Molecular Dynamics of Artificially Pair-Decoupled Systems: An Accurate Tool for Investigating the Importance of Intramolecular Couplings.

We propose a numerical technique to accurately simulate the vibrations of organic molecules in the gas phase, when pairs of atoms (or, in general, groups of degrees of freedom) are artificially decoupled, so that their motion is instantaneously decorrelated. The numerical technique we have developed is a symplectic integration algorithm that never requires computation of the force but requires estimates of the Hessian matrix. The theory we present to support our technique postulates a pair-decoupling Hamiltonian function, which parametrically depends on a decoupling coefficient α ∈ [0, 1]. The closer α is to 0, the more decoupled the selected atoms. We test the correctness of our numerical method on small molecular systems, and we apply it to study the vibrational spectroscopic features of salicylic acid at the Density Functional Theory ab initio level on a fitted potential. Our pair-decoupled simulations of salicylic acid show that decoupling hydrogen-bonded atoms do not significantly influence the frequencies of stretching modes, but enhance enormously the out-of-plane wagging and twisting motions of the hydroxyl and carboxyl groups to the point that the carboxyl and hydroxyl groups may overcome high potential energy barriers and change the salicylic acid conformation after a short simulation time. In addition, we found that the acidity of salicylic acid is more influenced by the dynamical couplings of the proton of the carboxylic group with the carbon ring than with the hydroxyl group.

Unsupervised Machine Learning Neural Gas Algorithm for Accurate Evaluations of the Hessian Matrix in Molecular Dynamics.

The Hessian matrix of the potential energy of molecular systems is employed not only in geometry optimizations or high-order molecular dynamics integrators but also in many other molecular procedures, such as instantaneous normal mode analysis, force field construction, instanton calculations, and semiclassical initial value representation molecular dynamics, to name a few. Here, we present an algorithm for the calculation of the approximated Hessian in molecular dynamics. The algorithm belongs to the family of unsupervised machine learning methods, and it is based on the neural gas idea, where neurons are molecular configurations whose Hessians are adopted for groups of molecular dynamics configurations with similar geometries. The method is tested on several molecular systems of different dimensionalities both in terms of accuracy and computational time versus calculating the Hessian matrix at each time-step, that is, without any approximation, and other Hessian approximation schemes. Finally, the method is applied to the on-the-fly, full-dimensional simulation of a small synthetic peptide (the 46 atom N-acetyl-l-phenylalaninyl-l-methionine amide) at the level of DFT-B3LYP-D/6-31G* theory, from which the semiclassical vibrational power spectrum is calculated.

Machine learning for vibrational spectroscopy via divide-and-conquer semiclassical initial value representation molecular dynamics with application to N-methylacetamide.

A machine learning algorithm for partitioning the nuclear vibrational space into subspaces is introduced. The subdivision criterion is based on Liouville's theorem, i.e., the best preservation of the unitary of the reduced dimensionality Jacobian determinant within each subspace along a probe full-dimensional classical trajectory. The algorithm is based on the idea of evolutionary selection, and it is implemented through a probability graph representation of the vibrational space partitioning. We interface this customized version of genetic algorithms with our divide-and-conquer semiclassical initial value representation method for the calculation of molecular power spectra. First, we benchmark the algorithm by calculating the vibrational power spectra of two model systems, for which the exact subspace division is known. Then, we apply it to the calculation of the power spectrum of methane. Exact calculations and full-dimensional semiclassical spectra of this small molecule are available and provide an additional test of the accuracy of the new approach. Finally, the algorithm is applied to the divide-and-conquer semiclassical calculation of the power spectrum of 12-atom trans-N-methylacetamide.

Parotid Gland Tumors and the Facial Nerve.

Various types of parotid gland tumors are discussed from nonneoplastic to both benign and malignant neoplasms. The anatomic relationship of the facial nerve is discussed as it exits the stylomastoid foramen and courses through the parotid gland. The effect of certain tumors on facial nerve function is also characterized. Details on which types of parotid tumors are more likely to affect facial nerve function and different prognostic predictors of return to function are evaluated. In addition, the prognostic value of tumor size and histologic type of parotid tumor is included.

Cost-effective analysis of unilateral vestibular weakness investigation.

OBJECTIVES: To evaluate the cost-effectiveness of obtaining a magnetic resonance imaging (MRI) in patients with abnormal electronystagmography (ENG) or videonystagmography (VNG) results. STUDY DESIGN: Retrospective chart review. SETTINGS: Academic specialty center. PATIENTS: Patients presenting with vertigo between January 1, 2010, and August 30, 2013. METHODS: Patients who fit the following abnormal criteria were included in the study: unilateral caloric weakness (≥20%), abnormal ocular motor testing, and nystagmus on positional testing. Patients with abnormal findings who then underwent MRI with gadolinium were evaluated. RESULTS: Of the 1,996 charts reviewed, there were 1,358 patients who met the inclusion criteria. The average age of these patients was 62 years (12-94 yr). The male:female ratio was approximately 1:2. Of the 1,358 patients, 253 received an MRI with the following pathologies: four vestibular schwannomas, three subcortical/periventricular white matter changes suspicious for demyelinating disease, four acute cerebellar/posterior circulation infarct, two vertebral artery narrowing, one pseudomeningocele of internal auditory canal, and two white matter changes indicative of migraines. The positive detection rate on MRI was 5.5% based on MRI findings of treatable pathologies causing vertigo. Average cost of an MRI is $1,200, thereby making the average cost of identifying a patient with a positive MRI finding $15,180. CONCLUSION: In our study, those patients with a positive MRI had a constellation of symptoms and findings (asymmetric sensorineural hearing loss, tinnitus, vertigo, and abnormal ENG/VNG). Cost-effectiveness can be improved by ordering an MRI only when clinical examination and VNG point toward a central pathology. Clinical examination and appropriate testing should be factored when considering the cost-effectiveness of obtaining an MRI in patients with abnormal ENG/VNG findings.

Dexamethasone's effect in the retrocochlear auditory centers of a noise-induced hearing loss mouse model.

OBJECTIVE: Examine prophylactic effects of dexamethasone (Dex) in retrocochlear auditory centers in a noise-induced hearing loss (NIHL) mouse model. STUDY DESIGN: Prospective animal study. SETTING: Academic research center. SUBJECTS AND METHODS: Thirty-two mice were divided into control, untreated, saline (2 and 10 µL), and Dex (2 and 10 µL) groups. Dex was applied intratympanically (IT) prior to 110 to 120 dB noise over 6 hours. Auditory brainstem response (ABR) and distortion product otoacoustic emission (DPOAE) were performed at 1 day, 1 week, 1 month, and 2 months. Retrocochlear neuronal cells were labeled with FluoroGold and counted. Hair cells of the organ of Corti were labeled with fluorescein isothiocyanate-conjugated phalloidin and counted. RESULTS: Auditory brainstem response thresholds of untreated NIHL, 2 and 10 µL IT saline, and 2 and 10 µL IT Dex were 21.7 ± 2.9 dB, 20 ± 0 dB, 20 ± 5 dB, 18.3 ± 2.9 dB, and 18.3 ± 2.9 dB, respectively. At 1-day post NIHL, all groups demonstrated profound hearing loss. At 2 weeks, 2 and 10 µL Dex thresholds improved to 47.5 ± 3.5 dB and 48.8 ± 18.9 dB, respectively, whereas the untreated and saline groups remained unchanged. Mean cell counts in the cochlear nucleus (CN), superior olivary complex (SOC), and lateral lemniscus (LL) of control mice were 1483 ± 190, 2807 ± 67, and 112 ± 20, respectively. After acoustic trauma, the untreated, saline, and 2 µL Dex groups yielded decreased neuronal counts in the SOC. In contrast, the 10 µL Dex group had 1883 ± 186 (CN), 2774 ± 182 (SOC), and 166 ± 18 (LL). There was sporadic hair cell loss for all traumatized groups. CONCLUSION: Our NIHL mouse model demonstrated dose-dependent Dex pretreatment otoprotection against NIHL with preservation of retrocochlear auditory neurons.

Cost analysis of asymmetric sensorineural hearing loss investigations.

OBJECTIVES/HYPOTHESIS: The purpose of this study is to critically evaluate the typical cost of asymmetrical sensorineural hearing loss (ASNHL) work-up, and to compare the positive predictive value from this common presenting symptom. STUDY DESIGN: Retrospective chart review from two major otolaryngology centers. METHODS: We reviewed charts from patients presenting to New York Eye and Ear Infirmary between January 1, 2006 and December 31, 2006, and the University of Minnesota between December 1, 2002 and November 30, 2007 with ASNHL. Diagnostic information included magnetic resonance imaging (MRI) and serum laboratory values (antinuclear antibodies, erythrocyte sedimentation rate, Lyme, rapid plasma reagin, and thyroid-stimulating hormone). We calculated positive rate according to each item of diagnosis. To estimate cost-benefit, we further calculated the average cost for identifying a patient with a positive result. RESULTS: The total cost was $263,535, whereas the average cost for identifying a positive patient was $146,40.81. The total lab cost was $16,935 and the total imaging cost was $246,600. The average cost for identifying a positive patient based on MRI was $61,650 and $2,109 based on lab values. Of the 247 patients, only six patients (2.4%)-one patient with acoustic neuroma, two patients with syphilis, and three patients with Lyme--were identified with treatable pathology. CONCLUSIONS: A comprehensive ASNHL work-up may not be applicable to all patients. Laboratory serologic tests are highly cost effective in diagnosing treatable causes of ASNHL, such as syphilis and Lyme. Although radiographic imaging with MRI is not as cost effective, its value in detecting for acoustic neuroma is undeniable.

Activation of the Gal1 gene of yeast by pairs of 'non-classical' activators.

Eukaryotic transcriptional activators work by recruiting to DNA the transcriptional machinery, including protein complexes required for chromatin modification, transcription initiation, and elongation. Which of these complexes must be directly recruited to trigger transcription? We test various "non-classical" transcription activators (comprising a component of the transcriptional machinery fused to a DNA binding domain) for their abilities to activate transcription of a chromosomally integrated reporter in yeast. Among these newly constructed fusion proteins, none efficiently activated transcription when working on its own. However, in several instances transcription was activated by a pair of such fusion proteins tethered to adjacent sites on DNA. In each of these cases, one fusion protein bore a component of the SAGA complex, and the other bore a component of the Mediator complex. Transcription was also activated by certain tripartite fusion proteins comprising a Mediator and a SAGA component fused to a DNA binding domain. The results are consistent with the finding that the classical activator Gal4, working at the GAL1 promoter, activates transcription by (at least in part) independently recruiting SAGA and Mediator.