Exploring the Pharmacophore of Novel Synthetic Peptide Activators of type I-alpha cGMP-Dependent Protein Kinase

cGMP-dependent protein kinase (PKG, cGPK) is a serine-threonine kinase of the AGC-kinase family. Although PKG type Ia plays a prominent role in the control of blood-flow and blood pressure, no current hypertension therapies target this enzyme.1 A PKG-targeted therapy would establish a first-in-class treatment for patients with uncontrolled blood pressure and may provide a clinically relevant alternative to existing antihypertensive therapies. Dostmann et al. developed novel peptides derived from the crystal structure of PKG Ia, which are helical in solution and found to activate the kinase independent of cGMP and were demonstrated to lower blood pressure in vivo.2,3 Two consecutive phenylalanine residues were identified as a central element of the putative pharmacophore within the full-length peptide. However, a shortened peptide derivative, called S1.5 (here SP), was found to have increased potency and thus has been suggested as a potential lead compound for further development. The aim of this thesis is to reevaluate the pharmacophore and specifically the role of the phenylalanine residues in context of the SP peptide. In this study, analogs of SP were designed using an alanine-scanning approach to analyze the role of specific amino acids in the activation mechanism. By employing recombinant PKG Ia, kinetic parameters were determined using a specific radiometric assay.4,5 We found that substituting either or both phenylalanine residues for alanine did not impair the peptide’s potency or efficacy. However, deleting one phenylalanine greatly diminished activity. This phenotype could be rescued by substituting either of two positively charged lysine residues N-terminal to the pharmacophore for alanine. These results indicate that the interactions between the kinase and these novel synthetic peptides are more complex and involve unidentified amino acids. Furthermore, the results presented here will serve to evaluate the role of N-terminal residues in peptide binding and the rescue phenotype discovered in this study

Publisher Correction: An engineered human Fc domain that behaves like a pH-toggle switch for ultra-long circulation persistence.

An amendment to this paper has been published and can be accessed via a link at the top of the paper

Do young children get the message? The effects of repeated video viewing on explicit and implicit information

The aim of this study was to explore the effects of repeat viewing on comprehension of explicitly and implicitly presented information in an animated movie. Seventy-three pre-school children watched an animated film and were tested for comprehension after either their single or fifth viewing. Only children&rsquo;s comprehension of explicitly presented information was facilitated by repeat viewing. However, post hoc analyses revealed that children&rsquo;s explicit and implicit comprehension of a central character Thunderbolt significantly increased across viewing conditions, whereas, repeat viewing only facilitated children&rsquo;s explicit comprehension of the central character Patch. The theoretical and practical implications of these findings are discussed.<br /

New Hubble Space Telescope Discoveries of Type Ia Supernovae at z > 1: Narrowing Constraints on the Early Behavior of Dark Energy

We have discovered 21 new Type Ia supernovae (SNe Ia) with the Hubble Space Telescope (HST) and have used them to trace the history of cosmic expansion over the last 10 billion years. These objects, which include 13 spectroscopically confirmed SNe Ia at z > 1, were discovered during 14 epochs of reimaging of the GOODS fields North and South over two years with the Advanced Camera for Surveys on HST. Together with a recalibration of our previous HST-discovered SNe Ia, the full sample of 23 SNe Ia at z > 1 provides the highest-redshift sample known. Combined with previous SN Ia datasets, we measured H(z) at discrete, uncorrelated epochs, reducing the uncertainty of H(z>1) from 50% to under 20%, strengthening the evidence for a cosmic jerk--the transition from deceleration in the past to acceleration in the present. The unique leverage of the HST high-redshift SNe Ia provides the first meaningful constraint on the dark energy equation-of-state parameter at z >1. The result remains consistent with a cosmological constant (w(z)=-1), and rules out rapidly evolving dark energy (dw/dz >>1). The defining property of dark energy, its negative pressure, appears to be present at z>1, in the epoch preceding acceleration, with ~98% confidence in our primary fit. Moreover, the z>1 sample-averaged spectral energy distribution is consistent with that of the typical SN Ia over the last 10 Gyr, indicating that any spectral evolution of the properties of SNe Ia with redshift is still below our detection threshold.Comment: typos, references corrected, minor additions to exposition 82 pages, 17 figures, 6 tables. Data also available at: http://braeburn.pha.jhu.edu/~ariess/R06. Accepted, Astrophysical Journal vol. 656 for March 10, 200

Completeness of Communicable Disease Reporting, North Carolina, USA, 1995–1997 and 2000–2006

Reporting proportions were <50% for 49 of the 53 diseases evaluated

Cryptic Eimeria genotypes are common across the southern but not northern hemisphere

The phylum Apicomplexa includes parasites of medical, zoonotic and veterinary significance. Understanding the global distribution and genetic diversity of these protozoa is of fundamental importance for efficient, robust and long-lasting methods of control. Eimeria spp. cause intestinal coccidiosis in all major livestock animals and are the most important parasites of domestic chickens in terms of both economic impact and animal welfare. Despite having significant negative impacts on the efficiency of food production, many fundamental questions relating to the global distribution and genetic variation of Eimeria spp. remain largely unanswered. Here, we provide the broadest map yet of Eimeria occurrence for domestic chickens, confirming that all the known species (Eimeria acervulina, Eimeria brunetti, Eimeria maxima, Eimeria mitis, Eimeria necatrix, Eimeria praecox, Eimeria tenella) are present in all six continents where chickens are found (including 21 countries). Analysis of 248 internal transcribed spacer sequences derived from 17 countries provided evidence of possible allopatric diversity for species such as E. tenella (FST values ⩽0.34) but not E. acervulina and E. mitis, and highlighted a trend towards widespread genetic variance. We found that three genetic variants described previously only in Australia and southern Africa (operational taxonomic units x, y and z) have a wide distribution across the southern, but not the northern hemisphere. While the drivers for such a polarised distribution of these operational taxonomic unit genotypes remains unclear, the occurrence of genetically variant Eimeria may pose a risk to food security and animal welfare in Europe and North America should these parasites spread to the northern hemisphere

Moderate intensity intermittent lifestyle physical activity is associated with better executive function in older adults

Executive functions are among the first cognitive abilities to decline with age and age-related executive function slowing predisposes older adults to cognitive disorders and disease. Intermittent Lifestyle Physical Activity (ILPA) reflects brief, unplanned activity that occurs during routine daily activities and is operationalized as activity bouts &lt;60s. Our understanding of short bouts of habitual physical activity and executive functions is limited. We tested the hypothesis that greater amounts of ILPA in moderate and vigorous intensity domains would be associated with better executive function in older adults. Forty older adults (26 females, 68 ± 6, &gt;55 years; body mass index: 26.6 ± 4.3 kg/m2) completed a Trail-Making-Task and wore an activPAL 24-hr/day for 6.2 ± 1.8-days. For each intensity, total time and time spent in bouts &lt;60 s were determined. Trail A (processing speed) and Trail B (cognitive flexibility) were completed in 25.8 ± 8.2 s and 63.2 ± 26.2 s, respectively. Non-parametric Spearman's rank correlations report that moderate ILPA (3.2 ± 3.2 min/day) and total-moderate physical activity (20.1 ± 16.0 min/day) were associated with faster Trail A (total-moderate physical activity: ρ=−0.48; moderate-ILPA: ρ = −0.50; both, p &lt; 0.003) and Trail B time (total-moderate physical activity: ρ = 0.36; moderate-ILPA: ρ = −0.46; both, p &lt; 0.020). However, the results show no evidence of an association with either vigorous physical activity or light physical activity (total time or ILPA bouts: all, p &gt; 0.180). Moderate physical activity accumulated in longer bouts (&gt;60 s) was not associated with Trail B time (p = 0.201). Therefore, more total moderate physical activity and shorter bouts (&lt;60 s) may result in better executive functions in older adults

Retrospective evaluation of hypertrophic cardiomyopathy in 68 dogs

BACKGROUND: There is a lack of clinical data on hypertrophic cardiomyopathy (HCM) in dogs. HYPOTHESIS/OBJECTIVES: To investigate signalment, clinical signs, diagnostic findings, and survival in dogs with HCM. ANIMALS: Sixty-eight client-owned dogs. METHODS: Retrospective multicenter study. Medical records were searched between 2003 and 2015. The diagnosis of left ventricular (LV) hypertrophy was made by echocardiographic examination. RESULTS: Three hundred and forty-five dogs with LV hypertrophy were identified, of which 277 were excluded. The remaining 68 dogs were 0.3 to 14 years old and predominantly <10 kg (85%), and without a sex predilection. Twenty-four % were Shih Tzu and 24% terrier breeds. Most (80%) had a systolic heart murmur. Owner-determined exercise intolerance (37%) and syncope (18%) were most commonly reported signs. The majority (84%) of dogs had symmetrical LV hypertrophy, whereas asymmetrical septal and LV free wall hypertrophy was observed in 9% and 6% of dogs, respectively. Isolated basal interventricular septal hypertrophy was not observed. Commonly recorded were systolic anterior motion of the mitral valve (60%) and LV diastolic dysfunction (89% of dogs where diastolic function was evaluated). Six dogs died unexpectedly, and 3 developed congestive heart failure. Known survival times were between 1 day and 114 months after diagnosis. CONCLUSIONS AND CLINICAL IMPORTANCE: Hypertrophic cardiomyopathy in dogs should be considered as a differential diagnosis if LV hypertrophy is identified. Small breed dogs are overrepresented, and it is uncommon for dogs with HCM to develop CHF although sudden death can occur