MicroRNAs in pulmonary arterial remodeling

Pulmonary arterial remodeling is a presently irreversible pathologic hallmark of pulmonary arterial hypertension (PAH). This complex disease involves pathogenic dysregulation of all cell types within the small pulmonary arteries contributing to vascular remodeling leading to intimal lesions, resulting in elevated pulmonary vascular resistance and right heart dysfunction. Mutations within the bone morphogenetic protein receptor 2 gene, leading to dysregulated proliferation of pulmonary artery smooth muscle cells, have been identified as being responsible for heritable PAH. Indeed, the disease is characterized by excessive cellular proliferation and resistance to apoptosis of smooth muscle and endothelial cells. Significant gene dysregulation at the transcriptional and signaling level has been identified. MicroRNAs are small non-coding RNA molecules that negatively regulate gene expression and have the ability to target numerous genes, therefore potentially controlling a host of gene regulatory and signaling pathways. The major role of miRNAs in pulmonary arterial remodeling is still relatively unknown although research data is emerging apace. Modulation of miRNAs represents a possible therapeutic target for altering the remodeling phenotype in the pulmonary vasculature. This review will focus on the role of miRNAs in regulating smooth muscle and endothelial cell phenotypes and their influence on pulmonary remodeling in the setting of PAH

Polymorphism of the Fractalkine Receptor CX3CR1 and Systemic Sclerosis-associated Pulmonary Arterial Hypertension

Fractalkine (FKN) and its receptor CX3CR1 are critical mediators in the vascular and tissue damage of several chronic diseases, including systemic sclerosis (SSc) and pulmonary arterial hypertension (PAH). Interestingly, the V249I and T280M genetic polymorphisms influence CX3CR1 expression and function. We investigated whether these polymorphisms are associated with PAH secondary to SSc. CX3CR1 genotypes were analyzed by PCR and sequencing in 76 patients with limited SSc and 204 healthy controls. PAH was defined by colorDoppler echocardiography. Homozygosity for 249II as well as the combined presence of 249II and 280MM were significantly more frequent in patients with SSc compared to controls (17 vs 6%, p = 0.0034 and 5 vs 1%, p = 0.0027, respectively). The 249I and 280M alleles were associated with PAH (odd ratio [OR] 2.2, 95% confidence interval [CI] 1.01-4.75, p = 0.028 and OR 7.37, 95%CI: 2.45-24.60, p = 0.0001, respectively). In conclusion, the increased frequencies of 249I and 280M CX3CR1 alleles in a subgroup of patients with SSc-associated PAH suggest a role for the fractalkine system in the pathogenesis of this condition. Further, the 249I allele might be associated with susceptibility to SSc

Tensile Properties of the Murine Ventral Vertical Midline Incision

In clinical surgery, the vertical midline abdominal incision is popular but associated with healing failures. A murine model of the ventral vertical midline incision was developed in order to study the healing of this incision type.The strength of the wild type murine ventral abdominal wall in the midline was contained within the dermis; the linea alba made a negligible contribution. Unwounded abdominal wall had a downward trend (nonsignificant) in maximal tension between 12 and 29 weeks of age. The incision attained 50% of its final strength by postoperative day 40. The maximal tension of the ventral vertical midline incision was nearly that of unwounded abdominal wall by postwounding day 60; there was no difference in unwounded vs. wounded maximal tension at postwounding day 120.After 120 days of healing, the ventral vertical midline incision in the wild type mouse was not significantly different from age-matched nonwounded controls. About half of the final incisional strength was attained after 6 weeks of healing. The significance of this work was to establish the kinetics of wild type incisional healing in a model for which numerous genotypes and genetic tools would be available for subsequent study

AMP-Activated Kinase Restricts Rift Valley Fever Virus Infection by Inhibiting Fatty Acid Synthesis

The cell intrinsic innate immune responses provide a first line of defense against viral infection, and often function by targeting cellular pathways usurped by the virus during infection. In particular, many viruses manipulate cellular lipids to form complex structures required for viral replication, many of which are dependent on de novo fatty acid synthesis. We found that the energy regulator AMPK, which potently inhibits fatty acid synthesis, restricts infection of the Bunyavirus, Rift Valley Fever Virus (RVFV), an important re-emerging arthropod-borne human pathogen for which there are no effective vaccines or therapeutics. We show restriction of RVFV both by AMPK and its upstream activator LKB1, indicating an antiviral role for this signaling pathway. Furthermore, we found that AMPK is activated during RVFV infection, leading to the phosphorylation and inhibition of acetyl-CoA carboxylase, the first rate-limiting enzyme in fatty acid synthesis. Activating AMPK pharmacologically both restricted infection and reduced lipid levels. This restriction could be bypassed by treatment with the fatty acid palmitate, demonstrating that AMPK restricts RVFV infection through its inhibition of fatty acid biosynthesis. Lastly, we found that this pathway plays a broad role in antiviral defense since additional viruses from disparate families were also restricted by AMPK and LKB1. Therefore, AMPK is an important component of the cell intrinsic immune response that restricts infection through a novel mechanism involving the inhibition of fatty acid metabolism

Altered mRNA expression of genes related to nerve cell activity in the fracture callus of older rats: A randomized, controlled, microarray study

BACKGROUND: The time required for radiographic union following femoral fracture increases with age in both humans and rats for unknown reasons. Since abnormalities in fracture innervation will slow skeletal healing, we explored whether abnormal mRNA expression of genes related to nerve cell activity in the older rats was associated with the slowing of skeletal repair. METHODS: Simple, transverse, mid-shaft, femoral fractures with intramedullary rod fixation were induced in anaesthetized female Sprague-Dawley rats at 6, 26, and 52 weeks of age. At 0, 0.4, 1, 2, 4, and 6 weeks after fracture, a bony segment, one-third the length of the femur, centered on the fracture site, including the external callus, cortical bone, and marrow elements, was harvested. cRNA was prepared and hybridized to 54 Affymetrix U34A microarrays (3/age/time point). RESULTS: The mRNA levels of 62 genes related to neural function were affected by fracture. Of the total, 38 genes were altered by fracture to a similar extent at the three ages. In contrast, eight neural genes showed prolonged down-regulation in the older rats compared to the more rapid return to pre-fracture levels in younger rats. Seven genes were up-regulated by fracture more in the younger rats than in the older rats, while nine genes were up-regulated more in the older rats than in the younger. CONCLUSIONS: mRNA of 24 nerve-related genes responded differently to fracture in older rats compared to young rats. This differential expression may reflect altered cell function at the fracture site that may be causally related to the slowing of fracture healing with age or may be an effect of the delayed healing

Metformin reduces liver glucose production by inhibition of fructose-1-6-bisphosphatase.

Metformin is a first-line drug for the treatment of individuals with type 2 diabetes, yet its precise mechanism of action remains unclear. Metformin exerts its antihyperglycemic action primarily through lowering hepatic glucose production (HGP). This suppression is thought to be mediated through inhibition of mitochondrial respiratory complex I, and thus elevation of 5'-adenosine monophosphate (AMP) levels and the activation of AMP-activated protein kinase (AMPK), though this proposition has been challenged given results in mice lacking hepatic AMPK. Here we report that the AMP-inhibited enzyme fructose-1,6-bisphosphatase-1 (FBP1), a rate-controlling enzyme in gluconeogenesis, functions as a major contributor to the therapeutic action of metformin. We identified a point mutation in FBP1 that renders it insensitive to AMP while sparing regulation by fructose-2,6-bisphosphate (F-2,6-P2), and knock-in (KI) of this mutant in mice significantly reduces their response to metformin treatment. We observe this during a metformin tolerance test and in a metformin-euglycemic clamp that we have developed. The antihyperglycemic effect of metformin in high-fat diet-fed diabetic FBP1-KI mice was also significantly blunted compared to wild-type controls. Collectively, we show a new mechanism of action for metformin and provide further evidence that molecular targeting of FBP1 can have antihyperglycemic effects

PRIMUS: ONE- and TWO-HALO GALACTIC CONFORMITY at 0.2 < z < 1

We test for galactic conformity at 0.2 < z < 1.0 to a projected distance of 5Mpc using spectroscopic redshifts from the PRism MUlti-object Survey (PRIMUS). Our sample consists of ∼60,000 galaxies in five separate fields covering a total of ∼5.5 square degrees, which allows us to account for cosmic variance. We identify star-forming and quiescent "isolated primary" (i.e., central) galaxies using isolation criteria and cuts in specific star formation rate. We match the redshift and stellar mass distributions of these samples to control for correlations between quiescent fraction and redshift and stellar mass. We detect a significant (σ) one-halo conformity signal, or an excess of star-forming neighbors around star-forming central galaxies, of ∼5% on scales of 0-1 Mpc and a 2.5σ two-halo signal of ∼1% on scales of 1-3 Mpc. These signals are weaker than those detected in the Sloan Digital Sky Survey and are consistent with galactic conformity being the result of large-scale tidal fields and reflecting assembly bias. We also measure the star-forming fraction of central galaxies at fixed stellar mass as a function of large-scale environment and find that central galaxies are more likely to be quenched in overdense environments, independent of stellar mass. However, we find that environment does not affect the star formation efficiency of central galaxies, as long as they are forming stars. We test for redshift and stellar mass dependence of the conformity signal within our sample and show that large volumes and multiple fields are required at intermediate redshift to adequately account for cosmic variance

PRIMUS: ONE- and TWO-HALO GALACTIC CONFORMITY at 0.2 < z < 1

We test for galactic conformity at 0.2 < z < 1.0 to a projected distance of 5Mpc using spectroscopic redshifts from the PRism MUlti-object Survey (PRIMUS). Our sample consists of ∼60,000 galaxies in five separate fields covering a total of ∼5.5 square degrees, which allows us to account for cosmic variance. We identify star-forming and quiescent "isolated primary" (i.e., central) galaxies using isolation criteria and cuts in specific star formation rate. We match the redshift and stellar mass distributions of these samples to control for correlations between quiescent fraction and redshift and stellar mass. We detect a significant (σ) one-halo conformity signal, or an excess of star-forming neighbors around star-forming central galaxies, of ∼5% on scales of 0-1 Mpc and a 2.5σ two-halo signal of ∼1% on scales of 1-3 Mpc. These signals are weaker than those detected in the Sloan Digital Sky Survey and are consistent with galactic conformity being the result of large-scale tidal fields and reflecting assembly bias. We also measure the star-forming fraction of central galaxies at fixed stellar mass as a function of large-scale environment and find that central galaxies are more likely to be quenched in overdense environments, independent of stellar mass. However, we find that environment does not affect the star formation efficiency of central galaxies, as long as they are forming stars. We test for redshift and stellar mass dependence of the conformity signal within our sample and show that large volumes and multiple fields are required at intermediate redshift to adequately account for cosmic variance

PRIMUS: EFFECTS of GALAXY ENVIRONMENT on the QUIESCENT FRACTION EVOLUTION at z < 0.8

We investigate the effects of galaxy environment on the evolution of the quiescent fraction (fQ) from z = 0.8 to 0.0 using spectroscopic redshifts and multi-wavelength imaging data from the PRIsm MUlti-object Survey (PRIMUS) and the Sloan Digital Sky Survey (SDSS). Our stellar mass limited galaxy sample consists of ∼14,000 PRIMUS galaxies within z = 0.2-0.8 and ∼64,000 SDSS galaxies within z = 0.05-0.12. We classify the galaxies as quiescent or star-forming (SF) based on an evolving specific star formation cut, and as low or high density environments based on fixed cylindrical aperture environment measurements on a volume-limited environment defining population. For quiescent and SF galaxies in low or high density environments, we examine the evolution of their stellar mass function (SMF). Then using the SMFs we compute fQ (M∗) and quantify its evolution within our redshift range. We find that the quiescent fraction is higher at higher masses and in denser environments. The quiescent fraction rises with cosmic time for all masses and environments. At a fiducial mass of 1010.5 M⊙, from z ∼ 0.7 to 0.1, the quiescent fraction rises by 15% at the lowest environments and by 25% at the highest environments we measure. These results suggest that for a minority of galaxies their cessation of star formation is due to external influences on them. In other words, in the recent universe a substantial fraction of the galaxies that cease forming stars do so due to internal processes