Diacylglycerol - PKC Epsilon - Insulin Receptor as a Key Regulatory Axis of Hepatic and White Adipose Tissue Insulin Signaling

Type 2 diabetes (T2D) is a chronic condition that currently affects 463 million people worldwide and is expected to affect 700 million people by the year of 2045. People with T2D suffer from many downstream conditions, such as cardiovascular diseases and stroke, vision loss, renal function impairment and amputations due to limb extremity damages, and are also much more susceptible to severe COVID-19 conditions. This devastating disease not only inflicts severe personal suffering on the individuals affected but also inflicts a huge economic burden on the society. For example, the annual cost of diagnosed diabetes in United States is estimated to be $327B in 2017. Therefore, understanding the mechanisms underlying the pathogenesis of T2D is of great importance, and effective therapeutic inventions can then be developed to remediate the situation.Insulin resistance is the primary characteristic of T2D, where insulin fails to activate downstream signaling pathways, causing excessive glucose build-up in the circulation and tissues starved from critical nutrients. In the human body, liver serves as the center of numerous metabolic functions and is pivotal in regulating glucose homeostasis. Hepatic insulin resistance (HIR) significantly contributes to hyperglycemia via increased hepatic glucose output and decreased hepatic glucose storage. Understanding the mechanism of HIR is thus critical. Nonalcoholic fatty liver disease (NAFLD) is strongly associated with HIR, however, the key lipid species and molecular mechanisms linking these conditions are widely debated. We developed a subcellular fractionation method to quantify diacylglycerol (DAG) stereoisomers and ceramides in the endoplasmic reticulum (ER), mitochondria, plasma membrane (PM), lipid droplets and cytosol. Acute knockdown (KD) of diacylglycerol acyltransferase-2 (DGAT2) in liver induced HIR in rats. This was due to PM sn-1,2-DAG accumulation, which promoted PKCε activation, and insulin receptor kinase (IRK)-T1160 phosphorylation resulting in decreased IRK-Y1162 phosphorylation. Liver PM sn-1,2-DAG content and IRK-T1160 phosphorylation were also higher in humans with HIR. In rats, liver-specific PKCε KD ameliorated high-fat diet (HFD)-induced HIR by lowering IRK-T1160 phosphorylation, while liver-specific overexpression of constitutively active PKCε-induced HIR by promoting IRK-T1160 phosphorylation. White adipose tissue (WAT) is also of great regulatory importance in glucose metabolism. Insulin-mediated suppression of WAT lipolysis is an important anabolic function that is dysregulated in the state of overnutrition. However, the mechanism of short-term HFD-induced WAT insulin resistance is poorly understood. Based on our studies in the liver and preliminary studies in the WAT, we hypothesize that a short-term HFD causes WAT insulin resistance through a similar mechanism. Increases in PM sn-1,2-DAG content, which promotes PKCε activation, impairs insulin signaling by phosphorylating IRK-T1160. To test this hypothesis, we assessed WAT insulin action in 7-day HFD-fed versus regular chow diet-fed rats during a hyperinsulinemic-euglycemic clamp. HFD feeding caused WAT insulin resistance, reflected by reductions in both insulin-mediated WAT glucose uptake and suppression of WAT lipolysis. These changes were specifically associated with increased PM sn-1,2-DAG content, increased PKCε activation and impaired insulin-stimulated IRK-Y1162 phosphorylation. In order to examine the role of IRK-T1160 phosphorylation in mediating lipid-induced WAT insulin resistance, we examined these same parameters in short-term HFD-fed IRKT1150A mice (IRK-T1150 is the mouse homolog of human IRK-T1160). Similar to the rat study, short-term HFD feeding induced WAT insulin resistance in WT control mice but failed to induce WAT insulin resistance in IRKT1150A mice. Taken together these data demonstrate that the PM sn-1,2-DAG - PKCε - IRK-T1160 phosphorylation pathway plays an important role in mediating lipid-induced hepatic and WAT insulin resistance and represents a potential therapeutic target to improve insulin sensitivity in the liver and WAT

Restorative Properties of Semi-Outdoor Space in the Workplace: Towards an atmospheric quality of architecture

The biophilic design philosophy embraces the creation of dynamic multi-sensory built environments through the incorporation of nature for its restorative properties, including the restoration of attentional capacity, reduction of stress, and improvement of mood. However, current literature focuses almost exclusively on the visual experience while neglecting the thermal sense. This thesis argues for the central role played by thermal sense in occupants’ restorative experience of nature within the built environment. Experimental methods are used to address the question “To what extent does the thermal realm contribute to the multisensory experience of nature and its restorative benefits in semi-outdoor environments?” A pre-and-post-test experiment was conducted to compare the restorative effects of a workplace semi-outdoor space presenting two distinct thermal scenarios, one devoid of adaptive opportunities, just direct sunlight exposure, and the other condition including the adaptive opportunity for subjects to select between direct sunlight or shade. The experiment used a multisensory virtual reality method to simulate the dynamic environmental conditions of an actual semi-outdoor space. Significant associations between thermal pleasure, thermal adaptive opportunities, and restorative benefits were found. This study observed cultural differences in participants’ thermal preferences and restorative outcomes. Relationships between the thermal realm and psychological restoration were proposed based on the empirical findings. This project brings empirical evidence to the architectural discourse and critique of ‘ocular-centrism’ and advocates the key role of thermal pleasure and delight within the biophilia theme in contemporary architecture. The methodological innovation and findings from the project invite new lines of inquiry that focus on the psychological benefits of thermal pleasure in the outdoor urban context

Heavy Neutral Leptons at Muon Colliders

The future high-energy muon colliders, featuring both high energy and low background, could play a critical role in our searches for new physics. The smallness of neutrino mass is a puzzle of particle physics. Broad classes of solutions to the neutrino puzzles can be best tested by seeking the partners of SM light neutrinos, dubbed as heavy neutral leptons (HNLs), at muon colliders. We can parametrize HNLs in terms of the mass $m_N$ and the mixing angle with $\ell$-flavor $U_\ell$. In this work, we focus on the regime $m_N > O(100)$ GeV and study the projected sensitivities on the $|U_\ell|^2 - m_N$ plane with the full-reconstructable HNL decay into a hadronic $W$ and a charged lepton. The projected reach in $|U_\ell|^2$ leads to the best sensitivities in the TeV realm.Comment: 33 pages, 10 figure

Properties of gapped systems in AdS/BCFT

We study the conductivities and entanglement structures of two different holographic gapped systems at zero density in the presence of boundaries within AdS/BCFT. The first gapped system is described by the Einstein-scalar gravity and the second one is the dual of AdS soliton geometry. We show that in both these two systems the bulk and boundary conductivities along the spatial direction of the boundary of BCFT are trivial. For the first system, when we increase the size of the subsystem the renormalized entanglement entropy is always non-negative and monotonically decreasing with discontinuous, or continuous, or smooth behavior, depending on the effective tension of the brane. While for the AdS soliton with a boundary, the renormalized entanglement entropy only exhibits a discontinuous drop when we increase the size of the subsystem.Comment: 36 pages, 17 figures, published versio

Parameter Estimation of Stellar Mass Binary Black Holes under the Network of TianQin and LISA

We present a Bayesian parameter estimation progress to infer the stellar mass binary black hole properties by TianQin, LISA, and TianQin+LISA. Two typical Stellar-mass Black Hole Binary systems, GW150914 and GW190521 are chosen as the fiducial sources. In this work, we establish the ability of TianQin to infer the parameters of those systems and first apply the full frequency response in TianQin's data analysis. We obtain the parameter estimation results and explain the correlation between them. We also find the TianQin+LISA could marginally increase the parameter estimation precision and narrow the $1\sigma$ area compared with TianQin and LISA individual observations. We finally demonstrate the importance of considering the effect of spin when the binaries have a non-zero component spin and great derivation will appear especially on mass, coalescence time and sky location.Comment: 17 pages, 6 figures, comments welcom

Self-interacting neutrinos: Solution to Hubble tension versus experimental constraints

Exotic self-interactions among the Standard Model neutrinos have been proposed as a potential reason behind the tension in the expansion rate, $H_0$, of the universe inferred from different observations. We constrain this proposal using electroweak precision observables, rare meson decays, and neutrinoless double-$β$ decay. In contrast to previous works, we emphasize the importance of carrying out this study in a framework with full Standard Model gauge invariance. We implement this first by working with a relevant set of Standard Model effective field theory operators and subsequently by considering a UV completion in the inverse seesaw model. We find that the scenario in which all flavors of neutrinos self-interact universally is strongly constrained, disfavoring a potential solution to the $H_0$ problem in this case. The scenario with self-interactions only among tau neutrinos is the least constrained and can potentially be consistent with a solution to the $H_0$ problem

Heavy Neutral Leptons from Stopped Muons and Pions

Stopped muons, which are generic in pion-at-rest experiments, can shed light on heavy neutral leptons (HNLs) in unexplored parameter spaces. If the HNL is lighter than the muon, the HNL can be produced from decays of muons and pions.The HNL will travel from the production location and decay into visible Standard Model (SM) modes, leaving signals inside downstream detectors. We find that in the case that the HNL dominantly mixes with muon neutrinos, the LSND constraint on the mixing angle squared is stronger than all the previous constraints by more than an order of magnitude. In this study, we recast the LSND measurement of the $\nu-e$ scattering. Future experiments such as PIP2-BD could further improve the sensitivity, provided they can distinguish the HNL events from backgrounds induced by the SM neutrinos.Comment: 13 pages, 2 figure

Flavor-changing light bosons with accidental longevity

We consider a model with a complex scalar field that couples to $(e,\mu)$ or $(\mu,\tau)$ within the "longevity" window: $[|m_{l_1} - m_{l_2}|, m_{l_1} + m_{l_2}]$ in which $l_1$ and $l_2$ are the two different charged leptons. Within such a mass window, even a relatively large coupling (e.g. of the size commensurate with the current accuracy/discrepancy in the muon $g-2$ experiment) leads to long lifetimes and macroscopic propagation distance between production and decay points. We propose to exploit several existing neutrino experiments and one future experiment to probe the parameter space of this model. For the $\mu-e$ sector, we exploit the muonium decay branching ratio and the production and decay sequence at the LSND experiment, excluding the parametric region suggested by $g_\mu -2$ anomaly. For the $\tau-\mu$ sector, we analyze three main production mechanisms of scalars at beam dump experiments: the Drell-Yan process, the heavy meson decay, and the muon scattering. We explore the constraints from the past CHARM and NuTeV experiments, and evaluate sensitivity for the proposed beam dump experiment, SHiP. The latter can thoroughly probe the parameter space relevant for the $g_\mu - 2$ anomaly.Comment: 30 pages, 9 figures and comments welcom