Afferents integration and neural adaptive control of breathing

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Mechanical Engineering, 2011.Cataloged from PDF version of thesis.Includes bibliographical references.The respiratory regulatory system is one of the most extensively studied homeostatic systems in the body. Despite its deceptively mundane physiological function, the mechanism underlying the robust control of the motor act of breathing in the face of constantly changing internal and external challenges throughout one's life is still poorly understood. Traditionally, control of breathing has been studied with a highly reductionist approach, with specific stimulus-response relationships being taken to reflect distinct feedback/feedforward control laws. It is assumed that the overall respiratory response could be described as the linear sum of all unitary stimulus-response relationships under a Sherringtonian framework. Such a divide-and-conquer approach has proven useful in predicting the independent effects of specific chemical and mechanical inputs. However, it has limited predictive power for the respiratory response in realistic disease states when multiple factors come into play. Instead, vast amounts of evidence have revealed the existence of complex interactions of various afferent-efferent signals in defining the overall respiratory response. This thesis aims to explore the nonlinear interaction of afferents in respiratory control. In a series of computational simulations, it was shown that the respiratory response in humans during muscular exercise under a variety of pulmonary gas exchange defects is consistent with an optimal interaction of mechanical and chemical afferents. This provides a new understanding on the impacts of pulmonary gas exchange on the adaptive control of the exercise respiratory response. Furthermore, from a series of in-vivo neurophysiology experiments in rats, it was discovered that certain respiratory neurons in the dorsolateral pons in the rat brainstem integrate central and peripheral chemoreceptor afferent signals in a hypoadditive manner. Such nonlinear interaction evidences classical (Pavlovian) conditioning of chemoreceptor inputs that modulate the respiratory rhythm and motor output. These findings demonstrate a powerful gain modulation function for control of breathing by the lower brain. The computational and experimental studies in this thesis reveal a form of associative learning important for adaptive control of respiratory regulation, at both behavioral and neuronal levels. Our results shed new light for future experimental and theoretical elucidation of the mechanism of respiratory control from an integrative modeling perspective.by Chung Tin.Ph.D

The simplest massive S-matrix: from minimal coupling to Black Holes

In this paper, we explore the physics of electromagnetically and gravitationally coupled massive higher spin states from the on-shell point of view. Starting with the three-point amplitude, we focus on the simplest amplitude which is characterized by matching to minimal coupling in the UV. In the IR such amplitude leads to g = 2 for arbitrary charged spin states, and the best high energy behavior for a given spin. We proceed to construct the (gravitational) Compton amplitude for generic spins. We find that the leading deformation away from minimal coupling, in the gravitation sector, will lead to inconsistent factorizations and are thus forbidden. As the corresponding deformation in the gauge sector encodes the anomalous magnetic dipole moment, this leads to the prediction that for systems with gauge2 =gravity relations, such as perturbative string theory, all charged states must have g = 2. It is then natural to ask for generic spin, what is the theory that yields such minimal coupling. By matching to the one body effective action, remarkably we verify that for large spins, the answer is Kerr black holes. This identification is then an on-shell avatar of the no hair theorem. Finally using this identification as well as the newly constructed Compton amplitudes, we proceed to compute the spin dependent pieces for the classical potential at 2PM order up to degree four in spin operator of either black holes.Comment: 78 pages 4 figures V2. Improved discussion on the computation procedure of the classical potential, the issue of polynomial ambiguities and update on references. We've also included the complete list of new results involving up to degree four in spin operators of either black hole v3 Typos corrected, published versio

An Asian Study of the Monetary and Banking Liquidity Impact on Share Prices

Following Friedman’s hypothesis that credit expansion will follow a monetary and liquidity binge, we used data from 1968-2012 in Asia (Japan, Korea, China and India) to explore this hypothesis.Our results from applying single and cointegration equations provided empirical support to the above hypothesis. This liquidity binge following a monetary impact on share prices was tested in four major Asian economies.As per the theory’s prediction, monetary changes led to a positive banking liquidity effect, based on lengthy quarterly equations using the dynamic OLS method. We also showed that banking liquidity changes have a significant positive effect on share prices, after controlling for the effects of earning changes, regime changes and the global financial crisis. These findings, obtained after solutions to serious econometric issues in existing studies, appear to provide a clear verification of theory on the monetary effect on banking liquidity and banking liquidity’s effect on share prices

Up-regulation of dorsal root ganglia BDNF and trkB receptor in inflammatory pain: an in vivo and in vitro study

<p>Abstract</p> <p>Background</p> <p>During inflammation, immune cells accumulate in damaged areas and release pro-inflammatory cytokines and neurotrophins. Brain-derived neurotrophic factor (BDNF) plays a neuromodulatory role in spinal cord dorsal horn via the post-synaptic tyrosine protein kinase B (trkB) receptor to facilitate pain transmission. However, the precise role of BDNF and trkB receptor in the primary sensory neurons of dorsal root ganglia (DRG) during inflammation remains to be clarified. The aim of this study was to investigate whether and how BDNF-trkB signaling in the DRG is involved in the process of inflammatory pain.</p> <p>Methods</p> <p>We used complete Freund's adjuvant- (CFA-) induced and tumor necrosis factor-α- (TNF-α-) induced inflammation in rat hindpaw as animal models of inflammatory pain. Quantification of protein and/or mRNA levels of pain mediators was performed in separate lumbar L3-L5 DRGs. The cellular mechanism of TNF-α-induced BDNF and/or trkB receptor expression was examined in primary DRG cultures collected from pooled L1-L6 DRGs. Calcitonin gene-related peptide (CGRP), BDNF and substance P release were also evaluated by enzyme immunoassay.</p> <p>Results</p> <p>CFA injection into rat hindpaw resulted in mechanical hyperalgesia and significant increases in levels of TNF-α in the inflamed tissues, along with enhancement of BDNF and trkB receptor as well as the pain mediators CGRP and transient receptor potential vanilloid receptor subtype 1 (TRPV1) in DRG. Direct injection of TNF-α into rat hindpaw resulted in similar effects with retrograde transport of TNF-α along the saphenous nerve to DRG during CFA-induced inflammation. Primary DRG cultures chronically treated with TNF-α showed significant enhancement of mRNA and protein levels of BDNF and trkB receptor, BDNF release and trkB-induced phospho-ERK1/2 signal. Moreover, CGRP and substance P release were enhanced in DRG cultures after chronic TNF-α treatment or acute BDNF stimulation. In addition, we found that BDNF up-regulated trkB expression in DRG cultures.</p> <p>Conclusions</p> <p>Based on our current experimental results, we conclude that inflammation and TNF-α up-regulate the BDNF-trkB system in DRG. This phenomenon suggests that up-regulation of BDNF in DRG may, in addition to its post-synaptic effect in spinal dorsal horn, act as an autocrine and/or paracrine signal to activate the pre-synaptic trkB receptor and regulate synaptic excitability in pain transmission, thereby contributing to the development of hyperalgesia.</p

Analytic approaches to clinical validation of results from preclinical models of glioblastoma:A systematic review

INTRODUCTION: Analytic approaches to clinical validation of results from preclinical models are important in assessment of their relevance to human disease. This systematic review examined consistency in reporting of glioblastoma cohorts from The Cancer Genome Atlas (TCGA) or Chinese Glioma Genome Atlas (CGGA) and assessed whether studies included patient characteristics in their survival analyses. METHODS: We searched Embase and Medline on 02Feb21 for studies using preclinical models of glioblastoma published after Jan2008 that used data from TCGA or CGGA to validate the association between at least one molecular marker and overall survival in adult patients with glioblastoma. Main data items included cohort characteristics, statistical significance of the survival analysis, and model covariates. RESULTS: There were 58 eligible studies from 1,751 non-duplicate records investigating 126 individual molecular markers. In 14 studies published between 2017 and 2020 using TCGA RNA microarray data that should have the same cohort, the median number of patients was 464.5 (interquartile range 220.5–525). Of the 15 molecular markers that underwent more than one univariable or multivariable survival analyses, five had discrepancies between studies. Covariates used in the 17 studies that used multivariable survival analyses were age (76.5%), pre-operative functional status (35.3%), sex (29.4%) MGMT promoter methylation (29.4%), radiotherapy (23.5%), chemotherapy (17.6%), IDH mutation (17.6%) and extent of resection (5.9%). CONCLUSION: Preclinical glioblastoma studies that used TCGA for validation did not provide sufficient information about their cohort selection and there were inconsistent results. Transparency in reporting and the use of analytic approaches that adjust for clinical variables can improve the reproducibility between studies