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

The International Intellectual Property Commercialization Council’s 3rd Annual U.S. Conference: The State of Innovation in the Union

The International Intellectual Property Commercialization Council (“IIPCC”) presented its third annual policy conference at the United States Capitol on May 6, 2019. The conference’s theme explored the question of “what is the state of innovation in the United States?” Panelists included The Honorable Andrei Iancu – Under Secretary of Commerce for Intellectual Property and Director of the United States Patent and Trademark Office; Dr. Carl J. Schramm – University Professor, Syracuse University and Former President of the Ewing Marion Kauffman Foundation; Mr. Patrick Kilbride – Senior Vice President of the Global Innovation Policy Center (“GIPC”) at the U.S. Chamber of Commerce; and Mr. Colman Ragan – Vice President and General Counsel, North America IP Litigation at Teva Pharmaceuticals, who all shared their perspectives on the state of innovation. A lead off panel including local entrepreneurs, intellectual property specialists, federal government specialists, and academics allowed this panel to provide a “boots on the ground” perspective

Explicit processing of verbal and spatial features during letter-location binding modulates oscillatory activity of a fronto-parietal network.

The present study investigated the binding of verbal and spatial features in immediate memory. In a recent study, we demonstrated incidental and asymmetrical letter-location binding effects when participants attended to letter features (but not when they attended to location features) that were associated with greater oscillatory activity over prefrontal and posterior regions during the retention period. We were interested to investigate whether the patterns of brain activity associated with the incidental binding of letters and locations observed when only the verbal feature is attended differ from those reflecting the binding resulting from the controlled/explicit processing of both verbal and spatial features. To achieve this, neural activity was recorded using magnetoencephalography (MEG) while participants performed two working memory tasks. Both tasks were identical in terms of their perceptual characteristics and only differed with respect to the task instructions. One of the tasks required participants to process both letters and locations. In the other, participants were instructed to memorize only the letters, regardless of their location. Time–frequency representation of MEG data based on the wavelet transform of the signals was calculated on a single trial basis during the maintenance period of both tasks. Critically, despite equivalent behavioural binding effects in both tasks, single and dual feature encoding relied on different neuroanatomical and neural oscillatory correlates. We propose that enhanced activation of an anterior–posterior dorsal network observed in the task requiring the processing of both features reflects the necessity for allocating greater resources to intentionally process verbal and spatial features in this task

Development and Optimization of Gas-Assisted Gravity Drainage (GAGD) Process for Improved Light Oil Recovery

This is the final report describing the evolution of the project ''Development and Optimization of Gas-Assisted Gravity Drainage (GAGD) Process for Improved Light Oil Recovery'' from its conceptual stage in 2002 to the field implementation of the developed technology in 2006. This comprehensive report includes all the experimental research, models developments, analyses of results, salient conclusions and the technology transfer efforts. As planned in the original proposal, the project has been conducted in three separate and concurrent tasks: Task 1 involved a physical model study of the new GAGD process, Task 2 was aimed at further developing the vanishing interfacial tension (VIT) technique for gas-oil miscibility determination, and Task 3 was directed at determining multiphase gas-oil drainage and displacement characteristics in reservoir rocks at realistic pressures and temperatures. The project started with the task of recruiting well-qualified graduate research assistants. After collecting and reviewing the literature on different aspects of the project such gas injection EOR, gravity drainage, miscibility characterization, and gas-oil displacement characteristics in porous media, research plans were developed for the experimental work to be conducted under each of the three tasks. Based on the literature review and dimensional analysis, preliminary criteria were developed for the design of the partially-scaled physical model. Additionally, the need for a separate transparent model for visual observation and verification of the displacement and drainage behavior under gas-assisted gravity drainage was identified. Various materials and methods (ceramic porous material, Stucco, Portland cement, sintered glass beads) were attempted in order to fabricate a satisfactory visual model. In addition to proving the effectiveness of the GAGD process (through measured oil recoveries in the range of 65 to 87% IOIP), the visual models demonstrated three possible multiphase mechanisms at work, namely, Darcy-type displacement until gas breakthrough, gravity drainage after breakthrough and film-drainage in gas-invaded zones throughout the duration of the process. The partially-scaled physical model was used in a series of experiments to study the effects of wettability, gas-oil miscibility, secondary versus tertiary mode gas injection, and the presence of fractures on GAGD oil recovery. In addition to yielding recoveries of up to 80% IOIP, even in the immiscible gas injection mode, the partially-scaled physical model confirmed the positive influence of fractures and oil-wet characteristics in enhancing oil recoveries over those measured in the homogeneous (unfractured) water-wet models. An interesting observation was that a single logarithmic relationship between the oil recovery and the gravity number was obeyed by the physical model, the high-pressure corefloods and the field data

Modern microwave methods in solid state inorganic materials chemistry: from fundamentals to manufacturing

No abstract available

The Effect of Patients’ Met Expectations on Consultation Outcomes. A Study with Family Medicine Residents

OBJECTIVES: To know the patients’ expectations and the fulfillment of these at family medicine consultations by resident doctors and to assess their effect on some consultation outcomes. DESIGN: A prospective cohort study. PARTICIPANTS: Patients attending family medicine consultations held by 38 resident doctors: 1,301 eligible patients, 702 filled in all questionnaires. MEASUREMENTS: Before each visit, the patients’ expectations about that particular consultation were registered. Right after the visit was over, their perception of several aspects of the communicative interaction with the doctor was measured. Later, patients were interviewed on the phone to know how their expectations had been fulfilled, how satisfied they were about the consultation, how they had followed the doctor’s suggestions, if they were going to seek further care for the same cause later, and the evolution of their clinical problem. Logistic regression was the main analysis used. RESULTS: The most common expectations were the doctor showing interest and listening (30.5%), getting some information about the diagnosis (16.3%), and sharing problems and doubts (11.1%). The rate of main expectations that were met was 76.5%. Satisfaction with the encounter was associated with the clinical evolution [odds ratio (OR) 2.23; confidence interval (CI): 1.32–3.75], and the fulfilling of the patients’ main or two main expectations was significantly related to all the measured outcomes (satisfaction OR 3.51, CI: 1.73–7.8; adherence OR 1.80, CI: 1.11–2.92; clinical evolution OR 1.54, CI: 1.01–2.35; and seeking further care later OR 0.54, CI:0.36–0.81) CONCLUSIONS: Patients prioritize expectations of a more general sort when they attend primary care consultations and residents fulfill these acceptably. The fulfillment of expectations seems to affect the studied outcomes more than other factors

Search for squarks and gluinos in events with isolated leptons, jets and missing transverse momentum at s√=8 TeV with the ATLAS detector

The results of a search for supersymmetry in final states containing at least one isolated lepton (electron or muon), jets and large missing transverse momentum with the ATLAS detector at the Large Hadron Collider are reported. The search is based on proton-proton collision data at a centre-of-mass energy s√=8 TeV collected in 2012, corresponding to an integrated luminosity of 20 fb−1. No significant excess above the Standard Model expectation is observed. Limits are set on supersymmetric particle masses for various supersymmetric models. Depending on the model, the search excludes gluino masses up to 1.32 TeV and squark masses up to 840 GeV. Limits are also set on the parameters of a minimal universal extra dimension model, excluding a compactification radius of 1/R c = 950 GeV for a cut-off scale times radius (ΛR c) of approximately 30

Measurements of fiducial and differential cross sections for Higgs boson production in the diphoton decay channel at s√=8 TeV with ATLAS

Measurements of fiducial and differential cross sections are presented for Higgs boson production in proton-proton collisions at a centre-of-mass energy of s√=8 TeV. The analysis is performed in the H → γγ decay channel using 20.3 fb−1 of data recorded by the ATLAS experiment at the CERN Large Hadron Collider. The signal is extracted using a fit to the diphoton invariant mass spectrum assuming that the width of the resonance is much smaller than the experimental resolution. The signal yields are corrected for the effects of detector inefficiency and resolution. The pp → H → γγ fiducial cross section is measured to be 43.2 ±9.4(stat.) − 2.9 + 3.2 (syst.) ±1.2(lumi)fb for a Higgs boson of mass 125.4GeV decaying to two isolated photons that have transverse momentum greater than 35% and 25% of the diphoton invariant mass and each with absolute pseudorapidity less than 2.37. Four additional fiducial cross sections and two cross-section limits are presented in phase space regions that test the theoretical modelling of different Higgs boson production mechanisms, or are sensitive to physics beyond the Standard Model. Differential cross sections are also presented, as a function of variables related to the diphoton kinematics and the jet activity produced in the Higgs boson events. The observed spectra are statistically limited but broadly in line with the theoretical expectations