Human IGF-I propeptide A promotes articular chondrocyte biosynthesis and employs glycosylation-dependent heparin binding

Background Insulin-like growth factor I (IGF-I) is a key regulator of chondrogenesis, but its therapeutic application to articular cartilage damage is limited by rapid elimination from the repair site. The human IGF-I gene gives rise to three IGF-I propeptides (proIGF-IA, proIGF-IB and proIGF-IC) that are cleaved to create mature IGF-I. In this study, we elucidate the processing of IGF-I precursors by articular chondrocytes, and test the hypotheses that proIGF-I isoforms bind to heparin and regulate articular chondrocyte biosynthesis. Methods Human IGF-I propeptides and mutants were overexpressed in bovine articular chondrocytes. IGF-I products were characterized by ELISA, western blot and FPLC using a heparin column. The biosynthetic activity of IGF-I products on articular chondrocytes was assayed for DNA and glycosaminoglycan that the cells produced. Results Secreted IGF-I propeptides stimulated articular chondrocyte biosynthetic activity to the same degree as mature IGF-I. Of the three IGF-I propeptides, only one, proIGF-IA, strongly bound to heparin. Interestingly, heparin binding of proIGF-IA depended on N-glycosylation at Asn92 in the EA peptide. To our knowledge, this is the first demonstration that N-glycosylation determines the binding of a heparin-binding protein to heparin. Conclusion The biosynthetic and heparin binding abilities of proIGF-IA, coupled with its generation of IGF-I, suggest that proIGF-IA may have therapeutic value for articular cartilage repair. General significance These data identify human pro-insulin-like growth factor IA as a bifunctional protein. Its combined ability to bind heparin and augment chondrocyte biosynthesis makes it a promising therapeutic agent for cartilage damage due to trauma and osteoarthritis

3D-Image Analysis of the Impact of Toothpaste Abrasivity on the Progression of Simulated Non-Carious Cervical Lesions

Objectives To investigate the effect of toothpaste abrasive level on the progression of non-carious cervical lesions (NCCLs) using 3D-image subtraction. Methods Upper first premolars were allocated into seven groups (n = 16) of toothpaste/abrasive slurries: A-Zeodent113/5%, B-Zeodent124/10%, C-Zeodent103/15%, D-Sensodyne Pronamel, E-Crest Cavity-Protection, F-Crest Pro-Health-Whitening, and G-Deionized water (DIW). Teeth were mounted on acrylic blocks, and their root surfaces covered with acrylic resin, except for 2-mm near the cemento-enamel junction that was exposed to toothbrushing. Specimens were brushed with the slurries for 5000-, 15,000-, 35,000- and 65,000-strokes. Impressions were taken at baseline and after each brushing time, and then scanned by a 3D optical profilometer. Dentine volume loss was calculated by image subtraction software and subjected to mixed-model ANOVA and multiple comparison tests (α = 0.05). Results No significant differences among slurries were observed at 5000 and 15,000. At 35,000, F showed higher loss than all other groups except C, which did not differ from the others. At 65,000, F (4.19 ± 3.29 mm3) showed the highest loss, followed by C (2.33 ± 1.47 mm3), which differed from all the other groups except B (1.85 ± 0.91 mm3). Groups B, A (1.35 ± 0.65 mm3), D (1.17 ± 0.48 mm3), E (1.40 ± 0.68 mm3) and G (1.12 ± 0.73 mm3) did not differ from each other. Groups F and C showed significant increase of volume loss starting at 35,000, while B, A, D and E only at 65,000; no increase loss was observed for G. Conclusions 3D-image subtraction was able to quantify and differentiate tooth loss, but only at advanced stages. The progression of NCCLs was more evident and faster for highly abrasive slurries. Clinical significance Upon root dentin exposure, brushing with lower abrasive dentifrices is advisable to reduce the risk for NCCLs development

In situ Fluoride Response of Caries Lesions with Different Mineral Distributions at Baseline

The present in situ study investigated the fluoride response of caries lesions with similar mineral loss but two distinct mineral distributions (low- and high-‘R’, calculated as the ratio of mineral loss to lesion depth). Sixteen subjects wore eight gauze-covered enamel specimens with preformed lesions placed buccally on their mandibular partial dentures for periods up to 4 weeks. The participants brushed twice daily for 1 min with an 1,100 ppm F (as NaF) dentifrice. After 3 and 4 weeks, specimens were retrieved and analyzed microradiographically (TMR) and by quantitative light fluorescence (QLF). TMR results revealed that low- and high-R lesions showed opposite behaviors – low-R lesions further demineralized, whereas high-R lesions exhibited some remineralization. In comparison, lesion depth increased in low-R, but remained unchanged in high-R lesions; R decreased in both, but more in high-R lesions; mineral density at the lesion surface remained unchanged in low-R, but increased in high-R lesions. Differences in mineral loss between lesion types increased further between 3 and 4 weeks. QLF did not mirror TMR results as low-R lesions were found to remineralize, whereas high-R lesions remained unchanged. It is likely that low-R lesions differ from high-R lesions chemically and microstructurally; therefore rendering low-R lesion more susceptible to further dissolution. During lesion formation, low-R in contrast to high-R lesions may not lose all of the solubility-determining impurities such as magnesium and carbonate, which can reprecipitate again in different mineral phases within the lesion. In conclusion, mineral distribution at baseline directly impacts in situ lesion response to fluoride

Attitudes and Biases of Health Professionals Toward Individuals with Disabilities: An Evidence-Based Practice Project

This Evidence-Based Practice (EBP) project considered the following question: What are the attitudes and biases of health professionals toward individuals with disabilities and what are the implications for training

SYNZIP Protein Interaction Toolbox: in Vitro and in Vivo Specifications of Heterospecific Coiled-Coil Interaction Domains

The synthetic biology toolkit contains a growing number of parts for regulating transcription and translation, but very few that can be used to control protein association. Here we report characterization of 22 previously published heterospecific synthetic coiled-coil peptides called SYNZIPs. We present biophysical analysis of the oligomerization states, helix orientations, and affinities of 27 SYNZIP pairs. SYNZIP pairs were also tested for interaction in two cell-based assays. In a yeast two-hybrid screen, >85% of 253 comparable interactions were consistent with prior in vitro measurements made using coiled-coil microarrays. In a yeast-signaling assay controlled by coiled-coil mediated scaffolding, 12 SYNZIP pairs were successfully used to down-regulate the expression of a reporter gene following treatment with α-factor. Characterization of these interaction modules dramatically increases the number of available protein interaction parts for synthetic biology and should facilitate a wide range of molecular engineering applications. Summary characteristics of 27 SYNZIP peptide pairs are reported in specification sheets available in the Supporting Information and at the SYNZIP Web site [http://keatingweb.mit.edu/SYNZIP/].National Science Foundation (U.S.) (NSF award MCB 0950233)National Institutes of Health (U.S.) (grant RO1 GM55040)National Institutes of Health (U.S.) (grant PN2 EY016546)National Institutes of Health (U.S.) (grant P50 GMO81879)National Science Foundation (U.S.). Synthetic Biology Engineering Research CenterHoward Hughes Medical Institut

Measurements of Higgs boson production and couplings in diboson final states with the ATLAS detector at the LHC

Measurements are presented of production properties and couplings of the recently discovered Higgs boson using the decays into boson pairs, H →γ γ, H → Z Z∗ →4l and H →W W∗ →lνlν. The results are based on the complete pp collision data sample recorded by the ATLAS experiment at the CERN Large Hadron Collider at centre-of-mass energies of √s = 7 TeV and √s = 8 TeV, corresponding to an integrated luminosity of about 25 fb−1. Evidence for Higgs boson production through vector-boson fusion is reported. Results of combined fits probing Higgs boson couplings to fermions and bosons, as well as anomalous contributions to loop-induced production and decay modes, are presented. All measurements are consistent with expectations for the Standard Model Higgs boson

Standalone vertex finding in the ATLAS muon spectrometer

A dedicated reconstruction algorithm to find decay vertices in the ATLAS muon spectrometer is presented. The algorithm searches the region just upstream of or inside the muon spectrometer volume for multi-particle vertices that originate from the decay of particles with long decay paths. The performance of the algorithm is evaluated using both a sample of simulated Higgs boson events, in which the Higgs boson decays to long-lived neutral particles that in turn decay to bbar b final states, and pp collision data at √s = 7 TeV collected with the ATLAS detector at the LHC during 2011

Measurement of the top quark-pair production cross section with ATLAS in pp collisions at \sqrt{s}=7\TeV

A measurement of the production cross-section for top quark pairs(\ttbar) in $pp$ collisions at \sqrt{s}=7 \TeV is presented using data recorded with the ATLAS detector at the Large Hadron Collider. Events are selected in two different topologies: single lepton (electron $e$ or muon $\mu$) with large missing transverse energy and at least four jets, and dilepton ($ee$, $\mu\mu$ or $e\mu$) with large missing transverse energy and at least two jets. In a data sample of 2.9 pb-1, 37 candidate events are observed in the single-lepton topology and 9 events in the dilepton topology. The corresponding expected backgrounds from non-\ttbar Standard Model processes are estimated using data-driven methods and determined to be $12.2 \pm 3.9$ events and $2.5 \pm 0.6$ events, respectively. The kinematic properties of the selected events are consistent with SM \ttbar production. The inclusive top quark pair production cross-section is measured to be \sigmattbar=145 \pm 31 ^{+42}_{-27} pb where the first uncertainty is statistical and the second systematic. The measurement agrees with perturbative QCD calculations.Comment: 30 pages plus author list (50 pages total), 9 figures, 11 tables, CERN-PH number and final journal adde

Measurement of the top quark pair cross section with ATLAS in pp collisions at √s=7 TeV using final states with an electron or a muon and a hadronically decaying τ lepton

A measurement of the cross section of top quark pair production in proton-proton collisions recorded with the ATLAS detector at the Large Hadron Collider at a centre-of-mass energy of 7 TeV is reported. The data sample used corresponds to an integrated luminosity of 2.05 fb -1. Events with an isolated electron or muon and a τ lepton decaying hadronically are used. In addition, a large missing transverse momentum and two or more energetic jets are required. At least one of the jets must be identified as originating from a b quark. The measured cross section, σtt-=186±13(stat.)±20(syst.)±7(lumi.) pb, is in good agreement with the Standard Model prediction

Measurement of the production cross section for W-bosons in association with jets in pp collisions at s=7 TeV with the ATLAS detector

This Letter reports on a first measurement of the inclusive W + jets cross section in proton-proton collisions at a centre-of-mass energy of 7 TeV at the LHC, with the ATLAS detector. Cross sections, in both the electron and muon decay modes of the W-boson, are presented as a function of jet multiplicity and of the transverse momentum of the leading and next-to-leading jets in the event. Measurements are also presented of the ratio of cross sections sigma (W + >= n)/sigma(W + >= n - 1) for inclusive jet multiplicities n = 1-4. The results, based on an integrated luminosity of 1.3 pb(-1), have been corrected for all known detector effects and are quoted in a limited and well-defined range of jet and lepton kinematics. The measured cross sections are compared to particle-level predictions based on perturbative QCD. Next-to-leading order calculations, studied here for n <= 2, are found in good agreement with the data. Leading-order multiparton event generators, normalized to the NNLO total cross section, describe the data well for all measured jet multiplicitie