Biomedical subjects

S C Hendy

Publications and source records attributed to S C Hendy.

12 recordsLinked to original sources

PubMed2006

Reentrant adhesion behavior in nanocluster deposition.

We simulate the collision of atomic clusters with a weakly attractive surface using molecular dynamics in a regime between soft landing and fragmentation, where the cluster undergoes large deformation but remains intact. As a function of incident kinetic energy, we find a transition from adhesion to reflection at low kinetic energies. We also identify a second adhesive regime at intermediate kinetic energies, where strong deformation of the cluster leads to an increase in contact area and adhesive energy.

Journal Article↗

PubMed2006

Superheating and solid-liquid phase coexistence in nanoparticles with nonmelting surfaces.

We present a phenomenological model of melting in nanoparticles with facets that are only partially wet by their liquid phase. We show that in this model, as the solid nanoparticle seeks to avoid coexistence with the liquid, the microcanonical melting temperature can exceed the bulk melting point and that the onset of coexistence is a first-order transition. We show that these results are consistent with molecular dynamics simulations of aluminum nanoparticles which remain solid above the bulk melting temperature.

Journal Article↗

PubMed2005

Static, transient, and dynamic phase coexistence in metal nanoclusters.

Molecular dynamics simulations are used to examine static and dynamic coexistence between solid and liquid phases in nanoscale silver, copper, and nickel clusters. We find static coexistence in the 561-atom copper icosahedron, the 561-atom silver icosahedron, and the 923-atom nickel icosahedron, and in cluster sizes above these thresholds, but not in smaller clusters. Nonetheless, in smaller clusters we typically observe either dynamic coexistence between fully solid and liquid states or transient coexistence which is essentially dynamic coexistence between a fully solid state and a solid-liquid state.

Journal Article↗

PubMed2005

Transition from icosahedral to decahedral structure in a coexisting solid-liquid nickel cluster.

We have used molecular dynamics simulations to construct a microcanonical caloric curve for a 1415 atom Ni icosahedron. Prior to melting, the Ni cluster exhibits static solid-liquid phase coexistence. Initially, a partial icosahedral structure coexists with a partially wetting melt. However, at energies very close to the melting point the icosahedral structure is replaced by a truncated decahedral structure that is almost fully wet by the melt. This structure remains until the cluster fully melts. The transition appears to be driven by a preference for the melt to wet the decahedral structure.

Journal Article↗

PubMed2005

Effect of patterned slip on micro- and nanofluidic flows.

We consider the flow of a Newtonian fluid in a nano- or microchannel with walls that have patterned variations in slip length. We formulate a set of equations to describe the effects on an incompressible Newtonian flow of small variations in slip and solve these equations for slow flows. We test these equations using molecular dynamics simulations of flow between two walls which have patterned variations in wettability. Good qualitative agreement and a reasonable degree of quantitative agreement is found between the theory and molecular dynamics simulations. The results of both analyses show that patterned wettability can be used to induce complex variations in flow. Finally we discuss the implications of our results for the design of microfluidic mixers using slip.

Journal Article↗

PubMed2000

Two classes of androgen receptor elements mediate cooperativity through allosteric interactions.

Genes uniquely regulated by the androgen receptor (AR) typically contain multiple androgen response elements (AREs) that in isolation are of low DNA binding affinity and transcriptional activity. However, specific combinations of AREs in their native promoter context result in highly cooperative DNA binding by AR and high levels of transcriptional activation. We demonstrate that the natural androgen-regulated promoters of prostate specific antigen and probasin contain two classes of AREs dictated by their primary nucleotide sequence that function to mediate cooperativity. Class I AR-binding sites display conventional guanine contacts. Class II AR-binding sites have distinctive atypical sequence features and, upon binding to AR, the DNA structure is dramatically altered through allosteric interactions with the receptor. Class II sites stabilize AR binding to adjacent class I sites and result in synergistic transcriptional activity and increased hormone sensitivity. We have determined that the specific nucleotide variation within the AR binding sites dictate differential functions to the receptor. We have identified the role of individual nucleotides within class II sites and predicted consensus sequences for class I and II sites. Our data suggest that this may be a universal mechanism by which AR achieved unique regulation of target genes through complex allosteric interactions dictated by primary binding sequences.

Allosteric Regulation↗

PubMed1999

Determinants of DNA sequence specificity of the androgen, progesterone, and glucocorticoid receptors: evidence for differential steroid receptor response elements.

While androgen, progesterone, and glucocorticoid receptors perform distinct physiological functions by regulating unique sets of genes, in vitro they can transactivate a common high-affinity DNA-binding target. Naturally occurring steroid response elements display nucleotide divergence that lowers binding affinity in comparison to the optimal binding element, but enhances receptor-type specificity. We investigated the role of nucleotide deviations within the DNA-binding site for contribution to steroid receptor specificity. We hypothesized that receptor specificity drives the evolution of binding site sequence, rather than strictly receptor-binding affinity. Receptor-selective targets can evolve by some nucleotides selected on the basis of additional bond energy, and others may be selected by differential tolerance to discourage binding from inappropriate receptors. To identify receptor-specific binding sites, we mimicked these dual selection pressures in a receptor-competitive environment in which DNA binding sites for the androgen or progesterone receptors were selected in the presence of the glucocorticoid receptor. These analyses also demonstrated that steroid receptors strongly select nucleotides in the spacer and flanking regions of the half-site and do so in an asymmetric fashion, indicating that steroid receptors interact with DNA in an allosteric manner that affects the transcriptional activation potential.

Amino Acid Sequence↗

PubMed1996

Retinoid X receptor alters the determination of DNA binding specificity by the P-box amino acids of the thyroid hormone receptor.

Nuclear hormone receptors bind to hormone response elements in DNA consisting of two half-sites of 6 base pairs. The P-box amino acids of each receptor determine the identities of the central nucleotides of the half-site. 57 P-box variants of the human thyroid hormone receptor (hT3Rbeta) were used to demonstrate the relationship between P-box sequence and DNA binding specificity by homodimers and heterodimers formed with the retinoid X receptor (RXR). In general, the formation of heterodimers relieved many of the constraints on the compatibility of hT3Rbeta P-box sequences with DNA binding. Effects were most dramatic for heterodimers bound to a direct repeat spaced by four base pairs. RXR also overrides the P-box-derived DNA binding specificity of hT3Rbeta when heterodimers are bound to inverted or everted repeat elements. These effects of RXR are most pronounced on AGGTCA half-sites but are squelched when the RXR partner of the heterodimer is bound to an AGGACA half-site. The influence of RXR on hT3Rbeta DNA binding specificity varies with the orientation of half-sites in the element, the identity of the fourth base pair of the half-site, and the spacing between the half-sites of direct repeats. These differences suggest that the DNA binding domains of RXR-hT3Rbeta heterodimers are not positioned equivalently on the various elements, affecting the manner in which the P-box amino acids of hT3Rbeta interact with base pairs within the half-site.

Amino Acid Sequence↗

PubMed1995

Relationship between P-box amino acid sequence and DNA binding specificity of the thyroid hormone receptor. The effects of half-site sequence in everted repeats.

The three P-box amino acids in the DNA recognition alpha-helix of steroid/thyroid hormone receptors participate in the discrimination of the central base pairs of the hexameric half-sites of receptor response elements in DNA. A series of 57 variants of the beta isoform of the human thyroid hormone receptor were constructed in which the 19 possible amino acid substitutions were incorporated at each of the three P-box positions. The effects of these substitutions on the sequence specificity of the DNA binding activity of the receptor were analyzed using 16 everted repeat elements which differed in sequence in the two central base pairs of the hexameric half-sites. Only receptors with glutamate or aspartate as the first P-box amino acid had detectable DNA binding affinity on everted repeats with AGGNCA half-sites. Only those receptors with alanine, glycine, serine, or proline in the second P-box position were able to bind to this same group of everted repeat elements. In contrast, many of the variant receptors with substitutions at the third P-box position were capable of binding to the AGGNCA group of repeat elements. The actual substitutions at the third P-box position that were compatible with binding depended upon the identity of the fourth base pair of the AGGNCA half-sites. Of the remaining 12 everted repeat sequences, only those with AGTTCA or AGTCCA half-sites were able to bind any of the receptors. In addition to wild type receptor, several variant receptors with amino acid substitutions in either the first or third P-box position were able to bind to the everted repeat with AGTTCA half-sites. The everted repeat with AGTCCA half-sites was bound by receptors with a DGG, NGG, or EGQ P-box sequence, but not the wild type receptor which has an EGG P-box sequence. These data demonstrate that all three P-box positions of the thyroid hormone receptor function to discriminate between half-sites that differ in sequence at the third and fourth base pairs.

Amino Acid Sequence↗

PubMed1995

Relationship between P-box amino acid sequence and DNA binding specificity of the thyroid hormone receptor. The effects of sequences flanking half-sites in thyroid hormone response elements.

The three P-box amino acids in the DNA recognition alpha-helix of steroid/thyroid hormone receptors participate in the discrimination of the central base pairs of the hexameric half-sites of receptor response elements in DNA. Using a series of variant receptors incorporating all 19 possible substitutions for each individual P-box amino acid of the human thyroid hormone receptor (hT3R beta), we demonstrated that the first P-box position must have a glutamate, and the second P-box position must have either an alanine or a glycine for high affinity binding to everted repeat elements with half-site sequences of AGGNCA. In the present study, the influence of half-site flanking sequence on the compatibility of P-box amino acids in hT3R beta with DNA binding was investigated. When a 5' sequence of CTG flanked AGGNCA half-sites in an everted repeat, several additional P-box variant receptors were able to bind to the DNA that were not able to bind when the half-sites were flanked with the 5' sequence CAG. Flanking sequence had the most dramatic effects on amino acid substitutions at the first P-box position, with smaller effects observed at the second P-box position and only subtle effects observed at the third P-box position. Expansion of the number of P-box sequences compatible with binding of hT3R beta to thyroid hormone response elements required the thymidine in the CTG flanking sequence, an everted repeat of the AGGNCA half-sites, and an intermolecular interaction in the C terminus of the receptor.

Amino Acid Sequence↗

PubMed1994

The effects of P-box substitutions in thyroid hormone receptor on DNA binding specificity.

Three "P-box" amino acids within the DNA recognition alpha-helix of members of the steroid hormone and thyroid hormone families of nuclear receptors are known to determine the identity of two of the six base pairs within the half-sites of cognate DNA elements. We introduced P-box substitutions derived from different members of the thyroid hormone/estrogen receptor (T3R/ER) family into the beta-isoform of human thyroid hormone receptor (hT3R beta) and tested the DNA binding and transactivation activities of these mutants using thyroid hormone response elements (TREs) with half-sites composed of different sequences and arranged in different orientations. Different P-box sequences derived from the T3R/ER family resulted in distinct DNA binding specificities determined by the fourth base pair of the half-site. Thyroid hormone receptor mutants containing EGA, EAA, EGS substitutions for the wild type EGG P-box bound with wild type affinity to consensus AGGTCA half-sites, regardless of orientation. TREs composed of AGGACA half-sites bound hT3R beta s with an EGG or EAA P-box sequence, but not those with EGA or EGS P-box sequence. A reversal of this specificity was observed on a direct repeat TRE with AGGGCA half-sites. Additionally, an ESG P-box substitution in hT3R beta prevented the receptor from binding to a direct repeat as a homodimer, but this mutant could bind as a heterodimer with retinoid X receptor or to the everted repeat TRE from the chicken lysozyme promoter.

Amino Acid Sequence↗

PubMed1993

Functional analysis of the amino acids in the DNA recognition alpha-helix of the human thyroid hormone receptor.

The roles in DNA binding and transcriptional activation of individual amino acids in the putative recognition alpha-helix of the first zinc finger of the beta-isoform of the human thyroid hormone receptor (hT3R beta) have been probed by site-directed mutagenesis. Alanine substitutions of highly conserved residues involved in the folding of this zinc finger abolished the binding of hT3R beta to various thyroid response elements. A similar effect was observed for alanine substitutions of those conserved residues in hT3R beta that were expected to make specific contacts to DNA bases common to all hormone response elements. The three P-box amino acids have previously been shown to be essential for discrimination of the base pairs that differ between the DNA binding sites for related steroid/thyroid hormone receptors. In hT3R beta, the P-box residues are E, G, and G; the results of this study show that alanine substitution of the glutamic acid dramatically reduces DNA binding activity by hT3R beta, while the substitution of either glycine has little or no effect on DNA binding. The effects of alanine substitutions on hT3R beta transcriptional activation properties were consistent with the effect of these substitutions on DNA binding properties, with the exception of the second P-box amino acid. T3R beta substituted with alanine at this position is substantially more defective in transcriptional activation than it is in specific DNA binding. These results indicate that there are two separate mechanisms of response element discrimination by P-box amino acids of steroid/thyroid hormone receptors, one which operates at the level of DNA recognition and a second which operates at the level of transcriptional activation.

Amino Acid Sequence↗