Experimentally-calibrated population of models predicts and explains inter-subject variability in cardiac cellular\ud electrophysiology

Cellular and ionic causes of variability in the electrophysiological activity of hearts from individuals of the same species are unknown. However, improved understanding of this variability is key to enable prediction of the response of specific hearts to disease and therapies. Limitations of current mathematical modeling and experimental techniques hamper our ability to provide insight into variability. Here we describe a methodology to unravel the ionic determinants of inter-subject variability exhibited in experimental recordings, based on the construction and calibration of populations of models. We illustrate the methodology through its application to rabbit Purkinje preparations, due to their importance in arrhythmias and safety pharmacology assessment. We consider a set of equations describing the biophysical processes underlying rabbit Purkinje electrophysiology and we construct a population of over 10,000 models by randomly assigning specific parameter values corresponding to ionic current conductances and kinetics. We calibrate the model population by closely comparing simulation output and experimental recordings at three pacing frequencies. We show that 213 of the 10,000 candidate models are fully consistent with the experimental dataset. Ionic properties in the 213 models cover a wide range of values, including differences up to ±100% in several conductances. Partial correlation analysis shows that particular combinations of ionic properties determine the precise shape, amplitude and rate dependence of specific action potentials. Finally, we demonstrate that the population of models calibrated using data obtained under physiological conditions quantitatively predicts the action potential duration prolongation caused by exposure to four concentrations of the potassium channel blocker dofetilide

Molecular cytogenetic aberrations in patients with multiple myeloma studied by interphase fluorescence in situ hybridization

Background: Multiple myeloma (MM) is an incurable hematological disorder characterized by the accumulation of malignant plasma cells within the bone marrow (BM). The clinical heterogeneity of MM is dictated by the cytogenetic aberrations present in the clonal plasma cells (PCs). Cytogenetic studies in MM are hampered by the hypoproliferative nature of plasma cells in MM. Therefore, fluorescence in situ hybridization (FISH) analysis combined with magnetic-activated cell sorting (MACS) is an attractive alternative for evaluation of numerical and structural chromosomal changes in MM. Methods: Interphase FISH studies with three different specific probes for the regions containing 13q14.3 (D13S319), 14q32 (IGHC/IGHV) and 1q12(CEP1 ) were performed in 48 MM patients. Interphase FISH studies with LSI IGH/CCND1, LSI IGH/FGFR3, and LSI IGH/MAF probes were used to detect t(11;14)(q13;q32), t(4;14)(p16;q32), and t(14;16)(q32;q23) in patients with 14q32 rearrangement. Results: Molecular cytogenetic aberrations were found in 40 (83.3%) of the 48 MM patients. 13 patients (27.1%) simultaneously had 13q deletion/monosomy 13 [del(13q14)], illegitimate IGH rearrangement and chromosome 1 abnormality. Del(13q14) was detected in 21 cases (43.7%), and illegitimate IGH rearrangements in 29 (60.4%) including 6 with t(11;14) and 5 with t(4;14). None of 9 patients with illegitimate IGH rearrangements and without t(11;14) or t(4;14) we detected had t(14;16) (q32;q23). 24 of the 48 MM patients (50%) had chromosome 1 abnormalities. Among 21 patients with del(13q14), 15 patients had Amp1q12;16 had IgH rearrangements. Whereas, among 27 cases without del(13q14), 8 had Amp1q12; 13 had IgH rearrangements. There was a strong association between del(13q14) and Amp1q12(c2 = 8.26, р < 0.01), and between del(13q14) and IgH rearrangement(c2 = 3.88, p < 0.05). Conclusion: 13q deletion/monosomy 13, IGH rearrangement and chromosome 1 abnormality are frequent in MM. They are not randomly distributed, but strongly interconnected. Interphase FISH technique combined with MACS using CD138-specific antibody is a highly sensitive technique at detecting molecular cytogenetic aberrations in MM.Обоснование: множественная миелома (MM) — неизлечимое гематологическое заболевание, характеризирующееся накоплением злокачественных плазматических клеток в костном мозге (КM). Клиническая гетерогенность MM определяется цитогенетическими аберрациями, присутствующими в клоне плазматических клеток (ПК). Цитогенетические исследования MM осложнены гипопролиферативными особенностями ПК. В связи с этим флуоресцентная гибридизация in situ (FISH) в комбинации с сортировкой клеток, активированных магнитными полями (MACS) представляется достойной альтернативой методам оценки точечных и структурных изменений хромосом при MM. Методы: интерфазные исследования методом FISH с использованием трех различных специфических зондов для участков, содержащих 13q14.3 (D13S319), 14q32 (IGHC/IGHV) и 1q12(CEP1), проводили у 48 больных с MM. Интерфазные исследования методом FISH с использованием зондов LSI IGH/CCND1, LSI IGH/FGFR3 и LSI IGH/MAF применяли для детекции t(11;14)(q13;q32), t(4;14)(p16;q32), и t(14;16)(q32;q23) у пациентов с перестройкой 14q32. Результаты: молекулярные цитогенетические аберрации выявляли у 40 (83,3%) из 48 больных с MM. У 13 пациентов (27,1%) одновременно определены 13q делеция/моносомия 13 [del(13q14)], аномальная перестройка IGH и аномалия хромосомы 1. Del(13q14) детектировали в 21 случае (43,7%), а аномальные перестройки IGH — в 29 (60,4%), в том числе у 6 пациентов с t(11;14) и 5 с t(4;14). Ни у одного из 9 больных с аномальными перестройками IGH и без t(11;14) или t(4;14) не выявляли транслокацию t(14;16) (q32;q23). У 24 из 48 пациентов с MM (50%) определяли аномалии хромосомы 1. В группе из 21 больных с del(13q14) в 15 случаях имелись перестройки IgH Amp1q12;16. В то же время из 27 случаев без del(13q14) у 8 содержались Amp1q12; в 13 случаях отмечали перестройки IgH. Выявлена взаимосвязь между del(13q14) и Amp1q12(χ2 = 8,26, p < 0,01) и между del(13q14) и перестройками IgH (χ2 = 3,88, p < 0,05). Выводы: 13q делецию/моносомию 13, перестройку IGH и аномалию хромосомы 1 часто отмечают при MM, причем их распределение не случайно и тесно взаимосвязано. Интерфазный анализ FISH в комбинации с MACS с использованием CD138-специфичных антител является высокочувствительным методом детекции молекулярных цитогенетических аберраций при MM

Yang-Mills Interactions and Gravity in Terms of Clifford Algebra

A model of Yang-Mills interactions and gravity in terms of the Clifford algebra Cl(0,6) is presented. The gravity and Yang-Mills actions are formulated as different order terms in a generalized action. The feebleness of gravity as well as the smallness of the cosmological constant and theta terms are discussed at the classical level. The invariance groups, including the de Sitter and the Pati-Salam SU(4) subgroups, consist of gauge transformations from either side of an algebraic spinor. Upon symmetry breaking via the Higgs fields, the remaining symmetries are the Lorentz SO(1,3), color SU(3), electromagnetic U(1)_EM, and an additional U(1). The first generation leptons and quarks are identified with even and odd parts of spinor idempotent projections. There are still several shortcomings with the current model. Further research is needed to fully recover the standard model results.Comment: 20 pages, to appear in Advances in Applied Clifford Algebra

Observation of Parity Violation in the Omega-minus -> Lambda + K-minus Decay

The alpha decay parameter in the process Omega-minus -> Lambda + K-minus has been measured from a sample of 4.50 million unpolarized Omega-minus decays recorded by the HyperCP (E871) experiment at Fermilab and found to be [1.78 +/- 0.19(stat) +/- 0.16(syst)]{\times}10^{-2}. This is the first unambiguous evidence for a nonzero alpha decay parameter, and hence parity violation, in the Omega-minus -> Lambda + K-minus decay.Comment: 10 pages, 7 figure

Aharonov-Bohm spectral features and coherence lengths in carbon nanotubes

The electronic properties of carbon nanotubes are investigated in the presence of disorder and a magnetic field parallel or perpendicular to the nanotube axis. In the parallel field geometry, the $\phi_{0}(=hc/e)$-periodic metal-insulator transition (MIT) induced in metallic or semiconducting nanotubes is shown to be related to a chirality-dependent shifting of the energy of the van Hove singularities (VHSs). The effect of disorder on this magnetic field-related mechanism is considered with a discussion of mean free paths, localization lengths and magnetic dephasing rate in the context of recent experiments.Comment: 22 pages, 6 Postscript figures. submitted to Phys. Rev.

HyperCP: A high-rate spectrometer for the study of charged hyperon and kaon decays

The HyperCP experiment (Fermilab E871) was designed to search for rare phenomena in the decays of charged strange particles, in particular CP violation in $\Xi$ and $\Lambda$ hyperon decays with a sensitivity of $10^{-4}$. Intense charged secondary beams were produced by 800 GeV/c protons and momentum-selected by a magnetic channel. Decay products were detected in a large-acceptance, high-rate magnetic spectrometer using multiwire proportional chambers, trigger hodoscopes, a hadronic calorimeter, and a muon-detection system. Nearly identical acceptances and efficiencies for hyperons and antihyperons decaying within an evacuated volume were achieved by reversing the polarities of the channel and spectrometer magnets. A high-rate data-acquisition system enabled 231 billion events to be recorded in twelve months of data-taking.Comment: 107 pages, 45 Postscript figures, 14 tables, Elsevier LaTeX, submitted to Nucl. Instrum. Meth.

The energy spectrum of all-particle cosmic rays around the knee region observed with the Tibet-III air-shower array

We have already reported the first result on the all-particle spectrum around the knee region based on data from 2000 November to 2001 October observed by the Tibet-III air-shower array. In this paper, we present an updated result using data set collected in the period from 2000 November through 2004 October in a wide range over 3 decades between $10^{14}$ eV and $10^{17}$ eV, in which the position of the knee is clearly seen at around 4 PeV. The spectral index is -2.68 $\pm$ 0.02(stat.) below 1PeV, while it is -3.12 $\pm$ 0.01(stat.) above 4 PeV in the case of QGSJET+HD model, and various systematic errors are under study now.Comment: 12 pages, 7 figures, accepted by Advances in space researc

Targeted Heating of Mitochondria Greatly Augments Nanoparticle-Mediated Cancer Chemotherapy

Cancer is the second leading cause of mortality globally. Various nanoparticles have been developed to improve the efficacy and safety of chemotherapy, photothermal therapy, and their combination for treating cancer. However, most of the existing nanoparticles are low in both subcellular precision and drug loading content (80% at an ultrahigh feeding ratio of 1:1. In combination with near infrared (NIR, 808 nm) laser irradiation, the tumor weight in the Py@Si-TH-DOX treatment group is 8.5 times less than that in the Py@Si-H-DOX (i.e., DOX-laden nanoparticles without mitochondrial targeting) group, suggesting targeted heating of mitochondria is a valuable strategy for enhancing chemotherapy to combat cancer

Moon Shadow by Cosmic Rays under the Influence of Geomagnetic Field and Search for Antiprotons at Multi-TeV Energies

We have observed the shadowing of galactic cosmic ray flux in the direction of the moon, the so-called moon shadow, using the Tibet-III air shower array operating at Yangbajing (4300 m a.s.l.) in Tibet since 1999. Almost all cosmic rays are positively charged; for that reason, they are bent by the geomagnetic field, thereby shifting the moon shadow westward. The cosmic rays will also produce an additional shadow in the eastward direction of the moon if cosmic rays contain negatively charged particles, such as antiprotons, with some fraction. We selected 1.5 x10^{10} air shower events with energy beyond about 3 TeV from the dataset observed by the Tibet-III air shower array and detected the moon shadow at $\sim 40 \sigma$ level. The center of the moon was detected in the direction away from the apparent center of the moon by 0.23$^\circ$ to the west. Based on these data and a full Monte Carlo simulation, we searched for the existence of the shadow produced by antiprotons at the multi-TeV energy region. No evidence of the existence of antiprotons was found in this energy region. We obtained the 90% confidence level upper limit of the flux ratio of antiprotons to protons as 7% at multi-TeV energies.Comment: 13pages,4figures; Accepted for publication in Astroparticle Physic

Electromagnetic and Hadron Calorimeters in the MIPP Experiment

The purpose of the MIPP experiment is to study the inclusive production of photons, pions, kaons and nucleons in pi, K and p interactions on various targets using beams from the Main Injector at Fermilab. The function of the calorimeters is to measure the production of forward-going neutrons and photons. The electromagnetic calorimeter consist of 10 lead plates interspersed with proportional chambers. It was followed by the hadron calorimeter with 64 steel plates interspersed with scintillator. The data presented were collected with a variety of targets and beam momenta from 5 GeV/c to 120 GeV/c. The energy calibration of both calorimeters with electrons, pions, kaons, and protons is discussed. The resolution for electrons was found to be 0.27/sqrt(E), and for hadrons the resolution was 0.554/sqrt(E) with a constant term of 2.6%. The performance of the calorimeters was tested on a neutron sample