Multidimensional signals and analytic flexibility: Estimating degrees of freedom in human speech analyses

Recent empirical studies have highlighted the large degree of analytic flexibility in data analysis which can lead to substantially different conclusions based on the same data set. Thus, researchers have expressed their concerns that these researcher degrees of freedom might facilitate bias and can lead to claims that do not stand the test of time. Even greater flexibility is to be expected in fields in which the primary data lend themselves to a variety of possible operationalizations. The multidimensional, temporally extended nature of speech constitutes an ideal testing ground for assessing the variability in analytic approaches, which derives not only from aspects of statistical modeling, but also from decisions regarding the quantification of the measured behavior. In the present study, we gave the same speech production data set to 46 teams of researchers and asked them to answer the same research question, resulting insubstantial variability in reported effect sizes and their interpretation. Using Bayesian meta-analytic tools, we further find little to no evidence that the observed variability can be explained by analysts’ prior beliefs, expertise or the perceived quality of their analyses. In light of this idiosyncratic variability, we recommend that researchers more transparently share details of their analysis, strengthen the link between theoretical construct and quantitative system and calibrate their (un)certainty in their conclusions

The influence of additives on the delivery of paclitaxel from bioresorbable PLGA films

The study of the influences of additives on the drug delivery characteristics from PLGA thin films as a coating on angioplasty balloons was reported in this thesis. The objective is to investigate the use of additives as a means to control and modulate the delivery of paclitaxel from PLGA thin films. The release profiles obtained from the first part of the study with different types of PLGA show linear dependence on the concentration of terminal carboxylic acid end-groups of PLGA, which also regulates the degradation of PLGA films. The concentration of these end-groups is determined by the molecular weight of PLGA. The changes in molecular weight of PLGA resulted in changes in the hydration and mechanical behavior of these bioresorbable polyester thin films. However, despite the immiscibility and phase separation with the incorporation of additives with PLGA through blending, the mechanical properties of the PLGA films evaluated under simulated physiological conditions were not affected. The hydration of PLGA films played an important role in influencing the rate of hydrolytic degradation and drug release behavior. The incorporation of long chain additives with PLGA resulted in large phase-separated domains which gave rise to large pores, high mass loss and high initial burst release of paclitaxel from the dissolution and leaching of additives upon hydration. The degradation rates of PLGA were reduced by the diffusion of the acidic by-products through these large water-filled pores, which would have otherwise accumulated and contributed to the autocatalysis of PLGA. The incorporation of short chain additives with PLGA resulted in high hydration rates and high paclitaxel release rates. While paclitaxel and additives were preferentially co-localized, a statistical correlation was established between the release of paclitaxel and the leaching of additives upon hydration that can be sustained, controlled and modulated based on the concentration, molecular weight and the functionality of additives.Doctor of Philosophy (MSE

Nanoparticle-assay marker interaction: effects on nanotoxicity assessment

Protein-based cytotoxicity assays such as lactate dehydrogenase (LDH) and tumor necrosis factor-alpha (TNF-α) are commonly used in cytotoxic evaluation of nanoparticles (NPs) despite numerous reports on possible interactions with protein markers in these assays that can confound the results obtained. In this study, conventional cytotoxicity assays where assay markers may (LDH and TNF- α) or may not (PicoGreen and WST-8) come into contact with NPs were used to evaluate the cytotoxicity of NPs. The findings revealed selective interactions between negatively charged protein assay markers (LDH and TNF- α) and positively charged ZnO NPs under abiotic conditions. The adsorption and interaction with these protein assay markers were strongly influenced by surface charge, concentration, and specific surface area of the NPs, thereby resulting in less than accurate cytotoxic measurements, as observed from actual cell viability measurements. An improved protocol for LDH assay was, therefore, proposed and validated by eliminating any effects associated with protein–particle interactions. In view of this, additional measures and precautions should be taken when evaluating cytotoxicity of NPs with standard protein-based assays, particularly when they are of opposite charges.ASTAR (Agency for Sci., Tech. and Research, S’pore

Microencapsulation of dye- and drug-loaded particles for imaging and controlled release of multiple drugs

A polymeric microcapsule that can house different drug-loaded particles using a simple emulsion packaging technique is presented. Compared to the neat microparticles, microcapsules simultaneously release multiple drugs in a sustained manner. These microcapsules could provide a means of controlling release of multiple drugs

SMAD3 deficiency promotes inflammatory aortic aneurysms in angiotensin II–infused mice via activation of iNOS

Ninety percent of the patients carrying distinct SMAD3 mutations develop aortic aneurysms and dissections, called aneurysms-osteoarthritis syndrome (AOS). However, the etiology and molecular events downstream of SMAD3 leading to the pathogenesis of aortic aneurysms in these patients still remain elusive. Therefore, we aimed to investigate the vascular phenotypes of SMAD3-knockout mice. Methods and Results‒We showed that angiotensin II-induced vascular inflammation, but not hypertension, leads to aortic aneurysms and dissections, ultimately causing aortic rupture and death in these mice. Lipopolysaccharide-triggered inflammation confirmed that enhanced aortic macrophage recruitment was essential for aneurysm formation in angiotensin II-infused SMAD3-knockout mice. In contrast, phenylephrine-triggered hypertension alone was insufficient to induce aortic aneurysms in these mice. Using uniaxial tensile and contractility tests, we showed that SMAD3 deficiency resulted in defective aortic biomechanics and physiological functions, which caused weakening of the aortic wall and predisposed these mice to aortic aneurysms. Chromatin immunoprecipitation (ChIP) and re-ChIP assays revealed that the underlying mechanism involved an aberrant upregulation of inducible nitric oxide synthase (iNOS)-derived nitric oxide production and an activation of elastolytic matrix metalloproteinases 2 and 9. Administration of clodronate-liposomes and iNOS inhibitor completely abrogated these aortic conditions, thereby identifying iNOS-mediated nitric oxide secretion from macrophages as the downstream event of SMAD3 that drives this severe pathology. Conclusions‒Macrophage depletion and iNOS antagonism represent two promising approaches for preventing aortic aneurysms related to SMAD3 mutations and merit further investigation as adjunctive strategies for the life-threatening manifestations of AOS.Published versio

Calcium phosphate coated Keratin–PCL scaffolds for potential bone tissue regeneration

The incorporation of hydroxyapatite (HA) nanoparticles within or on the surface of electrospun polymeric scaffolds is a popular approach for bone tissue engineering. However, the fabrication of osteoconductive composite scaffolds via benign processing conditions still remains a major challenge to date. In this work, a new method was developed to achieve a uniform coating of calcium phosphate (CaP) onto electrospun keratin–polycaprolactone composites (Keratin–PCL). Keratin within PCL was crosslinked to decrease its solubility, before coating of CaP. A homogeneous coating was achieved within a short time frame (~ 10 min) by immersing the scaffolds into Ca2 + and (PO4)3 − solutions separately. Results showed that the incorporation of keratin into PCL scaffolds not only provided nucleation sites for Ca2 + adsorption and subsequent homogeneous CaP surface deposition, but also facilitated cell–matrix interactions. An improvement in the mechanical strength of the resultant composite scaffold, as compared to other conventional coating methods, was also observed. This approach of developing a biocompatible bone tissue engineering scaffold would be adopted for further in vitro osteogenic differentiation studies in the future.ASTAR (Agency for Sci., Tech. and Research, S’pore)NMRC (Natl Medical Research Council, S’pore

Collagen–cellulose composite thin films that mimic soft-tissue and allow stem-cell orientation

Mechanical properties of collagen films are less than ideal for biomaterial development towards musculoskeletal repair or cardiovascular applications. Herein, we present a collagen–cellulose composite film (CCCF) compared against swine small intestine submucosa in regards to mechanical properties, cell growth, and histological analysis. CCCF was additionally characterized by FE-SEM, NMR, mass spectrometry, and Raman Microscopy to elucidate its physical structure, collagen–cellulose composition, and structure activity relationships. Mechanical properties of the CCCF were tested in both wet and dry environments, with anisotropic stress–strain curves that mimicked soft-tissue. Mesenchymal stem cells, human umbilical vein endothelial cells, and human coronary artery smooth muscle cells were able to proliferate on the collagen films with specific cell orientation. Mesenchymal stem cells had a higher proliferation index and were able to infiltrate CCCF to a higher degree than small intestine submucosa. With the underlying biological properties, we present a collagen–cellulose composite film towards forthcoming biomaterial-related applications