Binding of molecules to DNA and other semiflexible polymers

A theory is presented for the binding of small molecules such as surfactants to semiflexible polymers. The persistence length is assumed to be large compared to the monomer size but much smaller than the total chain length. Such polymers (e.g. DNA) represent an intermediate case between flexible polymers and stiff, rod-like ones, whose association with small molecules was previously studied. The chains are not flexible enough to actively participate in the self-assembly, yet their fluctuations induce long-range attractive interactions between bound molecules. In cases where the binding significantly affects the local chain stiffness, those interactions lead to a very sharp, cooperative association. This scenario is of relevance to the association of DNA with surfactants and compact proteins such as RecA. External tension exerted on the chain is found to significantly modify the binding by suppressing the fluctuation-induced interaction.Comment: 15 pages, 7 figures, RevTex, the published versio

Sputum RNA signature in allergic asthmatics following allergen bronchoprovocation test

Background: Inhaled allergen challenge is a validated disease model of allergic asthma offering useful pharmacodynamic assessment of pharmacotherapeutic effects in a limited number of subjects. Objectives: To evaluate whether an RNA signature can be identified from induced sputum following an inhaled allergen challenge, whether a RNA signature could be modulated by limited doses of inhaled fluticasone, and whether these gene expression profiles would correlate with the clinical endpoints measured in this study. Methods: Thirteen non-smoking, allergic subjects with mild-to-moderate asthma participated in a randomised, placebo-controlled, 2-period cross-over study following a single-blind placebo run-in period. Each period consisted of three consecutive days, separated by a wash-out period of at least 3 weeks. Subjects randomly received inhaled fluticasone ((FP) MDI; 500 mcg BID×5 doses in total) or placebo. On day 2, house dust mite extract was inhaled and airway response was measured by FEV1 at predefined time points until 7 h post-allergen. Sputum was induced by NaCl 4.5%, processed and analysed at 24 h pre-allergen and 7 and 24 h post-allergen. RNA was isolated from eligible sputum cell pellets (<80% squamous of 500 cells), amplified according to NuGEN technology, and profiled on Affymetrix arrays. Gene expression changes from baseline and fluticasone treatment effects were evaluated using a mixed effects ANCOVA model at 7 and at 24 h post-allergen challenge. Results: Inhaled allergen-induced statistically significant gene expression changes in sputum, which were effectively blunted by fluticasone (adjusted p<0.025). Forty-seven RNA signatures were selected from these responses for correlation analyses and further validation. This included Th2 mRNA levels for cytokines, chemokines, high-affinity IgE receptor FCER1A, histamine receptor HRH4, and enzymes and receptors in the arachidonic pathway. Individual messengers from the 47 RNA signatures correlated significantly with lung function and sputum eosinophil counts. Conclusion: Our RNA extraction and profiling protocols allowed reproducible assessments of inflammatory signatures in sputum including quantification of drug effects on this response in allergic asthmatics. This approach offers novel possibilities for the development of pharmacodynamic (PD) biomarkers in asthma

Immune modulation via T regulatory cell enhancement:Disease-modifying therapies for autoimmunity and their potential for chronic allergic and inflammatory diseases-An EAACI position paper of the Task Force on Immunopharmacology (TIPCO)

Therapeutic advances using targeted biologicals and small-molecule drugs have achieved significant success in the treatment of chronic allergic, autoimmune, and inflammatory diseases particularly for some patients with severe, treatment-resistant forms. This has been aided by improved identification of disease phenotypes. Despite these achievements, not all severe forms of chronic inflammatory and autoimmune diseases are successfully targeted, and current treatment options, besides allergen immunotherapy for selected allergic diseases, fail to change the disease course. T cell–based therapies aim to cure diseases through the selective induction of appropriate immune responses following the delivery of engineered, specific cytotoxic, or regulatory T cells (Tregs). Adoptive cell therapies (ACT) with genetically engineered T cells have revolutionized the oncology field, bringing curative treatment for leukemia and lymphoma, while therapies exploiting the suppressive functions of Tregs have been developed in nononcological settings, such as in transplantation and autoimmune diseases. ACT with Tregs are also being considered in nononcological settings such as cardiovascular disease, obesity, and chronic inflammatory disorders. After describing the general features of T cell–based approaches and current applications in autoimmune diseases, this position paper reviews the experimental models testing or supporting T cell–based approaches, especially Treg-based approaches, in severe IgE-mediated responses and chronic respiratory airway diseases, such as severe asthma and COPD. Along with an assessment of challenges and unmet needs facing the application of ACT in these settings, this article underscores the potential of ACT to offer curative options for patients with severe or treatment-resistant forms of these immune-driven disorders

Metabolic pathways in immune senescence and inflammaging: Novel therapeutic strategy for chronic inflammatory lung diseases. An EAACI position paper from the Task Force for Immunopharmacology

The accumulation of senescent cells drives inflammaging and increases morbidity of chronic inflammatory lung diseases. Immune responses are built upon dynamic changes in cell metabolism that supply energy and substrates for cell proliferation, differentiation, and activation. Metabolic changes imposed by environmental stress and inflammation on immune cells and tissue microenvironment are thus chiefly involved in the pathophysiology of allergic and other immune‐driven diseases. Altered cell metabolism is also a hallmark of cell senescence, a condition characterized by loss of proliferative activity in cells that remain metabolically active. Accelerated senescence can be triggered by acute or chronic stress and inflammatory responses. In contrast, replicative senescence occurs as part of the physiological aging process and has protective roles in cancer surveillance and wound healing. Importantly, cell senescence can also change or hamper response to diverse therapeutic treatments. Understanding the metabolic pathways of senescence in immune and structural cells is therefore critical to detect, prevent, or revert detrimental aspects of senescence‐related immunopathology, by developing specific diagnostics and targeted therapies. In this paper, we review the main changes and metabolic alterations occurring in senescent immune cells (macrophages, B cells, T cells). Subsequently, we present the metabolic footprints described in translational studies in patients with chronic asthma and chronic obstructive pulmonary disease (COPD), and review the ongoing preclinical studies and clinical trials of therapeutic approaches aiming at targeting metabolic pathways to antagonize pathological senescence. Because this is a recently emerging field in allergy and clinical immunology, a better understanding of the metabolic profile of the complex landscape of cell senescence is needed. The progress achieved so far is already providing opportunities for new therapies, as well as for strategies aimed at disease prevention and supporting healthy aging

Relativistic Calculation of two-Electron one-Photon and Hypersatellite Transition Energies for 12≤Z≤3012\leq Z\leq30 Elements

Energies of two-electron one-photon transitions from initial double K-hole states were computed using the Dirac-Fock model. The transition energies of competing processes, the K$\alpha$ hypersatellites, were also computed. The results are compared to experiment and to other theoretical calculations.Comment: accepted versio

Proxy Measures of Fitness Suggest Coastal Fish Farms Can Act as Population Sources and Not Ecological Traps for Wild Gadoid Fish

Background: Ecological traps form when artificial structures are added to natural habitats and induce mismatches between habitat preferences and fitness consequences. Their existence in terrestrial systems has been documented, yet little evidence suggests they occur in marine environments. Coastal fish farms are widespread artificial structures in coastal ecosystems and are highly attractive to wild fish. Methodology/Principal Findings: To investigate if coastal salmon farms act as ecological traps for wild Atlantic cod (Gadus morhua) and saithe (Pollachius virens), we compared proxy measures of fitness between farm-associated fish and control fish caught distant from farms in nine locations throughout coastal Norway, the largest coastal fish farming industry in the world. Farms modified wild fish diets in both quality and quantity, thereby providing farm-associated wild fish with a strong trophic subsidy. This translated to greater somatic (saithe: 1.06–1.12 times; cod: 1.06–1.11 times) and liver condition indices (saithe: 1.4–1.8 times; cod: 2.0–2.8 times) than control fish caught distant from farms. Parasite loads of farm-associated wild fish were modified from control fish, with increased external and decreased internal parasites, however the strong effect of the trophic subsidy overrode any effects of altered loads upon condition. Conclusions and Significance: Proxy measures of fitness provided no evidence that salmon farms function as ecological traps for wild fish. We suggest fish farms may act as population sources for wild fish, provided they are protected from fishing while resident at farms to allow their increased condition to manifest as greater reproductive output.Funding was provided by the Norwegian Research Council Havet og kysten program to the CoastACE project (no: 173384)

Gene Variants in the Novel Type 2 Diabetes Loci CDC123/CAMK1D, THADA, ADAMTS9, BCL11A, and MTNR1B Affect Different Aspects of Pancreatic β-Cell Function

OBJECTIVE - Recently, results from a meta-analysis of genome-wide association studies have yielded a number of novel type 2 diabetes loci. However, conflicting results have been published regarding their effects on insulin secretion and insulin sensitivity. In this study we used hyperglycemic clamps with three different stimuli to test associations between these novel loci and various measures of β-cell function. RESEARCH DESIGN AND METHODS - For this study, 336 participants, 180 normal glucose tolerant and 156 impaired glucose tolerant, underwent a 2-h hyperglycemic clamp. In a subset we also assessed the response to glucagon-like peptide (GLP)-1 and arginine during an extended clamp (n = 123). All subjects were genotyped for gene variants in JAZF1, CDC123/CAMK1D, TSPAN8/LGR5, THADA, ADAMTS9, NOTCH2/ADAMS30, DCD, VEGFA, BCL11A, HNF1B, WFS1, and MTNR1B. RESULTS - Gene variants in CDC123/CAMK1D, ADAMTS9, BCL11A, and MTNR1B affected various aspects of the insulin response to glucose (all P < 6.9 × 10-3). The THADA gene variant was associated with lower β-cell response to GLP-1 and arginine (both P < 1.6 × 1

Comparative gustatory responses in four species of gerbilline rodents

Integrated taste responses to chemical stimulation of the tongue were recorded from the intact chorda tympani nerve in four species of gerbils ( Meriones libycus, M. shawi, M. unguiculatus and Psammomys obesus ).Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/47116/1/359_2004_Article_BF00618177.pd