Solid State Physics

Contains research objectives and reports on four research projects

α-Helix stabilization by co-operative side chain charge-reinforced interactions to phosphoserine in a basic kinase-substrate motif

How cellular functions are regulated through protein phosphorylation events that promote or inhibit protein–protein interactions (PPIs) is key to understanding regulatory molecular mechanisms. Whilst phosphorylation can orthosterically or allosterically influence protein recognition, phospho-driven changes in the conformation of recognition motifs are less well explored. We recently discovered that clathrin heavy chain recognizes phosphorylated TACC3 through a helical motif that, in the unphosphorylated protein, is disordered. However, it was unclear whether and how phosphorylation could stabilize a helix in a broader context. In the current manuscript, we address this challenge using poly-Ala-based model peptides and a suite of circular dichroism and nuclear magnetic resonance spectroscopies. We show that phosphorylation of a Ser residue stabilizes the α-helix in the context of an Arg(i−3)pSeri Lys(i+4) triad through charge-reinforced side chain interactions with positive co-operativity, whilst phosphorylation of Thr induces an opposing response. This is significant as it may represent a general method for control of PPIs by phosphorylation; basic kinase-substrate motifs are common with 55 human protein kinases recognizing an Arg at a position −3 from the phosphorylated Ser, whilst the Arg(i−3)Seri Lys(i+4) is a motif found in over 2000 human proteins

Negative Differential Resistivity and Positive Temperature Coefficient of Resistivity effect in the diffusion limited current of ferroelectric thin film capacitors

We present a model for the leakage current in ferroelectric thin- film capacitors which explains two of the observed phenomena that have escaped satisfactory explanation, i.e. the occurrence of either a plateau or negative differential resistivity at low voltages, and the observation of a Positive Temperature Coefficient of Resistivity (PTCR) effect in certain samples in the high-voltage regime. The leakage current is modelled by considering a diffusion-limited current process, which in the high-voltage regime recovers the diffusion-limited Schottky relationship of Simmons already shown to be applicable in these systems

Non‐restrictive interventions to reduce self‐harm amongst children in mental health inpatient settings: Systematic review and narrative synthesis

Rates of self-harm amongst children appear to be increasing. This presents challenges for practitioners responsible for maintaining the safety of children admitted to mental health inpatient settings. Policy guidelines recommend that practitioners should aim to avoid the use of restrictive practices for children. It is currently unclear, however, what evidence-based alternatives to restrictive practices are available. We aimed to identify what non-restrictive interventions have been proposed to reduce self-harm amongst children in mental health inpatient settings and to evaluate the evidence supporting their use in clinical practice. A systematic search of five databases (CINAHL, Embase, Ovid MEDLINE, APA Psycinfo, and Cochrane) was conducted to identify articles reporting on non-restrictive interventions aimed at reducing self-harm amongst children in mental health inpatient settings. Articles were quality assessed and relevant data were extracted and synthesized using narrative synthesis. Searches identified relatively few relevant articles (n = 7) and these were generally of low methodological quality. The underlying theoretical assumptions and putative mechanisms of change for the interventions described were often unclear. Despite concerns about the rates of self-harm amongst children in mental health inpatient settings, there is a lack of high-quality research to inform clinical practice. There is an urgent need to develop effective non-restrictive interventions aimed at reducing self-harm for children using inpatient mental health services. Intervention development should be theoretically informed and be conducted in collaboration with people who have lived experience of this issue

A first-principles study of oxygen vacancy pinning of domain walls in PbTiO3

We have investigated the interaction of oxygen vacancies and 180-degree domain walls in tetragonal PbTiO3 using density-functional theory. Our calculations indicate that the vacancies do have a lower formation energy in the domain wall than in the bulk, thereby confirming the tendency of these defects to migrate to, and pin, the domain walls. The pinning energies are reported for each of the three possible orientations of the original Ti-O-Ti bonds, and attempts to model the results with simple continuum models are discussed.Comment: 8 pages, with 3 postscript figures embedded. Uses REVTEX and epsf macros. Also available at http://www.physics.rutgers.edu/~dhv/preprints/lh_dw/index.htm

AMP second national workshop. Asthma Management Program

Powerpoint presentation presented at the Asthma Management Program: Second National Workshop, Stamford Plaza Sydney Airport Hote

Inhibition of Aurora‐A/N‐Myc protein–protein interaction using peptidomimetics: Understanding the role of peptide cyclization

Using N‐Myc61‐89 as a starting template we showcase the systematic use of truncation and maleimide constraining to develop peptidomimetic inhibitors of the N‐Myc/Aurora‐A protein–protein interaction (PPI); a potential anticancer drug discovery target. The most promising of these – N‐Myc73‐94‐N85C/G89C‐mal, is shown to favour a more Aurora‐A compliant binding ensemble in comparison to the linear wild‐type sequence as observed through fluorescence anisotropy competition assays, circular dichroism (CD) and nuclear magnetic resonance (NMR) experiments. Further in silico investigation of this peptide in its Aurora‐A bound state, by molecular dynamics (MD) simulations, imply (i) the bound conformation is more stable as a consequence of the constraint, which likely suppresses dissociation and (ii) the constraint may make further stabilizing interactions with the Aurora‐A surface. Taken together this work unveils the first orthosteric N‐Myc/Aurora‐A inhibitor and provides useful insights on the biophysical properties and thus design of constrained peptides, an attractive therapeutic modality

Evaluating the Evidence for Transmission Distortion in Human Pedigrees

Children of a heterozygous parent are expected to carry either allele with equal probability. Exceptions can occur, however, due to meiotic drive, competition among gametes, or viability selection, which we collectively term “transmission distortion” (TD). Although there are several well-characterized examples of these phenomena, their existence in humans remains unknown. We therefore performed a genome-wide scan for TD by applying the transmission disequilibrium test (TDT) genome-wide to three large sets of human pedigrees of European descent: the Framingham Heart Study (FHS), a founder population of European origin (HUTT), and a subset of the Autism Genetic Resource Exchange (AGRE). Genotyping error is an important confounder in this type of analysis. In FHS and HUTT, despite extensive quality control, we did not find sufficient evidence to exclude genotyping error in the strongest signals. In AGRE, however, many signals extended across multiple SNPs, a pattern highly unlikely to arise from genotyping error. We identified several candidate regions in this data set, notably a locus in 10q26.13 displaying a genome-wide significant TDT in combined female and male transmissions and a signature of recent positive selection, as well as a paternal TD signal in 6p21.1, the same region in which a significant TD signal was previously observed in 30 European males. Neither region replicated in FHS, however, and the paternal signal was not visible in sperm competition assays or as allelic imbalance in sperm. In maternal transmissions, we detected no strong signals near centromeres or telomeres, the regions predicted to be most susceptible to female-specific meiotic drive, but we found a significant enrichment of top signals among genes involved in cell junctions. These results illustrate both the potential benefits and the challenges of using the TDT to study transmission distortion and provide candidates for investigation in future studies

Dzyaloshinskii-Moriya Interaction and Spiral Order in Spin-orbit Coupled Optical Lattices

We show that the recent experimental realization of spin-orbit coupling in ultracold atomic gases can be used to study different types of spin spiral order and resulting multiferroic effects. Spin-orbit coupling in optical lattices can give rise to the Dzyaloshinskii-Moriya (DM) spin interaction which is essential for spin spiral order. By taking into account spin-orbit coupling and an external Zeeman field, we derive an effective spin model in the Mott insulator regime at half filling and demonstrate that the DM interaction in optical lattices can be made extremely strong with realistic experimental parameters. The rich finite temperature phase diagrams of the effective spin models for fermions and bosons are obtained via classical Monte Carlo simulations.Comment: 7 pages, 5 figure

Association of Lifestyle Factors With Abdominal Subcutaneous and Visceral Adiposity: The Framingham Heart Study

OBJECTIVE— The purpose of this study was to assess the relationship between lifestyle factors and abdominal subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) in a community-based setting