Miracle-dz/UniFAR-FTUs huggingface dataset:
Use of Docking Peptides to Design Modular Substrates with High Efficiency for MAP Kinase ERK

The mitogen-activated protein (MAP) kinase ERK plays a key role in the regulation of cellular proliferation. Mutations in the ERK cascade occur in 30% of malignant tumors. Thus understanding how the kinase identifies its cognate substrates as well as monitoring the activity of ERK is central to cancer research and therapeutic development. ERK binds to its protein targets, both downstream substrates and upstream activators, via a binding site distinct from the catalytic site of ERK. The substrate sequences that bind, or dock, to these sites on ERK influence the efficiency of phosphorylation. For this reason, simple peptide substrates containing only phosphorylation sequences typically possess low efficiencies for ERK. Appending short docking peptides derived from full-length protein substrates and activators of ERK to a phosphorylation sequence increased the affinity of ERK for the phosphorylation sequence by as much as 200-fold, while only slightly diminishing the maximal velocity of the reaction. The efficiency of the phosphorylation reaction was increased by up to 150 fold, while the specificity of the substrate for ERK was preserved. Simple, modular peptide substrates which can be easily tailored to possess high phosphorylation efficiencies will enhance our understanding of the regulation of ERK and provide a tool for the development of new kinase assays.
Expression of a mutant p 193 / CUL 7 molecule confers resistance to MG 132-and etoposide-induced apoptosis independent of p 53 or Parc binding

p193/CUL7 is an E3 ubiquitin ligase initially identified as an SV40 Large T Antigen binding protein. Expression of a dominant interfering variant of mouse p193/CUL7 (designated 1152stop) conferred resistance to MG132and etoposide-induced apoptosis in U2OS cells. Immune precipitation/Western analyses revealed that endogenous p193/CUL7 formed a complex with Parc (a recently identified parkin-like ubiquitin ligase) and p53. Apoptosis resistance did not result from 1152stop-mediated disruption of the endogenous p193/CUL7 binding partners. Moreover, 1152stop molecule did not directly bind to endogenous p193/CUL7, Parc or p53. These data suggested a role for p193/CUL7 in the regulation of apoptosis independently of p53 and Parc activity.
Dierent actions of protein kinase C isoforms a and e on gastric acid secretion

1 The phorbol ester TPA, an activator of protein kinase C (PKC), inhibits cholinergic stimulation of gastric acid secretion but increases basal H secretion. 2 Since these contradictory ®ndings suggest the action of dierent PKC isozymes we analysed the role of calcium-dependent PKC-a, and calcium-independent PKC-e in gastric acid secretion. 3 Inhibition of PKC-a by the indolocarbazole GoÈ 6976 revealed that about 28% of carbacholinduced acid secretion was inhibited by PKC-a. In the presence of GoÈ 6976 approximately 64% of the carbachol-induced signal transduction is mediated by Ca/calmodulin-dependent protein kinase II (CaMKII), and 14% is conveyed by PKC-e as deduced from the inhibition with the bisindolylmaleimide Ro 31-8220. 4 Inhibition of carbachol-induced acid secretion by TPA was accompanied by a decrease in CaMKII activity. 5 The stimulation of basal acid secretion by TPA was biphasic with a peak at a very low concentration (10 pM), resulting in an activation of the calcium-sensor CaMKII. The activation was determined with a phosphospeci®c polyclonal antibody against active CaMKII. The TPA-induced increase of H secretion was sensitive to the cell-permeable Ca-chelator BAPTA/AM, Ro 31-8220, and the CaMKII-inhibitor KN-62, but not to GoÈ 6976. 6 Since TPA induced the translocation of PKC-e but not of PKC-a in resting parietal cells, PKC-e seems to be at least responsible for an initial elevation of free intracellular calcium to initiate TPAinduced acid secretion. 7 Our data indicate the dierent roles of two PKC isoforms: PKC-e activation appears to facilitate cholinergic stimulation of H-secretion likely by increasing intracellular calcium. In contrast, PKC-a activation attenuates acid secretion accompanied by a down-regulation of CaMKII activity. British Journal of Pharmacology (2002) 136, 938 ± 946
man-biting rate and age-composition

The reduction in average age of a vector population after application of a residual insecticide is commonly interpreted under the implicit assumption that the vector population is uniformly exposed to the insecticide. This assumption maximizes the calculated impact of the insecticide on the vectorial capacity. An alternative assumption, namely that the vector population is composed of two subpopulations, one endophilic and exposed, the other exophilic and not exposed, leads to a much smaller calculated impact of insecticide on the vectorial capacity. This is illustrated with data collected before and after application of propoxur in the Garki District, Kano State, Nigeria. These data were also used to estimate, on the one hand, before spraying, theproportion ofblood meals taken by Anopheles gambiae s.l. on man that are followed by rest indoors, and on the other hand, after spraying, the proportion exposed after the first blood meal, according to the model of non-uniform exposure; the two estimates agree fairly well. The discussion compares the models of uniform and non-uniform exposure in terms of plausibility and concludes that the latter is more realistic. It is therefore prudent to take it into account when evaluating the impact of insecticides on the transmission of malaria.
Limitations of Gene × Environment Interaction Models in Psychiatry

Background—Psychiatric disorders run in families, and early twin, family and adoption studies confirmed that this was due in part to shared genetic inheritance. While candidate gene studies largely failed to reliably identify genetic variants associated with psychiatric disorders, genomewide association studies are beginning to do so. However, the proportion of phenotypic variance explained remains well below what would be expected from previous heritability estimates. Scope—We review possible reasons for this “missing heritability”, and in particular whether incorporating gene by environment interactions into our models will substantially improve our understanding of the aetiology of psychiatric disorders, and inform clinical perceptions and practice. Findings—We discuss potential limitations of the gene by environment interaction approach. In particular, we discuss whether these are likely to be a major contributor to psychiatric disorders at the level of the specific interaction (as opposed to at an aggregate level). Conclusions—Gene by environment interaction studies offered initial promise that a far greater proportion of phenotypic variance could be explained by incorporating measures of environmental exposures into genetic studies. However, in our opinion there are few (if any) clear examples of gene by environment interactions in psychiatry, and their scope for informing either our understanding of disease pathology or clinical practice remains limited at present.
AKT 1 is associated with schizophrenia across multiple symptom dimensions in the Irish Study of High Density Schizophrenia Families ( ISHDSF )

Background—The phosphatidylinositol 3-kinase (PI3K)-AKT signal transduction pathway is critical to cell growth and survival. In vitro functional studies indicate that the candidate schizophrenia susceptibility gene DTNBP1 influences AKT signaling to promote neuronal viability. The AKT1 gene has also been implicated in schizophrenia by association studies and decreased protein expression in the brains of schizophrenic patients.
Role for Mitogen Activated Protein Kinase p38α in Lung Epithelial Branching Morphogenesis

In the early stages of lung development, the endoderm undergoes extensive and stereotypic branching morphogenesis. During this process, a simple epithelial bud develops into a complex tree-like system of tubes specialized for the transport and exchange of gas with blood. The endodermal cells in the distal tips of the developing lung express a special set of genes, have a higher proliferation rate than proximal part, undergo shape change and initiate branching morphogenesis. In this study, we found that of the four p38 genes, only p38α mRNA is localized specifically to the distal endoderm suggesting a role in the regulation of budding morphogenesis. Chemical inhibitors specific for the p38α and p38β isoforms suppress budding of embryonic mouse lung explants and isolated endoderm in vitro. Specific knockdown of p38α in cultured lung endoderm using shRNA also inhibited budding morphogenesis, consistent with the chemical inhibition of the p38 signaling pathway. Disruption of p38α did not affect proliferation or expression of the distal cell markers, Sox9 and Erm. However, the amount of E-cadherin protein increased significantly and ectopic expression of E-cadherin also impaired budding of endoderm in vitro. These results suggest that p38α modulates epithelial cellcell interactions and possibly cell rearrangement during branching morphogenesis. This study provides the first evidence that p38α is involved in the morphogenesis of an epithelial organ.
Neural correlates of conceptual object priming in young and older adults: An event-related fMRI study

In this event-related fMRI study, we investigated age-related differences in brain activity associated with conceptual repetition priming in young and older adults. Participants performed a speeded “living/non-living” classification task with three repetitions of familiar objects. Both young and older adults showed a similar magnitude of behavioral priming to repeated objects and evidencing repetition-related activation reductions in fusiform gyrus, superior occipital, middle and inferior temporal cortex, as well as inferior frontal and insula regions. The neural priming effect in young adults was extensive and continued through both the second and third stimulus repetitions, whereas neural priming in older adults was markedly attenuated and reached floor at the second repetition. In young adults, greater neural priming in multiple brain regions correlated with greater behavioral facilitation whereas in older adults, only activation reduction in the left inferior frontal correlated with faster behavioral responses. These findings provide evidence for altered neural priming in older adults despite preserved behavioral priming, and suggest the possibility that age-invariant behavioral priming is observed as a result of more sustained neural processing of stimuli in older adults which may be a form of compensatory neural activity. © 2012 Elsevier Inc. All rights reserved. Address Correspondence to: Soledad Ballesteros, Department of Basic Psychology II, Universidad Nacional de Educación a Distancia, Juan del Rosal, 10, 28040, Madrid, Spain, mballesteros@psi.uned. es, Tel. : 34 91 3986227, Fax: 34 91 2987958. *These Authors contributed equally to this manuscript. DISCLOSURE ESTATEMENT There are no actual or potential conflict of interest. The data contained in the manuscript being submitted have not been previously published, have not been submitted elsewhere and will not be submitted elsewhere while under consideration at Neurobiology of Aging. All authors have reviewed the contents of the manuscript being submitted, approve of its contents and validate the accuracy of the data. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Author Manuscript Neurobiol Aging. Author manuscript; available in PMC 2014 May 20. Published in final edited form as: Neurobiol Aging. 2013 April ; 34(4): 1254–1264. doi:10.1016/j.neurobiolaging. 2012.09. 019. N IH -P A A uhor M anscript N IH -P A A uhor M anscript N IH -P A A uhor M anscript
Upregulation of the let-7 microRNA with precocious development in lin-12/Notch hypermorphic C. elegans mutants

The lin-12/Notch signaling pathway is conserved from worms to humans and is a master regulator of metazoan development. Here, we demonstrate that lin-12/Notch gain-of-function (gf) animals display precocious alae at the L4 larval stage with a significant increase in let-7 expression levels. Furthermore, lin-12(gf) animals display a precocious and higher level of let-7 gfp transgene expression in seam cells at L3 stage. Interestingly, lin-12(gf) mutant rescued the lethal phenotype of let-7 mutants similar to other known heterochronic mutants. We propose that lin-12/Notch signaling pathway functions in late developmental timing, upstream of or in parallel to the let-7 heterochronic pathway. Importantly, the human microRNA let-7a was also up-regulated in various human cell lines in response to Notch1 activation, suggesting an evolutionarily-conserved cross-talk between let-7 and the canonical lin-12/Notch signaling pathway.
Mechanisms test bed math model modification and simulation support

This report summarizes the work performed under contract NAS8-38771 in support of the Marshall Space Flight Center Six Degree of Freedom Motion Facility and Flight Robotics Laboratory. The contract activities included the development of the two flexible body and Remote Manipulator System simulations, Dynamic Overhead Target Simulator control system and operating software, Global Positioning System simulation, and Manipulator Coupled Spacecraft Controls Testbed. Technical support was also provided for the Lightning Imaging Sensor and Solar X-Ray Imaging programs. The cover sheets and introductory sections for the documentation written under this contract are provided as an appendix.
A benefit cost analysis of dry-cow mastitis therapy in dairy cattle in Ontario

Data collected from 297 dairy farms in Ontario were analyzed to investigate the economic consequences of using dry-cow antibiotic therapy, and to demonstrate the elements of an economic evaluation. Benefit/cost ratios ranged from 0.5 to 31.0 depending on the methods used to assess the benefits of therapy. In general, within the assumptions outlined in this analysis, dry-cow therapy was found to be economically advantageous. However, many factors can influence milk production and somatic cell counts. In this observational study, it is possible that some such factors were confounded with the use of dry-cow therapy, and may have biased the estimates of economic impact.
H-13 C Separated Local Field Spectroscopy of Uniformly 13 C Labeled Peptides and Proteins

By incorporating homonuclear decoupling on both the 1H and 13C channels it is feasible to obtain high-resolution two-dimensional separated local field spectra of peptides and proteins that are 100% labeled with 13C. Dual-PISEMO (Polarization Inversion Spin Exchange Modulated Observation) can be performed as a conventional two-dimensional experiment, or with windowed detection as a one-dimensional experiment that offers flexibility as a building block for Shiftless and other multidimensional triple-resonance experiments with the inclusion of 15N irradiation. The triple-resonance MAGC probe used to perform these experiments at 500 MHz is described.
Nucleic Acids Research

The DNA sequence of 2210 nucleotides including the gene for the "51 kd" chlorophyll a-conjugated thylakoid membrane protein associated with the photosystem II reaction center of spinach has been determined. This protein is functionally identical with the P68 chlorophyll a apoprotein that catalyses the primary light-induced photoc emical processes of photosystem II (Camm, E.L. and Green, B.R. (1983) Biochim. Biophys. Acta 724 291-293). The only large open reading frame in the sequence consists of 508 triplets encoding a protein of molecular mass of 56,246 kd. The deduced amino acid sequence shows clustering of hydrophobic residues into seven core regions which probably traverse the membrane, and a large hydrophilic domain of about 200 amino acids interspersed between span VI and VII. Potential transcription promotor and terminator signals flanking the structural gene show prokaryotic-like features. Seven discrete RNA species ranging in size from 2.0 to over 5.0 kilobases display complementarity to apoprotein coding sequences implying that the region can be polycistronically transcribed. The primary transcript includes information for at least two further genes coding for subunits of the cytochrome b/f complex.
Essential Yeast Tcpl Protein Affects Actin and Microtubules

Previously, we showed that the yeast Saccharomyces cerevisiae cold-sensitive mutation tcpl-I confers growth arrest concomitant with cytoskeletal disorganization and disruption of microtubule-mediated processes. We have identified two new recessive mutations, tcpl-2 and tcpl-3, that confer heatand cold-sensitive growth. Cells carrying tcpl alleles were analyzed after exposure to the appropriate restrictive temperatures by cell viability tests, differential contrast microscopy, fluorescent, and immunofluorescent microscopy of DNA, tubulin, and actin and by determining the DNA content per cell. All three mutations conferred unique phenotypes indicative of cytoskeletal dysfunction. A causal relationship between loss of Tcplp function and the development of cytoskeletal abnormalities was established by double mutant analyses. Novel phenotypes indicative of allele-specific genetic interactions were observed when tcpl-l was combined in the same strain with tubl-1, tub2-402, actl-1, and actl-4, but not with other tubulin or actin mutations or with mutations in other genes affecting the cytoskeleton. Also, overproduction of wild-type Tcplp partially suppressed growth defects conferred by actl-l and actl-4. Furthermore, Tcplp was localized to the cytoplasm and the cell cortex. Based on our results, we propose that Tcplp is required for normal development and function of actin and microtubules either through direct or indirect interaction with the major cytoskeletal components.
Examination of Correction to Historical SST Data Using Long-term Coastal SST Data Taken around Japan

Folland and Parker (1995) proposed the correction (so-called bucket correction) to historical sea surface temperature (SST) data from ship reports such as the Comprehensive Ocean-Atmosphere Data Set (GOADS). In order to examine the validation of this correction, comparison is made between SST data and long-term coastal SST (CSST) data taken at nine stations around Japan. For this purpose, we extract SST data in the adjacent areas surrounding nine CSST stations, from the files of COADS and the Kobe Collection data which have been recently released by the Japan Meteorological Agency and the Japan Weather Association. As a result, it is found that the data of five CSST stations among nine stations are suitable for comparison. When Folland and Parker's correction is adopted to the historical SST data, the systematic biases in monthly mean SST anomalies have been corrected almost perfectly at three stations, and the biases at the other two stations have been reduced by 40-50%.
BJRD15963 1..6

Objective: We evaluated whether patients with earlystage non-small-cell lung cancers (NSCLCs) treated with stereotactic body radiation therapy (SBRT) without full prescription dose coverage of the planning target volume (PTV) had inferior outcomes. Methods: The SBRT regimen was 54Gy in three fractions. Dosimetric constraints were as per the Radiation Therapy Oncology Group 0236 guidelines. All patients underwent four-dimensional CT (4D-CT) simulation. The internal target volume (ITV) was defined using 4D-CT, and the PTV was defined as a 6-mm longitudinal and a 3-mm axial expansion from the ITV. If normal tissue constraints were beyond tolerance, ITV-based dosing was employed where priority was made for full ITV coverage at the expense of PTV coverage. Patients with and without full PTV dose coverage were compared, and control rates were estimated using Kaplan–Meier analysis. Results: 120 NSCLC cases were evaluated with 81% having adequate PTV dose coverage. ITV and PTV were significantly larger in the cohort with inadequate PTV dose coverage (p50.0085 and p50.0038, respectively), and the mean ITV and PTV doses were higher in patients with adequate PTV dose coverage (p50.002 and p,0.0001, respectively). The 3-year local control ratewas 100% for both cohorts. Therewas no difference in 3-year regional control (p50.36), diseasespecific survival (p50.79) or overall survival (p50.73). Conclusion: When delivering a highly ablative SBRT regimen for early-stage NSCLC, full-dose coverage of the ITV is sufficient for local control. Advances in knowledge: Our data are among the first to evaluate the utility of PTV margins in a highly ablative SBRT regimen and suggest that when dosing constraints cannot be met, full tumouricidal dose coverage of the ITV is sufficient for local control.
EXPERIMENTAL MEASUREMENT OF THE STIFFNESS OF THE CUPULA

An experimental procedure is described which consists of cutting the canal duct, inserting a micropipette and administering known volumetric displacements to the cupula. The cupula is made visible by dying the endolymph. Known displacements are administered to the cupula, and the time constant of the return to its equilibrium position is measured. With this information, the stiffness of the cupula is calculated. The experiment was successfully carried out on five White King pigeons. The mean stiffness found is somewhat less than other results reported in the literature, and reasons for this discrepancy are noted.
Characterizing the Tumor Response to CA4P Treatment

Purpose—The purpose of this study was to examine the pathophysiologic impact of CA4P treatment in regions of tumors that ultimately either necrose or survive treatment with such agents. Methods and Materials—Proliferation, perfusion, vessel density, and VEGF expression were analyzed in the KHT tumor model following CA4P treatment. Analyses were conducted in the whole tumor and the tumor periphery. Results—Perfusion in the tumor periphery decreased 4 hours after treatment but returned to baseline 20 hours later. Whole tumor perfusion also decreased 4 hours after treatment, but did not return to baseline. Vessel density decreased in the tumor as a whole, but not in the tumor periphery. No significant effect on VEGF expression was observed, but a decrease in proliferation in the whole tumor and the periphery was noted. Conclusions—The present studies have shown that those areas of the tumor that survive CA4P treatment are affected by CA4P exposure, though only transiently. The decrease in perfusion could negatively impact therapies utilizing the combination of CA4P and conventional anticancer agents by decreasing drug delivery and tissue oxygenation. These findings suggest that the timing of CA4P treatments when used in conjunction with conventional anticancer therapies should be considered carefully.