Prediction of Chameleonic Efficiency

Chameleonic properties, i. e., the capacity of a molecule to hide polarity in non-polar environments and expose it in water, help achieving sufficient permeability and solubility for drug molecules with high MW. We present models of experimental measures of polarity for a set of 24 FDA approved drugs (MW 405-1113) and one PROTAC (MW 1034). Conformational ensembles in aqueous and non-polar environments were generated using molecular dynamics. A linear regression model that predicts chromatographic apparent polarity (EPSA) with a mean unsigned error of 10 Ų was derived based on separate terms for donor, acceptor, and total molecular SASA. A good correlation (R²=0.92) with an experimental measure of hydrogen bond donor potential, Δlog P_oct-tol, was found for the mean hydrogen bond donor SASA of the conformational ensemble scaled with Abraham's A hydrogen bond acidity. Two quantitative measures of chameleonic behaviour, the chameleonic efficiency indices, are introduced. We envision that the methods presented herein will be useful to triage designed molecules and prioritize those with the best chance of achieving acceptable permeability and solubility.     

Effect of temperature on raw whole milk density and its potential impact on milk payment in the dairy industry

The objective of this study was to determine the effect of temperature on whole milk density measured at four different temperatures: 5, 10, 15, and 20 °C. A total of ninety-three individual milk samples were collected from morning milking of thirty-two Holstein Friesian dairy cows, of national average genetic merit, once every two weeks over a period of 4 weeks and were assessed by Fourier transform infrared spectroscopy for milk composition analysis. Density of the milk was evaluated using two different analytical methods: a portable density meter DMA35 and a standard desktop model DMA4500M (Anton Paar GmbH, UK). Milk density was analysed with a linear mixed model with the fixed effects of sampling period, temperature and analysis method; triple interaction of sampling period x analysis method x temperature; and the random effect of cow to account for repeated measures. The effect of temperature on milk density (ρ) was also evaluated including temperature (t) as covariate with linear and quadratic effects within each analytic method. The regression equation describing the curvature and density–temperature relationship for the DMA35 instrument was ρ = 1.0338−0.00017T−0.0000122T² (R² = 0.64), while it was ρ = 1.0334 + 0.000057T−0.00001T² (R² = 0.61) for DMA4500 instrument. The mean density determined with DMA4500 at 5 °C was 1.0334 g cm⁻³, with corresponding figures of 1.0330, 1.0320 and 1.0305 g cm⁻³ at 10, 15 and 20 °C, respectively. The milk density values obtained in this study at specific temperatures will help to address any bias in weight–volume calculations and thus may also improve the financial and operational control for the dairy processors in Ireland and internationally.     

Categorical observers for metamerism

A method is proposed to generate categorical colour observer functions (individual colour matching functions) for any field size based on the CIE 2006 system of physiological observer functions. The method combines proposed categorical observer techniques of Sarkar et al with a physiologically-based individual observer model of Asano et al and a clustering technique to produce the optimal set of categorical observers. The number of required categorical observers varies depending on an application with as many as 50 required to predict individual observers' matches when a laser projector is viewed. However, 10 categorical observers are sufficient to represent colour-normal populations for personalized colour imaging. The proposed and recommended categorical observers represent a robust and inclusive technique to examine and quantify observer metamerism in any application of colorimetry.     

Cerebral microbleeds and cognitive decline in a hemodialysis patient: Case report and review of literature

Cerebral microbleeds (CMBs) are small hemosiderin deposits indicative of prior cerebral microscopic hemorrhage and previously thought to be clinically silent. Recent population‐based cross‐sectional studies and prospective longitudinal cohort studies have revealed association between CMB and cognitive dysfunction. In the general population, CMBs are associated with age, hypertension, and cerebral amyloid angiopathy. In the chronic kidney disease (CKD) population, diminished estimated glomerular filtration rate has been found to be an independent risk factor for CMB, raising the possibility that a uremic milieu may predispose to microbleeds. In the end‐stage renal disease (ESRD) population on hemodialysis, the incidence of microbleeds is significantly higher compared with a control group without history of CKD or stroke. We present an ESRD patient on chronic hemodialysis with a history of gradual cognitive decline and progressive CMBs. Through this case and literature review, we illustrate the need to develop detection and prediction models to treat this frequent development in ESRD patients.     

Failed Neuroprotection of Combined Inhibition of L-Type and ASIC1a Calcium Channels with Nimodipine and Amiloride

Effective pharmacological neuroprotection is one of the most desired aims in modern medicine. We postulated that a combination of two clinically used drugs—nimodipine (L-Type voltage-gated calcium channel blocker) and amiloride (acid-sensing ion channel inhibitor)—might act synergistically in an experimental model of ischaemia, targeting the intracellular rise in calcium as a pathway in neuronal cell death. We used organotypic hippocampal slices of mice pups and a well-established regimen of oxygen-glucose deprivation (OGD) to assess a possible neuroprotective effect. Neither nimodipine (at 10 or 20 µM) alone or in combination with amiloride (at 100 µM) showed any amelioration. Dissolved at 2.0 Vol.% dimethyl-sulfoxide (DMSO), the combination of both components even increased cell damage (p = 0.0001), an effect not observed with amiloride alone. We conclude that neither amiloride nor nimodipine do offer neuroprotection in an in vitro ischaemia model. On a technical note, the use of DMSO should be carefully evaluated in neuroprotective experiments, since it possibly alters cell damage.     

Evaluation of standard and real fire exposures on thermal response of rail car floor assembly

This work developed a computational methodology to evaluate and compare standard fire exposures such as those outlined in ASTM E119 with real fire exposures and determine the difference in the temperature rise of a rail car floor assembly. The real fire exposures simulated in this work were identified in a review of incidents and consisted of a constantly-fed diesel fuel spill, a localized trash fire, and a gasoline spill simulated from a collision of the railcar with an automobile. These realistic fire exposures were applied to a variety of exemplar rail cars representative of single-level and bi-level passenger cars. These floor assembly models exposed to realistic fires were simulated in Fire Dynamics Simulator (FDS). The thermal exposure at the underside of railcar provided by FDS was coupled with a thermal model in ABAQUS, which provided the evolution of temperature in different components of the floor assembly. The standard scenarios were simulated for 2 hours instead of the typical 30 minutes to identify the appropriate exposure duration in ASTM E119, which can better represent a real fire scenario. The average and maximum temperatures predicted at the unexposed surface for both scenarios were compared with the threshold values given in NFPA 130.     

Word length and lexical activation: Longer is better.

Many models of spoken word recognition posit the existence of lexical and sublexical representations, with excitatory and inhibitory mechanisms used to affect the activation levels of such representations. Bottom-up evidence provides excitatory input, and inhibition from phonetically similar representations leads to lexical competition. In such a system, long words should produce stronger lexical activation than short words, for 2 reasons: Long words provide more bottom-up evidence than short words, and short words are subject to greater inhibition due to the existence of more similar words. Four experiments provide evidence for this view. In addition, reaction-time-based partitioning of the data shows that long words generate greater activation that is available both earlier and for a longer time than is the case for short words. As a result, lexical influences on phoneme identification are extremely robust for long words but are quite fragile and condition-dependent for short words. Models of word recognition must consider words of all lengths to capture the true dynamics of lexical activation. (PsycINFO Database Record (c) 2010 APA, all rights reserved)