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At least 865 records · Page 48Linked to original sources
PubMed2004

Genetic contribution to dental arch size variation in Australian twins.

The aim of this study was to quantify the relative contributions of genetic and environmental factors to variations in dental arch breadth, length and palatal height in a sample of Australian twins, and to estimate heritabilities using modern model-fitting methods. Dental casts of 20 male and 24 female monozygous (MZ) twin pairs, 17 male and 8 female dizygous (DZ) twin pairs, and 9 opposite-sexed DZ twin pairs were selected from the collection of records of twins housed at the Adelaide Dental School. The mean ages of subjects were 15.8 +/- 3.5 years (MZ) and 17.0 +/- 4.7 years (DZ). Dental casts were scanned using a contact-type 3D scanner, PICZA interfaced to a personal computer running 3D-Rugle3 software. Data were subjected to univariate genetic analysis with the structural equation modelling package, Mx, using the normal assumptions of the twin model. A model incorporating additive genetic (A) and unique environmental (E) variation was found to be the most parsimonious for dental arch breadth and length, and palatal height. Estimates of heritability for dental arch breadth ranged from 0.49 to 0.92, those for arch length from 0.86 to 0.94, and those for palatal height were 0.80 and 0.81, respectively. These results indicate a high genetic contribution to the variation in dental arch dimensions in mainly teenage twins.

Adolescent↗
PubMed2002

Ability of E. coli cyclic AMP receptor protein to differentiate cyclic nucelotides: effects of single site mutations.

Escherichia coli cyclic AMP receptor protein (CRP) is a global transcriptional regulator which controls the expression of many different genes. Although different cyclic nucleotides can bind to CRP with almost equal affinity, only in the presence of cAMP could wild-type CRP bind to specific DNA sequences. Molecular genetic studies have identified a class of mutants, CRP*, which either do not require exogenous cAMP for activation or can be activated by cGMP. Thus, these mutants might aid in identifying the structural elements that are involved in the modulation of CRP to correctly differentiate the messages embedded in cyclic nucleotides. In this in vitro study, five CRP* mutants, namely, D53H, S62F, G141Q, G141K, and L148R, were tested for their abilities to bind the lac promoter sequence and the effects of cyclic nucleotides in modulating DNA sequence recognition. For comparison, non-CRP* mutants K52N, T127L, H159L, and K52N/H159L were studied. cCMP and cGMP can replace cAMP as an allosteric effector in all of these CRP mutants except S62F and non-CRP* mutants. The D53H, G141Q, G141K, and L148R mutants exhibit significantly higher affinity for the lac promoter sequence than wild-type CRP while S62F and the non-CRP* mutants exhibit reduced affinity. To probe the pathway of communication, the energetics of subunit assembly in these mutants were monitored by sedimentation equilibrium, and the conformational states of these mutants were probed by proteolysis and accessibility of Cys178 to chemical modifications. Results from these studies imply that signals due to mutations are mostly transmitted through the subunit interface. Thus, residues in CRP outside of the cyclic nucleotide binding site modulate the ability of CRP to differentiate these three cyclic nucleotides through long-range communication. Furthermore, this study shows that CRP* mutations do not impart any unique properties to CRP except that the DNA binding constants are shifted to a regime of higher affinity.

Cyclic AMP↗
PubMed2001

Structure of rat BCKD kinase: nucleotide-induced domain communication in a mitochondrial protein kinase.

Mitochondrial protein kinases (mPKs) are molecular switches that down-regulate the oxidation of branched-chain alpha-ketoacids and pyruvate. Elevated levels of these metabolites are implicated in disease states such as insulin-resistant Type II diabetes, branched-chain ketoaciduria, and primary lactic acidosis. We report a three-dimensional structure of a member of the mPK family, rat branched-chain alpha-ketoacid dehydrogenase kinase (BCK). BCK features a characteristic nucleotide-binding domain and a four-helix bundle domain. These two domains are reminiscent of modules found in protein histidine kinases (PHKs), which are involved in two-component signal transduction systems. Unlike PHKs, BCK dimerizes through direct interaction of two opposing nucleotide-binding domains. Nucleotide binding to BCK is uniquely mediated by both potassium and magnesium. Binding of ATP induces disorder-order transitions in a loop region at the nucleotide-binding site. These structural changes lead to the formation of a quadruple aromatic stack in the interface between the nucleotide-binding domain and the four-helix bundle domain, where they induce a movement of the top portion of two helices. Phosphotransfer induces further ordering of the loop region, effectively trapping the reaction product ADP, which explains product inhibition in mPKs. The BCK structure is a prototype for all mPKs and will provide a framework for structure-assisted inhibitor design for this family of kinases.

Adenosine Diphosphate↗
PubMed2003

The catalytic domain of Escherichia coli Lon protease has a unique fold and a Ser-Lys dyad in the active site.

ATP-dependent Lon protease degrades specific short-lived regulatory proteins as well as defective and abnormal proteins in the cell. The crystal structure of the proteolytic domain (P domain) of the Escherichia coli Lon has been solved by single-wavelength anomalous dispersion and refined at 1.75-A resolution. The P domain was obtained by chymotrypsin digestion of the full-length, proteolytically inactive Lon mutant (S679A) or by expression of a recombinant construct encoding only this domain. The P domain has a unique fold and assembles into hexameric rings that likely mimic the oligomerization state of the holoenzyme. The hexamer is dome-shaped, with the six N termini oriented toward the narrower ring surface, which is thus identified as the interface with the ATPase domain in full-length Lon. The catalytic sites lie in a shallow concavity on the wider distal surface of the hexameric ring and are connected to the proximal surface by a narrow axial channel with a diameter of approximately 18 A. Within the active site, the proximity of Lys(722) to the side chain of the mutated Ala(679) and the absence of other potential catalytic side chains establish that Lon employs a Ser(679)-Lys(722) dyad for catalysis. Alignment of the P domain catalytic pocket with those of several Ser-Lys dyad peptide hydrolases provides a model of substrate binding, suggesting that polypeptides are oriented in the Lon active site to allow nucleophilic attack by the serine hydroxyl on the si-face of the peptide bond.

ATP-Dependent Proteases↗
PubMed1998

WinXAS: a program for X-ray absorption spectroscopy data analysis under MS-Windows.

WinXAS is a new X-ray absorption spectroscopy (XAS) data-analysis program. It runs under the operating system MS-Windows 95/NT and offers several unique features. It has a user-friendly graphical environment and is capable of reading a variety of data formats. It contains a number of useful numerical algorithms beyond those used in conventional XAS analysis and offers a simple interface to the ab-initio theoretical code FEFF. The availability of fast macros in WinXAS makes it particularly useful for on-line data examination at synchrotron radiation facilities during XAS experiments as well as for the analysis of multiple-scan data such as those from time-resolved experiments.

Journal Article↗
PubMed2005

A critical analysis of the Brazilian response to HIV/AIDS: lessons learned for controlling and mitigating the epidemic in developing countries.

The Brazilian National AIDS Program is widely recognized as the leading example of an integrated HIV/AIDS prevention, care, and treatment program in a developing country. We critically analyze the Brazilian experience, distinguishing those elements that are unique to Brazil from the programmatic and policy decisions that can aid the development of similar programs in other low- and middle-income and developing countries.Among the critical issues that are discussed are human rights and solidarity, the interface of politics and public health, sexuality and culture, the integration of prevention and treatment, the transition from an epidemic rooted among men who have sex with men to one that increasingly affects women, and special prevention and treatment programs for injection drug users.

Acquired Immunodeficiency Syndrome↗
PubMed1992

New histopathologic findings in drug eruptions.

Several new findings associated with hyperpigmentation have been reported in the past decade, the most notable being amiodarone-induced hyperpigmentation, which was shown to demonstrate both a lymphocytic dermatitis as well as yellowish brown granules that can be found within several cell types. The nature of this material has not been elucidated, although the drug or one of its metabolites composes at least a portion of the granules. The nature of the clofazimine-induced hyperpigmentation was shown to be caused by the accumulation of a ceroid lipofuscin within lipid-laden macrophages. Several chemotherapy-induced clinical and histologic changes have been reported in the past decade because of new chemotherapeutic drugs, better recognition of histologic reaction patterns, and the use of higher dosages by oncologists. A unique dermatitis, cutaneous eruption of lymphocyte recovery--although not directly due to use of chemotherapeutic agents--occurs after the return of immunocompetent lymphocytes in the peripheral circulation and skin, producing a maculopapular eruption that demonstrates a nonspecific superficial perivascular dermatitis on biopsy. Another clinically specific reaction, chemotherapy-induced acral erythema, demonstrates a nonspecific histologic pattern characterized by an interface dermatitis. Specific histologic patterns were reported for reactions following use of etoposide--starburst cells--and of busulfan--large atypical keratinocytes. There have been reports of new reactions due to chemotherapeutic agents involving sweat glands: neutrophilic eccrine hidradenitis, characterized by neutrophils and necrosis; and syringosquamous metaplasia, a histologic reaction of the sweat duct characterized by squamous metaplasia. New inflammatory reaction patterns include drug-induced generalized pustular toxic erythema, which histologically shows subcorneal pustules and occasional eosinophils. Cephalosporins were reported to produce a syndrome that clinically and histologically resembles pemphigus. Naproxen is reported to produce a clinical and histologic reaction similar to porphyria cutanea tarda. Quinine and piroxicam both induce a photosensitive dermatitis that histologically shows a nonspecific spongiotic dermatitis. A histologically unique reaction pattern manifesting as a lichenoid giant cell dermatitis may be produced by use of either methyldopa or chlorothiazide. Both phenytoin and carbamazepine produce a dermatitis that histologically imitates mycosis fungoides. Finally, phytonadione injections may produce a clinical and histologic reaction that resembles morphea.

Amiodarone↗
PubMed2006

Combustion oxidization synthesis of unique cage-like nanotetrapod ZnO and its optical property.

Cage-like nano-tetrapod ZnO is a novel structure, which was successfully synthesized by combustion oxidation at 850 degrees C. No catalyst or carrier gases were used. Thorough SEM and TEM analyses revealed that the linking legs of the tetrapod ZnO can have or not interface. The formation or not of an interface is discussed and it was attributed to different growth process of the cage-like ZnO nano-tetrapod. Enhanced UV emission peak at the wavelength of 375 nm, featuring high intensity and narrow width, indicates a highly crystalline structure. A green emission, recorded at 502 nm, was related to the defects of the surface of the branching configuration as well as to the ZnO nuclei of the cage-like nano-tetrapod ZnO.

Crystallography, X-Ray↗
PubMed2005

Single-molecule fluorescence detection in microfluidic channels--the Holy Grail in muTAS?

Both single-molecule detection (SMD) methods and miniaturization technologies have developed very rapidly over the last ten years. By merging these two techniques, it may be possible to achieve the optimal requirements for the analysis and manipulation of samples on a single molecule scale. While miniaturized structures and channels provide the interface required to handle small particles and molecules, SMD permits the discovery, localization, counting and identification of compounds. Widespread applications, across various bioscience/analytical science fields, such as DNA-analysis, cytometry and drug screening, are envisaged. In this review, the unique benefits of single fluorescent molecule detection in microfluidic channels are presented. Recent and possible future applications are discussed.

Biosensing Techniques↗
PubMed2004

A molecular dissection of the interaction between the transcription factor Gata-1 zinc finger and DNA.

The production of circulating blood cells from bone marrow stem cells during hematopoiesis is accompanied by overall changes in gene expression which cause production of required functional proteins, such as hemoglobin in erythroid cells, as well as control of cell growth, preventing apoptosis of differentiating cells. Hematopoietic gene regulation is controlled by several specific transcription factors, including the factor Gata-1, which is required for erythrocyte maturation. Based on contacts observed in the NMR structure of the cGata-1 binding domain in complex with DNA, the protein's key DNA interface is interesting in being quite hydrophobic in nature, due to the presence of three leucine side chains protruding toward the DNA. Given the T-rich composition of the GATA DNA binding site, it is possible that thymine's unique 5-methyl group may mediate some of these hydrophobic contacts to increase the stability of binding. The hypothesis that thymine methyl groups are important to the free energy of binding between Gata and DNA is tested by measuring binding of an oligonucleotide substrate in which individual thymine bases are substituted with uracil. To test for any important base-pair specific interactions which may be hydrogen-bonded in character, we have also assayed Gata binding to oligonucleotides with base analogs which cannot make hydrogen bonds. We report that out of the binding site's five thymine methyl groups, only one appeared to make a notable contribution to binding affinity, with removal causing a loss of less than 1kcal/mol of binding free energy. On the other hand, perturbing the potential hydrogen-bonding surface of the DNAs major groove was found to cause a larger decrease in binding affinity than removal of any of the thymine methyl groups, with a loss of 2-3kcal/mol of binding free energy.

Amino Acid Sequence↗
PubMed2004

Crystallography and mutagenesis point to an essential role for the N-terminus of human mitochondrial ClpP.

We have determined a 2.1 A crystal structure for human mitochondrial ClpP (hClpP), the proteolytic component of the ATP-dependent ClpXP protease. HClpP has a structure similar to that of the bacterial enzyme, with the proteolytic active sites sequestered within an aqueous chamber formed by face-to-face assembly of the two heptameric rings. The hydrophobic N-terminal peptides of the subunits are bound within the narrow (12 A) axial channel, positioned to interact with unfolded substrates translocated there by the associated ClpX chaperone. Mutation or deletion of these residues causes a drastic decrease in ClpX-mediated protein and peptide degradation. Residues 8-16 form a mobile loop that extends above the ring surface and is also required for activity. The 28 amino acid C-terminal domain, a unique feature of mammalian ClpP proteins, lies on the periphery of the ring, with its proximal portion forming a loop that extends out from the ring surface. Residues at the start of the C-terminal domain impinge on subunit interfaces within the ring and affect heptamer assembly and stability. We propose that the N-terminal peptide of ClpP is a structural component of the substrate translocation channel and may play an important functional role as well.

Amino Acid Sequence↗
PubMed2003

A novel vertical attenuated total reflectance photochemical flow-through reaction cell for Fourier transform infrared spectroscopy.

A unique photochemical cell design and two experiments are presented, which illustrate the usefulness of flow-through attenuated total reflectance (ATR) Fourier transform infrared (FT-IR) spectroscopy as a technique for investigating photochemical reactions at the mineral-water interface. The kinetics of the photolysis reaction of potassium oxalate (K(2)C(2)O(4)) in a ferric iron solution and oxalate adsorbed onto goethite (alpha-FeOOH) were investigated to show the capabilities of the cell. Due to complicated kinetics, the adsorption experiment demonstrates not only the types of complex problems, that may exist at the mineral-water interface, but also the ability for this novel cell design to address them.

Chemistry Techniques, Analytical↗
PubMed2006

The adaptor protein Nck interacts with Fas ligand: Guiding the death factor to the cytotoxic immunological synapse.

The Fas ligand (FasL) is a key death factor of cytotoxic T lymphocytes and natural killer cells. It is stored intracellularly as a transmembrane protein of secretory lysosomes. Upon activation, these vesicles are transported to the cytotoxic immunological synapse (IS), and FasL becomes exposed to the cell surface to trigger cell death through ligation of its receptor Fas (CD95) on the target cell. We propose that the FasL-associated adaptor protein Nck is involved in the actin-dependent transport of FasL-bearing secretory lysosomes to the IS. Nck binds to the proline-rich portion of FasL and alters its subcellular distribution when coexpressed in 293T cells. In T lymphocytes, endogenous Nck partially colocalizes with lysosome-associated FasL. When T cell clones or lines are exposed to target cells, both proteins and other components of secretory lysosomes (i.e., granzyme B or cathepsin D) are transported to the cell-cell interface. The present data suggest that T cell receptor engagement provokes a rapid, tyrosine kinase- and actin-dependent transport of Nck-associated FasL-carrying lysosomes to the contact area. Our observations support the previous notion that the unique cytoplasmic tail of FasL is crucial for its directed transport to the cell surface and into the assembling cytotoxic IS.

Adaptor Proteins, Signal Transducing↗
PubMed2006

A microrotary motor powered by bacteria.

Biological molecular motors have a number of unique advantages over artificial motors, including efficient conversion of chemical energy into mechanical work and the potential for self-assembly into larger structures, as is seen in muscle sarcomeres and bacterial and eukaryotic flagella. The development of an appropriate interface between such biological materials and synthetic devices should enable us to realize useful hybrid micromachines. Here we describe a microrotary motor composed of a 20-mum-diameter silicon dioxide rotor driven on a silicon track by the gliding bacterium Mycoplasma mobile. This motor is fueled by glucose and inherits some of the properties normally attributed to living systems.

Energy Metabolism↗
PubMed2004

NMR study of nucleotide-induced changes in the nucleotide binding domain of Thermus thermophilus Hsp70 chaperone DnaK: implications for the allosteric mechanism.

We present an NMR investigation of the nucleotide-dependent conformational properties of a 44-kDa nucleotide binding domain (NBD) of an Hsp70 protein. Conformational changes driven by ATP binding and hydrolysis in the N-terminal NBD are believed to allosterically regulate substrate affinity in the C-terminal substrate binding domain. Several crystal structures of Hsc70 NBDs in different nucleotide states have, however, not shown significant structural differences. We have previously reported the NMR assignments of the backbone resonances of the NBD of the bacterial Hsp70 homologue Thermus thermophilus DnaK in the ADP-bound state. In this study we show, by assigning the NBD with the ATP/transition state analogue, ADP.AlFx, bound, that it closely mimics the ATP-bound state. Chemical shift difference mapping of the two nucleotide states identified differences in a cluster of residues at the interface between subdomains 1A and 1B. Further analysis of the spectra revealed that the ATP state exhibited a single conformation, whereas the ADP state was in slow conformational exchange between a form similar to the ATP state and another state unique to the ADP-bound form. A model is proposed of the allosteric mechanism based on the nucleotide state altering the balance of a dynamic equilibrium between the open and closed states. The observed chemical shift perturbations were concentrated in an area close to a previously described J-domain binding channel, confirming the importance of that region in the allosteric mechanism.

Adenosine Diphosphate↗
PubMed1998

Experience implementing a DICOM 3.0 multivendor teleradiology network.

OBJECTIVE: The ISIS Center at Georgetown University received a grant from the U.S. Army to act as systems integrator for a project to design, develop, and implement a commercial off-the-shelf teleradiology system to support the U.S. troops in Bosnia-Herzegovina. The goal of the project was to minimize troop movement while providing primary diagnosis to military personnel. This paper focuses on Digital Imaging Communications in Medicine (DICOM) 3.0 related issues that arose from this type of teleradiology implementation. The objective is to show that using the DICOM standard provides a good starting point for systems integration but is not a plug-and-play operation. METHODS: Systems were purchased that were based on the DICOM 3.0 standard. The modalities implemented in this effort were computed radiography (CR), computed tomography (CT), film digitization (FD), and ultrasonography (US). Dry laser printing and multiple-display workstations were critical components of this network. The modalities and output devices were integrated using the DICOM 3.0 standard. All image acquisition from the modalities is directly to a workstation. The workstation distributes the images to other local and remote workstations, to the dry laser printer, and to other vendors' workstations using the DICOM 3.0 standard. All systems were integrated and tested prior to deployment or purchase. Local and wide area networking were also tested prior to implementation of the deployable radiology network. RESULTS: The results of the integration of the multivendor network were positive. Eventually, all vendors' systems did communicate. Software configuration and operational changes were made to many systems in order to facilitate this communication. Often, software fixes or patches were provided by a vendor to modify their DICOM 3.0 implementation to allow better communications with another vendor's system. All systems were commercially available, and any modifications or changes provided became part of the vendor's commercially available package. CONCLUSION: Seven DICOM interfaces were implemented for this project, and none was achieved without modification of configuration files, changes or patches in vendor software, or operational changes. Some of the problems encountered included missing or ignored required data elements, padding of data values, unique study identifiers (UID), and the use of application entity titles. The difficulties with multivendor connectivity lie in the understanding and interpretation of standards such as DICOM 3.0. The success of this network proves that these problems can be overcome and a clinically successful network implemented utilizing multiple vendors' systems.

Computer Communication Networks↗
PubMed2002

The chemical organization of signaling interactions.

MOTIVATION: Cellular chemical signaling pathways form complex networks that are beginning to be studied at the level of chemical kinetics and databases of reactions. Chemical reaction details are traditionally represented as lists of reactions and rates. This does not map readily to the block diagram representation familiar to biologists, and obscures the functional organization of signaling networks. This study examines motifs in signaling chemistry and reports common features that may help to formalize such a mapping between pathway block diagrams and the chemistry. The same motifs may facilitate data representation and provide functional abstraction of the chemistry. RESULTS: I classified 74 interactions between 25 signaling pathways in terms of shared chemical motifs. All interactions in this dataset consist of a few communicating molecules from one set of pathways, and a replicating set of reactions and molecules from another. Each unique combination of interacting pathways duplicates the chemical reaction scheme of this replicating set, but involves different rate constants. Signaling pathways can therefore be described in an object-oriented manner as sets of core reactions with well-defined interfaces between pathways. This generalization lends itself to designing simulators and databases for signaling networks. AVAILABILITY: Software and example models are freely available from http://www.ncbs.res.in/~bhalla/examples/EGFR_example.html.

Computational Biology↗