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PubMed2003

The fatigue strength of compact bone in torsion.

We have conducted a series of fatigue tests on samples of bovine compact bone loaded in cyclic torsion. The fatigue strength (i.e. the range of stress needed to cause failure in a given number of cycles) was found to be lower than the fatigue strength of the same material in compression by more than a factor of two. We also tested intact chicken metatarsals and found a similar reduction in strength compared to compression testing of chicken tibiae. These results were predicted using a theoretical model in which fatigue failure was assumed to be dependent on the growth of microcracks, oriented approximately parallel to the bone's longitudinal axis but having misorientation angles of up to 30 degrees. An effective stress range was derived which is a function of the normal and shear stresses, and thus of the Mode I and Mode II stress intensities experienced by the crack. These results may have important consequences for the understanding of fatigue in bone in vivo; relatively small amounts of longitudinal shear stress, which are often ignored in analysis, may contribute significantly to fatigue failures. This may shed light on the phenomenon of stress fractures and on the need for repair and adaptation in living bone.

Animals↗
PubMed2002

Ribosome-associated factor Y adopts a fold resembling a double-stranded RNA binding domain scaffold.

Escherichia coli protein Y (pY) binds to the small ribosomal subunit and stabilizes ribosomes against dissociation when bacteria experience environmental stress. pY inhibits translation in vitro, most probably by interfering with the binding of the aminoacyl-tRNA to the ribosomal A site. Such a translational arrest may mediate overall adaptation of cells to environmental conditions. We have determined the 3D solution structure of a 112-residue pY and have studied its backbone dynamic by NMR spectroscopy. The structure has a betaalphabetabetabetaalpha topology and represents a compact two-layered sandwich of two nearly parallel alpha helices packed against the same side of a four-stranded beta sheet. The 23 C-terminal residues of the protein are disordered. Long-range angular constraints provided by residual dipolar coupling data proved critical for precisely defining the position of helix 1. Our data establish that the C-terminal region of helix 1 and the loop linking this helix with strand beta2 show significant conformational exchange in the ms- micro s time scale, which may have relevance to the interaction of pY with ribosomal subunits. Distribution of the conserved residues on the protein surface highlights a positively charged region towards the C-terminal segments of both alpha helices, which most probably constitutes an RNA binding site. The observed betaalphabetabetabetaalpha topology of pY resembles the alphabetabetabetaalpha topology of double-stranded RNA-binding domains, despite limited sequence similarity. It appears probable that functional properties of pY are not identical to those of dsRBDs, as the postulated RNA-binding site in pY does not coincide with the RNA-binding surface of the dsRBDs.

Amino Acid Sequence↗
PubMed2002

Sudden and unpredictable below-surface ablation pattern changes by CO2 laser beams: a qualitative description of five macroscopic cases observed in PMMA with high probability to occur during surgery in low-water-content tissues.

OBJECTIVE: This paper describes five cases of macroscopic irregular CO(2) laser-beam ablation patterns that can generate below-surface complications during surgery. These five cases are related to curved reflected beams, curved craters generation with abnormal superficial thermal damage, and craters that show irregular wall contours. Although these alterations have been observed during irradiation in PMMA samples (polymethilmethacrylate), it is possible that similar unpredictable changes also happen in low-water-content, hard and uniform biological tissues such as compact bone, enamel, and dentin. This fact can predict severe impacts on the quality of the final surgical outcome, especially there where precision surgery techniques are required. A qualitative description about the possible causes of these effects and how to avoid them during surgery have been suggested too. BACKGROUND DATA: In the past decades, daily surgery and research studies have provided useful information about the interaction between medical CO(2) laser beams and animal, human, and other biological tissues. Several mathematical models describe with acceptable accuracy all the ablative properties of the 10.6 microm laser beam. Very few studies describe the presence and address the consequences of the ablative aberrations, which can frequently and randomly happen during laser surgery. The probability that these changes happen in below-surface, therefore invisible, parts of the biologic media under treatment makes the whole matter crucial, even in cases of traditional surgery. Where gross mass removals are considered, the presence of unpredictable and sudden deviations from the expected traditional cone-shaped patterns raise several questions about safety. The continuous need for properly engineered medical laser-beam devices, online laser-beam monitoring, and real-time control becomes mandatory in modern surgery. MATERIALS AND METHODS: The equipment used in this study was provided by the National Cancer Institute of Milan, Milan, Italy, and by the Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel. A large TEM-mode laser-beam device (Valfivre, Italy) and TEM00 laser-beam device (Synrad, USA), both coupled to 2.5- and 5-inch focusing lenses, have been used to irradiate, at 10 Watts nominal output, on the focal spot, several PMMA blocks (3 x 2 x 4 x 2 x 2 cm) up to 10 sec CW. For one set of experiments, a metallic, well-polished mirror was placed against one surface of each sample to simulate possible internal beam reflections caused by generic metallic surgical instruments, such as conventional scalpels or clamps. RESULTS: The experimental evidence of five major and unpredicted changes in the shape of craters produced by CO(2 )laser beams in PMMA are shown in photos and discussed in a qualitative way. Several physical and thermodynamic phenomena are proposed to identify and therefore minimize or avoid the causes of these events. CONCLUSION: The results discussed in this paper show how important it is to constantly and carefully observe both the irradiated tissue's or media's structure and the beam's broadening under surface during the ablation process. Fume attenuation of the incoming laser beam, fume escape paths, internal beam interference phenomena, media's microstructural changes and, perhaps more importantly, their combination can offer good explanations of all the described phenomena. In summary, the presence of fumes in at least two out of the five reported cases plays a key role in aberrant crater generation processes. Therefore, the author recommends paying extra attention to them in order to provide a higher quality outcome in Surgery where CO(2) laser beams are deployed.

Adipose Tissue↗
PubMed2001

Effects of ligand binding on the association properties and conformation in solution of retinoic acid receptors RXR and RAR.

In higher eukaryotes, vitamin A derived metabolites such as 9-cis and all-trans retinoic acid (RA), are involved in the regulation of several essential physiological processes. Their pleiotropic physiological effects are mediated through direct binding to cognate nuclear receptors RXRs and RARs that act as regulated transcription factors belonging to the superfamily of nuclear hormone receptors. Hormone binding to the structurally conserved ligand-binding domain (LBD) of these receptors triggers a conformational change that principally affects the conserved C-terminal transactivation helix H12 involved in transcriptional activation. We report an extensive biophysical solution study of RAR alpha, RXR alpha LBDs and their corresponding RXR alpha/RAR alpha LBD heterodimers combining analytical ultracentrifugation (AUC), small-angle X-ray and neutron scattering (SAXS and SANS) and ab initio three-dimensional shape reconstruction at low resolution. We show that the crystal structures of RXRs and RARs LBDs correlate well with the average conformations observed in solution. Furthermore we demonstrate the effects of 9-cisRA and all-transRA binding on the association properties and conformations of RXR alpha and RAR alpha LBDs in solution. The present study shows that in solution RAR alpha LBD behaves as a monomer in both unliganded and liganded forms. It confirms the existence in solution of a ligand-induced conformational change towards a more compact form of the LBD. It also confirms the stability of the predicted RXR alpha/RAR alpha LBD heterodimers in solution. SAS measurements performed on three different types of RXR alpha/RAR alpha LBD heterodimers (apo/apo, apo/holo and holo/holo) with respect to their ligand-binding site occupancy show the existence of three conformational states depending on the progressive binding of RA stereoisomers on RAR alpha and RXR alpha LBD subunits in the heterodimeric context. These results suggest that the subunits are structurally independent within the heterodimers. Our study also underlines the particular behaviour of RXR alpha LBD. In solution unliganded RXR alpha LBD is observed as two species that are unambiguously identified as homotetramers and homodimers. Molecular modelling combined with SAS data analysis allows us to propose a structural model for this autorepressed apo-tetramer. In contrast to the monomeric state observed in the crystal structure, our data show that in solution active holo-RXR alpha LBD bound to 9-cisRA is a homodimer regardless of the protein concentration. This study demonstrates the crucial role of ligands in the regulation of homodimeric versus heterodimeric association state of RXR in the NR signalling pathways.

Apoproteins↗
PubMed2006

Irreducible representation for nucleotide sequence physical properties and self-consistency of nearest-neighbor dimer sets.

A compact representation of usual DNA/RNA four-nucleotide sets based on molecular affinity classes is proposed. In a geometrical correspondence to this formulation, it follows that intrinsic tetrahedral symmetry correlates nucleotide properties. This representation also leads to a proper decomposition frame for any sequence-dependent physical expectation. Thermodynamic and other physical properties of nucleotide sequences are most often stated within the scope of nearest-neighbor models and decomposed in terms of dimer properties. The inverse problem of obtaining dimer set properties is, however, well known to be ill-posed due to sequence composition closure relations. Analysis of the dimer set composition and structure within the novel tetrahedral formulation provides important self-consistency relations, solving the ill posed nature of the original formulation. As an applied example, we analyze DNA oligomer duplex free energy data available on the literature. It is shown that imposition of stringent self-consistency relations does not decrease fit quality to the experimental data set. On the other hand, an improved dimer set with physically consistent free energies is obtained. Meaningful corrections to previous determinations are found when the self-consistent set is applied to calculate free energies for sequences with composition order bias.

Base Sequence↗
PubMed1998

Mental walking through a complex maze influences lateralized ultradian rhythms.

Subjects of two experimental groups, 10 males and 10 females in each group, explored artificial environments represented by compact city mazes. The mazes, a simple and a complex one, were generated by means of a computer program. After turning the program on, a scene with houses, streets, and alleys appeared on a TV screen. The subjects sat in front of the screen and manoeuvered through the simple or the complex maze with the help of a hand-operated device. Correspondingly the street scenes changed in such a way that the subject had the illusion of a normal pace. Each subject explored one maze for eight hours. Every 15 min. an experimenter interrupted the subject's walk and measured tactile discrimination in either hand. Ultradian periodic variations in the tactile error rate of the right and left hands with periods of 2 or 3 hours are found. They are considered manifestations of endogenous rhythms operating separately in the left and right cerebral hemispheres. As demonstrated in a previous paper, lateralized ultradian rhythms in tactile discrimination are different for males and females when tested under quiet laboratory conditions. The present paper shows that the rhythms are specifically influenced in both sexes by the spatial complexity of an artificial environment (maze). These findings are discussed from an evolutionary point of view.

Activity Cycles↗
PubMedDate not supplied

Unraveling the effect of changes in conformation and compactness at the antibody V(L)-V(H) interface upon antigen binding.

We have analyzed conformational changes that occur at the interface between the light (V(L)) and heavy (V(H)) chains in antibody variable fragments upon binding to antigens. We wrote and applied the Tiny Probe program that computes the buried atomic contact surface area of three-dimensional structures to evaluate changes in compactness of the V(L)-V(H) interface between bound and unbound antibodies. We found three categories of these changes, which correlated with the size of the antigen. Upon binding, medium-sized nonprotein antigens cause an opening of the V(L)-V(H) interface (less compact), small antigens or haptens cause a closure of the interface (more compact), whereas large protein antigens have little effect on the compactness of the V(L)-V(H) interface. The largest changes in the atomic buried contact surface area at the V(L)-V(H) interface occur in residue pairs providing two 'shock absorbers' between the edge beta-strands of the V(L) and V(H) beta-sheets forming the antibody binding site. Importantly, the correlation between the size of antigens and conformational changes indicates that the V(L)-V(H) interface in antibodies plays a significant role in the antigen binding process. Furthermore, as the energy involved in such a motion is significant (up to 3 kcal/mol), these results provide a general mechanism for how residues distant from the combining site can significantly alter the affinity of an antibody for its antigen. Thus, mutations introduced at the V(L)-V(H) interface can be used to change antibody binding affinity with antigens. Due to the tightly packed V(L)-V(H) interface, the introduction of random mutations is not advisable. Rather our analysis suggests that concerted mutations of residues preceding CDRL2 and following CDRH3 or residues preceding CDRH2 and at the end of CDRL3 are most likely to alter or improve antigen binding affinity.

Antigen-Antibody Reactions↗
PubMed2003

Commissioning and quality assurance of the Pinnacle(3) radiotherapy treatment planning system for external beam photons.

The commissioning of a Pinnacle(3) treatment planning system is described. Four Elekta linear accelerators were commissioned for external beam photons. Measured data were used to derive parameter values for the Pinnacle(3) beam model by (1). fitting a Monte Carlo model of the accelerator head to measured data and then extracting the parameters for the Pinnacle(3) beam model, and by (2). using the auto-modelling facility within Pinnacle(3). Both of these methods yielded dose distributions in accord with published recommendations. A separate small-field beam model, customized for an in-house compact blocking system, was also created, which satisfied appropriate acceptance criteria for stereotactically guided conformal brain treatments. Inhomogeneous, oblique, asymmetrical and irregular fields were also assessed, with calculated and measured doses agreeing to within +/-3%. Dose-volume histogram calculation was found to be accurate to within +/-5% dose or volume for a grid size of 4 mm x 4 mm x 4 mm, with better accuracy being achieved for finer grids. Isocentric doses were compared between Pinnacle(3)'s collapsed cone convolution algorithm and the Bentley-Milan algorithm within the Target-2 treatment planning system. Dose differences were generally less than 3% in the dose prescribed, with larger values for breast plans, where the Pinnacle(3) algorithm calculated scatter more accurately. Pelvic and thoracic plans were also verified using an anthropomorphic phantom, with local dose differences between calculated and delivered dose of up to 8%, but mainly less than 3%, and with no systematic difference. Ionization chamber verifications using START and RT-01 trial procedures demonstrated differences between calculated and measured doses of less than 2%. Following satisfactory performance in the commissioning process, Pinnacle(3) has now been introduced into routine clinical use.

Algorithms↗
PubMed1997

The native sequence determines sidechain packing in a protein, but does optimal sidechain packing determine the native sequence?

Globular proteins have highly compact structures and the corresponding packing interactions are widely considered as the principal determinant of the native structure. It is therefore important that theoretical approaches to protein design explicitly take in account packing, which requires that a full atomic representation of the designed protein is maintained. As a first step towards this goal, we have developed in this report an inverse folding algorithm with the aim of specifically designing amino acid sequences which optimise sidechain packing for a given protein fold. The design is performed by a global Monte Carlo optimisation in sequence space, with constant amino acid composition and a full-atom representation of the various protein models. Packing is defined by a Lennard-Jones potential. The program was tested by designing stable sequence variants for the chymotrypsin inhibitor fold. The final protein models showed an increase in intramolecular atomic contacts and a decrease in the overall volume compared to the native structure. Starting from the backbone only of the target structure, the algorithm did gradually retrieve reliable though limited sequence information. Higher compatibility might be achieved by improving the potential, however our results suggest that packing interactions are an essential element of a yet-to-be-defined successful energy function for protein design.

Algorithms↗
PubMed2006

Elucidating quantitative stability/flexibility relationships within thioredoxin and its fragments using a distance constraint model.

Numerous quantitative stability/flexibility relationships, within Escherichia coli thioredoxin (Trx) and its fragments are determined using a minimal distance constraint model (DCM). A one-dimensional free energy landscape as a function of global flexibility reveals Trx to fold in a low-barrier two-state process, with a voluminous transition state. Near the folding transition temperature, the native free energy basin is markedly skewed to allow partial unfolded forms. Under native conditions the skewed shape is lost, and the protein forms a compact structure with some flexibility. Predictions on ten Trx fragments are generally consistent with experimental observations that they are disordered, and that complementary fragments reconstitute. A hierarchical unfolding pathway is uncovered using an exhaustive computational procedure of breaking interfacial cross-linking hydrogen bonds that span over a series of fragment dissociations. The unfolding pathway leads to a stable core structure (residues 22-90), predicted to act as a kinetic trap. Direct connection between degree of rigidity within molecular structure and non-additivity of free energy is demonstrated using a thermodynamic cycle involving fragments and their hierarchical unfolding pathway. Additionally, the model provides insight about molecular cooperativity within Trx in its native state, and about intermediate states populating the folding/unfolding pathways. Native state cooperativity correlation plots highlight several flexibly correlated regions, giving insight into the catalytic mechanism that facilitates access to the active site disulfide bond. Residual native cooperativity correlations are present in the core substructure, suggesting that Trx can function when it is partly unfolded. This natively disordered kinetic trap, interpreted as a molten globule, has a wide temperature range of metastability, and it is identified as the "slow intermediate state" observed in kinetic experiments. These computational results are found to be in overall agreement with a large array of experimental data.

Computer Simulation↗
PubMed2005

Modeling of temporomandibular joint function using MRI and jaw-tracking technologies--mechanics.

The study of mechanics of the temporomandibular joint (TMJ) is important because its dysfunction and breakdown could be, at least partially, of mechanical origin. The incongruity of the articular surfaces of the TMJ is compensated by a fibrocartilaginous articular disc. Its dislocation and failure seem to be closely related to the development of osteoarthritis of the TMJ. The analysis of mandibular kinematics permits the detection and assessment of irregularities of TMJ function due to internal obstacles such as a displaced articular disc. Furthermore, the measurement of the dynamic relationship between the articular surfaces of the TMJ is useful to determine the strains undergone by the disc that if too high might compromise its integrity. The development of our research in TMJ mechanics has evolved from the acquisition of the traces of single mandibular points to an accurate and compact description of mandibular motion, in which the mechanical advantage of jaw muscles, and forces and torques acting on the jaw are considered as well. The combination of three-dimensional software models of TMJ anatomies obtained from MRI and jaw tracking with six degrees of freedom permits a subject-specific dynamic analysis of the intra-articular space, providing insight into individual disc deformation during function and TMJ loading. Studies performed with this system indicate that both TMJs are loaded during chewing, the balancing more so than the working joint. In fact, during chewing, the intra-articular distance is smaller for hard than for soft food, on closing than on opening, on the balancing than on the working side. This last finding is confirmed by static biting experiments, in which the condyle-fossa distance decreases more on the side contralateral to the bite force, depending on its magnitude. Also studies on the dynamics of compression areas indicate that plowing can occur through the disc during function, especially mediolaterally, due to stress field translation. This effect might contribute to cartilage wear and fatigue also because the disc is weaker mediolaterally. Further data indicate that the lateral area of the disc is mostly exposed to a higher mechanical energy density. This will be more intensively investigated using finite element method.

Biomechanical Phenomena↗
PubMed2004

Predicting protein-peptide interactions via a network-based motif sampler.

MOTIVATION: Many protein-protein interactions are mediated by peptide recognition modules (PRMs), compact domains that bind to short peptides, and play a critical role in a wide array of biological processes. Recent experimental protein interaction data provide us with an opportunity to examine whether we may explain, or even predict their interactions by computational sequence analysis. Such a question was recently posed by the use of random peptide screens to characterize the ligands of one such PRM, the SH3 domain. RESULTS: We describe a general computational procedure for identifying the ligand peptides of PRMs by combining protein sequence information and observed physical interactions into a simple probabilistic model and from it derive an interaction-mediated de novo motif-finding framework. Using a recent all-versus-all yeast two-hybrid SH3 domain interaction network, we demonstrate that our technique can be used to derive independent predictions of interactions mediated by SH3 domains. We show that only when sequence information is combined with such all versus all protein interaction datasets, are we capable of identifying motifs with sufficient sensitivity and specificity for predicting interactions. The algorithm is general so that it may be applied to other PRM domains (e.g. SH2, WW, PDZ). AVAILABILITY: The Netmotsa software and source code, as part of a general Gibbs motif sampling library, are available at http://sf.net/projects/netmotsa

Algorithms↗
PubMed1991

Computer modeling 16 S ribosomal RNA.

A three-dimensional structure for 16 S RNA has been produced with a computer protocol that is not dependent on human intervention. This protocol improves upon traditional modeling techniques by using distance geometry to fold the molecule in an objective and reproducible fashion. The method is based on the secondary structure of RNA and treats the molecule as a set of double-stranded helices that are linked by flexible single-strands of variable length. Data derived from chemical cross-linking studies of 16 S RNA and tertiary phylogenetic relationships provide the constraints used to fold the molecule into a compact three-dimensional form. Possibly subjective evaluation of the input data are transformed into verifiable quantitative parameters. Relationships based on general locations within the 30 S subunit or on protein-RNA interactions have been specifically excluded. The resolution of the model exceeds that of electron micrographs and approaches that obtained in preliminary X-ray crystal structures. The model size of 245 x 190 x 140 A is compatible with that of the 30 S subunit as determined by electron microscopy. The volume of the model is 1.87 x 10(6) A which is similar to that of the small subunit in a preliminary X-ray crystal structure. The radius of gyration of the model structure of 76 A is intermediate to that seen for partially denatured and fully folded 16 S RNA. Computer graphics are used to display the results in a manner that maximizes the opportunities for human visual interpretation of the models. A format for displaying the structures has been developed that will make it possible for researchers who have not devoted themselves to ribosomal modeling to comprehend and make use of the information that the models embody. On this basis the computer-generated models are compared with models developed by other researchers and with structural data not included in the folding parameter data set.

Base Sequence↗
PubMed2006

Application of fracture mechanics to failure in manatee rib bone.

BACKGROUND: The Florida manatee (Trichechus manatus latirostris) is listed as endangered by the U.S. Department of the Interior. Manatee ribs have different microstructure from the compact bone of other mammals. Biomechanical properties of the manatee ribs need to be better understood. Fracture toughness (K(C)) has been shown to be a good index to assess the mechanical performance of bone. Quantitative fractography can be used in concert with fracture mechanics equations to identify fracture initiating defects/cracks and to calculate the fracture toughness of bone materials. METHOD OF APPROACH: Fractography is a standard technique for analyzing fracture behavior of brittle and quasi-brittle materials. Manatee ribs are highly mineralized and fracture in a manner similar to quasi-brittle materials. Therefore, quantitative fractography was applied to determine the fracture toughness of manatee ribs. RESULTS: Average fracture toughness values of small flexure specimens from six different sizes of manatees ranged from 1.3 to 2.6 MPa(m)(12). Scanning electron microscope (SEM) images show most of the fracture origins were at openings for blood vessels and interlayer spaces. CONCLUSIONS: Quantitative fractography and fracture mechanics can be combined to estimate the fracture toughness of the material in manatee rib bone. Fracture toughness of subadult and calf manatees appears to increase as the size of the manatee increases. Average fracture toughness of the manatee rib bone materials is less than the transverse fracture toughness of human and bovine tibia and femur.

Animals↗
PubMed2003

Active control of the growth trajectory of broiler chickens based on online animal responses.

The objective of the research reported here was to control the growth trajectory of broiler chickens during the production process based on an adaptive compact dynamic process model. More specifically, the daily feed supply was calculated, based on a model-based control algorithm, with the aim of following a previously defined target growth trajectory as close as possible. For the modeling of the dynamic growth response of broiler chickens to the control input, feed supply, an online parameter estimation was used. The developed control algorithm was able to grow the birds according to different target trajectories ranging from restricted (final BW of 1,800 g and 1,945 g in experiments 1 and 3, respectively) to compensatory growth trajectories (final BW of 2,400 g and 2,100 g in experiments 2 and 4, respectively). The mean relative error (MRE) between the different predefined target growth trajectories and the realized growth trajectories ranged from 3.7% to 6.0%. With a few exceptions, the numerical values of feed conversion ratio and mortality after wk 1 were lower and the values of uniformity index were higher in the controlled groups compared with animals fed ad libitum. As a conclusion, it can be stated that integration of dynamic data-based modeling approaches with new hardware and sensing techniques to measure information from the animals should make it possible to control broiler growth trajectories.

Algorithms↗
PubMed2001

Biochemical characterization of the structure-specific DNA-binding protein Cmb1 from Schizosaccharomyces pombe.

Cmb1, a novel HMG box protein from Schizosaccharomyces pombe, has been characterized biochemically using glutaraldehyde cross-linking, gel-filtration and analytical ultracentrifugation. It was identified as a monomeric, non-spherical protein, with a tendency to aggregate in solution. Limited proteolysis with trypsin and chymotrypsin showed that the C-terminal HMG box was a compact, proteolytically stable domain and the N-terminal region of Cmb1 was relatively unstructured and more easily digested. As Cmb1 was previously identified as a potential mismatch-binding protein, the binding constants and stoichiometry for both homoduplex and heteroduplex DNA were determined using an IASys resonant mirror biosensor. Cmb1 indeed demonstrated a tighter association with mismatched DNA, especially with the C/Delta-mismatch. Expression constructs of Cmb1 were made to study the sections of the protein involved in DNA binding. Constructs with the N-terminal region absent revealed that the C-terminal HMG box was the primary DNA-binding region. The presence of the N-terminal region did, however, facilitate tighter binding to both homoduplex and heteroduplex DNA. The amino acid residues isoleucine 14 and leucine 39 were located as putative intercalating residues using structure guided homology modelling. The model templates were derived from two distinct HMG:DNA complexes: HMG-D bound to homoduplex DNA and HMG 1 bound to cisplatin DNA. Binding studies using the Cmb1 HMG box with point mutations in these residues showed that isoleucine 14 was important for the binding of Cmb1 to homoduplex DNA, but affected binding to mismatches to a lesser extent. In contrast, leucine 39 appeared to have a more significant function in binding to mismatched DNA.

Amino Acid Sequence↗
PubMed2005

Interplay between chemical reactions and transport in structured spaces.

The main motivation behind this study is to understand the interplay between the reactions and transport in a geometries that are not compact. Typical examples of compact geometries are a box or a sphere. A network made of containers C(1) , C(2),..., C(N) and tubes is an example of the space that is structured and noncompact. In containers, particles react with the rate lambda. Tubes connecting containers allow for the exchange of chemicals with the transport rate D. A situation is considered where a number of reactants is small and kinetics is noise dominated. A method is presented that can be used to calculate the average and higher moments of the reaction time. A number of different chemical reactions are studied and their performance compared in various ways. Two schemes are discussed in general, the reaction on a fixed geometry ensemble (ROGE) and the geometry on a fixed reaction ensemble, examples are given in the ROGE case. The most important findings are as follows. (i) There is a large number of reactions that run faster in a networklike geometry. Such reactions contain antagonistic catalytic influences in the intermediate stages of a reaction scheme that are best dealt with in a networklike structure. (ii) Antagonistic catalytic influences are hard to identify since they are strongly connected to the pattern of injected molecules (inject pattern) and depend on the choice of molecules that have to be synthesized at the end (task pattern). (iii) The reaction time depends strongly on the details of the inject and task patterns.

Algorithms↗
PubMed1992

Unusual aspects of in vitro RNA processing in the 3' regions of the GAL1, GAL7, and GAL10 genes in Saccharomyces cerevisiae.

A striking feature of the 3'-end regions in polymerase II transcripts of Saccharomyces cerevisiae adjacent to their processing and polyadenylation sites is the lack of well-defined signal elements. Nonetheless, essential signals have seemed to be confined to compact regions in vivo, and we find that a short RNA with only 70 bases of GAL7 sequence upstream and 8 to 10 bases downstream of the poly(A) addition site is processed in vitro, as is an analogous CYC1 pre-RNA. Specific polyadenylation of a precleaved species further delimits the poly(A) signal and rules out obligatory coupling between cleavage and poly(A) addition. Although little proximal and even less distal sequence is required for accurate cleavage with CYC1 and GAL7, we have been unable to identify common features to which processing could be ascribed. We therefore turned to the coregulated set of genes in the galactose cluster (GAL1, GAL7, and GAL10) to assay their corresponding pre-mRNAs in vitro, in hopes of finding a common theme. By contrast to GAL7, short pre-mRNAs corresponding to GAL1 and GAL10 fail to be cleaved detectably, and only much longer transcripts are susceptible to processing. This indicates that signals, even if preserved, are more widely dispersed than the poly(A) addition site, and these results are unchanged whether extracts are from cells grown on glucose or galactose. As a further surprise, RNAs corresponding to the antisense orientation of the 3'-end regions of all three GAL genes are also effective substrates for the processing machinery in vitro. Computer analysis reveals the presence of polydisperse dyad symmetries that might account for these observations.

Base Sequence↗