Publications by authors named "William H Miller"

130 Publications

Pathology in Practice.

J Am Vet Med Assoc 2020 Apr;256(7):779-782

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http://dx.doi.org/10.2460/javma.256.7.779DOI Listing
April 2020

Elevated circulating Th2 but not group 2 innate lymphoid cell responses characterize canine atopic dermatitis.

Vet Immunol Immunopathol 2020 Mar 24;221:110015. Epub 2020 Jan 24.

Baker Institute for Animal Health and Department of Microbiology and Immunology, Ithaca, NY 14853, USA; Department of Immunology, University of Washington, Seattle, WA 98109, USA. Electronic address:

Atopic dermatitis (AD) is an allergic skin disease that causes significant morbidity and affects multiple species. AD is highly prevalent in companion dogs, and the clinical management of the disease remains challenging. An improved understanding of the immunologic and genetic pathways that lead to disease could inform the development of novel treatments. In allergic humans and mouse models of AD, the disease is associated with Th2 and group 2 innate lymphoid cell (ILC2) activation that drives type 2 inflammation. Type 2 inflammation also appears to be associated with AD in dogs, but gaps remain in our understanding of how key type 2-associated cell types such as canine Th2 cells and ILC2s contribute to the pathogenesis of canine AD. Here, we describe previously uncharacterized canine ILC2-like cells and Th2 cells ex vivo that produced type 2 cytokines and expressed the transcription factor Gata3. Increased circulating Th2 cells were associated with chronic canine AD. Single-cell RNA sequencing revealed a unique gene expression signature in T cells in dogs with AD. These findings underline the importance of pro-allergic Th2 cells in orchestrating AD and provide new methods and pathways that can inform the development of improved therapies.
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http://dx.doi.org/10.1016/j.vetimm.2020.110015DOI Listing
March 2020

Verification of I-131Yields from the neutron irradiation of tellurium.

Appl Radiat Isot 2019 Sep 3;151:52-61. Epub 2019 May 3.

University of Missouri Research Reactor, Columbia, MO, 65211, USA.

The production of I-131 for use in medicine can be accomplished by the neutron irradiation of tellurium, typically in the form of TeO. Unfortunately, the literature contains conflicting data concerning the I-131 yield as a function of neutron fluence, target mass, irradiation time and post-irradiation decay. In this work, the activity of the I-131 was determined using calculations and experimental verifications based on the interplay of these variables.
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http://dx.doi.org/10.1016/j.apradiso.2019.05.001DOI Listing
September 2019

Trajectory-adjusted electronic zero point energy in classical Meyer-Miller vibronic dynamics: Symmetrical quasiclassical application to photodissociation.

J Chem Phys 2019 May;150(19):194110

Department of Chemistry and Kenneth S. Pitzer Center for Theoretical Chemistry, University of California, Berkeley, California 94720, USA and Chemical Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA.

An electronic zero-point energy (ZPE) adjustment protocol is presented within the context of the symmetrical quasiclassical (SQC) quantization of the electronic oscillator degrees of freedom (DOF) in classical Meyer-Miller (MM) vibronic dynamics for the molecular dynamics treatment of electronically nonadiabatic processes. The "adjustment" procedure maintains the same initial and final distributions of coordinates and momenta in the electronic oscillator DOF as previously given by the SQC windowing protocol but modifies the ZPE parameter in the MM Hamiltonian, on a per trajectory basis, so that the initial nuclear forces are precisely those corresponding to the initial electronic quantum state. Examples demonstrate that this slight modification to the standard SQC/MM approach significantly improves treatment of the multistate nonadiabatic dynamics following a Franck-Condon type vertical excitation onto a highly repulsive potential energy surface as is typical in the photodissociation context.
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http://dx.doi.org/10.1063/1.5094458DOI Listing
May 2019

External ear cytological results and resident flora of clinically normal alpacas (Vicugna pacos).

Vet Dermatol 2019 Aug 30;30(4):337-e94. Epub 2019 Apr 30.

Department of Clinical Sciences, College of Veterinary Medicine, Cornell University, 930 Campus Road, Ithaca, NY, 14853, USA.

Background: Otitis is common in alpacas. Suppurative otitis media/interna can be an extension from the external ear canal or from a respiratory infection. Cytological evaluation provides rapid and inexpensive information to assist in therapeutic decision; to date, there is no published information regarding the normal cytological results and flora of the alpaca external ear canal.

Hypothesis/objectives: To describe normal resident cytological findings and flora and possible variation over time, we sampled clinically normal alpaca external ear canals during two different seasons.

Animals: Fifty privately owned, healthy alpacas of different ages and sexes in two northeastern United States flocks.

Methods And Materials: One ear per alpaca had both cytological swabs (ectoparasites, inflammatory and epithelial cells, bacteria and yeast) and sterile swabs (bacterial and fungal cultures) taken. This was done in August 2017 and repeated in January 2018.

Results: Yeast organisms were noted cytologically in 2-4% of the samples. Prevalence of total yeast genera was 6% in August and 30% in January. Cytologically, rod-shaped bacteria [maximum 4-10/high power field (HPF); median 0-0.5/HPF] were seen in 50% of alpacas in August and 26% in January. Coccal bacteria (maximum 6-10/HPF; median 0/HPF) were seen in 32% of alpacas in August and 16% in January. No statistically significant findings were noted between sampling months. Common bacterial genera isolated in August were Bacillus (44%), Arthrobacter (40%) and nonhaemolytic Staphylococcus (26%), and in January were Bacillus (42%) and Pantoea (38%).

Conclusions And Clinical Importance: This information may be useful when evaluating alpaca external ear canal samples, which subsequently may help dictate empirical therapy.
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http://dx.doi.org/10.1111/vde.12751DOI Listing
August 2019

A symmetrical quasi-classical windowing model for the molecular dynamics treatment of non-adiabatic processes involving many electronic states.

J Chem Phys 2019 Mar;150(10):104101

Department of Chemistry and Kenneth S. Pitzer Center for Theoretical Chemistry, University of California, Berkeley, California 94720, USA and Chemical Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA.

In the previous work of Cotton and Miller [J. Chem. Phys. 145, 144108 (2016)], an improved symmetrical quasi-classical (SQC) windowing model for the molecular dynamics treatment of electronically non-adiabatic processes was developed in order to extend the original SQC approach to the regime of weak-coupling between the electronic states. The improved SQC model-based on triangular-shaped window functions-handled the weak-coupling limit as intended and, as a bonus, was shown to be universally superior to the original square/histogram SQC windowing model over all coupling regimes, but only for treating systems of two electronic states, as no higher-dimensional generalization was evident. This paper, therefore, provides a generalized version for treating an arbitrary number of electronic states. By construction, the benefits of the two-state triangle model-seamless treatment of weak-coupling and improved accuracy in all coupling regimes-carry over to the generalized version. Far more significant, however, is that the new model provides vastly improved windowing statistics in higher dimensions, enabling the SQC simulation of electronically non-adiabatic processes involving many more relevant electronic states than was previously practical. Capabilities are demonstrated with respect to a 24 pigment trimer model of the Fenna-Matthews-Olson light-harvesting complex, as well as treating similar 48- and 96-electronic state model problems, illustrating the scaling properties of the new method.
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http://dx.doi.org/10.1063/1.5087160DOI Listing
March 2019

The symmetrical quasi-classical approach to electronically nonadiabatic dynamics applied to ultrafast exciton migration processes in semiconducting polymers.

J Chem Phys 2018 Jul;149(4):044101

Department of Chemistry and Kenneth S. Pitzer Center for Theoretical Chemistry, University of California, Berkeley, California 94720, USA and Chemical Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA.

In the last several years, a symmetrical quasi-classical (SQC) windowing model applied to the classical Meyer-Miller (MM) vibronic Hamiltonian has been shown to be a simple, efficient, general, and quite-accurate method for treating electronically nonadiabatic processes at the totally classical level. Here, the SQC/MM methodology is applied to ultrafast exciton dynamics in a Frenkel/site-exciton model of oligothiophene (OT) as a model of organic semiconductor polymers. In order to keep the electronic representation as compact and efficient as possible, the adiabatic version of the MM Hamiltonian was employed, with dynamical calculations carried out in the recently developed "kinematic momentum" representation, from which site/monomer-specific (diabatic) excitation probabilities were extracted using a new procedure developed in this work. The SQC/MM simulation results are seen to describe coherent exciton transport driven by planarization of a central torsion defect in the OT oligomer as well as to capture exciton self-trapping effects in good agreement with benchmark quantum calculations using the multi-layer multiconfiguration time-dependent Hartree approach. The SQC/MM calculations are also seen to significantly outperform the standard Ehrenfest approach, which shows serious discrepancies. These results are encouraging, not only because they illustrate a significant further application of the SQC/MM approach and its utility, but because they strongly suggest that classical mechanical simulations (with the potential for linear scaling efficiency) can be used to capture, quantitatively, important dynamical features of electronic excitation energy transfer in semiconducting polymers.
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http://dx.doi.org/10.1063/1.5037815DOI Listing
July 2018

Beta Skin Dosimetry using Passivated Planar Silicon Detector.

Appl Radiat Isot 2018 May 31;135:99-103. Epub 2018 Jan 31.

Missouri University Research Reactor, University of Missouri, USA.

Accurate measurement of beta skin dose remains a challenge. This dose is defined as the dose to the basil layer at 7 mg/cm (approximately 70 µm) below the surface of the skin and averaged over an area of 1 cm. This dose is dependent upon the energy of the beta contamination on the surface of the skin, the area of contamination and the attenuation of this radiation through the 7 mg/cm epidermal layer. Ideally, knowing the energy spectra of betas at this level below the surface of the skin would allow accurate prediction of dose. In this work, a Passivated Planar Silicon (PIPS) detector was tested by measuring beta spectra in a geometry simulating skin and, from that, estimating dose. Three calibrated beta sources were used, a low energy beta source, (Pm), a medium energy source, (Tl), and a high energy beta source, (Sr/Y) to cover the range of beta energies typically found in skin contamination events. Modelling utilized the MCNPX and VARSKIN 4.0 computer codes to calculate dose in skin and were found to be in good agreement with each other. Experimental measurements using a 300 µm thick, 3 cm PIPS and the three sources identified above showed good agreement with MCNPX results (and thus, also with VARSKIN). Finally, MCNPX modelling compared the dose rates from a commercially available, 100 µm thick, 1.5 cm PIPS detector and skin, and found that the beta dose could be accurately predicted within 17% over the range of beta energies tested. This result can be obtained with a single measurement and without the need for post data collection analysis.
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http://dx.doi.org/10.1016/j.apradiso.2018.01.026DOI Listing
May 2018

On the adiabatic representation of Meyer-Miller electronic-nuclear dynamics.

J Chem Phys 2017 Aug;147(6):064112

Department of Chemistry and Kenneth S. Pitzer Center for Theoretical Chemistry, University of California, Berkeley, California 94720, USA, and Chemical Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA.

The Meyer-Miller (MM) classical vibronic (electronic + nuclear) Hamiltonian for electronically non-adiabatic dynamics-as used, for example, with the recently developed symmetrical quasiclassical (SQC) windowing model-can be written in either a diabatic or an adiabatic representation of the electronic degrees of freedom, the two being a canonical transformation of each other, thus giving the same dynamics. Although most recent applications of this SQC/MM approach have been carried out in the diabatic representation-because most of the benchmark model problems that have exact quantum results available for comparison are typically defined in a diabatic representation-it will typically be much more convenient to work in the adiabatic representation, e.g., when using Born-Oppenheimer potential energy surfaces (PESs) and derivative couplings that come from electronic structure calculations. The canonical equations of motion (EOMs) (i.e., Hamilton's equations) that come from the adiabatic MM Hamiltonian, however, in addition to the common first-derivative couplings, also involve second-derivative non-adiabatic coupling terms (as does the quantum Schrödinger equation), and the latter are considerably more difficult to calculate. This paper thus revisits the adiabatic version of the MM Hamiltonian and describes a modification of the classical adiabatic EOMs that are entirely equivalent to Hamilton's equations but that do not involve the second-derivative couplings. The second-derivative coupling terms have not been neglected; they simply do not appear in these modified adiabatic EOMs. This means that SQC/MM calculations can be carried out in the adiabatic representation, without approximation, needing only the PESs and the first-derivative coupling elements. The results of example SQC/MM calculations are presented, which illustrate this point, and also the fact that simply neglecting the second-derivative couplings in Hamilton's equations (and presumably also in the Schrödinger equation) can cause very significant errors.
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http://dx.doi.org/10.1063/1.4995301DOI Listing
August 2017

Classical molecular dynamics simulation of electronically non-adiabatic processes.

Faraday Discuss 2016 12;195:9-30

Department of Chemistry and Kenneth S. Pitzer Center for Theoretical Chemistry, University of California, and Chemical Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA.

Both classical and quantum mechanics (as well as hybrids thereof, i.e., semiclassical approaches) find widespread use in simulating dynamical processes in molecular systems. For large chemical systems, however, which involve potential energy surfaces (PES) of general/arbitrary form, it is usually the case that only classical molecular dynamics (MD) approaches are feasible, and their use is thus ubiquitous nowadays, at least for chemical processes involving dynamics on a single PES (i.e., within a single Born-Oppenheimer electronic state). This paper reviews recent developments in an approach which extends standard classical MD methods to the treatment of electronically non-adiabatic processes, i.e., those that involve transitions between different electronic states. The approach treats nuclear and electronic degrees of freedom (DOF) equivalently (i.e., by classical mechanics, thereby retaining the simplicity of standard MD), and provides "quantization" of the electronic states through a symmetrical quasi-classical (SQC) windowing model. The approach is seen to be capable of treating extreme regimes of strong and weak coupling between the electronic states, as well as accurately describing coherence effects in the electronic DOF (including the de-coherence of such effects caused by coupling to the nuclear DOF). A survey of recent applications is presented to illustrate the performance of the approach. Also described is a newly developed variation on the original SQC model (found universally superior to the original) and a general extension of the SQC model to obtain the full electronic density matrix (at no additional cost/complexity).
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http://dx.doi.org/10.1039/c6fd00181eDOI Listing
December 2016

A new symmetrical quasi-classical model for electronically non-adiabatic processes: Application to the case of weak non-adiabatic coupling.

J Chem Phys 2016 Oct;145(14):144108

Department of Chemistry and Kenneth S. Pitzer Center for Theoretical Chemistry, University of California, Berkeley, California 94720, USA and Chemical Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA.

Previous work has shown how a symmetrical quasi-classical (SQC) windowing procedure can be used to quantize the initial and final electronic degrees of freedom in the Meyer-Miller (MM) classical vibronic (i.e, nuclear + electronic) Hamiltonian, and that the approach provides a very good description of electronically non-adiabatic processes within a standard classical molecular dynamics framework for a number of benchmark problems. This paper explores application of the SQC/MM approach to the case of very weak non-adiabatic coupling between the electronic states, showing (as anticipated) how the standard SQC/MM approach used to date fails in this limit, and then devises a new SQC windowing scheme to deal with it. Application of this new SQC model to a variety of realistic benchmark systems shows that the new model not only treats the weak coupling case extremely well, but it is also seen to describe the "normal" regime (of electronic transition probabilities ≳ 0.1) even more accurately than the previous "standard" model.
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http://dx.doi.org/10.1063/1.4963914DOI Listing
October 2016

Communication: Wigner functions in action-angle variables, Bohr-Sommerfeld quantization, the Heisenberg correspondence principle, and a symmetrical quasi-classical approach to the full electronic density matrix.

J Chem Phys 2016 Aug;145(8):081102

Department of Chemistry and Kenneth S. Pitzer Center for Theoretical Chemistry, University of California, and Chemical Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA.

It is pointed out that the classical phase space distribution in action-angle (a-a) variables obtained from a Wigner function depends on how the calculation is carried out: if one computes the standard Wigner function in Cartesian variables (p, x), and then replaces p and x by their expressions in terms of a-a variables, one obtains a different result than if the Wigner function is computed directly in terms of the a-a variables. Furthermore, the latter procedure gives a result more consistent with classical and semiclassical theory-e.g., by incorporating the Bohr-Sommerfeld quantization condition (quantum states defined by integer values of the action variable) as well as the Heisenberg correspondence principle for matrix elements of an operator between such states-and has also been shown to be more accurate when applied to electronically non-adiabatic applications as implemented within the recently developed symmetrical quasi-classical (SQC) Meyer-Miller (MM) approach. Moreover, use of the Wigner function (obtained directly) in a-a variables shows how our standard SQC/MM approach can be used to obtain off-diagonal elements of the electronic density matrix by processing in a different way the same set of trajectories already used (in the SQC/MM methodology) to obtain the diagonal elements.
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http://dx.doi.org/10.1063/1.4961551DOI Listing
August 2016

"Pigmentary incontinence" in the skin of the nasal plane from normal dogs?

Vet Dermatol 2016 08 9;27(4):323-4. Epub 2016 Jun 9.

College of Veterinary Medicine, Cornell University, Ithaca, NY, USA.

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http://dx.doi.org/10.1111/vde.12307DOI Listing
August 2016

The Symmetrical Quasi-Classical Model for Electronically Non-Adiabatic Processes Applied to Energy Transfer Dynamics in Site-Exciton Models of Light-Harvesting Complexes.

J Chem Theory Comput 2016 Mar 9;12(3):983-91. Epub 2016 Feb 9.

Department of Chemistry and Kenneth S. Pitzer Center for Theoretical Chemistry, University of California , Berkeley, California 94720, United States.

In a recent series of papers, it has been illustrated that a symmetrical quasi-classical (SQC) windowing model applied to the Meyer-Miller (MM) classical vibronic Hamiltonian provides an excellent description of a variety of electronically non-adiabatic benchmark model systems for which exact quantum results are available for comparison. In this paper, the SQC/MM approach is used to treat energy transfer dynamics in site-exciton models of light-harvesting complexes, and in particular, the well-known 7-state Fenna-Mathews-Olson (FMO) complex. Again, numerically "exact" results are available for comparison, here via the hierarchical equation of motion (HEOM) approach of Ishizaki and Fleming, and it is seen that the simple SQC/MM approach provides very reasonable agreement with the previous HEOM results. It is noted, however, that unlike most (if not all) simple approaches for treating these systems, because the SQC/MM approach presents a fully atomistic simulation based on classical trajectory simulation, it places no restrictions on the characteristics of the thermal baths coupled to each two-level site, e.g., bath spectral densities (SD) of any analytic functional form may be employed as well as discrete SD determined experimentally or from MD simulation (nor is there any restriction that the baths be harmonic), opening up the possibility of simulating more realistic variations on the basic site-exciton framework for describing the non-adiabatic dynamics of photosynthetic pigment complexes.
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http://dx.doi.org/10.1021/acs.jctc.5b01178DOI Listing
March 2016

Clindamycin for first-time or recurrent canine staphylococcal pyoderma.

Vet Dermatol 2016 Feb 24;27(1):62-3. Epub 2015 Nov 24.

College of Veterinary Medicine, Cornell University, Ithaca, NY 14853, USA.

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http://dx.doi.org/10.1111/vde.12275DOI Listing
February 2016

A Symmetrical Quasi-Classical Spin-Mapping Model for the Electronic Degrees of Freedom in Non-Adiabatic Processes.

J Phys Chem A 2015 Dec 31;119(50):12138-45. Epub 2015 Aug 31.

Department of Chemistry and Kenneth S. Pitzer Center for Theoretical Chemistry, University of California, Berkeley , Berkeley, California 94720, United States.

A recent series of papers has shown that a symmetrical quasi-classical (SQC) windowing procedure applied to the Meyer-Miller (MM) classical vibronic Hamiltonian provides a very good treatment of electronically nonadiabatic processes in a variety of benchmark model systems, including systems that exhibit strong quantum coherence effects and some which other approximate approaches have difficulty in describing correctly. In this paper, a different classical electronic Hamiltonian for the treatment of electronically nonadiabatic processes is proposed (and "quantized" via the SQC windowing approach), which maps the dynamics of F coupled electronic states to a set of F spin-(1)/2 degrees of freedom (DOF), similar to the Fermionic spin model described by Miller and White (J. Chem. Phys. 1986, 84, 5059). It is noted that this spin-mapping (SM) Hamiltonian is an exact Hamiltonian if treated as a quantum mechanical (QM) operator-and thus QM'ly equivalent to the MM Hamiltonian-but that an analytically distinct classical analogue is obtained by replacing the QM spin-operators with their classical counterparts. Due to their analytic differences, a practical comparison is then made between the MM and SM Hamiltonians (when quantized with the SQC technique) by applying the latter to many of the same benchmark test problems successfully treated in our recent work with the SQC/MM model. We find that for every benchmark problem the MM model provides (slightly) better agreement with the correct quantum nonadiabatic transition probabilities than does the new SM model. This is despite the fact that one might expect, a priori, a more natural description of electronic state populations (occupied versus unoccupied) to be provided by DOF with only two states, i.e., spin-(1)/2 DOF, rather than by harmonic oscillator DOF which have an infinite manifold of states (though only two of these are ever occupied).
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http://dx.doi.org/10.1021/acs.jpca.5b05906DOI Listing
December 2015

A DNA Hypomethylation Signature Predicts Antitumor Activity of LSD1 Inhibitors in SCLC.

Cancer Cell 2015 Jul;28(1):57-69

Cancer Epigenetics Department, GlaxoSmithKline, Collegeville, PA 19426, USA.

Epigenetic dysregulation has emerged as an important mechanism in cancer. Alterations in epigenetic machinery have become a major focus for targeted therapies. The current report describes the discovery and biological activity of a cyclopropylamine containing inhibitor of Lysine Demethylase 1 (LSD1), GSK2879552. This small molecule is a potent, selective, orally bioavailable, mechanism-based irreversible inactivator of LSD1. A proliferation screen of cell lines representing a number of tumor types indicated that small cell lung carcinoma (SCLC) is sensitive to LSD1 inhibition. The subset of SCLC lines and primary samples that undergo growth inhibition in response to GSK2879552 exhibit DNA hypomethylation of a signature set of probes, suggesting this may be used as a predictive biomarker of activity.
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http://dx.doi.org/10.1016/j.ccell.2015.06.002DOI Listing
July 2015

Communication: Note on detailed balance in symmetrical quasi-classical models for electronically non-adiabatic dynamics.

J Chem Phys 2015 Apr;142(13):131103

Department of Chemistry and Kenneth S. Pitzer Center for Theoretical Chemistry, University of California and Chemical Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA.

It is noted that the recently developed symmetrical quasi-classical (SQC) treatment of the Meyer-Miller (MM) model for the simulation of electronically non-adiabatic dynamics provides a good description of detailed balance, even though the dynamics which results from the classical MM Hamiltonian is "Ehrenfest dynamics" (i.e., the force on the nuclei is an instantaneous coherent average over all electronic states). This is seen to be a consequence of the SQC windowing methodology for "processing" the results of the trajectory calculation. For a particularly simple model discussed here, this is shown to be true regardless of the choice of windowing function employed in the SQC model, and for a more realistic full classical molecular dynamics simulation, it is seen to be maintained correctly for very long time.
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http://dx.doi.org/10.1063/1.4916945DOI Listing
April 2015

An alternative to the Sandmeyer approach to aryl iodides.

Chemistry 2015 Apr 10;21(17):6394-8. Epub 2015 Mar 10.

Department of Chemistry and Nebraska Center for Materials and Nanoscience, University of Nebraska, Lincoln, NE 68588-0304 (USA); Institute of Industrial Catalysis, College of Chemical Engineering, Zhejiang University of Technology, Hangzhou, Zhejiang 310014 (China).

Iodoarenes are important synthons for a wide range of organic transformations. Here we report a general strategy to prepare singly iodinated electron-rich aromatic compounds through the intermediacy of diaryliodonium salts. This process, which incorporates a phase separation that greatly simplifies product purification, is an attractive replacement for the Sandmeyer approach to iodoarenes that are otherwise difficult to access.
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http://dx.doi.org/10.1002/chem.201500151DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4412146PMC
April 2015

Symmetrical windowing for quantum states in quasi-classical trajectory simulations: application to electron transfer.

J Chem Phys 2014 Aug;141(8):084104

Department of Chemistry and Kenneth S. Pitzer Center for Theoretical Chemistry, University of California, and Chemical Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA.

It has recently been shown [S. J. Cotton and W. H. Miller, J. Chem. Phys. 139, 234112 (2013)] that a symmetrical windowing quasi-classical (SQC) approach [S. J. Cotton and W. H. Miller, J. Phys. Chem. A 117, 7190 (2013)] applied to the Meyer-Miller model [H.-D. Meyer and W. H. Miller, J. Chem. Phys. 70, 3214 (1979)] for the electronic degrees of freedom in electronically non-adiabatic dynamics is capable of quantitatively reproducing quantum mechanical results for a variety of test applications, including cases where "quantum" coherence effects are significant. Here we apply this same SQC methodology, within a flux-side correlation function framework, to calculate thermal rate constants corresponding to several proposed models of electron transfer processes [P. Huo, T. F. Miller III, and D. F. Coker, J. Chem. Phys. 139, 151103 (2013); A. R. Menzeleev, N. Ananth, and T. F. Miller III, J. Chem. Phys. 135, 074106 (2011)]. Good quantitative agreement with Marcus Theory is obtained over several orders of magnitude variation in non-adiabatic coupling. Moreover, the "inverted regime" in thermal rate constants (with increasing bias) known from Marcus Theory is also reproduced with good accuracy by this very simple classical approach. The SQC treatment is also applied to a recent model of photoinduced proton coupled electron transfer [C. Venkataraman, A. V. Soudackov, and S. Hammes-Schiffer, J. Chem. Phys. 131, 154502 (2009)] and population decay of the photoexcited donor state is found to be in reasonable agreement with results calculated via reduced density matrix theory.
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http://dx.doi.org/10.1063/1.4893345DOI Listing
August 2014

Classical mapping for Hubbard operators: application to the double-Anderson model.

J Chem Phys 2014 May;140(20):204106

School of Chemistry, The Sackler Faculty of Exact Sciences, Tel Aviv University, Tel Aviv 69978, Israel.

A classical Cartesian mapping for Hubbard operators is developed to describe the nonequilibrium transport of an open quantum system with many electrons. The mapping of the Hubbard operators representing the many-body Hamiltonian is derived by using analogies from classical mappings of boson creation and annihilation operators vis-à-vis a coherent state representation. The approach provides qualitative results for a double quantum dot array (double Anderson impurity model) coupled to fermionic leads for a range of bias voltages, Coulomb couplings, and hopping terms. While the width and height of the conduction peaks show deviations from the master equation approach considered to be accurate in the limit of weak system-leads couplings and high temperatures, the Hubbard mapping captures all transport channels involving transition between many electron states, some of which are not captured by approximate nonequilibrium Green function closures.
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http://dx.doi.org/10.1063/1.4878736DOI Listing
May 2014

A journey through chemical dynamics.

Authors:
William H Miller

Annu Rev Phys Chem 2014 ;65:1-19

Department of Chemistry and Kenneth S. Pitzer Center for Theoretical Chemistry, University of California, Berkeley, and Chemical Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California 94720; email:

The charge with the invitation to write this autobiographical article was to describe what led me to a career in science and to choose the specific topics and scientific directions I have pursued. This is thus a very personal story and by no means a scientific review of the work that is mentioned. As will be clear, this journey was not an orderly, well-thought-out plan, but just "happened," one step after the other.
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http://dx.doi.org/10.1146/annurev-physchem-040513-103720DOI Listing
April 2015

A quasi-classical mapping approach to vibrationally coupled electron transport in molecular junctions.

J Chem Phys 2014 Mar;140(10):104110

Department of Chemistry and Kenneth S. Pitzer Center for Theoretical Chemistry, University of California, and Chemical Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA.

We develop a classical mapping approach suitable to describe vibrationally coupled charge transport in molecular junctions based on the Cartesian mapping for many-electron systems [B. Li and W. H. Miller, J. Chem. Phys. 137, 154107 (2012)]. To properly describe vibrational quantum effects in the transport characteristics, we introduce a simple transformation rewriting the Hamiltonian in terms of occupation numbers and use a binning function to facilitate quantization. The approach provides accurate results for the nonequilibrium Holstein model for a range of bias voltages, vibrational frequencies, and temperatures. It also captures the hallmarks of vibrational quantum effects apparent in step-like structure in the current-voltage characteristics at low temperatures as well as the phenomenon of Franck-Condon blockade.
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http://dx.doi.org/10.1063/1.4867789DOI Listing
March 2014

Symmetrical windowing for quantum states in quasi-classical trajectory simulations: application to electronically non-adiabatic processes.

J Chem Phys 2013 Dec;139(23):234112

Department of Chemistry and Kenneth S. Pitzer Center for Theoretical Chemistry, University of California, Berkeley, and Chemical Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA.

A recently described symmetrical windowing methodology [S. J. Cotton and W. H. Miller, J. Phys. Chem. A 117, 7190 (2013)] for quasi-classical trajectory simulations is applied here to the Meyer-Miller [H.-D. Meyer and W. H. Miller, J. Chem. Phys. 70, 3214 (1979)] model for the electronic degrees of freedom in electronically non-adiabatic dynamics. Results generated using this classical approach are observed to be in very good agreement with accurate quantum mechanical results for a variety of test applications, including problems where coherence effects are significant such as the challenging asymmetric spin-boson system.
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http://dx.doi.org/10.1063/1.4845235DOI Listing
December 2013

Scaling dermatosis in three dogs associated with abnormal sebaceous gland differentiation.

Vet Dermatol 2014 Feb 17;25(1):23-e8. Epub 2013 Dec 17.

Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, 14853, USA.

Background: Abnormal sebaceous gland differentiation, so-called 'sebaceous gland dysplasia', is a rare condition described in the dog and the cat. Although little is known about this condition, it is thought that a genetic defect causes abnormal sebaceous gland development. Clinically, this condition occurs in young cats and dogs and is characterized by variable degrees of adherent scale, hair casts, poor coat quality and hypotrichosis.

Hypothesis/objective: Here, we describe the clinical presentation and treatment of three adult dogs with abnormal sebaceous gland differentiation.

Animals: Three adult dogs presented with a keratinization defect characterized by progressive scaling, hair casts, dull, dry, brittle hair coat and hypotrichosis beginning in puppyhood to early adulthood.

Methods: Multiple 6 mm punch skin biopsy samples were obtained from each dog. Treatments included various topical keratomodulatory agents, oral essential fatty acids and oral vitamin A.

Results: Histologically, all sebaceous glands were small and composed of a mixture of irregularly clustered basal reserve cells and mature sebocytes. With therapy, two of the dogs showed moderate to marked clinical improvement in scaling, hair casts and hair coat quality.

Conclusions And Clinical Importance: Although rare, 'sebaceous gland dysplasia' should be considered in cases where a primary keratinization defect is suspected. Given that abnormal sebaceous differentiation is a structural defect of the skin, treatment must be maintained and is aimed at ameliorating the clinical signs rather than curing the disease.
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http://dx.doi.org/10.1111/vde.12098DOI Listing
February 2014

Long residence time inhibition of EZH2 in activated polycomb repressive complex 2.

ACS Chem Biol 2014 Mar 31;9(3):622-9. Epub 2013 Dec 31.

Cancer Epigenetics Discovery Performance Unit, Cancer Research, Oncology R&D and ‡Platform Technology and Sciences, GlaxoSmithKline, 1250 S. Collegeville Road, Collegeville, Pennsylvania 19426, United States.

EZH2/PRC2 catalyzes transcriptionally repressive methylation at lysine 27 of histone H3 and has been associated with numerous cancer types. Point mutations in EZH2 at Tyr641 and Ala677 identified in non-Hodgkin lymphomas alter substrate specificity and result in increased trimethylation at histone H3K27. Interestingly, EZH2/PRC2 is activated by binding H3K27me3 marks on histones, and this activation is proposed as a mechanism for self-propagation of gene silencing. Recent work has identified GSK126 as a potent, selective, SAM-competitive inhibitor of EZH2 capable of globally decreasing H3K27 trimethylation in cells. Here we show that activation of PRC2 by an H3 peptide trimethylated at K27 is primarily an effect on the rate-limiting step (kcat) with no effect on substrate binding (Km). Additionally, GSK126 is shown to have a significantly longer residence time of inhibition on the activated form of EZH2/PRC2 as compared to unactivated EZH2/PRC2. Overall inhibition constant (Ki*) values for GSK126 were determined to be as low as 93 pM and appear to be driven by slow dissociation of inhibitor from the activated enzyme. The data suggest that activation of EZH2 allows the enzyme to adopt a conformation that possesses greater affinity for GSK126. The long residence time of GSK126 may be beneficial in vivo and may result in durable target inhibition after drug systemic clearance.
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http://dx.doi.org/10.1021/cb4008748DOI Listing
March 2014

Comparative biodistributions and dosimetry of [¹⁷⁷Lu]DOTA-anti-bcl-2-PNA-Tyr³-octreotate and [¹⁷⁷Lu]DOTA-Tyr³-octreotate in a mouse model of B-cell lymphoma/leukemia.

Nucl Med Biol 2014 Jan 18;41(1):36-42. Epub 2013 Oct 18.

Area of Pathobiology, University of Missouri, Columbia, MO; Research Service, Harry S. Truman Memorial Veterans' Hospital, Columbia, MO; Department of Veterinary Medicine and Surgery, University of Missouri, Columbia, MO.

Introduction: The B-cell lymphoma/leukemia-2 (bcl-2) proto-oncogene in non-Hodgkin's lymphoma (NHL) is a dominant inhibitor of apoptosis. We developed a (177)Lu-labeled bcl-2 antisense peptide nucleic acid (PNA)-peptide conjugate designed for dual modality NHL therapy, consisting of a radiopharmaceutical capable of simultaneously down-regulating apoptotic resistance and delivering cytotoxic internally emitted radiation.

Methods: DOTA-anti-bcl-2-Tyr(3)-octreotate was synthesized, labeled with (177)Lu, and purified using RP-HPLC. The PNA-peptide conjugate was evaluated in Mec-1 NHL-bearing mice and compared to [(177)Lu]DOTA-Tyr(3)-octreotate in biodistribution and excretion studies. These data were then used to generate in vivo dosimetry models.

Results: The PNA-peptide conjugate was readily prepared and radiolabeled in high yield and radiochemical purity. An in vivo blocking study determined that administration of 50 μg of non-radioactive PNA-peptide was the optimal mass for maximum delivery to the tumor. Based on that result, a dosing regimen of (177)Lu-PNA-peptide, for radiologic effect, followed by the optimal mass of non-radioactive compound, for antisense effect, was designed. Using that dosing regimen, biodistribution of the PNA-peptide showed uptake in the tumor with minimal washout over a 4-day period. Uptakes in receptor-positive normal organs were low and displayed nearly complete washout by 24h. Dosimetry models showed that the tumor absorbed dose of the PNA-peptide conjugate was approximately twice that of the peptide-only conjugate.

Conclusions: Biodistribution data showed specific tumor targeting of the (177)Lu-labeled PNA-peptide compound with minimal receptor-positive normal tissue uptake when compared to [(177)Lu]DOTA-Tyr(3)-octreotate. In vivo dosimetry models predicted a more favorable tumor absorbed dose from [(177)Lu]DOTA-anti-bcl-2-Tyr(3)-octreotate.
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http://dx.doi.org/10.1016/j.nucmedbio.2013.10.006DOI Listing
January 2014

Impaired renal function impacts negatively on vascular stiffness in patients with coronary artery disease.

BMC Nephrol 2013 Aug 13;14:173. Epub 2013 Aug 13.

Background: Chronic kidney disease (CKD) and coronary artery disease (CAD) are independently associated with increased vascular stiffness. We examined whether renal function contributes to vascular stiffness independently of CAD status.

Methods: We studied 160 patients with CAD and 169 subjects without CAD. The 4-variable MDRD formula was used to estimate glomerular filtration rate (eGFR); impaired renal function was defined as eGFR <60 mL/min. Carotid-femoral pulse wave velocity (PWV) was measured with the SphygmoCor® device. Circulating biomarkers were assessed in plasma using xMAP® multiplexing technology.

Results: Patients with CAD and impaired renal function had greater PWV compared to those with CAD and normal renal function (10.2 [9.1;11.2] vs 7.3 [6.9;7.7] m/s; P < 0.001). In all patients, PWV was a function of eGFR (β = -0.293; P < 0.001) even after adjustment for age, sex, systolic blood pressure, body mass index and presence or absence of CAD. Patients with CAD and impaired renal function had higher levels of adhesion and inflammatory molecules including E-selectin and osteopontin (all P < 0.05) compared to those with CAD alone, but had similar levels of markers of oxidative stress.

Conclusions: Renal function is a determinant of vascular stiffness even in patients with severe atherosclerotic disease. This was paralleled by differences in markers of cell adhesion and inflammation. Increased vascular stiffness may therefore be linked to inflammatory remodeling of the vasculature in people with impaired renal function, irrespective of concomitant atherosclerotic disease.
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http://dx.doi.org/10.1186/1471-2369-14-173DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3751647PMC
August 2013