Novel monoclonal antibodies against Pdx1 reveal feedback regulation of Pdx1 protein levels

The aim of this study was to characterize two monoclonal antibodies (F6A11 and F109-D12) generated against Pdx1 (pancreatic and duodenal homeobox-1), a homeodomain transcription factor, which is critical for pancreas formation as well as for normal pancreatic beta cell function. For production of monoclonal antibodies, we immunized Robertsonian POSF (RBF)mice with a GST-Pdx1 fusion protein containing a 68-amino acid C-terminal fragment of rat Pdx1. These monoclonal antibodies detect Pdx1 by western blotting and allow immunohistochemical detection of Pdx1 in both mouse and rat tissue. F6A11 and F109-D12 produce IHC staining patterns indistinguishable from that obtained with highly specific polyclonal Pdx1 antisera raised in rabbits and goats, when applied to embryonic or adult mouse pancreatic tissue. In contrast to previously generated polyclonal anti-Pdx1 antisera, we also demonstrate that F6A11 works for intracellular fluorescence activated cell sorting (FACS) staining of Pdx1. By using F6A11, we characterize the induction of Pdx1 in the Doxycycline (DOX) inducible insulinoma cell line INSrαβ-Pdx1 and follow the reduction of Pdx1 after removing Dox. Finally, we show that induction of exogenous Pdx1 leads to a reduction in endogenous Pdx1 levels, which suggests that a negative feedback loop is involved in maintaining correct levels of Pdx1 in the cell

Comments on gluon scattering amplitudes via AdS/CFT

In this article we consider n gluon color ordered, planar amplitudes in N=4 super Yang Mills at strong 't Hooft coupling. These amplitudes are approximated by classical surfaces in AdS_5 space. We compute the value of the amplitude for a particular kinematic configuration for a large number of gluons and find that the result disagrees with a recent guess for the exact value of the amplitude. Our results are still compatible with a possible relation between amplitudes and Wilson loops. In addition, we also give a prescription for computing processes involving local operators and asymptotic states with a fixed number of gluons. As a byproduct, we also obtain a string theory prescription for computing the dual of the ordinary Wilson loop, Tr P exp[ i\oint A ], with no couplings to the scalars. We also evaluate the quark-antiquark potential at two loops.Comment: 27 pages, 9 figures,v3:minor correction

Dissipation and noise in adiabatic quantum pumps

We investigate the distribution function, the heat flow and the noise properties of an adiabatic quantum pump for an arbitrary relation of pump frequency $\omega$ and temperature. To achieve this we start with the scattering matrix approach for ac-transport. This approach leads to expressions for the quantities of interest in terms of the side bands of particles exiting the pump. The side bands correspond to particles which have gained or lost a modulation quantum $\hbar \omega$. We find that our results for the pump current, the heat flow and the noise can all be expressed in terms of a parametric emissivity matrix. In particular we find that the current cross-correlations of a multiterminal pump are directly related a to a non-diagonal element of the parametric emissivity matrix. The approach allows a description of the quantum statistical correlation properties (noise) of an adiabatic quantum pump

Adiabatic quantum pump in the presence of external ac voltages

We investigate a quantum pump which in addition to its dynamic pump parameters is subject to oscillating external potentials applied to the contacts of the sample. Of interest is the rectification of the ac currents flowing through the mesoscopic scatterer and their interplay with the quantum pump effect. We calculate the adiabatic dc current arising under the simultaneous action of both the quantum pump effect and classical rectification. In addition to two known terms we find a third novel contribution which arises from the interference of the ac currents generated by the external potentials and the ac currents generated by the pump. The interference contribution renormalizes both the quantum pump effect and the ac rectification effect. Analysis of this interference effect requires a calculation of the Floquet scattering matrix beyond the adiabatic approximation based on the frozen scattering matrix alone. The results permit us to find the instantaneous current. In addition to the current generated by the oscillating potentials, and the ac current due to the variation of the charge of the frozen scatterer, there is a third contribution which represents the ac currents generated by an oscillating scatterer. We argue that the resulting pump effect can be viewed as a quantum rectification of the instantaneous ac currents generated by the oscillating scatterer. These instantaneous currents are an intrinsic property of a nonstationary scattering process.Comment: 11 pages, 1 figur

Association of germline variation with the survival of women with BRCA1/2 pathogenic variants and breast cancer

Germline genetic variation has been suggested to influence the survival of breast cancer patients independently of tumor pathology. We have studied survival associations of genetic variants in two etiologically unique groups of breast cancer patients, the carriers of germline pathogenic variants in BRCA1 or BRCA2 genes. We found that rs57025206 was significantly associated with the overall survival, predicting higher mortality of BRCA1 carrier patients with estrogen receptor-negative breast cancer, with a hazard ratio 4.37 (95% confidence interval 3.03-6.30, P = 3.1 × 10-9). Multivariable analysis adjusted for tumor characteristics suggested that rs57025206 was an independent survival marker. In addition, our exploratory analyses suggest that the associations between genetic variants and breast cancer patient survival may depend on tumor biological subgroup and clinical patient characteristics

Detecting the Dependent Evolution of Biosequences

A probabilistic graphical model is developed in order to detect the dependent evolution between different sites in biological sequences. Given a multiple sequence alignment for each molecule of interest and a phylogenetic tree, the model can predict potential interactions within or between nucleic acids and proteins. Initial validation of the model is carried out using tRNA sequence data. The model is able to accurately identify the secondary structure of tRNA as well as several known tertiary interactions

Associations of common breast cancer susceptibility alleles with risk of breast cancer subtypes in BRCA1 and BRCA2 mutation carriers

Introduction: More than 70 common alleles are known to be involved in breast cancer (BC) susceptibility, and several exhibit significant heterogeneity in their associations with different BC subtypes. Although there are differences in the association patterns between BRCA1 and BRCA2 mutation carriers and the general population for several loci, no study has comprehensively evaluated the associations of all known BC susceptibility alleles with risk of BC subtypes in BRCA1 and BRCA2 carriers. Methods: We used data from 15,252 BRCA1 and 8,211 BRCA2 carriers to analyze the associations between approximately 200,000 genetic variants on the iCOGS array and risk of BC subtypes defined by estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and triple-negative- (TN) status; morphologic subtypes; histological grade; and nodal involvement. Results: The estimated BC hazard ratios (HRs) for the 74 known BC alleles in BRCA1 carriers exhibited moderate correlations with the corresponding odds ratios from the general population. However, their associations with ER-positive BC in BRCA1 carriers were more consistent with the ER-positive as

Assessing associations between the AURKAHMMR-TPX2-TUBG1 functional module and breast cancer risk in BRCA1/2 mutation carriers

While interplay between BRCA1 and AURKA-RHAMM-TPX2-TUBG1 regulates mammary epithelial polarization, common genetic variation in HMMR (gene product RHAMM) may be associated with risk of breast cancer in BRCA1 mutation carriers. Following on these observations, we further assessed the link between the AURKA-HMMR-TPX2-TUBG1 functional module and risk of breast cancer in BRCA1 or BRCA2 mutation carriers. Forty-one single nucleotide polymorphisms (SNPs) were genotyped in 15,252 BRCA1 and 8,211 BRCA2 mutation carriers and subsequently analyzed using a retrospective likelihood appr

The performance of the jet trigger for the ATLAS detector during 2011 data taking

The performance of the jet trigger for the ATLAS detector at the LHC during the 2011 data taking period is described. During 2011 the LHC provided proton–proton collisions with a centre-of-mass energy of 7 TeV and heavy ion collisions with a 2.76 TeV per nucleon–nucleon collision energy. The ATLAS trigger is a three level system designed to reduce the rate of events from the 40 MHz nominal maximum bunch crossing rate to the approximate 400 Hz which can be written to offline storage. The ATLAS jet trigger is the primary means for the online selection of events containing jets. Events are accepted by the trigger if they contain one or more jets above some transverse energy threshold. During 2011 data taking the jet trigger was fully efficient for jets with transverse energy above 25 GeV for triggers seeded randomly at Level 1. For triggers which require a jet to be identified at each of the three trigger levels, full efficiency is reached for offline jets with transverse energy above 60 GeV. Jets reconstructed in the final trigger level and corresponding to offline jets with transverse energy greater than 60 GeV, are reconstructed with a resolution in transverse energy with respect to offline jets, of better than 4 % in the central region and better than 2.5 % in the forward direction

Genome-Wide Association Study in BRCA1 Mutation Carriers Identifies Novel Loci Associated with Breast and Ovarian Cancer Risk

BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7×10-8, HR = 1.14, 95% CI: 1.09-1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4×10-8, HR = 1.27, 95% CI: 1.17-1.38) and 4q32.3 (rs4691139, P = 3.4×10-8, HR = 1.20, 95% CI: 1.17-1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific associat