Endothelial toll-like receptor 4 maintains lung integrity via epigenetic suppression of p16INK4a.

We previously reported that the canonical innate immune receptor toll-like receptor 4 (TLR4) is critical in maintaining lung integrity. However, the molecular mechanisms via which TLR4 mediates its effect remained unclear. In the present study, we identified distinct contributions of lung endothelial cells (Ec) and epithelial cells TLR4 to pulmonary homeostasis using genetic-specific, lung- and cell-targeted in vivo methods. Emphysema was significantly prevented via the reconstituting of human TLR4 expression in the lung Ec of TLR4-/- mice. Lung Ec-silencing of TLR4 in wild-type mice induced emphysema, highlighting the specific and distinct role of Ec-expressed TLR4 in maintaining lung integrity. We also identified a previously unrecognized role of TLR4 in preventing expression of p16INK4a , a senescence-associated gene. Lung Ec-p16INK4a -silencing prevented TLR4-/- induced emphysema, revealing a new functional role for p16INK4a in lungs. TLR4 suppressed endogenous p16INK4a expression via HDAC2-mediated deacetylation of histone H4. These findings suggest a novel role for TLR4 in maintaining of lung homeostasis via epigenetic regulation of senescence-related gene expression

Coherent strong-coupling of terahertz magnons and phonons in a Van der Waals antiferromagnetic insulator

Emergent cooperative motions of individual degrees of freedom, i.e. collective excitations, govern the low-energy response of system ground states under external stimulations and play essential roles for understanding many-body phenomena in low-dimensional materials. The hybridization of distinct collective modes provides a route towards coherent manipulation of coupled degrees of freedom and quantum phases. In magnets, strong coupling between collective spin and lattice excitations, i.e., magnons and phonons, can lead to coherent quasi-particle magnon polarons. Here, we report the direct observation of a series of terahertz magnon polarons in a layered zigzag antiferromagnet FePS3 via far-infrared (FIR) transmission measurements. The characteristic avoided-crossing behavior is clearly seen as the magnon-phonon detuning is continuously changed via Zeeman shift of the magnon mode. The coupling strength g is giant, achieving 120 GHz (0.5 meV), the largest value reported so far. Such a strong coupling leads to a large ratio of g to the resonance frequency (g/{\omega}) of 4.5%, and a value of 29 in cooperativity (g^2/{\gamma}_{ph}{\gamma}_{mag}). Experimental results are well reproduced by first-principle calculations, where the strong coupling is identified to arise from phonon-modulated anisotropic magnetic interactions due to spin-orbit coupling. These findings establish FePS3 as an ideal testbed for exploring hybridization-induced topological magnonics in two dimensions and the coherent control of spin and lattice degrees of freedom in the terahertz regime

Growth Performance, Carcass Characteristics and Plasma Mineral Chemistry as Affected by Dietary Chloride and Chloride Salts Fed to Broiler Chickens Reared under Phase Feeding System

Requirements of dietary chloride (dCl) and chloride salts were determined by using 4×2 factorial arrangement under four phase feeding program. Four levels (0.31, 0.45, 0.59 and 0.73%) and two sources (NH4Cl and CaCl2) of the dCl were allocated to 1,472 chicks in eight dietary treatments in which each treatment was replicated four times with 46 birds per replicate. The four phase feeding program was comprised of four dietary phases: Prestarter (d 1 to 10), Starter (d 11 to 20), Grower (d 21 to 33) and Finisher (d 34 to 42); and diets were separately prepared for each phase. The cations, anions, pH, dissolved oxygen (DO), temperature, electrical conductivity (EC), total dissolved solids (TDS) and salinity were analyzed in drinking water and were not affected by dietary treatments. BW gain (BWG; p≤0.009) and feed:gain (FG; p≤0.03) were improved in CaCl2 supplemented diets during d 1 to 10. The maximum response of BWG and FG was observed at 0.38% and 0.42% dCl, respectively, for d 34 to 42. However, the level of dCl for BWG during d 21 to 33 (p≤0.04) and d 34 to 42 (p≤0.009) was optimized at 0.60% and 0.42%, respectively. The level of dCl for optimized feed intake (FI; p≤0.006), FG (p≤0.007) and litter moisture (LM; p≤0.001) was observed at 0.60%, 0.38% and 0.73%, respectively, for d 1 to 42. Water intake (DWI) was not affected by increasing dCl supplementation (p>0.05); however, the ratio between DWI and FI (DWI:FI) was found highest at 0.73% dCl during d 1 to 10 (p≤0.05) and d 21 to 33 (p≤0.009). Except for d 34 to 42 (p≤0.006), the increasing level of dCl did not result in a significant difference in mortality during any phase. Blood pH and glucose, and breast and thigh weights (percentage of dressed weight) were improved while dressing percentage (DP) and gastrointestinal health were exacerbated with NH4Cl as compared to CaCl2 supplemented diets (p≤0.001). Higher plasma Na+ and HCO3− and lower Cl− and Ca++ were observed in NH4Cl supplemented diets (p≤0.001). Increasing supplementation of dCl increased plasma Cl− (p≤0.04; quadratically) and linearly reduced plasma K+ (p≤0.001), Ca++ (p≤0.003), HCO3− (p≤0.001), and Na+ (p≤0.001; quadratically). Consequently, higher requirements of dietary chloride are suggested for feed intake; nevertheless, lower levels of dietary chloride are sufficient to support optimal BWG and FG with increasing age. The NH4Cl supplemented diets ameliorate breast and thigh meat yield along with overall energy balance (glucose)

Fusion of Optical Flow and Inertial Measurements for Robust Egomotion Estimation

In this paper we present a method for fusing optical flow and inertial measurements. To this end, we derive a novel visual error term which is better suited than the standard continuous epipolar constraint for extracting the information contained in the optical flow measurements. By means of an unscented Kalman filter (UKF), this information is then tightly coupled with inertial measurements in order to estimate the egomotion of the sensor setup. The individual visual landmark positions are not part of the filter state anymore. Thus, the dimensionality of the state space is significantly reduced, allowing for a fast online implementation. A nonlinear observability analysis is provided and supports the proposed method from a theoretical side. The filter is evaluated on real data together with ground truth from a motion capture system

p38 MAPK-Mediated Bmi-1 Down-Regulation and Defective Proliferation in ATM-Deficient Neural Stem Cells Can Be Restored by Akt Activation

A-T (ataxia telangiectasia) is a genetic disease caused by a mutation in the Atm (A-T mutated) gene that leads to neurodegeneration. Despite an increase in the numbers of studies in this area in recent years, the mechanisms underlying neurodegeneration in human A-T are still poorly understood. Previous studies demonstrated that neural stem cells (NSCs) isolated from the subventricular zone (SVZ) of Atm-/- mouse brains show defective self-renewal and proliferation, which is accompanied by activation of chronic p38 mitogen-activated protein kinase (MAPK) and a lower level of the polycomb protein Bmi-1. However, the mechanism underlying Bmi-1 down-regulation and its relevance to defective proliferation in Atm-/- NSCs remained unclear. Here, we show that over-expression of Bmi-1 increases self-renewal and proliferation of Atm-/- NSCs to normal, indicating that defective proliferation in Atm-/- NSCs is a consequence of down-regulation of Bmi-1. We also demonstrate that epidermal growth factor (EGF)-induced Akt phosphorylation renders Bmi-1 resistant to the proteasomal degradation, leading to its stabilization and accumulation in the nucleus. However, inhibition of the Akt-dependent Bmi-1 stabilizing process by p38 MAPK signaling reduces the levels of Bmi-1. Treatment of the Atm-/- NSCs with a specific p38 MAPK inhibitor SB203580 extended Bmi-1 posttranscriptional turnover and H2A ubiquitination in Atm-/- NSCs. Our observations demonstrate the molecular basis underlying the impairment of self-renewal and proliferation in Atm-/- NSCs through the p38 MAPK-Akt-Bmi-1-p21 signaling pathway

Adipose energy stores, physical work, and the metabolic syndrome: lessons from hummingbirds

Hummingbirds and other nectar-feeding, migratory birds possess unusual adaptive traits that offer important lessons concerning obesity, diabetes and the metabolic syndrome. Hummingbirds consume a high sugar diet and have fasting glucose levels that would be severely hyperglycemic in humans, yet these nectar-fed birds recover most glucose that is filtered into the urine. Hummingbirds accumulate over 40% body fat shortly before migrations in the spring and autumn. Despite hyperglycemia and seasonally elevated body fat, the birds are not known to become diabetic in the sense of developing polyuria (glucosuria), polydipsia and polyphagia. The tiny (3–4 g) Ruby-throated hummingbird has among the highest mass-specific metabolic rates known, and loses most of its stored fat in 20 h by flying up to 600 miles across the Gulf of Mexico. During the breeding season, it becomes lean and maintains an extremely accurate energy balance. In addition, hummingbirds can quickly enter torpor and reduce resting metabolic rates by 10-fold. Thus, hummingbirds are wonderful examples of the adaptive nature of fat tissue, and may offer lessons concerning prevention of metabolic syndrome in humans

Epigenetic inactivation of the NORE1 gene correlates with malignant progression of colorectal tumors

<p>Abstract</p> <p>Background</p> <p>NORE1 (RASSF5) is a newly described member of the RASSF family with Ras effector function. <it>NORE1 </it>expression is frequently inactivated by aberrant promoter hypermethylation in many human cancers, suggesting that NORE1 might be a putative tumor suppressor. However, expression and mutation status of <it>NORE1 </it>and its implication in colorectal tumorigenesis has not been evaluated.</p> <p>Methods</p> <p>Expression, mutation, and methylation status of <it>NORE1A </it>and <it>NORE1B </it>in 10 cancer cell lines and 80 primary tumors were characterized by quantitative PCR, SSCP, and bisulfite DNA sequencing analyses. Effect of NORE1A and NORE1B expression on tumor cell growth was evaluated using cell number counting, flow cytometry, and colony formation assays.</p> <p>Results</p> <p>Expression of <it>NORE1A </it>and <it>NORE1B </it>transcript was easily detectable in all normal colonic epithelial tissues, but substantially decreased in 7 (70%) and 4 (40%) of 10 cancer cell lines and 31 (38.8%) and 25 (31.3%) of 80 primary carcinoma tissues, respectively. Moreover, 46 (57.6%) and 38 (47.5%) of 80 matched tissue sets exhibited tumor-specific reduction of <it>NORE1A </it>and <it>NORE1B</it>, respectively. Abnormal reduction of <it>NORE1 </it>was more commonly observed in advanced stage and high grade tumors compared to early and low grade tumors. While somatic mutations of the gene were not identified, its expression was re-activated in all low expressor cells after treatment with the demethylating agent 5-aza-dC. Bisulfite DNA sequencing analysis of 31 CpG sites within the promoter region demonstrated that abnormal reduction of <it>NORE1A </it>is tightly associated with promoter CpG sites hypermethylation. Moreover, transient expression and siRNA-mediated knockdown assays revealed that both NORE1A and NORE1B decrease cellular growth and colony forming ability of tumor cells and enhance tumor cell response to apoptotic stress.</p> <p><b>Conclusion</b></p> <p>Our data indicate that epigenetic inactivation of <it>NORE1 </it>due to aberrant promoter hypermethylation is a frequent event in colorectal tumorigenesis and might be implicated in the malignant progression of colorectal tumors.</p

Co-Regulation of the DAF-16 Target Gene, cyp-35B1/dod-13, by HSF-1 in C. elegans Dauer Larvae and daf-2 Insulin Pathway Mutants

Insulin/IGF-I-like signaling (IIS) has both cell autonomous and non-autonomous functions. In some cases, targets through which IIS regulates cell-autonomous functions, such as cell growth and metabolism, have been identified. In contrast, targets for many non-autonomous IIS functions, such as C. elegans dauer morphogenesis, remain elusive. Here, we report the use of genomic and genetic approaches to identify potential non-autonomous targets of C. elegans IIS. First, we used transcriptional microarrays to identify target genes regulated non-autonomously by IIS in the intestine or in neurons. C. elegans IIS controls expression of a number of stress response genes, which were differentially regulated by tissue-restricted IIS. In particular, expression of sod-3, a MnSOD enzyme, was not regulated by tissue-restricted IIS on the microarrays, while expression of hsp-16 genes was rescued back to wildtype by tissue restricted IIS. One IIS target regulated non-autonomously by age-1 was cyp-35B1/dod-13, encoding a cytochrome P450. Genetic analysis of the cyp-35B1 promoter showed both DAF-16 and HSF-1 are direct regulators. Based on these findings, we propose that hsf-1 may participate in the pathways mediating non-autonomous activities of age-1 in C. elegans