Effects of oxidized low density lipoprotein, lipid mediators and statins on vascular cell interactions

The integrin heterodimer CD11b/CD18 (alpha M beta 2, Mac-1, CR3) expressed on monocytes or polymorphonuclear leukocytes (PMN) is a receptor for iC3b, fibrinogen, heparin, and for intercellular adhesion molecule (ICAM)-1 on endothelium, crucially contributing to vascular cell interactions in inflammation and atherosclerosis. In this report, we summarize our findings on the effects of lipid mediators and lipid-lowering drugs. Exposure of endothelial cells to oxidized low density lipoprotein (oxLDL) induces upregulation of ICAM-1 and increases adhesion of monocytic cells expressing Mac-1. Inhibition experiments show that monocytes use distinct ligands, i.e. ICAM-1 and heparan sulfate proteoglycans for adhesion to oxLDL-treated endothelium. An albumin-transferable oxLDL activity is inhibited by the antioxidant pyrrolidine dithiocarbamate (PDTC), while 8-epi-prostaglandin F2 alpha (8-epi-PGF2 alpha) or lysophosphatidylcholine had no effect, implicating yet unidentified radicals. Sequential adhesive! and signaling events lead to the firm adhesion of rolling PMN on activated and adherent platelets, which may occupy areas of endothelial denudation. Shear resistant arrest of PMN on thrombin-stimulated platelets in flow conditions requires distinct regions of Mac-1, involving its interactions with fibrinogen bound to platelet alpha llb beta 3, and with other platelet ligands. Both arrest and adhesion strengthening under flow are stimulated by platelet-activating factor and leukotriene B4, but not by the chemokine receptor CXCR2. We tested whether Mac-1-dependent monocyte adhesiveness is affected by inhibitors of hydroxy-methylglutaryl-Coenzyme A reductase (statins) which improve morbidity and survival of patients with coronary heart disease. As compared to controls, adhesion of isolated monocytes to endothelium ex vivo was increased in patients with hypercholesterolemia. Treatment with statins decreased total and low density lipoprotein (LDL) cholesterol plasma levels, surface expression of Mac-1, and resulted in a dramatic reduction of Mac,mediated monocyte adhesion to endothelium. The inhibition of monocyte adhesion was reversed by mevalonate but not LDL in vitro,indicating that isoprenoid precursors are crucial for adhesiveness of Mac-1. Such effects may crucially contribute to the clinical benefit of statins, independent of cholesterol-lowering, and may represent a paradigm for novel, anti-inflammatory mechanisms of action by this class of drugs

Anatomical Network Comparison of Human Upper and Lower, Newborn and Adult, and Normal and Abnormal Limbs, with Notes on Development, Pathology and Limb Serial Homology vs. Homoplasy

How do the various anatomical parts (modules) of the animal body evolve into very different integrated forms (integration) yet still function properly without decreasing the individual's survival? This long-standing question remains unanswered for multiple reasons, including lack of consensus about conceptual definitions and approaches, as well as a reasonable bias toward the study of hard tissues over soft tissues. A major difficulty concerns the non-trivial technical hurdles of addressing this problem, specifically the lack of quantitative tools to quantify and compare variation across multiple disparate anatomical parts and tissue types. In this paper we apply for the first time a powerful new quantitative tool, Anatomical Network Analysis (AnNA), to examine and compare in detail the musculoskeletal modularity and integration of normal and abnormal human upper and lower limbs. In contrast to other morphological methods, the strength of AnNA is that it allows efficient and direct empirical comparisons among body parts with even vastly different architectures (e.g. upper and lower limbs) and diverse or complex tissue composition (e.g. bones, cartilages and muscles), by quantifying the spatial organization of these parts-their topological patterns relative to each other-using tools borrowed from network theory. Our results reveal similarities between the skeletal networks of the normal newborn/adult upper limb vs. lower limb, with exception to the shoulder vs. pelvis. However, when muscles are included, the overall musculoskeletal network organization of the upper limb is strikingly different from that of the lower limb, particularly that of the more proximal structures of each limb. Importantly, the obtained data provide further evidence to be added to the vast amount of paleontological, gross anatomical, developmental, molecular and embryological data recently obtained that contradicts the long-standing dogma that the upper and lower limbs are serial homologues. In addition, the AnNA of the limbs of a trisomy 18 human fetus strongly supports Pere Alberch's ill-named "logic of monsters" hypothesis, and contradicts the commonly accepted idea that birth defects often lead to lower integration (i.e. more parcellation) of anatomical structures

Functional traits and phenotypic plasticity modulate species coexistence across contrasting climatic conditions

Functional traits are expected to modulate plant competitive dynamics. However, how traits and their plasticity in response to contrasting environments connect with the mechanisms determining species coexistence remains poorly understood. Here, we couple field experiments under two contrasting climatic conditions to a plant population model describing competitive dynamics between 10 annual plant species in order to evaluate how 19 functional traits, covering physiological, morphological and reproductive characteristics, are associated with species’ niche and fitness differences. We find a rich diversity of univariate and multidimensional associations, which highlight the primary role of traits related to water- and lightuse- efficiency for modulating the determinants of competitive outcomes. Importantly, such traits and their plasticity promote species coexistence across climatic conditions by enhancing stabilizing niche differences and by generating competitive trade-offs between species. Our study represents a significant advance showing how leading dimensions of plant function connect to the mechanisms determining the maintenance of biodiversity

Ammonia-Nitrogen Recovery from Synthetic Solution using Agricultural Waste Fibers

In this study, modification of Empty Fruit Bunch (EFB) fibers as a means to recover ammonianitrogen from a synthetic solution was investigated. Methods: The EFB fiber was modified using sodium hydroxide.Adsorption-desorption studies of ammonia nitrogen into the modified EFB fiber were investigated Findings: Theincrease in adsorption capacity was found to be proportional with the increase of pH up to 7, temperature and ammoniaconcentration. The maximum adsorption capacity is 0.53-10.89 mg/g. The attachment of ammonia nitrogen involves ionexchange-chemisorption. The maximum desorption capacity of 0.0999 mg/g. Applications: This study can be used as abaseline for designing a low cost adsorbent system for ammonia nitrogen recovery drainage and industrial wastewater aswell as EFBs-palm oil mill effluent composting

QCD and strongly coupled gauge theories : challenges and perspectives

We highlight the progress, current status, and open challenges of QCD-driven physics, in theory and in experiment. We discuss how the strong interaction is intimately connected to a broad sweep of physical problems, in settings ranging from astrophysics and cosmology to strongly coupled, complex systems in particle and condensed-matter physics, as well as to searches for physics beyond the Standard Model. We also discuss how success in describing the strong interaction impacts other fields, and, in turn, how such subjects can impact studies of the strong interaction. In the course of the work we offer a perspective on the many research streams which flow into and out of QCD, as well as a vision for future developments.Peer reviewe

Endoscopic Therapy of Colonic Liver Flexure Mucocele

Colorectal mucoceles usually arise in the appendix, and colonic disease is very rare. We report the first case of a mucocele of the colonic liver flexure that was treated successfully with endoscopy. A 36-year-old man was admitted to our hospital because of abdominal distension persisting for 3 days. Colonoscopic examination revealed a round polyp in the hepatic flexure, and we performed hot snare polypectomy with argon plasma coagulation. Histologically, the polypectomy specimen was confirmed to be a mucocele, with no neoplastic changes. Follow-up examinations at 6 and 12 months showed no evidence of recurrence

The N-Myc-responsive lncRNA MILIP promotes DNA double-strand break repair through non-homologous end joining

The protooncoprotein N-Myc, which is overexpressed in approximately 25% of neuroblastomas as the consequence of MYCN gene amplification, has long been postulated to regulate DNA double-strand break (DSB) repair in neuroblastoma cells, but experimental evidence of this function is presently scant. Here, we show that N-Myc transcriptionally activates the long noncoding RNA MILIP to promote nonhomologous end-joining (NHEJ) DNA repair through facilitating Ku70–Ku80 heterodimerization in neuroblastoma cells. High MILIP expression was associated with poor outcome and appeared as an independent prognostic factor in neuroblastoma patients. Knockdown of MILIP reduced neuroblastoma cell viability through the induction of apoptosis and inhibition of proliferation, retarded neuroblastoma xenograft growth, and sensitized neuroblastoma cells to DNA-damaging therapeutics. The effect of MILIP knockdown was associated with the accumulation of DNA DSBs in neuroblastoma cells largely due to decreased activity of the NHEJ DNA repair pathway. Mechanistical investigations revealed that binding of MILIP to Ku70 and Ku80 increased their heterodimerization, and this was required for MILIP-mediated promotion of NHEJ DNA repair. Disrupting the interaction between MILIP and Ku70 or Ku80 increased DNA DSBs and reduced cell viability with therapeutic potential revealed where targeting MILIP using Gapmers cooperated with the DNA-damaging drug cisplatin to inhibit neuroblastoma growth in vivo. Collectively, our findings identify MILIP as an N-Myc downstream effector critical for activation of the NHEJ DNA repair pathway in neuroblastoma cells, with practical implications of MILIP targeting, alone and in combination with DNA-damaging therapeutics, for neuroblastoma treatment

Classification of gluteal muscle contracture in children and outcome of different treatments

<p>Abstract</p> <p>Background</p> <p>Gluteal muscle contracture (GMC) is a clinical syndrome due to multiple etiologies in which hip movements may be severely limited. The aim of this study was to propose a detailed classification of GMC and evaluate the statistical association between outcomes of different management and patient conditions.</p> <p>Methods</p> <p>One hundred fifty-eight patients, who were treated between January 1995 and December 2004, were reviewed at a mean duration of follow-up of 4.8 years. Statistical analyses were performed using X²and Fisher's exact tests.</p> <p>Results</p> <p>Non-operative management (NOM), as a primary treatment, was effective in 19 of 49 patients (38.8%), while operative management was effective in all 129 patients, with an excellence rating of 83.7% (108/129). The outcome of NOM in level I patients was significantly higher than in level II and III patients (<it>P </it>< 0.05). The results of NOM and operative management in the child group were better than the adolescent group (<it>P </it>< 0.05). Complications in level III were more than in level II.</p> <p>Conclusion</p> <p>NOM was more effective in level I patients than in level II and III patients. Operative management was effective in patients at all levels, with no statistical differences between levels or types. We recommend NOM as primary treatment for level I patients and operative management for level II and III patients. Either NOM or operative management should be carried out as early as possible.</p

An Updated Meta-Analysis of Endothelial Nitric Oxide Synthase Gene: Three Well-Characterized Polymorphisms with Hypertension

BACKGROUND: Numerous individually underpowered association studies have been conducted on endothelial nitric oxide synthase (eNOS) genetic variants across different ethnic populations, however, the results are often irreproducible. We therefore aimed to meta-analyze three eNOS widely-evaluated polymorphisms, G894T (rs1799983) in exon 7, 4b/a in intron 4, and T-786C (rs2070744) in promoter region, in association with hypertension from both English and Chinese publications, while addressing between-study heterogeneity and publication bias. METHODS: Data were analyzed using Stata software (version 11.0), and random-effects model was applied irrespective of between-study heterogeneity, which was evaluated by subgroup and meta-regression analyses. Publication bias was weighed using the Egger's test and funnel plot. RESULTS: There were total 19284/26003 cases/controls for G894T, and 6890/6858 for 4b/a, and 5346/6392 for T-786C polymorphism. Overall comparison of allele 894T with 894G in all study populations yielded a 16% increased risk for hypertension (odds ratio [OR] = 1.16; 95% confidence interval [95% CI]: 1.07-1.27; P = 0.001), and particularly a 32% increased risk (95% CI: 1.16-1.52; P<0.0005) in Asians and a 40% increased risk (95% CI: 1.19-1.65; P<0.0005) in Chinese. Further subgroup analyses suggested that published languages accounted for the heterogeneity for G894T polymorphism. The overall OR of allele 4a versus 4b was 1.29 (95% CI: 1.13-1.46; P<0.0005) in all study populations, and this estimate was potentiated in Asians (OR = 1.42; 95% CI: 1.16-1.72; P<0.0005). For T-786C, ethnicity-stratified analyses suggested a significantly increased risk for -786C allele (OR = 1.25; 95% CI: 1.06-1.47; P = 0.007) and -786CC genotype (OR = 1.69; 95% CI: 1.20-2.38; P = 0.003) in Whites. As an aside, the aforementioned risk estimates reached significance after Bonferroni correction. Finally, meta-regression analysis on other study-level covariates failed to provide any significance for all polymorphisms. CONCLUSION: We, via a comprehensive meta-analysis, ascertained the role of eNOS G894T and 4b/a polymorphisms on hypertension in Asians, and T-786C polymorphism in Whites

Functional Deficits in nNOSμ-Deficient Skeletal Muscle: Myopathy in nNOS Knockout Mice

Skeletal muscle nNOSμ (neuronal nitric oxide synthase mu) localizes to the sarcolemma through interaction with the dystrophin-associated glycoprotein (DAG) complex, where it synthesizes nitric oxide (NO). Disruption of the DAG complex occurs in dystrophinopathies and sarcoglycanopathies, two genetically distinct classes of muscular dystrophy characterized by progressive loss of muscle mass, muscle weakness and increased fatigability. DAG complex instability leads to mislocalization and downregulation of nNOSμ; but this is thought to play a minor role in disease pathogenesis. This view persists without knowledge of the role of nNOS in skeletal muscle contractile function in vivo and has influenced gene therapy approaches to dystrophinopathy, the majority of which do not restore sarcolemmal nNOSμ. We address this knowledge gap by evaluating skeletal muscle function in nNOS knockout (KN1) mice using an in situ approach, in which the muscle is maintained in its normal physiological environment. nNOS-deficiency caused reductions in skeletal muscle bulk and maximum tetanic force production in male mice only. Furthermore, nNOS-deficient muscles from both male and female mice exhibited increased susceptibility to contraction-induced fatigue. These data suggest that aberrant nNOSμ signaling can negatively impact three important clinical features of dystrophinopathies and sarcoglycanopathies: maintenance of muscle bulk, force generation and fatigability. Our study suggests that restoration of sarcolemmal nNOSμ expression in dystrophic muscles may be more important than previously appreciated and that it should be a feature of any fully effective gene therapy-based intervention