4,078 research outputs found
A simulation-based method to evaluate the impact of product architecture on product evolvability
Products evolve over time via the continual redesigns of interdependent components. Product architecture, which is embodied in the structure of interactions among components, influences the ability for the product to be subsequently evolved. Despite extensive studies of change propagation via inter-component connections, little is known about the specific influences of product architecture on product evolvability. Related metrics and methods to assess the evolvability of products with given architectures are also under-developed. This paper proposes a simulation-based method to assess the isolated effect of product architecture on product evolvability by analyzing a design structure matrix. We define product evolvability as the ability of the productâs design to subsequently generate heritable performance-improving variations, and propose a quantitative measure for it. We demonstrate the proposed method by using it to investigate a wide spectrum of model-generated DSMs representing products with varied architectures, and show that modularity and inter-component influence cycles promote product evolvability. Our primary contribution is a repeatable method to assess and compare alternative product architectures for architecture selection or redesign for evolvability. A second contribution is the simulation-based evidence about the impacts of two particular product architectural patterns on product evolvability. Both contributions aim to aid in designing for evolvability.SUTD-MIT International Design Centre (IDC
In-Plane Orbital Texture Switch at the Dirac Point in the Topological Insulator Bi2Se3
Topological insulators are novel macroscopic quantum-mechanical phase of
matter, which hold promise for realizing some of the most exotic particles in
physics as well as application towards spintronics and quantum computation. In
all the known topological insulators, strong spin-orbit coupling is critical
for the generation of the protected massless surface states. Consequently, a
complete description of the Dirac state should include both the spin and
orbital (spatial) parts of the wavefunction. For the family of materials with a
single Dirac cone, theories and experiments agree qualitatively, showing the
topological state has a chiral spin texture that changes handedness across the
Dirac point (DP), but they differ quantitatively on how the spin is polarized.
Limited existing theoretical ideas predict chiral local orbital angular
momentum on the two sides of the DP. However, there have been neither direct
measurements nor calculations identifying the global symmetry of the spatial
wavefunction. Here we present the first results from angle-resolved
photoemission experiment and first-principles calculation that both show,
counter to current predictions, the in-plane orbital wavefunctions for the
surface states of Bi2Se3 are asymmetric relative to the DP, switching from
being tangential to the k-space constant energy surfaces above DP, to being
radial to them below the DP. Because the orbital texture switch occurs exactly
at the DP this effect should be intrinsic to the topological physics,
constituting an essential yet missing aspect in the description of the
topological Dirac state. Our results also indicate that the spin texture may be
more complex than previously reported, helping to reconcile earlier conflicting
spin resolved measurements
Biodistribution and pharmacokinetics of a telodendrimer micellar paclitaxel nanoformulation in a mouse xenograft model of ovarian cancer
Wenwu Xiao1, Juntao Luo2, Teesta Jain3, John Riggs3, Harry P Tseng1, Paul T Henderson3, Simon R Cherry4, Douglas Rowland4, Kit S Lam1,31Department of Biochemistry and Molecular Medicine, UC Davis Cancer Center, University of California Davis, Sacramento, CA; 2Department of Pharmacology, SUNY Upstate Cancer Research Institute, SUNY Upstate Medical University, Syracuse, NY; 3Department of Internal Medicine, Division of Hematology and Oncology, 4Department of Biomedical Engineering, UC Davis Cancer Center, University of California Davis, Davis, CABackground: A multifunctional telodendrimer-based micelle system was characterized for delivery of imaging and chemotherapy agents to mouse tumor xenografts. Previous optical imaging studies demonstrated qualitatively that these classes of nanoparticles, called nanomicelles, preferentially accumulate at tumor sites in mice. The research reported herein describes the detailed quantitative imaging and biodistribution profiling of nanomicelles loaded with a cargo of paclitaxel.Methods: The telodendrimer was covalently labeled with 125I and the nanomicelles were loaded with 14C-paclitaxel, which allowed measurement of pharmacokinetics and biodistribution in the mice using microSPECT/CT imaging and liquid scintillation counting, respectively.Results: The radio imaging data showed preferential accumulation of nanomicelles at the tumor site along with a slower clearance rate than paclitaxel formulated in Cremophor EL (Taxol®). Liquid scintillation counting confirmed that 14C-labeled paclitaxel sequestered in nanomicelles had increased uptake by tumor tissue and slower pharmacokinetics than Taxol.Conclusion: Overall, the results indicate that nanomicelle-formulated paclitaxel is a potentially superior formulation compared with Taxol in terms of water solubility, pharmacokinetics, and tumor accumulation, and may be clinically useful for both tumor imaging and improved chemotherapy applications.Keywords: telodendrimer, nanomicelle, paclitaxel, microSPECT/CT, imaging guided drug deliver
Enhanced pre-synaptic glutamate release in deep-dorsal horn contributes to calcium channel alpha-2-delta-1 protein-mediated spinal sensitization and behavioral hypersensitivity
Nerve injury-induced expression of the spinal calcium channel alpha-2-delta-1 subunit (Cavα2Ύ1) has been shown to mediate behavioral hypersensitivity through a yet identified mechanism. We examined if this neuroplasticity modulates behavioral hypersensitivity by regulating spinal glutamatergic neurotransmission in injury-free transgenic mice overexpressing the Cavα2Ύ1 proteins in neuronal tissues. The transgenic mice exhibited hypersensitivity to mechanical stimulation (allodynia) similar to the spinal nerve ligation injury model. Intrathecally delivered antagonists for N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxyl-5-methylisoxazole-4-propionic acid (AMPA)/kainate receptors, but not for the metabotropic glutamate receptors, caused a dose-dependent allodynia reversal in the transgenic mice without changing the behavioral sensitivity in wild-type mice. This suggests that elevated spinal Cavα2Ύ1 mediates allodynia through a pathway involving activation of selective glutamate receptors. To determine if this is mediated by enhanced spinal neuronal excitability or pre-synaptic glutamate release in deep-dorsal horn, we examined wide-dynamic-range (WDR) neuron excitability with extracellular recording and glutamate-mediated excitatory postsynaptic currents with whole-cell patch recording in deep-dorsal horn of the Cavα2Ύ1 transgenic mice. Our data indicated that overexpression of Cavα2Ύ1 in neuronal tissues led to increased frequency, but not amplitude, of miniature excitatory post synaptic currents mediated mainly by AMPA/kainate receptors at physiological membrane potentials, and also by NMDA receptors upon depolarization, without changing the excitability of WDR neurons to high intensity stimulation. Together, these findings support a mechanism of Cavα2Ύ1-mediated spinal sensitization in which elevated Cavα2Ύ1 causes increased pre-synaptic glutamate release that leads to reduced excitation thresholds of post-synaptic dorsal horn neurons to innocuous stimuli. This spinal sensitization mechanism may mediate at least partially the neuropathic pain states derived from increased pre-synaptic Cavα2Ύ1 expression
Higher expression of human kallikrein 10 in breast cancer tissue predicts tamoxifen resistance
The human tissue kallikreins are secreted serine proteases, encoded by a group of homologous genes clustered in tandem on chromosome 19q13.3-4. Human kallikrein 6 and human kallikrein 10 are two new members of this family. Recently, we developed highly sensitive and specific immunofluorometric assays for human kallikrein 6 and human kallikrein 10, which allow for their quantification in tissue extracts and biological fluids. Both human kallikrein 6 and human kallikrein 10 are found to be down-regulated in breast cancer cell lines, suggesting that they may be involved in breast cancer pathogenesis and progression. In this study, we investigated the potential value of human kallikrein 6 and human kallikrein 10 as prognostic and predictive factors in breast cancer. We quantified human kallikrein 6 and human kallikrein 10 protein levels in 749 breast tumour cytosolic extracts and correlated this data with various clinicopathological variables and patient outcomes. Human kallikrein 6 and human kallikrein 10 are positively correlated with each other. Higher human kallikrein 6 and human kallikrein 10 protein levels are associated with younger age, pre-menopausal, status and tumours which are negative for oestrogen and progesterone receptors. No correlation was found between human kallikrein 6 and human kallikrein 10 levels and tumour size, grade, and nodal status. Survival analysis showed that neither human kallikrein 6 nor human kallikrein 10 are related to the rate of relapse-free and overall survival. In the analysis with respect to response to tamoxifen therapy, although human kallikrein 6 levels were not associated with tamoxifen responsiveness, higher levels of human kallikrein 10 were significantly associated with a poor response rate. This association remained significant in the multivariate analysis. Furthermore, higher human kallikrein 10 levels were significantly related with a short progression-free and post-relapse overall survival after start of tamoxifen treatment for advanced disease. Taken together, our results suggest that although human kallikrein 6 and human kallikrein 10 are not prognostic markers for breast cancer, human kallikrein 10 is an independent predictive marker for response of tamoxifen therapy
On single and double soft behaviors in NLSM
In this paper, we study the single and double soft behaviors of tree level
off-shell currents and on-shell amplitudes in nonlinear sigma model(NLSM). We
first propose and prove the leading soft behavior of the tree level currents
with a single soft particle. In the on-shell limit, this single soft emission
becomes the Adler's zero. Then we establish the leading and sub-leading soft
behaviors of tree level currents with two adjacent soft particles. With a
careful analysis of the on-shell limit, we obtain the double soft behaviors of
on-shell amplitudes where the two soft particles are adjacent to each other. By
applying Kleiss-Kuijf (KK) relation, we further obtain the leading and
sub-leading behaviors of amplitudes with two nonadjacent soft particles.Comment: 41 pages, 6 tables, 9 figures, minor revised, more content about
nonadjacent double soft limit, update the reference
Alternative splicing in prostate cancer.
Androgen receptor (AR) splice variants (AR-Vs) have been implicated in the development and progression of metastatic prostate cancer. AR-Vs are truncated isoforms of the AR, a subset of which lack a ligand-binding domain and remain constitutively active in the absence of circulating androgens, thus promoting cancer cell proliferation. Consequently, AR-Vs have been proposed to contribute not only to resistance to anti-androgen therapies but also to resistance to radiotherapy in patients receiving combination therapy by promoting DNA repair. AR-Vs, such as AR-V7, have been associated with unfavourable clinical outcomes in patients; however, attempts to specifically inhibit or prevent the formation of AR-Vs have, to date, been unsuccessful. Thus, novel therapeutic strategies are desperately needed to address the oncogenic effects of AR-Vs, which can drive lethal forms of prostate cancer. Disruption of alternative splicing through modulation of the spliceosome is one such potential therapeutic avenue; however, our understanding of the biology of the spliceosome and how it contributes to prostate cancer remains incomplete, as reflected in the dearth of spliceosome-targeted therapeutic agents. In this Review, the authors outline the current understanding of the role of the spliceosome in the progression of prostate cancer and explore the therapeutic utility of manipulating alternative splicing to improve patient care
General Gauge Mediation with Gauge Messengers
We generalize the General Gauge Mediation formalism to allow for the
possibility of gauge messengers. Gauge messengers occur when charged matter
fields of the susy-breaking sector have non-zero F-terms, which leads to
tree-level, susy-breaking mass splittings in the gauge fields. A classic
example is that SU(5) / SU(3) x SU(2) x U(1) gauge fields could be gauge
messengers. We give a completely general, model independent, current-algebra
based analysis of gauge messenger mediation of susy-breaking to the visible
sector. Characteristic aspects of gauge messengers include enhanced
contributions to gaugino masses, (tachyonic) sfermion mass-squareds generated
already at one loop, and also at two loops, and significant one-loop A-terms,
already at the messenger scale.Comment: 79 pages, 5 figure
Classical kinetic energy, quantum fluctuation terms and kinetic-energy functionals
We employ a recently formulated dequantization procedure to obtain an exact
expression for the kinetic energy which is applicable to all kinetic-energy
functionals. We express the kinetic energy of an N-electron system as the sum
of an N-electron classical kinetic energy and an N-electron purely quantum
kinetic energy arising from the quantum fluctuations that turn the classical
momentum into the quantum momentum. This leads to an interesting analogy with
Nelson's stochastic approach to quantum mechanics, which we use to conceptually
clarify the physical nature of part of the kinetic-energy functional in terms
of statistical fluctuations and in direct correspondence with Fisher
Information Theory. We show that the N-electron purely quantum kinetic energy
can be written as the sum of the (one-electron) Weizsacker term and an
(N-1)-electron kinetic correlation term. We further show that the Weizsacker
term results from local fluctuations while the kinetic correlation term results
from the nonlocal fluctuations. For one-electron orbitals (where kinetic
correlation is neglected) we obtain an exact (albeit impractical) expression
for the noninteracting kinetic energy as the sum of the classical kinetic
energy and the Weizsacker term. The classical kinetic energy is seen to be
explicitly dependent on the electron phase and this has implications for the
development of accurate orbital-free kinetic-energy functionals. Also, there is
a direct connection between the classical kinetic energy and the angular
momentum and, across a row of the periodic table, the classical kinetic energy
component of the noninteracting kinetic energy generally increases as Z
increases.Comment: 10 pages, 1 figure. To appear in Theor Chem Ac
MegaGTA: a sensitive and accurate metagenomic gene-targeted assembler using iterative de Bruijn graphs
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