Truncated and Helix-Constrained Peptides with High Affinity and Specificity for the cFos Coiled-Coil of AP-1

Protein-based therapeutics feature large interacting surfaces. Protein folding endows structural stability to localised surface epitopes, imparting high affinity and target specificity upon interactions with binding partners. However, short synthetic peptides with sequences corresponding to such protein epitopes are unstructured in water and promiscuously bind to proteins with low affinity and specificity. Here we combine structural stability and target specificity of proteins, with low cost and rapid synthesis of small molecules, towards meeting the significant challenge of binding coiled coil proteins in transcriptional regulation. By iteratively truncating a Jun-based peptide from 37 to 22 residues, strategically incorporating i-->i+4 helix-inducing constraints, and positioning unnatural amino acids, we have produced short, water-stable, alpha-helical peptides that bind cFos. A three-dimensional NMR-derived structure for one peptide (24) confirmed a highly stable alpha-helix which was resistant to proteolytic degradation in serum. These short structured peptides are entropically pre-organized for binding with high affinity and specificity to cFos, a key component of the oncogenic transcriptional regulator Activator Protein-1 (AP-1). They competitively antagonized the cJun–cFos coiled-coil interaction. Truncating a Jun-based peptide from 37 to 22 residues decreased the binding enthalpy for cJun by ~9 kcal/mol, but this was compensated by increased conformational entropy (TDS ≤ 7.5 kcal/mol). This study demonstrates that rational design of short peptides constrained by alpha-helical cyclic pentapeptide modules is able to retain parental high helicity, as well as high affinity and specificity for cFos. These are important steps towards small antagonists of the cJun-cFos interaction that mediates gene transcription in cancer and inflammatory diseases

Twistors, Harmonics and Holomorphic Chern-Simons

We show that the off-shell N=3 action of N=4 super Yang-Mills can be written as a holomorphic Chern-Simons action whose Dolbeault operator is constructed from a complex-real (CR) structure of harmonic space. We also show that the local space-time operators can be written as a Penrose transform on the coset SU(3)/(U(1) \times U(1)). We observe a strong similarity to ambitwistor space constructions.Comment: 34 pages, 3 figures, v2: replaced with published version, v3: Added referenc

The local economic development processes in low-income countries: the case of the metropolis of Chegutu in Zimbabwe

Local authorities are widely regarded as catalysts accelerating localised processes of economic development in industrialised countries but in low-income countries they are perceived as dysfunctional, inefficient and ineffective in meeting and addressing societal demands. This abstract view is however, not grounded in empirical research. As such, utilising the case of the metropolis of Chegutu a survey was designed to empirically explicate the economic processes militating its economic development. The findings are useful to policy-makers, local government authorities and management scholars. The study's unique contribution lies in its examination of the processes of local economic development in a low-income country

Solution to the Ward Identities for Superamplitudes

Supersymmetry and R-symmetry Ward identities relate on-shell amplitudes in a supersymmetric field theory. We solve these Ward identities for (Next-to)^K MHV amplitudes of the maximally supersymmetric N=4 and N=8 theories. The resulting superamplitude is written in a new, manifestly supersymmetric and R-invariant form: it is expressed as a sum of very simple SUSY and SU(N)_R-invariant Grassmann polynomials, each multiplied by a "basis amplitude". For (Next-to)^K MHV n-point superamplitudes the number of basis amplitudes is equal to the dimension of the irreducible representation of SU(n-4) corresponding to the rectangular Young diagram with N columns and K rows. The linearly independent amplitudes in this algebraic basis may still be functionally related by permutation of momenta. We show how cyclic and reflection symmetries can be used to obtain a smaller functional basis of color-ordered single-trace amplitudes in N=4 gauge theory. We also analyze the more significant reduction that occurs in N=8 supergravity because gravity amplitudes are not ordered. All results are valid at both tree and loop level.Comment: 29 pages, published versio

The S-Matrix in Twistor Space

The simplicity and hidden symmetries of (Super) Yang-Mills and (Super)Gravity scattering amplitudes suggest the existence of a "weak-weak" dual formulation in which these structures are made manifest at the expense of manifest locality. We suggest that this dual description lives in (2,2) signature and is naturally formulated in twistor space. We recast the BCFW recursion relations in an on-shell form that begs to be transformed into twistor space. Our twistor transformation is inspired by Witten's, but differs in treating twistor and dual twistor variables more equally. In these variables the three and four-point amplitudes are amazingly simple; the BCFW relations are represented by diagrammatic rules that precisely define the "twistor diagrams" of Andrew Hodges. The "Hodges diagrams" for Yang-Mills theory are disks and not trees; they reveal striking connections between amplitudes and suggest a new form for them in momentum space. We also obtain a twistorial formulation of gravity. All tree amplitudes can be combined into an "S-Matrix" functional which is the natural holographic observable in asymptotically flat space; the BCFW formula turns into a quadratic equation for this "S-Matrix", providing a holographic description of N=4 SYM and N=8 Supergravity at tree level. We explore loop amplitudes in (2,2) signature and twistor space, beginning with a discussion of IR behavior. We find that the natural pole prescription renders the amplitudes well-defined and free of IR divergences. Loop amplitudes vanish for generic momenta, and in twistor space are even simpler than their tree-level counterparts! This further supports the idea that there exists a sharply defined object corresponding to the S-Matrix in (2,2) signature, computed by a dual theory naturally living in twistor space.Comment: V1: 46 pages + 23 figures. Less telegraphic abstract in the body of the paper. V2: 49 pages + 24 figures. Largely expanded set of references included. Some diagrammatic clarifications added, minor typo fixe

Contact Manifolds, Contact Instantons, and Twistor Geometry

Recently, Kallen and Zabzine computed the partition function of a twisted supersymmetric Yang-Mills theory on the five-dimensional sphere using localisation techniques. Key to their construction is a five-dimensional generalisation of the instanton equation to which they refer as the contact instanton equation. Subject of this article is the twistor construction of this equation when formulated on K-contact manifolds and the discussion of its integrability properties. We also present certain extensions to higher dimensions and supersymmetric generalisations.Comment: v3: 28 pages, clarifications and references added, version to appear in JHE

Spin-orbit density wave induced hidden topological order in URu2Si2

The conventional order parameters in quantum matters are often characterized by 'spontaneous' broken symmetries. However, sometimes the broken symmetries may blend with the invariant symmetries to lead to mysterious emergent phases. The heavy fermion metal URu2Si2 is one such example, where the order parameter responsible for a second-order phase transition at Th = 17.5 K has remained a long-standing mystery. Here we propose via ab-initio calculation and effective model that a novel spin-orbit density wave in the f-states is responsible for the hidden-order phase in URu2Si2. The staggered spin-orbit order 'spontaneous' breaks rotational, and translational symmetries while time-reversal symmetry remains intact. Thus it is immune to pressure, but can be destroyed by magnetic field even at T = 0 K, that means at a quantum critical point. We compute topological index of the order parameter to show that the hidden order is topologically invariant. Finally, some verifiable predictions are presented.Comment: (v2) Substantially modified from v1, more calculation and comparison with experiments are include

Activity profiles of elite wheelchair rugby players during competition

To quantify the activity profiles of elite wheelchair rugby and establish classification-specific arbitrary speed zones. Additionally, indicators of fatigue during full matches were explored. Methods: Seventy-five elite wheelchair rugby players from eleven national teams were monitored using a radio-frequency based, indoor tracking system across two international tournaments. Players who participated in complete quarters (n = 75) and full matches (n = 25) were included and grouped by their International Wheelchair Rugby Federation functional classification: group I (0-0.5), II (1.0-1.5), III (2.0-2.5) and IV (3.0-3.5). Results: During a typical quarter, significant increases in total distance (m), relative distance (m·minˉ¹), and mean speed (m·sˉ¹) were associated with an increase in classification group (P < 0.001), with the exception of group III and IV. However, group IV players achieved significantly higher peak speeds (3.82 ± 0.31 m·sˉ¹) than groups I (2.99 ± 0.28 m·sˉ¹), II (3.44 ± 0.26 m·sˉ¹) and III (3.67 ± 0.32 m·sˉ¹). Groups I and II differed significantly in match intensity during very low/low speed zones and the number of high-intensity activities in comparison with groups III and IV (P < 0.001). Full match analysis revealed that activity profiles did not differ significantly between quarters. Conclusions: Notable differences in the volume of activity were displayed across the functional classification groups. However, the specific on-court requirements of defensive (I and II) and offensive (III and IV) match roles appeared to influence the intensity of match activities and consequently training prescription should be structured accordingly

Labrador retrievers under primary veterinary care in the UK: demography, mortality and disorders

Abstract Background Labrador retrievers are reportedly predisposed to many disorders but accurate prevalence information relating to the general population are lacking. This study aimed to describe demography, mortality and commonly recorded diseases in Labrador retrievers under UK veterinary care. Methods The VetCompass™ programme collects electronic patient record data on dogs attending UK primary-care veterinary practices. Demographic analysis covered all33,320 Labrador retrievers in the VetCompass™ database under veterinary care during 2013 while disorder and mortality data were extracted from a random sample of 2074 (6.2%) of these dogs. Results Of the Labrador retrievers with information available, 15,427 (46.4%) were female and 15,252 (53.6%) were male. Females were more likely to be neutered than males (59.7% versus 54.8%, P <  0.001). The overall mean adult bodyweight was 33.0 kg (SD 6.1). Adult males were heavier (35.2 kg, SD 5.9 kg) than adult females (30.4 kg, SD 5.2 kg) (P <  0.001). The median longevity of Labrador retrievers overall was 12.0 years (IQR 9.9–13.8, range 0.0–16.0). The most common recorded colours were black (44.6%), yellow (27.8%) and liver/chocolate (reported from hereon as chocolate) (23.8%). The median longevity of non-chocolate coloured dogs (n = 139, 12.1 years, IQR 10.2–13.9, range 0.0–16.0) was longer than for chocolate coloured animals (n = 34, 10.7 years, IQR 9.0–12.4, range 3.8–15.5) (P = 0.028). Of a random sample of 2074 (6.2%) Labrador retrievers under care in 2013 that had full disorder data extracted, 1277 (61.6%) had at least one disorder recorded. The total number of dogs who died at any date during the study was 176. The most prevalent disorders recorded were otitis externa (n = 215, prevalence 10.4%, 95% CI: 9.1–11.8), overweight/obesity (183, 8.8%, 95% CI: 7.6–10.1) and degenerative joint disease (115, 5.5%, 95% CI: 4.6–6.6). Overweight/obesity was not statistically significantly associated with neutering in females (8.3% of entire versus 12.5% of neutered, P = 0.065) but was associated with neutering in males (4.1% of entire versus 11.4% of neutered, P < 0.001). The prevalence of otitis externa in black dogs was 12.8%, in yellow dogs it was 17.0% but, in chocolate dogs, it rose to 23.4% (P < 0.001). Similarly, the prevalence of pyo-traumatic dermatitis in black dogs was 1.1%, in yellow dogs it was 1.6% but in chocolate dogs it rose to 4.0% (P = 0.011). Conclusions The current study assists prioritisation of health issues within Labrador retrievers. The most common disorders were overweight/obesity, otitis externa and degenerative joint disease. Males were significantly heavier females. These results can alert prospective owners to potential health issues and inform breed-specific wellness checks

A Review of the Design Process for Implantable Orthopedic Medical Devices

The design process for medical devices is highly regulated to ensure the safety of patients. This paper will present a review of the design process for implantable orthopedic medical devices. It will cover the main stages of feasibility, design reviews, design, design verification, manufacture, design validation, design transfer and design changes