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During speech perception, linguistic elements such as consonants and vowels are extracted from a complex acoustic speech signal. The superior temporal gyrus (STG) participates in high-order auditory processing of speech, but how it encodes phonetic information is poorly understood. We used high-density direct cortical surface recordings in humans while they listened to natural, continuous speech to reveal the STG representation of the entire English phonetic inventory. At single electrodes, we found response selectivity to distinct phonetic features. Encoding of acoustic properties was mediated by a distributed population response. Phonetic features could be directly related to tuning for spectrotemporal acoustic cues, some of which were encoded in a nonlinear fashion or by integration of multiple cues. These findings demonstrate the acoustic-phonetic representation of speech in human STG.

Efforts to extend nanoparticle residence time in vivo have inspired many strategies in particle surface modifications to bypass macrophage uptake and systemic clearance. Here we report a top-down biomimetic approach in particle functionalization by coating biodegradable polymeric nanoparticles with natural erythrocyte membranes, including both membrane lipids and associated membrane proteins for long-circulating cargo delivery. The structure, size and surface zeta potential, and protein contents of the erythrocyte membrane-coated nanoparticles were verified using transmission electron microscopy, dynamic light scattering, and gel electrophoresis, respectively. Mice injections with fluorophore-loaded nanoparticles revealed superior circulation half-life by the erythrocyte-mimicking nanoparticles as compared to control particles coated with the state-of-the-art synthetic stealth materials. Biodistribution study revealed significant particle retention in the blood 72 h following the particle injection. The translocation of natural cellular membranes, their associated proteins, and the corresponding functionalities to the surface of synthetic particles represents a unique approach in nanoparticle functionalization.

In humans, listening to speech evokes neural responses in the motor cortex. This has been controversially interpreted as evidence that speech sounds are processed as articulatory gestures. However, it is unclear what information is actually encoded by such neural activity. We used high-density direct human cortical recordings while participants spoke and listened to speech sounds. Motor cortex neural patterns during listening were substantially different than during articulation of the same sounds. During listening, we observed neural activity in the superior and inferior regions of ventral motor cortex. During speaking, responses were distributed throughout somatotopic representations of speech articulators in motor cortex. The structure of responses in motor cortex during listening was organized along acoustic features similar to auditory cortex, rather than along articulatory features as during speaking. Motor cortex does not contain articulatory representations of perceived actions in speech, but rather, represents auditory vocal information. When we speak, we force air out of our lungs so that it passes over the vocal cords and causes them to vibrate. Movements of the jaw, lips and tongue can then shape the resulting sound wave into speech sounds. The brain’s outer layer, which is called the cortex, controls this process. More precisely, neighboring areas in the so-called motor cortex trigger the movements in a specific order to produce different sounds. Brain imaging experiments have also shown that the motor cortex is active when we listen to speech, as well as when we produce it. One theory is that when we hear a sound, such as the consonant ‘b’, the sound activates the same areas of motor cortex as those involved in producing that sound. This could help us to recognize and understand the sounds we hear. To test this theory, Cheung, Hamilton et al. studied how speech sounds activate the motor cortex by recording electrical signals directly from the brain’s surface in nine human volunteers who were undergoing a clinical evaluation for epilepsy surgery. This revealed that speaking activates many different areas of motor cortex. However, listening to the same sounds activates only a small subset of these areas. Contrary to what was thought, brain activity patterns in motor cortex during listening do not match those during speaking. Instead, they depend on the properties of the sounds. Thus, sounds that have similar acoustic properties but which require different movements to produce them, such as ‘b’ and ‘d’, activate the motor cortex in similar ways during listening, but not during speaking. Further research is now needed to work out why the motor cortex behaves differently when we hear as opposed to when we speak. Previous work has suggested that the region increases its activity during listening when the sounds heard are unclear, for example because of background noise. One testable idea therefore is that the motor cortex helps to enhance the processing of degraded sounds.

Global rates of type 2 diabetes in children and adolescents have increased significantly over the past three decades. Type 2 diabetes is a relatively new disease in this age group, and there is a dearth of information about how to structure treatment programs to manage its comorbidities and complications. In this paper, we describe the design and implementation of a personalized multidisciplinary, family-centered, pediatric and adolescent type 2 diabetes program at a tertiary pediatric center in Hamilton, Ontario, Canada. We report the process of designing and implementing such a program, and show that this multidisciplinary program led to improvement in glycated hemoglobin (n=17, 8% at baseline versus 6.4% at 1 year, 95% confidence interval (0.1-0.28), P-value <0.0001) and stabilized body mass index, with lowered C-peptide and no change in fitness or metabolic biomarkers of lipid metabolism and liver function. As type 2 diabetes becomes more prevalent in youth, the need for programs that successfully address the complex nature of this disease is central to its management and to mitigate its long-term adverse outcomes.

The peroxisome proliferator-activated receptor-alpha (PPARalpha), first identified in 1990 as a member of the nuclear receptor superfamily, has a central role in the regulation of numerous target genes encoding proteins that modulate fatty acid transport and catabolism. PPARalpha is the molecular target for the widely prescribed lipid-lowering fibrate drugs and the diverse class of chemicals collectively referred to as peroxisome proliferators. The lipid-lowering function of PPARalpha occurs across a number of mammalian species, thus demonstrating the essential role of this nuclear receptor in lipid homeostasis. In contrast, prolonged administration of PPARalpha agonists causes hepatocarcinogenesis, specifically in rats and mice, indicating that PPARalpha also mediates this effect. There is no strong evidence that the low-affinity fibrate ligands are associated with cancer in humans, but it still remains a possibility that chronic activation with high-affinity ligands could be carcinogenic in humans. It is now established that the species difference between rodents and humans in response to peroxisome proliferators is due in part to PPARalpha. The cascade of molecular events leading to liver cancer in rodents involves hepatocyte proliferation and oxidative stress, but the PPARalpha target genes that mediate this response are unknown. This review focuses on the current understanding of the role of PPARalpha in hepatocarcinogenesis and identifies future research directions that should be taken to delineate the mechanisms underlying PPARalpha agonist-induced hepatocarcinogenesis.

The human brain contains a remarkable sensory system that allows us to effortlessly process speech. The processing of speech begins at our ears, where speech sounds are converted into electrical signals that propagate up to our brain. How these signals are transformed from acoustic information into meaningful speech in the human cortex is still unknown. In this dissertation, high-density human direct cortical recordings were used to systematically detail the human speech processing system and address central linguistic theories of speech perception. In Chapter 2, we examine how the superior temporal gyrus, a brain area critically implicated in speech perception, encodes phonetic features of speech. We found single site response selectivity to distinct phonetic features and distributed population encoding mediated by acoustic properties, including pitch and voice-onset-time. In Chapter 3, we examine the representation of speech sounds in human motor cortex, a region controversially hypothesized to process articulatory gestures during perception. We found evidence that motor cortex does not represent articulatory representations of perceived actions in speech, but rather, auditory vocal information. These results are consistent with linguistic feature hierarchies organized around acoustic, rather than articulatory, features. Finally, built upon the principles of human speech electrophysiology, we developed a clinical cortical mapping tool to aid in the preservation of eloquent cortex, the details of which are described in Chapter 4. All together, this work lays a foundation for understanding the human speech processing system and developing clinical applications to aid the lives of thousands with neurological disorders, including epilepsy and brain tumors.

The peroxisome proliferator-activated receptor-[alpha] (PPAR[alpha]), first identified in 1990 as a member of the nuclear receptor superfamily, has a central role in the regulation of numerous target genes encoding proteins that modulate fatty acid transport and catabolism. PPAR[alpha] is the molecular target for the widely prescribed lipid-lowering fibrate drugs and the diverse class of chemicals collectively referred to as peroxisome proliferators. The lipid-lowering function of PPAR[alpha] occurs across a number of mammalian species, thus demonstrating the essential role of this nuclear receptor in lipid homeostasis. In contrast, prolonged administration of PPAR[alpha] agonists causes hepatocarcinogenesis, specifically in rats and mice, indicating that PPAR[alpha] also mediates this effect. There is no strong evidence that the low-affinity fibrate ligands are associated with cancer in humans, but it still remains a possibility that chronic activation with high-affinity ligands could be carcinogenic in humans. It is now established that the species difference between rodents and humans in response to peroxisome proliferators is due in part to PPAR[alpha]. The cascade of molecular events leading to liver cancer in rodents involves hepatocyte proliferation and oxidative stress, but the PPAR[alpha] target genes that mediate this response are unknown. This review focuses on the current understanding of the role of PPAR[alpha] in hepatocarcinogenesis and identifies future research directions that should be taken to delineate the mechanisms underlying PPAR[alpha] agonist-induced hepatocarcinogenesis.

Monolingual English-speaking (n = 25, M age = 5 years 6 months) and bilingual Cantonese-speaking ( n = 25, M age = 5 years 5 months) children's understanding of emotions and false belief were examined. Children were administered theory-of-mind (ToM) tasks from the Wellman & Liu (2004) Theory-of-Mind scale. These tasks examined children's understanding of false belief, belief-based emotions and real-apparent emotions. Bilingual Cantonese-speaking children completed ToM tasks in both English and Cantonese. English-speaking children completed the same number of tasks but in English only. Children's receptive language abilities were also assessed by completing the Peabody Picture Vocabulary Test (3rd Edition) (PPVT-III). Cantonese-speaking children completed the PPVT-III in English and a translated version in Cantonese. English-speaking children completed the PPVT-III both times in English. Although no significant cultural differences were seen in children's performance across false-belief and belief-emotion tasks, English-speaking children did significantly better then their Cantonese-speaking counterparts on the real-apparent emotion task. This suggests that compared to Cantonese-speaking children, English-speaking children have a more advanced understanding of how facial expressions may not reveal true emotions. Cultural similarities and differences are discussed in relation to specific cultural pathways responsible for ToM development.