An integrated dialect analysis tool using phonetics and acoustics

This study aimed to verify a computational phonetic and acoustic analysis tool created in the MATLAB environment. A dataset was obtained containing 3 broad American dialects (Northern, Western and New England) from the TIMIT database using words that also appeared in the Swadesh list. Each dialect consisted of 20 speakers uttering 10 sentences. Verification using phonetic comparisons between dialects was made by calculating the Levenshtein distance in Gabmap and the proposed software tool. Agreement between the linguistic distances using each analysis method was found. Each tool showed increasing linguistic distance as a function of increasing geographic distance, in a similar shape to Seguy's curve. The proposed tool was then further developed to include acoustic characterisation capability of inter dialect dynamics. Significant variation between dialects was found for the pitch, trajectory length and spectral rate of change for 7 of the phonetic vowels investigated. Analysis of the vowel area using the 4 corner vowels indicated that for male speakers, geographically closer dialects have smaller variations in vowel space area than those further apart. The female utterances did not show a similar pattern of linguistic distance likely due to the lack of one corner vowel /u/, making the vowel space a triangle

Application of Allometric Scaling to Nanochelator Pharmacokinetics

Deferoxamine (DFO) is an effective FDA-approved iron chelator; however, its use is considerably limited by off-target toxicities and an extremely cumbersome dose regimen involving daily infusions. The recent development of a deferoxamine-based nanochelator (DFO-NP) with selective renal excretion has shown promise in ameliorating iron overload and associated physiological complications in rodent models with a substantially improved safety profile. While the dose- and administration route-dependent pharmacokinetics (PK) of DFO-NPs have been recently characterized, the optimized PK model was not validated, and the prior studies did not directly address the clinical translatability of DFO-NPs into humans. In the present work, these gaps were addressed by applying allometric scaling of DFO-NP PK in rats to predict those in mice and humans. First, this approach predicted serum concentration–time profiles of DFO-NPs, which were similar to those experimentally measured in mice, validating the nonlinear disposition and absorption models for DFO-NPs across the species. Subsequently, we explored the utility of allometric scaling by predicting the PK profile of DFO-NPs in humans under clinically relevant dosing schemes. These in silico efforts demonstrated that the novel nanochelator is expected to improve the PK of DFO when compared to standard infusion regimens of native DFO. Moreover, reasonable formulation strategies were identified and discussed for both early clinical development and more sophisticated formulation development

Mechanism-Based Pharmacokinetic Modeling of Absorption and Disposition of a Deferoxamine-Based Nanochelator in Rats

Deferoxamine (DFO) is an effective FDA-approved iron chelator. However, its use is considerably limited by off-target toxicities and an extremely cumbersome dose regimen with daily infusions. The recent development of a deferoxamine-based nanochelator (DFO-NP) with selective renal excretion has shown promise in ameliorating animal models of iron overload with a substantially improved safety profile. To further the preclinical development of this promising nanochelator and to inform on the feasibility of clinical development, it is necessary to fully characterize the dose and administration-route-dependent pharmacokinetics and to develop predictive pharmacokinetic (PK) models describing absorption and disposition. Herein, we have evaluated the absorption, distribution, and elimination of DFO-NPs after intravenous and subcutaneous (SC) injection at therapeutically relevant doses in Sprague Dawley rats. We also characterized compartment-based model structures and identified model-based parameters to quantitatively describe the PK of DFO-NPs. Our modeling efforts confirmed that disposition could be described using a three-compartment mamillary model with elimination and saturable reabsorption both occurring from the third compartment. We also determined that absorption was nonlinear and best described by parallel saturable and first-order processes. Finally, we characterized a novel pathway for saturable SC absorption of an ultrasmall organic nanoparticle directly into the systemic circulation, which offers a novel strategy for improving drug exposure for nanotherapeutics