Comparison between the 5-day cosynch and 7-day estradiol-based protocols for synchronization of ovulation and timed artificial insemination in suckled BOS taurus BEEF cows

The objective was to compare pregnancy per AI and follicular dynamic in suckled Bos taurus beef cows treated with either a 7-day progesterone + estradiol-based protocol or a 5-day progesterone CoSynch protocol for timed artificial insemination (TAI) during four breeding seasons. We hypothesized that estrous cycle status, days postpartum (DPP), fat depth and plasma progesterone concentration differentially modify the effect of treatments. Every year, 9 days before initiation of each breeding season, cows were randomly assigned to one of two groups. Cows in the 7-d P + E group (n = 428) received a progesterone intravaginal device (DIB) and estradiol benzoate on Day −9. On Day −2 the device was removed, and cows received cloprostenol and estradiol cypionate. Forty-eight hours later (Day 0) cows received TAI. Cows in the 5-d P + CoS group (n = 428) received a DIB, and GnRH on Day −8. On Day −3, the device was removed, and cows received cloprostenol. A second dose of cloprostenol was given on Day −2. Cows received GnRH and TAI 72 h after device removal (Day 0). On Day −9, estrous cycle status was determined. In a subset of cows (n = 79) the size of the dominant follicle was determined between Days −2 and 0. In another subset of cows (n = 340), DPP, fat depth (mm) and plasma progesterone concentration (ng/mL) were evaluated on Day −9. Pregnancy per AI was determined 30 d after TAI. Pregnancy per AI was greater for cows in the 5-d P + CoS group than for cows in the 7-d P + E group (50.9% vs. 41.3%, P = 0.01) and was also greater in cyclic than in anestrus cows (54.3% vs. 33.2%, P < 0.0001). There was also a significant effect of breeding season (P = 0.0002) and sire (P = 0.03), and an interaction between treatment group and breeding season (P = 0.03). The dominant follicle was larger (P < 0.0001) in cows in the 5-d P + CoS group than the 7-d P + E group (10.7 ± 0.29 mm vs. 9.0 ± 0.28 mm). Pregnancy per AI was greater in cows with ≥55 DPP (47.0% vs. 29.6%, P = 0.001), fat depth ≥0.50 mm (44.7% vs. 29.7%), and with plasma progesterone concentration ≥1 ng/mL (47.2% vs. 28.7%, P = 0.01). In cows with plasma progesterone ≥1 ng/mL on Day −9, pregnancy per AI was greater in the 5-d P + CoS group (60.5%) than in the 7-d P + E group (34.9%), but there was no difference between treatment groups in cows with plasma progesterone < 1 ng/mL (P = 0.07). In conclusion, the 5-d P + CoS protocol resulted in greater size of the dominant follicle and pregnancy per AI in suckled Bos taurus beef cows subjected to TAI.Fil: Bilbao, María Guillermina. Universidad Nacional de La Pampa. Facultad de Ciencias Veterinarias; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Patagonia Confluencia; ArgentinaFil: Zapata, Luis Oscar. Universidad Nacional de La Pampa. Facultad de Ciencias Veterinarias; ArgentinaFil: Romero Harry, H.. Instituto Nacional de Tecnología Agropecuaria. Centro Regional La Pampa-San Luis. Estación Experimental Agropecuaria Anguil; ArgentinaFil: Perez Wallace, S.. Zoetis SRL; ArgentinaFil: Farcey, Maria Florencia. Universidad Nacional de La Pampa. Facultad de Ciencias Veterinarias; ArgentinaFil: Gelid, Lucas Fernando. Instituto Nacional de Tecnología Agropecuaria. Centro Regional La Pampa-San Luis. Estación Experimental Agropecuaria Anguil; ArgentinaFil: Palomares, R. A.. University of Georgia. College of Veterinary Medicine; Estados UnidosFil: Ferrer, M. S.. University of Georgia. College of Veterinary Medicine; Estados UnidosFil: Bartolome, Julian. Universidad Nacional de La Pampa. Facultad de Ciencias Veterinarias; Argentin

Evaluating the Quality of Research into a Single Prognostic Biomarker: A Systematic Review and Meta-analysis of 83 Studies of C-Reactive Protein in Stable Coronary Artery Disease

Background Systematic evaluations of the quality of research on a single prognostic biomarker are rare. We sought to evaluate the quality of prognostic research evidence for the association of C-reactive protein (CRP) with fatal and nonfatal events among patients with stable coronary disease. Methods and Findings We searched MEDLINE (1966 to 2009) and EMBASE (1980 to 2009) and selected prospective studies of patients with stable coronary disease, reporting a relative risk for the association of CRP with death and nonfatal cardiovascular events. We included 83 studies, reporting 61,684 patients and 6,485 outcome events. No study reported a prespecified statistical analysis protocol; only two studies reported the time elapsed (in months or years) between initial presentation of symptomatic coronary disease and inclusion in the study. Studies reported a median of seven items (of 17) from the REMARK reporting guidelines, with no evidence of change over time. The pooled relative risk for the top versus bottom third of CRP distribution was 1.97 (95% confidence interval [CI] 1.78–2.17), with substantial heterogeneity (I2 = 79.5). Only 13 studies adjusted for conventional risk factors (age, sex, smoking, obesity, diabetes, and low-density lipoprotein [LDL] cholesterol) and these had a relative risk of 1.65 (95% CI 1.39–1.96), I2 = 33.7. Studies reported ten different ways of comparing CRP values, with weaker relative risks for those based on continuous measures. Adjusting for publication bias (for which there was strong evidence, Egger's p<0.001) using a validated method reduced the relative risk to 1.19 (95% CI 1.13–1.25). Only two studies reported a measure of discrimination (c-statistic). In 20 studies the detection rate for subsequent events could be calculated and was 31% for a 10% false positive rate, and the calculated pooled c-statistic was 0.61 (0.57–0.66). Conclusion Multiple types of reporting bias, and publication bias, make the magnitude of any independent association between CRP and prognosis among patients with stable coronary disease sufficiently uncertain that no clinical practice recommendations can be made. Publication of prespecified statistical analytic protocols and prospective registration of studies, among other measures, might help improve the quality of prognostic biomarker research

Measuring Parton Densities in the Pomeron

We present a program to measure the parton densities in the pomeron using diffractive deep inelastic scattering and diffractive photoproduction, and to test the resulting parton densities by applying them to other processes such as the diffractive production of jets in hadron-hadron collisions. Since QCD factorization has been predicted NOT to apply to hard diffractive scattering, this program of fitting and using parton densities might be expected to fail. Its success or failure will provide useful information on the space-time structure of the pomeron.Comment: Contains revisions based on Phys. Rev. D referee comments. RevTeX version 3, epsf, 31 pages. Uuencoded compressed postscript figures appended. Uncompressed postscript files available at ftp://ftp.phys.psu.edu/pub/preprint/psuth136

A Cryogenic Silicon Interferometer for Gravitational-wave Detection

The detection of gravitational waves from compact binary mergers by LIGO has opened the era of gravitational wave astronomy, revealing a previously hidden side of the cosmos. To maximize the reach of the existing LIGO observatory facilities, we have designed a new instrument that will have 5 times the range of Advanced LIGO, or greater than 100 times the event rate. Observations with this new instrument will make possible dramatic steps toward understanding the physics of the nearby universe, as well as observing the universe out to cosmological distances by the detection of binary black hole coalescences. This article presents the instrument design and a quantitative analysis of the anticipated noise floor

Measurement of the vortex core in sub-100 nm Fe dots using polarized neutron scattering

We use polarized neutron scattering to obtain quantitative information about the magnetic state of sub-100 nm circular magnetic dots. Evidence for the transition from a single domain to a vortex state, as a function of the dot diameter and magnetic field, is found from magnetization curves and confirmed by micromagnetic and Monte-Carlo simulations. For 20 nm-thick Fe dots with diameters close to 60 nm, the vortex is the ground state. The magnetization of the vortex core (140 ± 50 emu/cm3) and its diameter (19 ± 4 nm) obtained from polarized neutron scattering are in agreement with simulations

Proteomic Identification of S-Nitrosylated Golgi Proteins: New Insights into Endothelial Cell Regulation by eNOS-Derived NO

<div><h3>Background</h3><p>Endothelial nitric oxide synthase (eNOS) is primarily localized on the Golgi apparatus and plasma membrane caveolae in endothelial cells. Previously, we demonstrated that protein S-nitrosylation occurs preferentially where eNOS is localized. Thus, in endothelial cells, Golgi proteins are likely to be targets for S-nitrosylation. The aim of this study was to identify S-nitrosylated Golgi proteins and attribute their S-nitrosylation to eNOS-derived nitric oxide in endothelial cells.</p> <h3>Methods</h3><p>Golgi membranes were isolated from rat livers. S-nitrosylated Golgi proteins were determined by a modified biotin-switch assay coupled with mass spectrometry that allows the identification of the S-nitrosylated cysteine residue. The biotin switch assay followed by Western blot or immunoprecipitation using an S-nitrosocysteine antibody was also employed to validate S-nitrosylated proteins in endothelial cell lysates.</p> <h3>Results</h3><p>Seventy-eight potential S-nitrosylated proteins and their target cysteine residues for S-nitrosylation were identified; 9 of them were Golgi-resident or Golgi/endoplasmic reticulum (ER)-associated proteins. Among these 9 proteins, S-nitrosylation of EMMPRIN and Golgi phosphoprotein 3 (GOLPH3) was verified in endothelial cells. Furthermore, S-nitrosylation of these proteins was found at the basal levels and increased in response to eNOS stimulation by the calcium ionophore A23187. Immunofluorescence microscopy and immunoprecipitation showed that EMMPRIN and GOLPH3 are co-localized with eNOS at the Golgi apparatus in endothelial cells. S-nitrosylation of EMMPRIN was notably increased in the aorta of cirrhotic rats.</p> <h3>Conclusion</h3><p>Our data suggest that the selective S-nitrosylation of EMMPRIN and GOLPH3 at the Golgi apparatus in endothelial cells results from the physical proximity to eNOS-derived nitric oxide.</p> </div

Defining the Critical Hurdles in Cancer Immunotherapy

ABSTRACT: Scientific discoveries that provide strong evidence of antitumor effects in preclinical models often encounter significant delays before being tested in patients with cancer. While some of these delays have a scientific basis, others do not. We need to do better. Innovative strategies need to move into early stage clinical trials as quickly as it is safe, and if successful, these therapies should efficiently obtain regulatory approval and widespread clinical application. In late 2009 and 2010 the Society for Immunotherapy of Cancer (SITC), convened an "Immunotherapy Summit" with representatives from immunotherapy organizations representing Europe, Japan, China and North America to discuss collaborations to improve development and delivery of cancer immunotherapy. One of the concepts raised by SITC and defined as critical by all parties was the need to identify hurdles that impede effective translation of cancer immunotherapy. With consensus on these hurdles, international working groups could be developed to make recommendations vetted by the participating organizations. These recommendations could then be considered by regulatory bodies, governmental and private funding agencies, pharmaceutical companies and academic institutions to facilitate changes necessary to accelerate clinical translation of novel immune-based cancer therapies. The critical hurdles identified by representatives of the collaborating organizations, now organized as the World Immunotherapy Council, are presented and discussed in this report. Some of the identified hurdles impede all investigators, others hinder investigators only in certain regions or institutions or are more relevant to specific types of immunotherapy or first-in-humans studies. Each of these hurdles can significantly delay clinical translation of promising advances in immunotherapy yet be overcome to improve outcomes of patients with cancer

Why Are Outcomes Different for Registry Patients Enrolled Prospectively and Retrospectively? Insights from the Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF).

Background: Retrospective and prospective observational studies are designed to reflect real-world evidence on clinical practice, but can yield conflicting results. The GARFIELD-AF Registry includes both methods of enrolment and allows analysis of differences in patient characteristics and outcomes that may result. Methods and Results: Patients with atrial fibrillation (AF) and ≥1 risk factor for stroke at diagnosis of AF were recruited either retrospectively (n = 5069) or prospectively (n = 5501) from 19 countries and then followed prospectively. The retrospectively enrolled cohort comprised patients with established AF (for a least 6, and up to 24 months before enrolment), who were identified retrospectively (and baseline and partial follow-up data were collected from the emedical records) and then followed prospectively between 0-18 months (such that the total time of follow-up was 24 months; data collection Dec-2009 and Oct-2010). In the prospectively enrolled cohort, patients with newly diagnosed AF (≤6 weeks after diagnosis) were recruited between Mar-2010 and Oct-2011 and were followed for 24 months after enrolment. Differences between the cohorts were observed in clinical characteristics, including type of AF, stroke prevention strategies, and event rates. More patients in the retrospectively identified cohort received vitamin K antagonists (62.1% vs. 53.2%) and fewer received non-vitamin K oral anticoagulants (1.8% vs . 4.2%). All-cause mortality rates per 100 person-years during the prospective follow-up (starting the first study visit up to 1 year) were significantly lower in the retrospective than prospectively identified cohort (3.04 [95% CI 2.51 to 3.67] vs . 4.05 [95% CI 3.53 to 4.63]; p = 0.016). Conclusions: Interpretations of data from registries that aim to evaluate the characteristics and outcomes of patients with AF must take account of differences in registry design and the impact of recall bias and survivorship bias that is incurred with retrospective enrolment. Clinical Trial Registration: - URL: http://www.clinicaltrials.gov . Unique identifier for GARFIELD-AF (NCT01090362)

Defining the critical hurdles in cancer immunotherapy

Scientific discoveries that provide strong evidence of antitumor effects in preclinical models often encounter significant delays before being tested in patients with cancer. While some of these delays have a scientific basis, others do not. We need to do better. Innovative strategies need to move into early stage clinical trials as quickly as it is safe, and if successful, these therapies should efficiently obtain regulatory approval and widespread clinical application. In late 2009 and 2010 the Society for Immunotherapy of Cancer (SITC), convened an "Immunotherapy Summit" with representatives from immunotherapy organizations representing Europe, Japan, China and North America to discuss collaborations to improve development and delivery of cancer immunotherapy. One of the concepts raised by SITC and defined as critical by all parties was the need to identify hurdles that impede effective translation of cancer immunotherapy. With consensus on these hurdles, international working groups could be developed to make recommendations vetted by the participating organizations. These recommendations could then be considered by regulatory bodies, governmental and private funding agencies, pharmaceutical companies and academic institutions to facilitate changes necessary to accelerate clinical translation of novel immune-based cancer therapies. The critical hurdles identified by representatives of the collaborating organizations, now organized as the World Immunotherapy Council, are presented and discussed in this report. Some of the identified hurdles impede all investigators; others hinder investigators only in certain regions or institutions or are more relevant to specific types of immunotherapy or first-in-humans studies. Each of these hurdles can significantly delay clinical translation of promising advances in immunotherapy yet if overcome, have the potential to improve outcomes of patients with cancer

A Cryogenic Silicon Interferometer for Gravitational-wave Detection

The detection of gravitational waves from compact binary mergers by LIGO has opened the era of gravitational wave astronomy, revealing a previously hidden side of the cosmos. To maximize the reach of the existing LIGO observatory facilities, we have designed a new instrument able to detect gravitational waves at distances 5 times further away than possible with Advanced LIGO, or at greater than 100 times the event rate. Observations with this new instrument will make possible dramatic steps toward understanding the physics of the nearby Universe, as well as observing the Universe out to cosmological distances by the detection of binary black hole coalescences. This article presents the instrument design and a quantitative analysis of the anticipated noise floor