Level-Based Analysis of the Population-Based Incremental Learning Algorithm

The Population-Based Incremental Learning (PBIL) algorithm uses a convex combination of the current model and the empirical model to construct the next model, which is then sampled to generate offspring. The Univariate Marginal Distribution Algorithm (UMDA) is a special case of the PBIL, where the current model is ignored. Dang and Lehre (GECCO 2015) showed that UMDA can optimise LeadingOnes efficiently. The question still remained open if the PBIL performs equally well. Here, by applying the level-based theorem in addition to Dvoretzky--Kiefer--Wolfowitz inequality, we show that the PBIL optimises function LeadingOnes in expected time $\mathcal{O}(n\lambda \log \lambda + n^2)$ for a population size $\lambda = \Omega(\log n)$, which matches the bound of the UMDA. Finally, we show that the result carries over to BinVal, giving the fist runtime result for the PBIL on the BinVal problem.Comment: To appea

Holonomy in the Schwarzschild-Droste Geometry

Parallel transport of vectors in curved spacetimes generally results in a deficit angle between the directions of the initial and final vectors. We examine such holonomy in the Schwarzschild-Droste geometry and find a number of interesting features that are not widely known. For example, parallel transport around circular orbits results in a quantized band structure of holonomy invariance. We also examine radial holonomy and extend the analysis to spinors and to the Reissner-Nordstr\"om metric, where we find qualitatively different behavior for the extremal ($Q = M$) case. Our calculations provide a toolbox that will hopefully be useful in the investigation of quantum parallel transport in Hilbert-fibered spacetimes.Comment: 18 Latex pages, 3 figures. Second replacement. This version as published in CQG with some misprints correcte

Double sampling of a faecal immunochemical test is not superior to single sampling for detection of colorectal neoplasia: a colonoscopy controlled prospective cohort study

<p>Abstract</p> <p>Background</p> <p>A single sampled faecal immunochemical test (FIT) has moderate sensitivity for colorectal cancer and advanced adenomas. Repeated FIT sampling could improve test sensitivity. The aim of the present study is to determine whether any of three different strategies of double FIT sampling has a better combination of sensitivity and specificity than single FIT sampling.</p> <p>Methods</p> <p>Test performance of single FIT sampling in subjects scheduled for colonoscopy was compared to double FIT sampling intra-individually. Test positivity of double FIT sampling was evaluated in three different ways: 1) "one of two FITs+" when at least one out of two measurements exceeded the cut-off value, 2) "two of two FITs+" when both measurements exceeded the cut-off value, 3) "mean of two FITs+" when the geometric mean of two FITs exceeded the cut-off value. Receiver operator curves were calculated and sensitivity of single and the three strategies of double FIT sampling were compared at a fixed level of specificity.</p> <p>Results</p> <p>In 124 of 1096 subjects, screen relevant neoplasia (SRN) were found (i.e. early stage CRC or advanced adenomas). At any cut-off, "two of two FITs+" resulted in the lowest and "one of two FITs+" in the highest sensitivity for SRN (range 35-44% and 42%-54% respectively). ROC's of double FIT sampling were similar to single FIT sampling. At specificities of 85/90/95%, sensitivity of any double FIT sampling strategy did not differ significantly from single FIT (p-values 0.07-1).</p> <p>Conclusion</p> <p>At any cut off, "one of two FITs+" is the most sensitive double FIT sampling strategy. However, at a given specificity level, sensitivity of any double FIT sampling strategy for SRN is comparable to single FIT sampling at a different cut-off value. None of the double FIT strategies has a superior combination of sensitivity and specificity over single FIT.</p

On the Effectiveness of Sampling for Evolutionary Optimization in Noisy Environments

Sampling has been often employed by evolutionary algorithms to cope with noise when solving noisy real-world optimization problems. It can improve the estimation accuracy by averaging over a number of samples, while also increasing the computation cost. Many studies focused on designing efficient sampling methods, and conflicting empirical results have been reported. In this paper, we investigate the effectiveness of sampling in terms of rigorous running time, and find that sampling can be ineffective. We provide a general sufficient condition under which sampling is useless (i.e., sampling increases the running time for finding an optimal solution), and apply it to analyzing the running time performance of (1+1)-EA for optimizing OneMax and Trap problems in the presence of additive Gaussian noise. Our theoretical analysis indicates that sampling in the above examples is not helpful, which is further confirmed by empirical simulation results

Modifications to the framework regions eliminate chimeric antigen receptor tonic signaling

Chimeric antigen receptor (CAR) tonic signaling, defined as spontaneous activation and release of proinflammatory cytokines by CAR-T cells, is considered a negative attribute because it leads to impaired antitumor effects. Here, we report that CAR tonic signaling is caused by the intrinsic instability of the mAb single-chain variable fragment (scFv) to promote self-aggregation and signaling via the CD3z chain incorporated into the CAR construct. This phenomenon was detected in a CAR encoding either CD28 or 4-1BB costimulatory endodomains. Instability of the scFv was caused by specific amino acids within the framework regions (FWR) that can be identified by computational modeling. Substitutions of the amino acids causing instability, or humanization of the FWRs, corrected tonic signaling of the CAR, without modifying antigen specificity, and enhanced the antitumor effects of CAR-T cells. Overall, we demonstrated that tonic signaling of CAR-T cells is determined by the molecular instability of the scFv and that computational analyses of the scFv can be implemented to correct the scFv instability in CAR-T cells with either CD28 or 4-1BB costimulation

Identification of high-spin proton configurations in Ba 136 and Ba 137

19 pags., 11 figs., 3 tabs.The high-spin structures of Ba136 and Ba137 are investigated after multinucleon-transfer (MNT) and fusion-evaporation reactions. Ba136 is populated in a Xe136+U238 MNT reaction employing the high-resolution Advanced GAmma Tracking Array (AGATA) coupled to the magnetic spectrometer PRISMA at the Laboratori Nazionali di Legnaro, Italy, and in two Be9+Te130 fusion-evaporation reactions using the High-efficiency Observatory for γ-Ray Unique Spectroscopy (HORUS) at the FN tandem accelerator of the University of Cologne, Germany. Furthermore, both isotopes are populated in an elusive reaction channel in the B11+Te130 fusion-evaporation reaction utilizing the HORUS γ-ray array. The level scheme above the Jπ=10+ isomer in Ba136 is revised and extended up to an excitation energy of approximately 5.5 MeV. From the results of angular-correlation measurements, the Ex=3707- and Ex=4920-keV states are identified as the bandheads of positive- and negative-parity cascades. While the high-spin regimes of both Te132 and Xe134 are characterized by high-energy 12+→10+ transitions, the Ba136E2 ground-state band is interrupted by negative-parity states only a few hundred keV above the Jπ=10+ isomer. Furthermore, spins are established for several hitherto unassigned high-spin states in Ba137. The new results close a gap along the high-spin structure of N<82 Ba isotopes. Experimental results are compared to large-scale shell-model calculations employing the GCN50:82, Realistic SM, PQM130, and SN100PN interactions. The calculations suggest that the bandheads of the positive-parity bands in both isotopes are predominantly of proton character.Furthermore, we express our thanks to Dr. E. Teruya and Dr. N. Yoshinaga from Saitama University, Japan, for providing the results of their shellmodel calculation with the PQM130 interaction. The research leading to these results has received funding from the German BMBF under Contracts No. 05P15PKFN9 TP1 and No. 05P18PKFN9 TP1, from the European Union Seventh Framework Programme FP7/2007-2013 under Grant Agreement No. 262010 - ENSAR, from the Spanish Ministerio de Ciencia e Innovación under Contract No. FPA2011-29854- C04, from the Spanish Ministerio de Economía y Competitividad under Contract No. FPA2014-57196-C5, and from the UK Science and Technology Facilities Council (STFC). L.K. and A.V. thank the Bonn-Cologne Graduate School of Physics and Astronomy (BCGS) for financial support. One of the authors (A. Gadea) has been supported by the Generalitat Valenciana, Spain, under Grant No. PROMETEOII/2014/019, and EU under the FEDER program

Cerebrovascular mental stress reactivity is impaired in hypertension

<p>Abstract</p> <p>Background</p> <p>Brachial artery reactivity in response to shear stress is altered in subjects with hypertension. Since endothelial dysfunction is generalized, we hypothesized that carotid artery (CA) reactivity would also be altered in hypertension.</p> <p>Purpose</p> <p>To compare (CA endothelium-dependent vasodilation in response to mental stress in normal and hypertensive subjects.</p> <p>Methods</p> <p>We evaluated CA reactivity to mental stress in 10 young healthy human volunteers (aged 23 ± 4 years), 20 older healthy volunteers (aged 49 ± 11 years) and in 28 patients with essential hypertension (aged 51 ± 13 years). In 10 healthy volunteers and 12 hypertensive subjects, middle cerebral artery (MCA) PW transcranial Doppler was performed before and 3 minutes after mental stress.</p> <p>Results</p> <p>Mental stress by Stroop color word conflict, math or anger recall tests caused CA vasodilation in young healthy subjects (0.61 ± 0.06 to 0.65 ± 0.07 cm, p < 0.05) and in older healthy subjects (0.63 ± 0.06 to 0.66 ± 0.07 cm, p < 0.05), whereas no CA vasodilation occurred in hypertensive subjects (0.69 ± 0.06 to 0.68 ± 0.07 cm; p, NS). CA blood flow in response to mental stress increased in young healthy subjects (419 ± 134 to 541 ± 209 ml, p < 0.01 vs. baseline) and in older healthy subjects (351 ± 114 to 454 ± 136 ml, p < 0.01 vs. baseline) whereas no change in blood flow (444 ± 143 vs. 458 ± 195 ml; p, 0.59) occurred in hypertensive subjects. There was no difference in the CA response to nitroglycerin in healthy and hypertensive subjects. Mental stress caused a significant increase in baseline to peak MCA systolic (84 ± 22 to 95 ± 22 cm/s, p < 0.05), diastolic (42 ± 12 to 49 ± 14 cm/s, p < 0.05) as well as mean (30 ± 13 to 39 ± 13 cm/s, p < 0.05) PW Doppler velocities in normal subjects, whereas no change in systolic (70 ± 18 to 73 ± 22 cm/s, p < 0.05), diastolic (34 ± 14 to 37 ± 14 cm/s, p = ns) or mean velocities (25 ± 9 to 26 ± 9 cm/s, p = ns) occurred in hypertensive subjects, despite a similar increase in heart rate and blood pressure in response to mental stress in both groups.</p> <p>Conclusion</p> <p>Mental stress produces CA vasodilation and is accompanied by an increase in CA and MCA blood flow in healthy subjects. This mental stress induced CA vasodilation and flow reserve is attenuated in subjects with hypertension and may reflect cerebral vascular endothelial dysfunction. Assessment of mental stress induced CA reactivity by ultrasound is a novel method for assessing the impact of hypertension on cerebrovascular endothelial function and blood flow reserve.</p

Promoter DNA Methylation of Oncostatin M receptor-β as a Novel Diagnostic and Therapeutic Marker in Colon Cancer

In addition to genetic changes, the occurrence of epigenetic alterations is associated with accumulation of both genetic and epigenetic events that promote the development and progression of human cancer. Previously, we reported a set of candidate genes that comprise part of the emerging “cancer methylome”. In the present study, we first tested 23 candidate genes for promoter methylation in a small number of primary colon tumor tissues and controls. Based on these results, we then examined the methylation frequency of Oncostatin M receptor-β (OSMR) in a larger number of tissue and stool DNA samples collected from colon cancer patients and controls. We found that OSMR was frequently methylated in primary colon cancer tissues (80%, 80/100), but not in normal tissues (4%, 4/100). Methylation of OSMR was also detected in stool DNA from colorectal cancer patients (38%, 26/69) (cut-off in TaqMan-MSP, 4). Detection of other methylated markers in stool DNA improved sensitivity with little effect on specificity. Promoter methylation mediated silencing of OSMR in cell lines, and CRC cells with low OSMR expression were resistant to growth inhibition by Oncostatin M. Our data provide a biologic rationale for silencing of OSMR in colon cancer progression and highlight a new therapeutic target in this disease. Moreover, detection and quantification of OSMR promoter methylation in fecal DNA is a highly specific diagnostic biomarker for CRC