic evaluation between February 1992 and December 1993. INTERVENTION: Diagnostic flexible hysteroscopy without anesthesia, cervical dilatation, or paracervical block. MEASUREMENTS AND MAIN RESULTS: A total of 417 women (mean age 42 yrs, range 16-84 yrs; 78 postmenopausal) were referred for evaluation during the study period. The most common indication for referral was abnormal uterine bleeding (86%). Hysteroscopy could not be completed in 29 women (7%), primarily because of cervical stenosis. Pain ratings obtained from 387 patients were as follows: easily acceptable discomfort, minimal discomfort during procedure, 133 (34.5%); acceptable discomfort, uncomfortable but easily bearable, 86 (22.2%); tolerable discomfort, equivalent to menstrual cramps and spasms, 106 (27.4%); barely tolerable pain, tolerable for short time only, 48 (12.4%); and intolerable pain, severe enough to stop the procedure before completion, 14 (3.6%). A single adverse event, a postprocedure temperature elevation, was easily treated with oral antibiotics. No pathology was identified in 183 (43%) of the women; 95 (22%) had polyps and 90 (21.5%) had fibroid tumors. The average duration of a procedure was 5 minutes. The charge for office hysteroscopy was $475. CONCLUSION: Flexible office hysteroscopy without anesthesia was well tolerated by the majority of the women. In addition, the procedure is far less expensive and time consuming than when it is performed in an operating room. We believe that it is a safe, well-tolerated, and cost-effective procedure of great diagnostic value.

Adolescent↗
PubMed2001

Approaches to solving the rigid receptor problem by identifying a minimal set of flexible residues during ligand docking.

BACKGROUND: Using fixed receptor sites derived from high-resolution crystal structures in structure-based drug design does not properly account for ligand-induced enzyme conformational change and imparts a bias into the discovery and design of novel ligands. We sought to facilitate the design of improved drug leads by defining residues most likely to change conformation, and then defining a minimal manifold of possible conformations of a target site for drug design based on a small number of identified flexible residues. RESULTS: The crystal structure of thymidylate synthase from an important pathogenic target Pneumocystis carinii (PcTS) bound to its substrate and the inhibitor, BW1843U89, is reported here and reveals a new conformation with respect to the structure of PcTS bound to substrate and the more conventional antifolate inhibitor, CB3717. We developed an algorithm for determining which residues provide 'soft spots' in the protein, regions where conformational adaptation suggests possible modifications for a drug lead that may yield higher affinity. Remodeling the active site of thymidylate synthase with new conformations for only three residues that were identified with this algorithm yields scores for ligands that are compatible with experimental kinetic data. CONCLUSIONS: Based on the examination of many protein/ligand complexes, we develop an algorithm (SOFTSPOTS) for identifying regions of a protein target that are more likely to accommodate plastically to regions of a drug molecule. Using these indicators we develop a second algorithm (PLASTIC) that provides a minimal manifold of possible conformations of a protein target for drug design, reducing the bias in structure-based drug design imparted by structures of enzymes co-crystallized with inhibitors.

Algorithms↗
PubMed2003

Bending properties of rotary nickel-titanium instruments.

OBJECTIVE: We sought to compare the bending properties of different rotary nickel-titanium instruments and to investigate the correlation between their bending moments and their cross-sectional surface areas. STUDY DESIGN: Resistance to bending was determined according to International Standards Organization publication 3630-1. The sample size was 10 files for each type, taper, and size. The cross-sectional surface area of all instruments was determined by using scanning electron microscope photographs of the cross section. The images were scanned and the area was calculated by using special software. Data were analyzed by using analysis of variance and the Student t test and the Newman-Keuls test for all pairwise comparisons. The strength of the correlation between the bending moment and the cross-sectional area was determined by computing the Pearson product moment correlation. RESULTS: Bending moments were significantly lower for ProFile and RaCe files than for all other files (P <.05). K3 files were significantly less flexible than all other instruments (P <.05). The correlation between stiffness and cross-sectional area was highly significant (r = 0.928; P <.0001). CONCLUSION: Nickel-titanium files with tapers greater than.04 should not be used for apical enlargement of curved canals because these files are considerably stiffer than are those with.02 or.04 tapers.

Analysis of Variance↗
PubMed2002

Nitric oxide released from iNOS in polymorphonuclear leukocytes makes them deformable in an autocrine manner.

The objective of this study was to determine whether endogenous nitric oxide (NO) derived from reaction catalyzed by the inducible isoform of NO synthase (iNOS: NOS II) in polymorphonuclear leukocytes (PMNs) makes the PMNs deformable. Previous studies have shown that NO increases the deformability of PMNs and decreases the sequestration of PMNs in the lungs. However, there was little information regarding the effect of PMN-derived NO on the cells' deformability. In the present study PMNs were isolated from the blood of rats 24h after ip injection of saline (control) or lipopolysaccharide (LPS), and expression of iNOS in the PMNs of the LPS group was confirmed by immunocytochemistry. PMN deformability was evaluated by measuring the pressure generated during their passage through a microfilter at a constant flow rate. The nitrite/nitrate content of the solution in which the isolated PMNs were incubated was measured by the Griess method. In the control group, no iNOS was detectable in the PMNs, and the nitrite/nitrate level in the PMN incubation solution was low. Deformability was unchanged after incubation with specific iNOS inhibitor aminoguanidine, but decreased after incubation with N-formyl-methionyl-leucyl-phenyl-alanine. In the LPS group, PMN deformability was decreased compared to that of the control group. iNOS was detectable in the PMNs, and the deformability further decreased after incubation with aminoguanidine. These results suggest that endogenous NO generated during reactions catalyzed by iNOS in PMNs makes them deformable in an autocrine manner.

Animals↗
PubMed2000

Development of computational and graphical tools for analysis of movement and flexibility in large molecules.

We developed a computer program for the calculation and display of the difference distance matrices (DDMs) of macromolecules that has the ability to compare multiple structures simultaneously. To demonstrate its use, a data set of atoms for superimposition of the HIV-1 reverse transcriptase enzyme was defined using the coordinates for the 21 available crystal structures of this enzyme and its complexes. The DDM technique for superimposition data set generation allows selection of atoms that are invariant in all structures, is free from user bias, and represents the most accurate and precise method of producing such subsets. Comparison of this technique was made against other published methods of generating superimposition data sets, and it was found that significant differences in magnitude and trends of atom movements are observed depending on which data set was used.

Computer Graphics↗
PubMed2001

Protein flexibility and dynamics using constraint theory.

A new approach is presented for determining the rigid regions in proteins and the flexible joints between them. The short-range forces in proteins are modeled as constraints and we use a recently developed formalism from graph theory to analyze flexibility in the bond network. Forces included in the analysis are the covalent bond-stretching and bond-bending forces, salt bridges, and hydrogen bonds. We use a local function to associate an energy with individual hydrogen bonds, which then can be included or excluded depending on the bond strength. Colored maps of the rigid and flexible regions provide a direct visualization of where the motion of the protein can take place, consistent with these distance constraints. We also define a flexibility index that quantifies the local density of flexible or floppy modes, in terms of the dihedral angles that remain free to rotate in each flexible region. A negative flexibility index provides a measure of the density of redundant bonds in rigid regions. A new application of this approach is to simulate the maximal range of possible motions of the flexible regions by introducing Monte Carlo changes in the free dihedral angles, subject to the distance constraints. This is done using a method that maintains closure of the rings formed by covalent and hydrogen bonds in the flexible parts of the protein, and van der Waals overlaps between atoms are avoided. We use the locus of the possible motions of HIV protease as an example: movies of its motion can be seen at http://www.pa.msu.edu/~lei.

Computer Simulation↗
PubMed2001

Continuum solvent molecular dynamics study of flexibility in interleukin-8.

Generalized Born continuum solvent methods have been shown to provide a reasonable description of the equilibrium thermodynamics of aqueous solvation in a variety of applications to peptides, proteins, and nucleic acids. Here we study the performance of these methods in molecular dynamics simulations of interleukin-8, comparing nanosecond-length explicit solvent simulations with those using the generalized Born model. In general, the simulations show similar results, although movement away from the initial NMR-determined structure and average fluctuations about the mean are slightly higher for the continuum solvent results. In both simulations, the two helices that are packed on top of the core sheet move closer together, resulting in a structure that more closely resembles the X-ray structure. Principal-component (quasiharmonic) analysis is used to analyze the motions of these helices in both of the simulations and in the NMR ensemble of structures. Prospects for making more general use of continuum solvent models in protein dynamics simulations are discussed.

Animals↗