Explore the vast range of titles available.

Sensory cortices modulate innate behaviors through corticofugal projections targeting phylogenetically-old brainstem nuclei. However, the principles behind the functional connectivity of these projections remain poorly understood. Here, we show that in mice visual cortical neurons projecting to the optic-tract and dorsal-terminal nuclei (NOT-DTN) possess distinct response properties and anatomical connectivity, supporting the adaption of an essential innate eye movement, the optokinetic reflex (OKR). We find that these corticofugal neurons are enriched in specific visual areas, and they prefer temporo-nasal visual motion, matching the direction bias of downstream NOT-DTN neurons. Remarkably, continuous OKR stimulation selectively enhances the activity of these temporo-nasally biased cortical neurons, which can efficiently promote OKR plasticity. Lastly, we demonstrate that silencing downstream NOT-DTN neurons, which project specifically to the inferior olive—a key structure in oculomotor plasticity, impairs the cortical modulation of OKR and OKR plasticity. Our results unveil a direction-selective cortico-brainstem pathway that adaptively modulates innate behaviors. The visual cortex adapts innate behaviors through its corticofugal projections to the brainstem. Here, authors show that this pathway sends unique brainstem neurons distinct behaviorally relevant signals, whose strength can plastically change to promote behavioral adaptation.

This dissertation examines the epistemic breakthroughs and complexities in the study of “things” (wu) in mid-Qing evidential learning, a prevailing intellectual movement in China circa 1750–1850 which sought for truth from solid facts. By focusing on the multifaceted natural and ritual objects in the Book of Odes (Shi), this work offers a new understanding of mid-Qing intellectual history from the perspective of historical epistemology. Overall, I argue for a parallel development and contending authority between the textual and material aspects of evidential learning, which, in giving rise to an emerging inwardness of wu, collectively shifted the focus of epistemic inquiry from the referential surface of cosmological “coherence” (li) to the well-ordered “textures” (li) of specific wu.Tracing back to the earlier cosmological tradition, this dissertation first demonstrates how the name and the object, text-derived features and natural traits had already merged into hermeneutical loops in the Song dynasty. These complicated wu were then incorporated into broader epistemic networks in the late Ming, creating an extensive referential surface which frequently left competing theses unresolved. I then elaborate how these unresolved problems were overcome through newly developed philological techniques such as ancient phonology, general pattern, and paleography, as well as intensified observations, frontier evidence, and technocratic inclination on the material side. Given the comparability of the newly revealed philological and material textures, the mid-Qing intellectual movement can be better categorized as a collective inquiry for the refined textures of specific wu.Nevertheless, due to varied epistemological takes and methodological preferences, these breakthroughs guaranteed no convergence in knowledge making. This dissertation then examines the fickle and frequently irreconcilable working premises behind bifurcating philological theses, as well as the contending evidential authorities between textual and material aspects of a holistic wu. Such complexities suggest both an internal explanation for the trivialization of philological learning and an indigenous propensity for disciplinary division in the nineteenth century. The specified yet holistic inquiry of wu, rigorous in the epistemic construction of “facts” while loose in the epistemological attaining of “truth,” displays an important epistemic mode between the fade of Neo-Confucian cosmology and the advent of disciplinary science.

The asexual freshwater planarian Dugesia japonica has emerged as a medium-throughput alternative animal model for neurotoxicology. We have previously shown that D. japonica are sensitive to organophosphorus pesticides (OPs) and characterized the in vitro inhibition profile of planarian cholinesterase (DjChE) activity using irreversible and reversible inhibitors. We found that DjChE has intermediate features of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Here, we identify two candidate genes (Djche1 and Djche2) responsible for DjChE activity. Sequence alignment and structural homology modeling with representative vertebrate AChE and BChE sequences confirmed our structural predictions, and show that both DjChE enzymes have intermediate sized catalytic gorges and disrupted peripheral binding sites. Djche1 and Djche2 were both expressed in the planarian nervous system, as anticipated from previous activity staining, but with distinct expression profiles. To dissect how DjChE inhibition affects planarian behavior, we acutely inhibited DjChE activity by exposing animals to either an OP (diazinon) or carbamate (physostigmine) at 1 µM for 4 days. Both inhibitors delayed the reaction of planarians to heat stress. Simultaneous knockdown of both Djche genes by RNAi similarly resulted in a delayed heat stress response. Furthermore, chemical inhibition of DjChE activity increased the worms’ ability to adhere to a substrate. However, increased substrate adhesion was not observed in Djche1/Djche2 (RNAi) animals or in inhibitor-treated day 11 regenerates, suggesting this phenotype may be modulated by other mechanisms besides ChE inhibition. Together, our study characterizes DjChE expression and function, providing the basis for future studies in this system to dissect alternative mechanisms of OP toxicity.

This article presents a novel method of shape memory polymer (SMP) processing for additive manufacturing, in particular, fused-deposition modeling (FDM). Critical extrusion process parameters have been experimented to determine an appropriate set of parameter values so that good-quality SMP filament could be made for FDM. In the FDM process, effects of different printing parameters such as extruder temperature and scanning speed on object printing quality are also studied. In all the process studies, we aim to achieve good-quality parts by evaluating part density, tensile strength, dimensional accuracy, and surface roughness. Based on these studies, sample SMP models have been successfully built. Due to the thermal sensitive nature of the printed SMP parts, they can potentially be used as fasteners in active assembly/disassembly, smart actuators, deployable structures for aero-space applications, etc.

Human cytochrome P450 (CYP) enzymes, as membrane-bound hemoproteins, play important roles in the detoxification of drugs, cellular metabolism, and homeostasis. In humans, almost 80% of oxidative metabolism and approximately 50% of the overall elimination of common clinical drugs can be attributed to one or more of the various CYPs, from the CYP families 1–3. In addition to the basic metabolic effects for elimination, CYPs are also capable of affecting drug responses by influencing drug action, safety, bioavailability, and drug resistance through metabolism, in both metabolic organs and local sites of action. Structures of CYPs have recently provided new insights into both understanding the mechanisms of drug metabolism and exploiting CYPs as drug targets. Genetic polymorphisms and epigenetic changes in CYP genes and environmental factors may be responsible for interethnic and interindividual variations in the therapeutic efficacy of drugs. In this review, we summarize and highlight the structural knowledge about CYPs and the major CYPs in drug metabolism. Additionally, genetic and epigenetic factors, as well as several intrinsic and extrinsic factors that contribute to interindividual variation in drug response are also reviewed, to reveal the multifarious and important roles of CYP-mediated metabolism and elimination in drug therapy.

Neuroendocrine carcinomas (NEC) are tumors expressing markers of neuronal differentiation that can arise at different anatomic sites but have strong histological and clinical similarities. Here we report the chromatin landscapes of a range of human NECs and show convergence to the activation of a common epigenetic program. With a particular focus on treatment emergent neuroendocrine prostate cancer (NEPC), we analyze cell lines, patient-derived xenograft (PDX) models and human clinical samples to show the existence of two distinct NEPC subtypes based on the expression of the neuronal transcription factors ASCL1 and NEUROD1. While in cell lines and PDX models these subtypes are mutually exclusive, single-cell analysis of human clinical samples exhibits a more complex tumor structure with subtypes coexisting as separate sub-populations within the same tumor. These tumor sub-populations differ genetically and epigenetically contributing to intra- and inter-tumoral heterogeneity in human metastases. Overall, our results provide a deeper understanding of the shared clinicopathological characteristics shown by NECs. Furthermore, the intratumoral heterogeneity of human NEPCs suggests the requirement of simultaneous targeting of coexisting tumor populations as a therapeutic strategy. Neuroendocrine carcinomas (NECs) arise from different anatomic sites, but have similar histological and clinical features. Here, the authors show that the epigenetic landscape of a range of NECs converges towards a common epigenetic state, while distinct subtypes occur within neuroendocrine prostate cancer contributing to intratumor heterogeneity in clinical samples.

Due to the development of intelligent decision-making, social network group decision making (SNGDM) has become increasingly valued. Self-persistence is a significant topic in SNGDM problems, while it is ignored in most existing research. Besides, existing opinion evolution models often ignore high-order interactions because they assume individuals only communicate with their friends or neighbors. With these issues in mind, the authors propose a multi-step interaction opinion dynamics model to manage the consensus in SNGDM problem with self-persistence evolution. Given the decision makers' social network information, the centrality degree, interaction strength, and high-order interactions are combined to construct a social influence network. Inspired by the social influence model, the authors develop an opinion dynamic consensus model which also describes the evolution of self-persistence in a group of decision makers. Finally, an example and detailed simulation experiment are presented to demonstrate the efficiency of the proposed consensus model.

c-MYC (MYC) is a major driver of prostate cancer tumorigenesis and progression. Although MYC is overexpressed in both early and metastatic disease and associated with poor survival, its impact on prostate transcriptional reprogramming remains elusive. We demonstrate that MYC overexpression significantly diminishes the androgen receptor (AR) transcriptional program (the set of genes directly targeted by the AR protein) in luminal prostate cells without altering AR expression. Analyses of clinical specimens reveal that concurrent low AR and high MYC transcriptional programs accelerate prostate cancer progression toward a metastatic, castration-resistant disease. Data integration of single-cell transcriptomics together with ChIP-seq uncover an increase in RNA polymerase II (Pol II) promoter-proximal pausing at AR-dependent genes following MYC overexpression without an accompanying deactivation of AR-bound enhancers. Altogether, our findings suggest that MYC overexpression antagonizes the canonical AR transcriptional program and contributes to prostate tumor initiation and progression by disrupting transcriptional pause release at AR-regulated genes. The role of MYC in transcriptional reprogramming in prostate cancer remains poorly characterized. Here, MYC overexpression antagonizes the canonical AR transcriptional program leading to prostate tumor initiation and progression by disrupting transcriptional pause release at AR-regulated genes.