Phosphorylation of the liver X receptors

AbstractThe liver X receptors (LXRs) function as nutritional sensors for cholesterol and have important roles in lipid metabolism, glucose homeostasis, and inflammation. We provide the first evidence that LXRs are phosphorylated proteins. Mutational analysis and metabolic labeling indicate LXRα is phosphorylated on serine 198 in the hinge region. This is a consensus target for the MAPK family. A phosphorylation-deficient mutant, LXRα S198A, remains nuclear and responds to ligands like the wild-type protein. The biological significance of LXR phosphorylation remains to be elucidated but could provide a novel mechanism for the regulation of LXR signaling pathways and cellular metabolism

Magnetic Field Amplification and Flat Spectrum Radio Quasars

We perform time-dependent, spatially-resolved simulations of blazar emission to evaluate several flaring scenarios related to magnetic-field amplification and enhanced particle acceleration. The code explicitly accounts for light-travel-time effects and is applied to flares observed in the flat spectrum radio quasar (FSRQ) PKS 0208-512, which show optical/{\gamma}-ray correlation at some times, but orphan optical flares at other times. Changes in both the magnetic field and the particle acceleration efficiency are explored as causes of flares. Generally, external Compton emission appears to describe the available data better than a synchrotron self-Compton scenario, and in particular orphan optical flares are difficult to produce in the SSC framework. X-ray soft-excesses, {\gamma}-ray spectral hardening, and the detections at very high energies of certain FSRQs during flares find natural explanations in the EC scenario with particle acceleration change. Likewise, optical flares with/without {\gamma}-ray counterparts can be explained by different allocations of energy between the magnetization and particle acceleration, which may be related to the orientation of the magnetic field relative to the jet flow. We also calculate the degree of linear polarization and polarization angle as a function of time for a jet with helical magnetic field. Tightening of the magnetic helix immediately downstream of the jet perturbations, where flares occur, can be sufficient to explain the increases in the degree of polarization and a rotation by >= 180 degree of the observed polarization angle, if light-travel-time effects are properly considered.Comment: 12 pages, 9 figures. Accepted for publication in MNRA

High-Throughput Drug Screening Identifies a Potent Wnt Inhibitor that Promotes Airway Basal Stem Cell Homeostasis.

Mechanisms underpinning airway epithelial homeostatic maintenance and ways to prevent its dysregulation remain elusive. Herein, we identify that β-catenin phosphorylated at Y489 (p-β-cateninY489) emerges during human squamous lung cancer progression. This led us to develop a model of airway basal stem cell (ABSC) hyperproliferation by driving Wnt/β-catenin signaling, resulting in a morphology that resembles premalignant lesions and loss of ciliated cell differentiation. To identify small molecules that could reverse this process, we performed a high-throughput drug screen for inhibitors of Wnt/β-catenin signaling. Our studies unveil Wnt inhibitor compound 1 (WIC1), which suppresses T-cell factor/lymphoid enhancer-binding factor (TCF/LEF) activity, reduces ABSC proliferation, induces ciliated cell differentiation, and decreases nuclear p-β-cateninY489. Collectively, our work elucidates a dysregulated Wnt/p-β-cateninY489 axis in lung premalignancy that can be modeled in vitro and identifies a Wnt/β-catenin inhibitor that promotes airway homeostasis. WIC1 may therefore serve as a tool compound in regenerative medicine studies with implications for restoring normal airway homeostasis after injury

The VWFA Is the Home of Orthographic Learning When Houses Are Used as Letters

Learning to read specializes a portion of the left mid-fusiform cortex for printed word recognition, the putative visual word form area (VWFA). This study examined whether a VWFA specialized for English is sufficiently malleable to support learning a perceptually atypical second writing system. The study utilized an artificial orthography, HouseFont, in which house images represent English phonemes. House images elicit category-biased activation in a spatially distinct brain region, the so-called parahippocampal place area (PPA). Using house images as letters made it possible to test whether the capacity for learning a second writing system involves neural territory that supports reading in the first writing system, or neural territory tuned for the visual features of the new orthography. Twelve human adults completed two weeks of training to establish basic HouseFont reading proficiency and underwent functional neuroimaging pre and post-training. Analysis of three functionally defined regions of interest (ROIs), the VWFA, and left and right PPA, found significant pre-training versus post-training increases in response to HouseFont words only in the VWFA. Analysis of the relationship between the behavioral and neural data found that activation changes from pre-training to post-training within the VWFA predicted HouseFont reading speed. These results demonstrate that learning a new orthography utilizes neural territory previously specialized by the acquisition of a native writing system. Further, they suggest VWFA engagement is driven by orthographic functionality and not the visual characteristics of graphemes, which informs the broader debate about the nature of category-specialized areas in visual association cortex

Chloride channels regulate differentiation and barrier functions of the mammalian airway.

The conducting airway forms a protective mucosal barrier and is the primary target of airway disorders. The molecular events required for the formation and function of the airway mucosal barrier, as well as the mechanisms by which barrier dysfunction leads to early onset airway diseases, remain unclear. In this study, we systematically characterized the developmental landscape of the mouse airway using single-cell RNA sequencing and identified remarkably conserved cellular programs operating during human fetal development. We demonstrated that in mouse, genetic inactivation of chloride channel Ano1/Tmem16a compromises airway barrier function, results in early signs of inflammation, and alters the airway cellular landscape by depleting epithelial progenitors. Mouse Ano1-/-mutants exhibited mucus obstruction and abnormal mucociliary clearance that resemble the airway defects associated with cystic fibrosis. The data reveal critical and non-redundant roles for Ano1 in organogenesis, and show that chloride channels are essential for mammalian airway formation and function

“Choking Under Pressure” in Older Drivers

Aging can impair executive control and emotion regulation, affecting driver decision-making and behavior, especially under stress. We used an interactive driving simulator to investigate ability to make safe left-turns across oncoming traffic under pressure in 13 older (\u3e 65 years old) and 16 middle-aged (35-56 years old) drivers. Drivers made left-turns at an uncontrolled intersection with moderately heavy oncoming traffic. Gaps between oncoming vehicles varied and increased gradually from 2 s to 10 s. Drivers made two left-turns with a vehicle honking aggressively behind (pressure condition), and two left-turns without the honking vehicle (control condition). Results showed that middle-aged drivers made more cautious turning decisions under pressure (by waiting for larger and safer gaps, p \u3c .001), but older drivers did not. Further, older driver turning paths deviated under pressure compared to the control condition (p \u3c .05), but the middle-aged group did not. Moreover, across all subjects, better executive function was significantly correlated with larger increases of accepted gap size from control to honking (p \u3c .01). The findings suggest that older drivers are more sensitive to traffic challenges from environmental pressure and that neural models of older driver performance and safety must factor in age-related changes in executive control and emotion processing

Synchronization modulation increases transepithelial potentials in MDCK monolayers through Na/K pumps

Peer reviewedPublisher PD

mHealth Series: Text messaging data collection of infant and young child feeding practice in rural China – a feasibility study

Face–to–face interviews by trained field workers are commonly used in household surveys. However, this data collection method is labor–intensive, time–consuming, expensive, prone to interviewer and recall bias and not easily scalable to increase sample representativeness. The study explored the feasibility of using text messaging to collect information on infant and young child feeding practice in rural China

Neuropsychological Predictors of Safety in Urban Left-Turn Scenarios

Left turns at urban intersections can be dangerous, especially when views are obstructed or pedestrians are present. Impairments in driver vision, motor, and cognition functions may further increase left-turn risk. We examined this problem in a simulated environment that included left-turn scenarios to study the driving behaviors of 28 drivers, ages 37 to 88 years, six of whom had “Useful Field of View” (UFOV) impairments. Subjects also completed a battery of neuropsychological tests. The simulated drive included an urban section with six left turns in three types of scenarios: 1) a semi truck blocking the view of oncoming traffic, 2) a lead vehicle obstruction, and 3) a pedestrian crossing ahead of the turning driver. Results showed a mean (SD) of 1.46 (1.60) collisions per driver (range 0 to 7), 83% of which occurred at intersections with semi trucks. Far visual acuity, contrast sensitivity, UFOV, Mini Mental State Examination, TrailMaking Test Part B, the Wisconsin Card Sort task, and age were all associated with the total number of collisions (Pearson correlation magnitudes between 0.37 to 0.77; p-values\u3c0.05). Spearman correlations were less significant. Findings indicate that visual obstruction by on oncoming semi-truck is a particularly dangerous left-turn situation

Phosphoantigen/IL2 Expansion and Differentiation of Vγ2Vδ2 T Cells Increase Resistance to Tuberculosis in Nonhuman Primates

Dominant Vγ2Vδ2 T-cell subset exist only in primates, and recognize phosphoantigen from selected pathogens including M. tuberculosis(Mtb). In vivo function of Vγ2Vδ2 T cells in tuberculosis remains unknown. We conducted mechanistic studies to determine whether earlier expansion/differentiation of Vγ2Vδ2 T cells during Mtb infection could increase immune resistance to tuberculosis in macaques. Phosphoantigen/IL-2 administration specifically induced major expansion and pulmonary trafficking/accumulation of phosphoantigen-specific Vγ2Vδ2 T cells, significantly reduced Mtb burdens and attenuated tuberculosis lesions in lung tissues compared to saline/BSA or IL-2 controls. Expanded Vγ2Vδ2 T cells differentiated into multifunctional effector subpopulations capable of producing anti-TB cytokines IFNγ, perforin and granulysin, and co-producing perforin/granulysin in lung tissue. Mechanistically, perforin/granulysin-producing Vγ2Vδ2 T cells limited intracellular Mtb growth, and macaque granulysin had Mtb-bactericidal effect, and inhibited intracellular Mtb in presence of perforin. Furthermore, phosphoantigen/IL2-expanded Vγ2Vδ2 T effector cells produced IL-12, and their expansion/differentiation led to enhanced pulmonary responses of peptide-specific CD4+/CD8+ Th1-like cells. These results provide first in vivo evidence implicating that early expansion/differentiation of Vγ2Vδ2 T effector cells during Mtb infection increases resistance to tuberculosis. Thus, data support a rationale for conducting further studies of the γδ T-cell-targeted treatment of established TB, which might ultimately help explore single or adjunctive phosphoantigen expansion of Vγ2Vδ2 T-cell subset as intervention of MDR-tuberculosis or HIV-related tuberculosis