Investigating the molecular mechanisms underlying touch in mice

Although mechanosensation might be the most ancient one among our five senses, the mechanotransduction mechanism underlying the sense of touch remains to be least understood. A Stomatin like protein-3 (STOML3) has been shown to be essential for touch sensation in mouse. However, the molecular mechanisms by which STOML3 contribute to mechanotransduction remain elusive. In the first chapter of the thesis, we suggest a novel mechanism by which STOML3 modulates sensory mechanostransduction. STOML3, via binding cholesterol, controls membrane mechanics, thus facilitates the force transfer and tunes the sensitivity of the mechanically gated channels, including Piezo channels. Several lines of evidence support this conclusion. First, STOML3 is detected in cholesterol enriched lipid raft. Depletion of cholesterol and deficiency of STOML3 in sensory neurons similarly and interdependently affect membrane mechanics and attenuate mechanosensitivity. Second, we demonstrate that an intact STOML3 is essential for maintaining membrane mechanics to sensitize mechanically gated Piezo1 and Piezo2 channels in heterologous systems. Such a stiffened membrane can be softened by either depleting cholesterol or genetic disruption of cholesterol binding of STOML3. Third, mutation of residue involved in cholesterol binding (STOML-P40S) fails to modulate the sensitivity of Piezo channels or restore the mechanosensitivity of STOML3-/- sensory neurons. Finally, using a behavioral test, we show that cholesterol depletion could attenuate tactile allodynia and this effect involves STOML3. Factoring all these together, we propose that the stiffened membrane by STOML3 is essential for sensory mechanotransdution in vitro and the tactile sensitivity in vivo. STOML3 has been previously shown to interact with and inhibit the activity of Acid-sensing ion channels (ASICs). However, little is known about how this works. In the second chapter of the thesis, we examined whether STOML3 requires cholesterol-rich lipid rafts for regulating the activities of its associated ASIC channels. We show disrupting cholesterol-rich lipid rafts with Methyl-β-cyclodextrin robustly increases the proton-gated ASICs-like current in sensory neurons from C57BL/6N but not STOML3-/- mice, suggesting that the regulation of acid-sensing ion channels by lipid rafts involves STOML3 in sensory neurons. In heterologous expression cells, cholesterol depletion increases proton-gated ASICs-mediated currents and abolishes the inhibition of STOML3 on ASIC channel activity. Collectively, we suggest the regulation of ASIC channel by STOML3 requires the involvement of cholesterol-rich lipid rafts in mouse sensory neurons. In summary, with the above mentioned work, we would like to propose that binding cholesterol might be a general mechanism for STOML3 to regulate its associated ion channels including Piezos and ASICs. Touch evoked pain is the most common symptom of chronic pain and the effective treatment is absent. Our work on STOML3 would provide therapeutic opportunity for treating chronic pain

Bilateral boundary control of an input delayed 2-D reaction-diffusion equation

In this paper, a delay compensation design method based on PDE backstepping is developed for a two-dimensional reaction-diffusion partial differential equation (PDE) with bilateral input delays. The PDE is defined in a rectangular domain, and the bilateral control is imposed on a pair of opposite sides of the rectangle. To represent the delayed bilateral inputs, we introduce two 2-D transport PDEs that form a cascade system with the original PDE. A novel set of backstepping transformations is proposed for delay compensator design, including one Volterra integral transformation and two affine Volterra integral transformations. Unlike the kernel equation for 1-D PDE systems with delayed boundary input, the resulting kernel equations for the 2-D system have singular initial conditions governed by the Dirac Delta function. Consequently, the kernel solutions are written as a double trigonometric series with singularities. To address the challenge of stability analysis posed by the singularities, we prove a set of inequalities by using the Cauchy-Schwarz inequality, the 2-D Fourier series, and the Parseval's theorem. A numerical simulation illustrates the effectiveness of the proposed delay-compensation method.Comment: 11 pages, 3 figures(including 8 sub-figures

Circadian rhythm of Liposcelis entomophila and Liposcelis paeta in paddy warehouse: Presentation

Booklice is a small but serious stored grain pest, and understanding the circadian rhythm of booklice help to control. In this study, circadian activity of booklice were monitored with sticky traps in the grain bulk surfaces of two warehouses stored paddy rice in two different provinces in China. The results showed that the species of booklice were different and were Liposcelis entomophila, and Liposcelisp paeta for Nanning’s and Zhanjiang’s warehouses respectively. In term of L.entomophila, its activity intensity gradually decreased from 0 am to 12 pm and reached the lowest level of daily activity at 12pm. After this, there was a steady and straight upward trend, and the peak of its activity intensity is reached at 8 pm. Its circadian activity trend can be represented as: y = - 0.971x3 + 21.88x2 - 139.5x + 353.4(x: time; y: quantity of booklice). Over the same period, the activity intensity of L.paeta varied greatly. It gradually increased, reached a peak at 8 am, dropped dramatically at 12 pm and then climbed the second peak at 6 pm.Booklice is a small but serious stored grain pest, and understanding the circadian rhythm of booklice help to control. In this study, circadian activity of booklice were monitored with sticky traps in the grain bulk surfaces of two warehouses stored paddy rice in two different provinces in China. The results showed that the species of booklice were different and were Liposcelis entomophila, and Liposcelisp paeta for Nanning’s and Zhanjiang’s warehouses respectively. In term of L.entomophila, its activity intensity gradually decreased from 0 am to 12 pm and reached the lowest level of daily activity at 12pm. After this, there was a steady and straight upward trend, and the peak of its activity intensity is reached at 8 pm. Its circadian activity trend can be represented as: y = - 0.971x3 + 21.88x2 - 139.5x + 353.4(x: time; y: quantity of booklice). Over the same period, the activity intensity of L.paeta varied greatly. It gradually increased, reached a peak at 8 am, dropped dramatically at 12 pm and then climbed the second peak at 6 pm

Anisotropic scattering characteristics of nanoparticles in different morphologies: improving the temperature uniformity of tumors during thermal therapy using forward scattering

Precise control of the thermal damage area is the key issue during thermal therapy, which can be achieved by manipulating the light propagation in biological tissue. In the present work, a method is proposed to increase the uniformity of the specific absorption rate (SAR) distribution in tumors during laser-induced thermal therapy, which is proved to be effective in reducing the thermal damage of healthy tissue. In addition, a better way of manipulating light propagation in biological tissue is explored. It is found that the anisotropic scattering characteristics of nanoparticles are strongly dependent on their shapes, sizes, orientations, and incident wavelengths, which will strongly affect the light propagation in nanoparticle embedded biological tissue. Therefore, to obtain a better outcome from photothermal therapy, the scattering properties of nanoparticles are very important factors that need to be taken into consideration, along with the absorption efficiency. Further investigation finds that nanoparticles that predominantly scatter to the forward direction are favorable in obtaining a larger penetration depth of light, which will improve the uniformity of SAR and temperature distributions. This paper is meaningful for the application of nanoparticle-assisted laser-induced thermal therapy

Autocorrelations of stellar light and mass at z~0 and ~1: From SDSS to DEEP2

We present measurements of projected autocorrelation functions w_p(r_p) for the stellar mass of galaxies and for their light in the U, B and V bands, using data from the third data release of the DEEP2 Galaxy Redshift Survey and the final data release of the Sloan Digital Sky Survey (SDSS). We investigate the clustering bias of stellar mass and light by comparing these to projected autocorrelations of dark matter estimated from the Millennium Simulations (MS) at z=1 and 0.07, the median redshifts of our galaxy samples. All of the autocorrelation and bias functions show systematic trends with spatial scale and waveband which are impressively similar at the two redshifts. This shows that the well-established environmental dependence of stellar populations in the local Universe is already in place at z=1. The recent MS-based galaxy formation simulation of Guo et al. (2011) reproduces the scale-dependent clustering of luminosity to an accuracy better than 30% in all bands and at both redshifts, but substantially overpredicts mass autocorrelations at separations below about 2 Mpc. Further comparison of the shapes of our stellar mass bias functions with those predicted by the model suggests that both the SDSS and DEEP2 data prefer a fluctuation amplitude of sigma_8 0.8 rather than the sigma_8=0.9 assumed by the MS.Comment: 10 pages, 4 figures, accepted for publication in Monthly Notices, minor revisions in tex

Mucosal-Associated Invariant T Cells Improve Nonalcoholic Fatty Liver Disease Through Regulating Macrophage Polarization

Mucosal-associated invariant T (MAIT) cells, a novel population of innate-like lymphocytes, have been involved in various inflammatory and autoimmune diseases. However, their role in the development of nonalcoholic fatty liver disease (NAFLD) remains unclear. In this study, we investigated the alterations of phenotype and immunological function of MAIT cells in NAFLD. Analysis of PBMCs in 60 patients with NAFLD and 48 healthy controls (HC) revealed that circulating MAIT cell frequency decreased in NAFLD, especially in the patients with higher serum levels of γ-glutamyl transferase or total triglyceride. Functional alterations of circulating MAIT cells were also detected in NAFLD patients, such as the increased production of IL-4 whereas the decreased production of IFN-γ and TNF-α. Furthermore, elevated expression of CXCR6 was observed in circulating MAIT cells of patients. Meanwhile, we found an increased number of MAIT cells in the livers of NAFLD, and the number was even greater in patients with higher NAFLD activity score. Moreover, activated MAIT cells induced monocytes/macrophages differentiation into M2 phenotype in vitro. Additionally, MAIT cells were enriched and displayed Th2 type cytokines profile in livers of wild type mice fed with methionine and choline deficient diet (MCD). Notably, mice deficient of MAIT cells exhibited more severe hepatic steatosis and inflammation upon MCD, accompanied with more CD11c+ proinflammatory macrophages (M1) and less CD206+ anti-inflammatory macrophages (M2) in livers. Our results indicate that MAIT cells protect against inflammation in NAFLD through producing regulatory cytokines and inducing anti-inflammatory macrophage polarization, which may provide novel therapeutic strategies for NAFLD

SDSS-IV MaNGA: properties of galaxies with kinematically decoupled stellar and gaseous components

We study the properties of 66 galaxies with kinematically misaligned gas and stars from MaNGA survey. The fraction of kinematically misaligned galaxies varies with galaxy physical parameters, i.e. M∗, SFR and sSFR. According to their sSFR, we further classify these 66 galaxies into three categories, 10 star-forming, 26 ‘Green Valley’ and 30 quiescent ones. The properties of different types of kinematically misaligned galaxies are different in that the starforming ones have positive gradient in Dn4000 and higher gas-phase metallicity, while the green valley/quiescent ones have negative Dn4000 gradients and lower gas-phase metallicity on average. There is evidence that all types of the kinematically misaligned galaxies tend to live in more isolated environment. Based on all these observational results, we propose a scenario for the formation of star-forming galaxies with kinematically misaligned gas and stars − the progenitor accretes misaligned gas from a gas-rich dwarf or cosmic web, the cancellation of angular momentum from gas–gas collisions between the pre-existing gas and the accreted gas largely accelerates gas inflow, leading to fast centrally concentrated star formation. The higher metallicity is due to enrichment from this star formation. For the kinematically misaligned green valley and quiescent galaxies, they might be formed through gas-poor progenitors accreting kinematically misaligned gas from satellites which are smaller in mass

AI is a viable alternative to high throughput screening: a 318-target study

: High throughput screening (HTS) is routinely used to identify bioactive small molecules. This requires physical compounds, which limits coverage of accessible chemical space. Computational approaches combined with vast on-demand chemical libraries can access far greater chemical space, provided that the predictive accuracy is sufficient to identify useful molecules. Through the largest and most diverse virtual HTS campaign reported to date, comprising 318 individual projects, we demonstrate that our AtomNet® convolutional neural network successfully finds novel hits across every major therapeutic area and protein class. We address historical limitations of computational screening by demonstrating success for target proteins without known binders, high-quality X-ray crystal structures, or manual cherry-picking of compounds. We show that the molecules selected by the AtomNet® model are novel drug-like scaffolds rather than minor modifications to known bioactive compounds. Our empirical results suggest that computational methods can substantially replace HTS as the first step of small-molecule drug discovery