Substrate stiffness regulates primary hepatocyte functions†

Liver fibrosis occurs as a consequence of chronic injuries from viral infections, metabolic disorders, and alcohol abuse. Fibrotic liver microenvironment (LME) is characterized by excessive deposition and aberrant turnover of extracellular matrix proteins, which leads to increased tissue stiffness. Liver stiffness acts as a vital cue in the regulation of hepatic responses in both healthy and diseased states; however, the effect of varying stiffness on liver cells is not well understood. There is a critical need to engineer in vitro models that mimic the liver stiffness corresponding to various stages of disease progression in order to elucidate the role of individual cellular responses. Here we employed polydimethyl siloxane (PDMS) based substrates with tunable mechanical properties to investigate the effect of substrate stiffness on the behavior of primary rat hepatocytes. To recreate physiologically relevant stiffness, we designed soft substrates (2 kPa) to represent the healthy liver and stiff substrates (55 kPa) to represent the diseased liver. Tissue culture plate surface (TCPS) served as the control substrate. We observed that hepatocytes cultured on soft substrates displayed a more differentiated and functional phenotype for a longer duration as compared to stiff substrates and TCPS. We demonstrated that hepatocytes on soft substrates exhibited higher urea and albumin synthesis. Cytochrome P450 (CYP) activity, another critical marker of hepatocytes, displayed a strong dependence on substrate stiffness, wherein hepatocytes on soft substrates retained 2.7 fold higher CYP activity on day 7 in culture, as compared to TCPS. We further observed that an increase in stiffness induced downregulation of key drug transporter genes (NTCP, UGT1A1, and GSTM-2). In addition, we observed that the epithelial cell phenotype was better maintained on soft substrates as indicated by higher expression of hepatocyte nuclear factor 4α, cytokeratin 18, and connexin 32. These results indicate that the substrate stiffness plays a significant role in modulating hepatocyte behavior. Our PDMS based liver model can be utilized to investigate the signaling pathways mediating the hepatocyte-LME communication to understand the progression of liver diseases

Brownian Thermal Noise in Multilayer Coated Mirrors

We analyze the Brownian thermal noise of a multi-layer dielectric coating, used in high-precision optical measurements including interferometric gravitational-wave detectors. We assume the coating material to be isotropic, and therefore study thermal noises arising from shear and bulk losses of the coating materials. We show that coating noise arises not only from layer thickness fluctuations, but also from fluctuations of the interface between the coating and substrate, driven by internal fluctuating stresses of the coating. In addition, the non-zero photoeleastic coefficients of the thin films modifies the influence of the thermal noise on the laser field. The thickness fluctuations of different layers are statistically independent, however, there exists a finite coherence between layers and the substrate-coating interface. Taking into account uncertainties in material parameters, we show that significant uncertainties still exist in estimating coating Brownian noise.Comment: 26 pages, 18 figure

Compromised vertebral structural and mechanical properties associated with progressive kidney disease and the effects of traditional pharmacological interventions

BACKGROUND/AIMS: Patients with chronic kidney disease mineral and bone disorder (CKD-MBD) have a significantly higher vertebral and non-vertebral fracture risk than the general population. Several preclinical models have documented altered skeletal properties in long bones, but few data exist for vertebral bone. The goal of this study was to examine the effects of progressive CKD on vertebral bone structure and mechanics and to determine the effects of treatment with either bisphosphonates or anti-sclerostin antibody in groups of animals with high or low PTH. METHODS: Animals with progressive kidney disease were left untreated, treated with calcium to lower PTH, zoledronic acid to lower remodeling without affecting PTH, anti-sclerostin antibody, or anti-sclerostin antibody plus calcium. Non-diseased, untreated littermates served as controls. Vertebral bone morphology (trabecular and cortical) and mechanical properties (structural and material-level) were assessed at 35 weeks of age by microCT and mechanical testing, respectively. RESULTS: CKD with high PTH resulted in 6-fold higher bone formation rate, significant reductions in the amount of trabecular and cortical bone, and compromised whole bone mechanical properties in the vertebra compared to normal animals. Treatments that reduced bone remodeling were effective in normalizing vertebral structure and mechanical properties only if the treatment reduced serum PTH. Similarly, treatment with anti-sclerostin antibody was effective in enhancing bone mass and mechanical properties but only if combined with PTH-suppressive treatment. CONCLUSIONS: CKD significantly altered both cortical and trabecular bone properties in the vertebra resulting in compromised mechanical properties and these changes can be normalized by interventions that involve reductions in PTH levels

Comparative Signature-Tagged Mutagenesis Identifies Pseudomonas Factors Conferring Resistance to the Pulmonary Collectin SP-A

The pulmonary collectin, surfactant protein A (SP-A), is a broad spectrum opsonin with microbicidal membrane permeabilization properties that plays a role in the innate immune response of the lung. However, the factors that govern SP-A's microbial specificity and the mechanisms by which it mediates membrane permeabilization and opsonization are not fully understood. In an effort to identify bacterial factors that confer susceptibility or resistance to SP-A, we used comparative signature-tagged mutagenesis to screen a library of 1,680 Pseudomonas aeruginosa mutants for evidence of differential pulmonary clearance in SP-A-sufficient (SP-A(+/+)) and SP-A-deficient (SP-A(−/−)) mice. Two SP-A-sensitive P. aeruginosa mutants harboring transposon insertions in genes required for salicylate biosynthesis (pch) and phosphoenolpyruvate-protein-phosphotransferase (ptsP) were recovered. The mutants were indistinguishable from the parental wild-type PA01 with regard to opsonization by SP-A, but they exhibited increased susceptibility to SP-A-mediated membrane permeabilization. These results suggest that bacterial gene functions that are required to maintain membrane integrity play crucial roles in resistance of P. aeruginosa to the permeabilizing effects of SP-A

Late Cenozoic evolution of the eastern margin of the Tibetan Plateau: Inferences from ^(40)Ar/^(39)Ar and (U-Th)/He thermochronology

High topography in central Asia is perhaps the most fundamental expression of the Cenozoic Indo-Asian collision, yet an understanding of the timing and rates of development of the Tibetan Plateau remains elusive. Here we investigate the Cenozoic thermal histories of rocks along the eastern margin of the plateau adjacent to the Sichuan Basin in an effort to determine when the steep topographic escarpment that characterizes this margin developed. Temperature-time paths inferred from ^(40)Ar/^(39)Ar thermochronology of biotite, multiple diffusion domain modeling of alkali feldspar ^(40)Ar release spectra, and (U-Th)/He thermochronology of zircon and apatite imply that rocks at the present-day topographic front of the plateau underwent slow cooling (30°–50°C/m.y.) coincident with exhumation from inferred depths of ∼8–10 km, at denudation rates of 1–2 mm/yr. Samples from the interior of the plateau continued to cool relatively slowly during the same time period (∼3°C/m.y.), suggesting limited exhumation (1–2 km). However, these samples record a slight increase in cooling rate (from <1 to ∼3°C/m.y.) at some time during the middle Tertiary; the tectonic significance of this change remains uncertain. Regardless, late Cenozoic denudation in this region appears to have been markedly heterogeneous, with the highest rates of exhumation focused at the topographic front of the plateau margin. We infer that the onset of rapid cooling at the plateau margin reflects the erosional response to the development of regionally significant topographic gradients between the plateau and the stable Sichuan Basin and thus marks the onset of deformation related to the development of the Tibetan Plateau in this region. The present margin of the plateau adjacent to and north of the Sichuan Basin is apparently no older than the late Miocene or early Pliocene (∼5–12 Ma)

Hamiltonian lattice QCD at finite chemical potential

At sufficiently high temperature and density, quantum chromodynamics (QCD) is expected to undergo a phase transition from the confined phase to the quark-gluon plasma phase. In the Lagrangian lattice formulation the Monte Carlo method works well for QCD at finite temperature, however, it breaks down at finite chemical potential. We develop a Hamiltonian approach to lattice QCD at finite chemical potential and solve it in the case of free quarks and in the strong coupling limit. At zero temperature, we calculate the vacuum energy, chiral condensate, quark number density and its susceptibility, as well as mass of the pseudoscalar, vector mesons and nucleon. We find that the chiral phase transition is of first order, and the critical chemical potential is $\mu_C =m_{dyn}^{(0)}$ (dynamical quark mass at $\mu=0$). This is consistent with $\mu_C \approx M_N^{(0)}/3$ (where $M_N^{(0)}$ is the nucleon mass at $\mu=0$).Comment: Final version appeared in Phys. Rev.

Galaxies Associated with z~4 Damped Lya Systems: I. Imaging and Photometric Selection

This paper describes the acquisition and analysis of imaging data for the identification of galaxies associated with z~4 damped Lya systems. We present deep BRI images of three fields known to contain four z~4 damped systems. We discuss the reduction and calibration of the data, detail the color criteria used to identify z~4 galaxies, and present a photometric redshift analysis to complement the color selection. We have found no galaxy candidates closer to the QSO than 7'' which could be responsible for the damped Lya systems. Assuming that at least one of the galaxies is not directly beneath the QSO, we set an upper limit on this damped Lya system of L < L*/4. Finally, we have established a web site to release these imaging data to the public.Comment: 12 pages, 6 embedded figures (3 color), 9 jpg figures. Higher quality ps versions of the images and the fits data are available at http://kingpin.ucsd.edu/~dlaimg, Accepted to the Astronomical Journal Jan 22, 200

Coulomb interactions at quantum Hall critical points of systems in a periodic potential

We study the consequences of long-range Coulomb interactions at the critical points between integer/fractional quantum Hall states and an insulator. We use low energy theories for such transitions in anyon gases in the presence of an external periodic potential. We find that Coulomb interactions are marginally irrelevant for the integer quantum Hall case. For the fractional case, depending upon the anyon statistics parameter, we find behavior similar to the integer case, or flow to a novel line of fixed points with exponents $z=1$, $\nu > 1$ stable against weak disorder in the position of the critical point, or run-away flow to strong coupling.Comment: 12 pages, REVTEX, 1 figur

Ferromagnetism in Diluted Magnetic Semiconductor Heterojunction Systems

Diluted magnetic semiconductors (DMSs), in which magnetic elements are substituted for a small fraction of host elements in a semiconductor lattice, can become ferromagnetic when doped. In this article we discuss the physics of DMS ferromagnetism in systems with semiconductor heterojunctions. We focus on the mechanism that cause magnetic and magnetoresistive properties to depend on doping profiles, defect distributions, gate voltage, and other system parameters that can in principle be engineered to yield desired results.Comment: 12 pages, 7 figures, review, special issue of Semicon. Sci. Technol. on semiconductor spintronic

Characterization of soluble bromide measurements and a case study of BrO observations during ARCTAS

A focus of the Arctic Research of the Composition of the Troposphere from Aircraft and Satellites (ARCTAS) mission was examination of bromine photochemistry in the spring time high latitude troposphere based on aircraft and satellite measurements of bromine oxide (BrO) and related species. The NASA DC-8 aircraft utilized a chemical ionization mass spectrometer (CIMS) to measure BrO and a mist chamber (MC) to measure soluble bromide. We have determined that the MC detection efficiency to molecular bromine (Br2), hypobromous acid (HOBr), bromine oxide (BrO), and hydrogen bromide (HBr) as soluble bromide (Br−) was 0.9±0.1, 1.06+0.30/−0.35, 0.4±0.1, and 0.95±0.1, respectively. These efficiency factors were used to estimate soluble bromide levels along the DC-8 flight track of 17 April 2008 from photochemical calculations constrained to in situ BrO measured by CIMS. During this flight, the highest levels of soluble bromide and BrO were observed and atmospheric conditions were ideal for the space-borne observation of BrO. The good agreement (R2 = 0.76; slope = 0.95; intercept = −3.4 pmol mol−1) between modeled and observed soluble bromide, when BrO was above detection limit (\u3e2 pmol mol−1) under unpolluted conditions (NOmol−1), indicates that the CIMS BrO measurements were consistent with the MC soluble bromide and that a well characterized MC can be used to derive mixing ratios of some reactive bromine compounds. Tropospheric BrO vertical column densities (BrOVCD) derived from CIMS BrO observations compare well with BrOTROPVCD from OMI on 17 April 2008