A measurement and modelling study of hair partition of neutral, cationic and anionic chemicals

Various neutral, cationic and anionic chemicals contained in hair care products can be absorbed into hair fiber to modulate physicochemical properties such as color, strength, style and volume. For environmental safety, there is also an interest in understanding hair absorption to wide chemical pollutants. There have been very limited studies on the absorption properties of chemicals into hair. Here, an experimental and modelling study has been carried out for the hair-water partition of a range of neutral, cationic and anionic chemicals at different pH. The data showed that hair-water partition not only depends on the hydrophobicity of the chemical but also the pH. The partition of cationic chemicals to hair increased with pH and this is due to their electrostatic interaction with hair increased from repulsion to attraction. For anionic chemicals, their hair-water partition coefficients decreased with increasing pH due to their electrostatic interaction with hair decreased from attraction to repulsion. Increase in pH didn’t change the partition of neutral chemicals significantly. Based on the new physicochemical insight of the pH effect on hair-water partition, a new QSPR model has been proposed, taking into account of both the hydrophobic interaction and electrostatic interaction of chemical with hair fiber

Effectiveness of End-of-Life Strategies to Improve Health Outcomes and Reduce Disparities in Rural Appalachia: An analytic codebook

Appalachia is one of the most medically underserved areas in the nation. The region has provider shortages and limited healthcare infrastructure. Children and adolescents in this area are in poor health and do not receive the needed quality care. Implementation of section 2302 of the 2010 Patient Protection and Affordable Care Act (ACA) enabled children enrolled in Medicaid/Children\u27s Health Insurance Program with a terminal illness to use hospice care while continuing treatment for their terminal illness. In addition to being more comprehensive than standard hospice care, this relatively new type of care is more culturally congruent with the end-of-life values of rural Appalachian families, who often view standard hospice as hastening death. The overall goal of this project was to investigate access to pediatric concurrent hospice care in Appalachia. Our central hypothesis was that concurrent care reduces rural/urban disparities in access to hospice care. Data from the Centers for Medicare and Medicaid Services (CMS) used in this project was used and included 1,788 children who resided in the Appalachian region– from January 1, 2011, to December 31, 2013. Observations with missing birth dates, death dates, and participants older than 21 years were removed from the final sample. Geographic Information Systems (GIS) databases were created to map the boundaries of the Appalachian region, hospice locations, and driving times to them

Optogenetic visualization of presynaptic tonic inhibition of cerebellar parallel fibers

© The Author(s), 2016. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Journal of Neuroscience 36 (2016): 5709-5723, doi:10.1523/JNEUROSCI.4366-15.2016.Tonic inhibition was imaged in cerebellar granule cells of transgenic mice expressing the optogenetic chloride indicator, Clomeleon. Blockade of GABAA receptors substantially reduced chloride concentration in granule cells due to block of tonic inhibition. This indicates that tonic inhibition is a significant contributor to the resting chloride concentration of these cells. Tonic inhibition was observed not only in granule cell bodies, but also in their axons, the parallel fibers (PFs). This presynaptic tonic inhibition could be observed in slices both at room and physiological temperatures, as well as in vivo, and has many of the same properties as tonic inhibition measured in granule cell bodies. GABA application revealed that PFs possess at least two types of GABAA receptor: one high-affinity receptor that is activated by ambient GABA and causes a chloride influx that mediates tonic inhibition, and a second with a low affinity for GABA that causes a chloride efflux that excites PFs. Presynaptic tonic inhibition regulates glutamate release from PFs because GABAA receptor blockade enhanced both the frequency of spontaneous EPSCs and the amplitude of evoked EPSCs at the PF-Purkinje cell synapse. We conclude that tonic inhibition of PFs could play an important role in regulating information flow though cerebellar synaptic circuits. Such cross talk between phasic and tonic signaling could be a general mechanism for fine tuning of synaptic circuits.This work was supported by National Institute of Mental Health Grants, Alfred P. Sloan Research Fellowship, Klingenstein Fellowship Award in the Neuroscience, Beckman Young Investigator Award, World Class Institute program of the National Research Foundation of Korea funded by Ministry of Education, Science, and Technology WCI 2009-003, National Research Foundation of Singapore CRP Grant, National Science Foundation Grant 1512826, and BRAIN Initiative MH106013.2016-11-2

Cortical Neural Stem Cell Lineage Progression Is Regulated by Extrinsic Signaling Molecule Sonic Hedgehog.

Neural stem cells (NSCs) in the prenatal neocortex progressively generate different subtypes of glutamatergic projection neurons. Following that, NSCs have a major switch in their progenitor properties and produce γ-aminobutyric acid (GABAergic) interneurons for the olfactory bulb (OB), cortical oligodendrocytes, and astrocytes. Herein, we provide evidence for the molecular mechanism that underlies this switch in the state of neocortical NSCs. We show that, at around E16.5, mouse neocortical NSCs start to generate GSX2-expressing (GSX2+) intermediate progenitor cells (IPCs). In vivo lineage-tracing study revealed that GSX2+ IPC population gives rise not only to OB interneurons but also to cortical oligodendrocytes and astrocytes, suggesting that they are a tri-potential population. We demonstrated that Sonic hedgehog signaling is both necessary and sufficient for the generation of GSX2+ IPCs by reducing GLI3R protein levels. Using single-cell RNA sequencing, we identify the transcriptional profile of GSX2+ IPCs and the process of the lineage switch of cortical NSCs

Electrotunable liquid sulfur microdroplets.

Manipulating liquids with tunable shape and optical functionalities in real time is important for electroactive flow devices and optoelectronic devices, but remains a great challenge. Here, we demonstrate electrotunable liquid sulfur microdroplets in an electrochemical cell. We observe electrowetting and merging of sulfur droplets under different potentiostatic conditions, and successfully control these processes via selective design of sulfiphilic/sulfiphobic substrates. Moreover, we employ the electrowetting phenomena to create a microlens based on the liquid sulfur microdroplets and tune its characteristics in real time through changing the shape of the liquid microdroplets in a fast, repeatable, and controlled manner. These studies demonstrate a powerful in situ optical battery platform for unraveling the complex reaction mechanism of sulfur chemistries and for exploring the rich material properties of the liquid sulfur, which shed light on the applications of liquid sulfur droplets in devices such as microlenses, and potentially other electrotunable and optoelectronic devices

Common dysregulation network in the human prefrontal cortex underlies two neurodegenerative diseases.

Using expression profiles from postmortem prefrontal cortex samples of 624 dementia patients and non-demented controls, we investigated global disruptions in the co-regulation of genes in two neurodegenerative diseases, late-onset Alzheimer's disease (AD) and Huntington's disease (HD). We identified networks of differentially co-expressed (DC) gene pairs that either gained or lost correlation in disease cases relative to the control group, with the former dominant for both AD and HD and both patterns replicating in independent human cohorts of AD and aging. When aligning networks of DC patterns and physical interactions, we identified a 242-gene subnetwork enriched for independent AD/HD signatures. This subnetwork revealed a surprising dichotomy of gained/lost correlations among two inter-connected processes, chromatin organization and neural differentiation, and included DNA methyltransferases, DNMT1 and DNMT3A, of which we predicted the former but not latter as a key regulator. To validate the inter-connection of these two processes and our key regulator prediction, we generated two brain-specific knockout (KO) mice and show that Dnmt1 KO signature significantly overlaps with the subnetwork (P = 3.1 × 10(-12)), while Dnmt3a KO signature does not (P = 0.017)

Genetic Selection for Enhanced Folding In Vivo Targets the Cys14-Cys38 Disulfide Bond in Bovine Pancreatic Trypsin Inhibitor

The periplasm provides a strongly oxidizing environment; however, periplasmic expression of proteins with disulfide bonds is often inefficient. Here, we used two different tripartite fusion systems to perform in vivo selections for mutants of the model protein bovine pancreatic trypsin inhibitor (BPTI) with the aim of enhancing its expression in Escherichia coli. This trypsin inhibitor contains three disulfides that contribute to its extreme stability and protease resistance. The mutants we isolated for increased expression appear to act by eliminating or destabilizing the Cys14-Cys38 disulfide in BPTI. In doing so, they are expected to reduce or eliminate kinetic traps that exist within the well characterized in vitro folding pathway of BPTI. These results suggest that elimination or destabilization of a disulfide bond whose formation is problematic in vitro can enhance in vivo protein folding. The use of these in vivo selections may prove a valuable way to identify and eliminate disulfides and other rate-limiting steps in the folding of proteins, including those proteins whose in vitro folding pathways are unknown. Antioxid. Redox Signal. 14, 973-984.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/90494/1/ars-2E2010-2E3712.pd

Analyzing Flow Patterns in Unsaturated Fractured Rock of Yucca Mountain Using an Integrated Modeling Approach

Abstract This paper presents a series of modeling investigations to characterize percolation patterns in the unsaturated zone of Yucca Mountain, Nevada, a proposed underground repository site for storing high-level radioactive waste. The investigations are conducted using a modeling approach that integrates a wide variety of moisture, pneumatic, thermal, and isotopic geochemical field data into a comprehensive three-dimensional numerical model through model calibration. This integrated modeling approach, based on a dualcontinuum formulation, takes into account the coupled processes of fluid and heat flow and chemical isotopic transport in Yucca Mountain's highly heterogeneous, unsaturated fractured tuffs. In particular, the model results are examined against different types of field-measured data and used to evaluate different hydrogeological conceptual models and their effects on flow patterns in the unsaturated zone. The objective of this work to provide understanding of percolation patterns and flow behavior through the unsaturated zone, which is a crucial issue in assessing repository performance. Introduction Since the 1980s, the unsaturated zone (UZ) of the highly heterogeneous, fractured tuff at Yucca Mountain, Nevada, has been investigated by the U.S. Department of Energy as a possible repository site for storing high-level radioactive waste. Characterization of flow and transport processes in fractured rock of the Yucca Mountain UZ has received significant attention and generated tremendous interest in scientific communities over the last two decades. During this long and extensive study, many types of data have been collected from the Yucca Mountain UZ, and these data have helped to develop a conceptual understanding of various physical processes within the UZ system. The complexity of geological conditions and physical processes within the Yucca Mountain has posed a tremendous challenge for site-characterization effort, while quantitative evaluation of fluid flow, chemical transport, and heat transfer has proven to be essential. The need for quantitative investigations of flow and transport at the Yucca Mountain site has motivated a continual effort in developing and applying large, mountain-scale flow and transport models [e.g., Wu et al., 1999a and The site characterization studies of the unsaturated tuff at the Nevada Test Site and at Yucca Mountain began in the late 1970s and early 1980s. Those early hydrological, geological, and geophysical investigations of Yucca Mountain and the surrounding region were conducted to assess the feasibility of the site as a geological repository for storing high-level radioactive waste and to provide conceptual understanding of UZ flow processes In the early 1990s, more progress was made in UZ model development. Wittwer et al. [1992, 1995] developed a three-dimensional (3-D) site-scale model that incorporated several geological and hydrological complexities, such as geological layering, degree of welding, fault offsets, and different matrix and fracture properties. The 3-D model handled fracture-matrix flow using an effective continuum method (ECM) and was applied to evaluate various assumptions concerning faults and infiltration patterns. Using the ECM concept, Ahlers et al. [1995a, 1995b] continued development of the UZ site-scale model with increased numerical and spatial resolution. Their studies considered more processes, such as gas and heat flow analyses, and introduced an inverse modeling approach for estimating model-input properties. However, more comprehensive UZ models were not developed until a couple of years later, when the UZ models were developed for total system performance assessment-viability assessment (TSPA-VA) [e.g., Wu et al., 1999a and The next generation of UZ models included those primarily developed for the TSPA-site recommendation (SR) calculations [e.g., Wu et al., 2002a; Moridis et al., 2003; Robinson et al., 2003]. These TSPA-SR models were enhanced from the TSPA-VA model. More 4 importantly, the newer models took into account the coupled processes of flow and transport in highly heterogeneous, unsaturated fractured porous rock, and were applied to analyzing the effect of current and future climates on radionuclide transport through the UZ system. The site-scale UZ flow and transport models developed during the site characterization of Yucca Mountain have built upon the past research as well as the above-referenced work and many other studies [e.g., McLaren et al., 2000; Robinson et al., 1996 and 1997; This paper presents the results of our continuing effort to develop a realistic and representative UZ flow model to characterize the Yucca Mountain UZ system. More specifically, we focus on analyzing unsaturated flow patterns in the Yucca Mountain UZ under various climates and different hydrogeological conceptual models using an integrated modeling approach. This effort integrates different field-observed data, such as water potential, liquid saturation, perched water, gas pressure, chloride, and temperature logs into one single 3-D UZ flow and transport model. Using the dual-permeability modeling approach, the integrated modeling effort provides consistent model predictions for different, but inter-related hydrological, pneumatical, geochemical, and geothermal processes in the UZ. More importantly, such an integrated modeling exercise will improve the model's capability and credibility in describing and predicting current and future conditions and processes of the UZ system. At the same time, the combined model calibration will present a consistent check on modeled percolation fluxes and reveal better insight into the UZ flow patterns. The modeling study of this work consists of (1) UZ model description; (2) model development and calibration using liquid saturation, water potential, perched water, and pneumatic data; (3) assessing percolation patterns and flow behavior using thermal and geochemical data; and (4) simulated percolation pattern analysis. Conceptual Model of UZ Flow Over the past two decades, extensive scientific investigations have been conducted for the site characterization of Yucca Mountain, including data collection from surface mapping, sampling from many deep and shallow boreholes, constructing underground tunnels, and field testing [e.g., Rousseau, 1998]. of faults and perched water on the UZ system. As illustrated in In fact, the PTn's capability of attenuating episodic percolation fluxes has been observed in field tests of water release into the PTn matrix In addition, the possibility for capillary barriers exists at both upper and lower PTn contacts, as well as within the PTn layers PTn layers. However, the extent of lateral flow diversion within the PTn remains a topic of debate. For example, a recent study using a conceptual model with transitional changes in rock properties argues that lateral diversion may be small Perched Water Perched water has been encountered in a number of boreholes at Yucca Mountain, including UZ-14, SD-7, SD-9, SD-12, NRG-7a, G-2, and WT-24 ( Perched water may occur where percolation flux exceeds the capacity of the geological media to transmit vertical flux in the UZ [Rousseau et al., 1998]. Several conceptual models have been investigated for explaining the genesis of perched water at Yucca Mountain [e.g., Wu et al., 1999b and Faults In addition to possible capillary and permeability barriers, major faults in the UZ are also expected to play an important role in controlling percolation flux. Permeability within faults is much higher than that in the surrounding tuff Pneumatic permeability measurements taken along portions of faults revealed low airentry pressures, indicating that large fracture apertures are present in the fault zones. Highly brecciated fault zones may act as vertical capillary barriers to lateral flow. Once water is diverted into a fault zone, however, its high permeability could facilitate rapid vertical flow through the unsaturated system Heterogeneity A considerable amount of field data, obtained from tens of boreholes, two underground tunnels, and hundreds of outcrop samples at the site, constrains the distribution of rock properties within different units. In general, field data indicate that the Yucca Mountain formation is more heterogeneous vertically than horizontally, such that layer-wise representations are found to provide reasonable approximations of the complex geological system. This is because many model calibration results using this approximation are able to match different types of observation data obtained from different locations and depths [e.g., Bandurraga and Bodvarsson, 1999; 8 In summary, as shown in Ambient water flow in the UZ system is at a quasi-steady state condition, subject to spatially varying net infiltration on the ground surface. Hydrogeological units/layers are internally homogeneous, unless interrupted by faults or altered. There may exist capillary barriers in the PTn unit, causing lateral flow. Perched water results from permeability barrier effects. Major faults serve as fast vertical flow pathways for laterally diverted flow. Numerical Modeling Approach and Model Description Because of the complexity of the UZ geological system and the highly nonlinear nature of governing equations for UZ flow and transport, numerical modeling approaches were used in this study. Numerical simulations were carried out using the TOUGH2 and T2R3D codes [Pruess, 1991; Wu et al., 1996]. Most UZ flow simulations in this study were performed using an unsaturated flow module of the TOUGH2 code, which solves Richards' equation. Two active phases (liquid and gas) and heat flow was simulated using a two-phase fluid and heat flow module. Tracer and geochemical transport runs were carried out with the T2R3D code. Numerical Model Grids There are two 3-D numerical model grids used in this study, as shown in plan view in consists of 980 mesh columns of fracture and matrix continua, 86,440 gridblocks, and 350,000 connections in a dual-permeability grid. Vertically, the thermal grid has an average of 45 computational grid layers. Modeling Fracture-Matrix Interaction Modeling fracture and matrix flow and interaction under multiphase, multicomponent, isothermal or nonisothermal conditions has been a key issue for simulating fluid and heat flow in the Yucca Mountain UZ. Different modeling approaches have been tested for handling fracture-matrix interaction at Yucca Mountain The dual-permeability methodology considers global flow and transport occurring not only between fractures but also between matrix gridblocks. In this approach, the rockvolume domain is represented by two overlapping (yet interacting) fracture and matrix 10 continua, and local fracture-matrix flow and transport is approximated as a quasi-steady state. When applied in this work, however, the traditional dual-permeability concept is first modified by using an active fracture model Model Input Parameters Since the Richards' and two-active-phases flow equations are used in modeling unsaturated flow of water and air through fracture and matrix, relative permeability and capillary pressure curves are needed for the two media. In addition, other intrinsic fracture and matrix properties are also needed, such as porosity, permeability, density, and fracture geometric parameters, as well as rock thermal properties. In our modeling study, the van Genuchten models of relative permeability and capillary pressure functions The model input parameters of fractured and matrix rock were determined by two steps: (1) using field and laboratory measurements Model Boundary Conditions The ground surface of the mountain (or the tuff-alluvium contact in the area of significant alluvial cover) is taken as the top model boundary, while the water table is treated as the bottom model boundary. For flow simulations, net infiltration is applied to fractures along the top boundary using a source term. The bottom boundary at the water table is treated as a Dirichlet-type boundary. All the lateral boundaries, as shown in Net infiltration of water, resulting from precipitation that penetrates the top-soil layer of the mountain, is the most important factor affecting the overall hydrological, geochemical and thermal-hydrological behavior of the UZ. Net infiltration is the ultimate source of groundwater recharge and deep-zone percolation through the UZ, and provides a vehicle for transporting radionuclides from the repository to the water table. To cover the various possible scenarios and uncertainties of current and future climates at Yucca Mountain, we have incorporated a total of nine net infiltration maps, provided by US Geological Survey (USGS) scientists [Hevesi and Flint, 2000; As shown in Model Calibration The complexities of the heterogeneous geological formation at the Yucca Mountain UZ, A total of 18 flow simulation scenarios are studied in this work, as listed in In these calibrations, the gas flow model uses the UZ thermal model grid Comparison of model simulation results and field-measured pneumatic data for boreholes UZ-7a is shown in Flow Patterns and Analyses The primary objective of modeling UZ flow at Yucca Mountain is to estimate percolation flux through the UZ system. This is because percolation is the most critical factor that affects overall repository performance under current and future climates. However, in situ Past studies [e.g., Wu et al., 2002a] have shown that it is very difficult even to quantify the range of percolation fluxed by using hydrological data alone. Percolation patterns inside the UZ strongly depend on infiltration rates and their spatial distribution, among other factors. Therefore, over the past two decades, significant research effort has been devoted to estimating the infiltration rates [e.g., Flint et al., 1996; Hevesi and Flint, 2000; 17 Simulated Percolation Fluxes Percolation Patterns at Repository: Percolation fluxes at the repository horizon, as predicted using 18 3-D UZ flow simulation results of Flow Pattern Analyses Simulated In this study, heat flow simulations use the 3-D thermal model grid Temperature distributions at the bottom boundary of the thermal model are taken from deep-borehole-measured temperature profiles All Cl transport simulations were run using the T2R3D code for 100,000 years to approximate the current, steady-state condition under the infiltration scenarios considered. Chloride is treated as a conservative component transported through the UZ, subject to advection, diffusion, and first-order delay. The mechanical dispersion effect through the fracture-matrix system was ignored. A constant molecular diffusion coefficient of 2.032 × 10 -9 m 2 /s is used for matrix diffusion for Cl and the half-life for radioactive decay is 301,000 years. Concluding Remarks This paper presents a large-scale modeling study to characterize percolation patterns in the unsaturated zone of Yucca Mountain, Nevada, a proposed underground repository site for storing high-level radioactive waste. The modeling studies are conducted using an integrated modeling approach, which incorporates a wide variety of field data into a This study summarizes our current research effort to characterize UZ flow patterns at Yucca Mountain. Even with the significant progress made in quantitative evaluation of UZ flow and transport processes at the site using numerical models over the last two decades, there still exist a number of limitations and shortcomings with these models and their results. In general, accuracy and reliability of UZ site-scale models and simulation results are critically dependent on the accuracy of estimated model-related properties and other types of input parameters as well as hydrogeological conceptual models. The main limitations and uncertainties with the current UZ site-scale models are (1) the lack of indepth knowledge of the mountain system (including the geological and conceptual models and the availability of field and laboratory data), and (2) the approximations of a large volume-averaged modeling approach. As a result, continual research effort is still 26 needed toward a better understanding of the Yucca Mountain UZ system

CXCR5+PD-1+ follicular helper CD8 T cells control B cell tolerance

Many autoimmune diseases are characterized by the production of autoantibodies. The current view is that CD4+ T follicular helper (Tfh) cells are the main subset regulating autoreactive B cells. Here we report a CXCR5+PD1+ Tfh subset of CD8+ T cells whose development and function are negatively modulated by Stat5. These CD8+ Tfh cells regulate the germinal center B cell response and control autoantibody production, as deficiency of Stat5 in CD8 T cells leads to an increase of CD8+ Tfh cells, resulting in the breakdown of B cell tolerance and concomitant autoantibody production. CD8+ Tfh cells share similar gene signatures with CD4+ Tfh, and require CD40L/CD40 and TCR/MHCI interactions to deliver help to B cells. Our study thus highlights the diversity of follicular T cell subsets that contribute to the breakdown of B-cell tolerance

Thrombospondin receptor α2δ-1 promotes synaptogenesis and spinogenesis via postsynaptic Rac1

Astrocytes control excitatory synaptogenesis by secreting thrombospondins (TSPs), which function via their neuronal receptor, the calcium channel subunit α2δ-1. α2δ-1 is a drug target for epilepsy and neuropathic pain; thus the TSP–α2δ-1 interaction is implicated in both synaptic development and disease pathogenesis. However, the mechanism by which this interaction promotes synaptogenesis and the requirement for α2δ-1 for connectivity of the developing mammalian brain are unknown. In this study, we show that global or cell-specific loss of α2δ-1 yields profound deficits in excitatory synapse numbers, ultrastructure, and activity and severely stunts spinogenesis in the mouse cortex. Postsynaptic but not presynaptic α2δ-1 is required and sufficient for TSP-induced synaptogenesis in vitro and spine formation in vivo, but an α2δ-1 mutant linked to autism cannot rescue these synaptogenesis defects. Finally, we reveal that TSP–α2δ-1 interactions control synaptogenesis postsynaptically via Rac1, suggesting potential molecular mechanisms that underlie both synaptic development and pathology