Polypathologies and Animal Models of Traumatic Brain Injury.

Traumatic brain injury (TBI) is an important health issue for the worldwide population, as it causes long-term pathological consequences for a diverse group of individuals. We are yet to fully elucidate the significance of TBI polypathologies, such as neuroinflammation and tau hyperphosphorylation, and their contribution to the development of chronic traumatic encephalopathy (CTE) and other neurological conditions. To advance our understanding of TBI, it is necessary to replicate TBI in preclinical models. Commonly used animal models include the weight drop model; these methods model human TBI in various ways and in different animal species. However, animal models have not demonstrated their clinical utility for identifying therapeutic interventions. Many interventions that were successful in improving outcomes for animal models did not translate into clinical benefit for patients. It is important to review current animal models and discuss their strengths and limitations within a TBI context. Modelling human TBI in animals encounters numerous challenges, yet despite these barriers, the TBI research community is working to overcome these difficulties. Developments include advances in biomarkers, standardising, and refining existing models. This progress will improve our ability to model TBI in animals and, therefore, enhance our understanding of TBI and, potentially, how to treat it.

Dynamic signatures of electronically nonadiabatic coupling in sodium hydride: a rigorous test for the symmetric quasi-classical model applied to realistic, ab initio electronic states in the adiabatic representation.

Sodium hydride (NaH) in the gas phase presents a seemingly simple electronic structure making it a potentially tractable system for the detailed investigation of nonadiabatic molecular dynamics from both computational and experimental standpoints. The single vibrational degree of freedom, as well as the strong nonadiabatic coupling that arises from the excited electronic states taking on considerable ionic character, provides a realistic chemical system to test the accuracy of quasi-classical methods to model population dynamics where the results are directly comparable against quantum mechanical benchmarks. Using a simulated pump-probe type experiment, this work presents computational predictions of population transfer through the avoided crossings of NaH via symmetric quasi-classical Meyer-Miller (SQC/MM), Ehrenfest, and exact quantum dynamics on realistic, ab initio potential energy surfaces. The main driving force for population transfer arises from the ground vibrational level of the D1Σ+ adiabatic state that is embedded in the manifold of near-dissociation C1Σ+ vibrational states. When coupled through a sharply localized first-order derivative coupling most of the population transfers between t = 15 and t = 30 fs depending on the initially excited vibronic wavepacket. While quantum mechanical effects are expected due to the reduced mass of NaH, predictions of the population dynamics from both the SQC/MM and Ehrenfest models perform remarkably well against the quantum dynamics benchmark. Additionally, an analysis of the vibronic structure in the nonadiabatically coupled regime is presented using a variational eigensolver methodology.

Translation of 11C-labeled tracer synthesis to a CGMP environment as exemplified by [11C]ER176 for PET imaging of human TSPO.

Radiotracers labeled with carbon-11 (t1/2 = 20.4 min) are widely used with positron emission tomography for biomedical research. Radiotracers must be produced for positron emission tomography studies in humans according to prescribed time schedules while also meeting current good manufacturing practice. Translation of an experimental radiosynthesis to a current good manufacturing practice environment is challenging. Here we exemplify such translation with a protocol for the production of an emerging radiotracer for imaging brain translocator protein 18 kDa, namely [11C]ER176. This radiotracer is produced by rapid conversion of cyclotron-produced [11C]carbon dioxide into [11C]iodomethane, which is then used to treat N-desmethyl-ER176 in the presence of base (tBuOK) at room temperature for 5 min. [11C]ER176 is separated in high purity by reversed-phase HPLC and formulated for intravenous injection in sterile ethanol-saline. The radiosynthesis is reliable and takes 50 min. Quality control takes another 20 min. All aspects of the protocol, including quality control, are discussed.

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

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.

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

The production of I-131 for use in medicine can be accomplished by the neutron irradiation of tellurium, typically in the form of TeO2. 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.

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

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.

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

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.

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

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.

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

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.

Beta Skin Dosimetry using Passivated Planar Silicon Detector.

Accurate measurement of beta skin dose remains a challenge. This dose is defined as the dose to the basil layer at 7 mg/cm2 (approximately 70 µm) below the surface of the skin and averaged over an area of 1 cm2. 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/cm2 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, (147Pm), a medium energy source, (204Tl), and a high energy beta source, (90Sr/90Y) 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 cm2 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 cm2 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.

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

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.

Classical molecular dynamics simulation of electronically non-adiabatic processes.

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).

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

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.

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.

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.

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

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.