The contribution of epigenetics in Sjögren's Syndrome.

International audience: Sjögren's syndrome (SS) is a chronic autoimmune epithelitis that combines exocrine gland dysfunctions and lymphocytic infiltrations. While the pathogenesis of SS remains unclear, its etiology is multifunctional and includes a combination of genetic predispositions, environmental factors, and epigenetic factors. Recently, interest has grown in the involvement of epigenetics in autoimmune diseases. Epigenetics is defined as changes in gene expression, that are inheritable and that do not entail changes in the DNA sequence. In SS, several epigenetic mechanisms are defective including DNA demethylation that predominates in epithelial cells, an abnormal expression of microRNAs, and abnormal chromatin positioning-associated with autoantibody production. Last but not least, epigenetic modifications are reversible as observed in minor salivary glands from SS patients after B cell depletion using rituximab. Thus epigenetic findings in SS open new perspectives for therapeutic approaches as well as the possible identification of new biomarkers

Studies of Prevention, Treatment and Mechanisms of Heart Failure in the Aging Spontaneously Hypertensive Rat

The spontaneously hypertensive rat (SHR) is an animal model of genetic hypertension which develops heart failure with aging, similar to man. The consistent pattern of a long period of stable hypertrophy followed by a transition to failure provides a useful model to study mechanisms of heart failure with aging and test treatments at differing phases of the disease process. The transition from compensated hypertrophy to failure is accompanied by changes in cardiac function which are associated with altered active and passive mechanical properties of myocardial tissue; these events define the physiologic basis for cardiac decompensation. In examining the mechanism for myocardial tissue dysfunction, studies have demonstrated a central role for neurohormonal activation, and specifically the renin-angiotensin-aldosterone system. Pharmacologic attenuation of this system at differing points in the course of the process suggests that prevention but not reversal of myocardial tissue dysfunction is possible. The roles of the extracellular matrix, apoptosis, intracellular calcium, beta-adrenergic stimulation, microtubules, and oxygen supply-demand relationships in ultimately mediating myocardial tissue dysfunction are reviewed. Studies suggest that while considerable progress has been made in understanding and treating the transition to failure, our current state of knowledge is limited in scope and we are not yet able to define specific mechanisms responsible for tissue dysfunction. It will be necessary to integrate information on the roles of newly discovered, and as yet undiscovered, genes and pathways to provide a clearer understanding of maladaptive remodeling seen with heart failure. Understanding the mechanism for tissue dysfunction is likely to result in more effective treatments for the prevention and reversal of heart failure with aging. It is anticipated that the SHR model will assist us in reaching these important goals.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/45828/1/10741_2004_Article_391524.pd

Virtual target screening to rapidly identify potential protein targets of natural products in drug discovery

Inherent biological viability and diversity of natural products make them a potentially rich source for new therapeutics. However, identification of bioactive compounds with desired therapeutic effects and identification of their protein targets is a laborious, expensive process. Extracts from organism samples may show desired activity in phenotypic assays but specific bioactive compounds must be isolated through further separation methods and protein targets must be identified by more specific phenotypic and in vitro experimental assays. Still, questions remain as to whether all relevant protein targets for a compound have been identified. The desire is to understand breadth of purposing for the compound to maximize its use and intellectual property, and to avoid further development of compounds with insurmountable adverse effects. Previously we developed a Virtual Target Screening system that computationally screens one or more compounds against a collection of virtual protein structures. By scoring each compound-protein interaction, we can compare against averaged scores of synthetic drug-like compounds to determine if a particular protein would be a potential target of a compound of interest. Here we provide examples of natural products screened through our system as we assess advantages and shortcomings of our current system in regards to natural product drug discovery

Shedding light on sporopollenin chemistry, with reference to UV reconstructions

Sporopollenin, which forms the outer wall of pollen and spores, contains a chemical signature of ultraviolet-B flux via concentrations of UV-B absorbing compounds (UACs), providing a proxy for reconstructing UV irradiance through time. Although Fourier transform infrared (FTIR) spectroscopy provides an efficient means of measuring UAC concentrations, nitrogen-containing compounds have the potential to bias the aromatic and hydroxyl bands used to quantify and standardise UAC abundances. Here, we explore the presence and possible influence of nitrogen in UV reconstruction via an FTIR study of Lycopodium spores from a natural shading gradient. We show that the UV-sensitive aromatic peak at 1510 cm− 1 is clearly distinguishable from the amide II peak at 1550 cm− 1, and the decrease in aromatic content with increased shading can be reconstructed using standardisation approaches that do not rely on the 3300 cm− 1 hydroxyl band. Isolation of the sporopollenin results in the loss of nitrogen-related peaks from the FTIR spectra, while the aromatic gradient remains. This confirms the lack of nitrogen in sporopollenin and its limited potential for impacting on palaeo-UV reconstructions. FTIR is therefore an appropriate tool for quantifying UACs in spores and pollen, and information on UV flux should be obtainable from fossil or processed samples

Target and Beam-Target Spin Asymmetries in Exclusive Pion Electroproduction for \u3cem\u3eQ\u3c/em\u3e\u3csup\u3e2\u3c/sup\u3e \u3e 1 GeV\u3csup\u3e2\u3c/sup\u3e. II. \u3cem\u3eep\u3c/em\u3e → \u3cem\u3eeπ\u3c/em\u3e\u3csup\u3e0\u3c/sup\u3e\u3cem\u3ep\u3c/em\u3e

Beam-target double-spin asymmetries and target single-spin asymmetries were measured for the exclusive π0 electroproduction reaction γ∗p → pπ0, expanding an analysis of the γ∗p → nπ+ reaction from the same experiment. The results were obtained from scattering of 6-GeV longitudinally polarized electrons off longitudinally polarized protons using the CEBAF Large Acceptance Spectrometer at Jefferson Laboratory. The kinematic ranges covered are 1.1 \u3c W \u3c 3 GeV and 1 \u3c Q2 \u3c 6 GeV2. Results were obtained for about 5700 bins in W, Q2, cos(θ∗), and ϕ∗. The beam-target asymmetries were found to generally be greater than zero, with relatively modest ϕ∗ dependence. The target asymmetries exhibit very strong ϕ∗ dependence, with a change in sign occurring between results at low W and high W, in contrast to π+ electroproduction. Reasonable agreement is found with phenomenological fits to previous data for W \u3c 1.6 GeV, but significant differences are seen at higher W. When combined with cross-sectional measurements, as well as π+ observables, the present results will provide powerful constraints on nucleon resonance amplitudes at moderate and large values of Q2, for resonances with masses as high as 2.4 GeV

Exclusive Photoproduction of \u3cem\u3eπ\u3c/em\u3e\u3csup\u3e0\u3c/sup\u3e Up to Large Values of Mandlestam Variables \u3cem\u3es\u3c/em\u3e, \u3cem\u3et\u3c/em\u3e, and \u3cem\u3eu\u3c/em\u3e with CLAS

Exclusive photoproduction cross sections have been measured for the process γp → pπ0[e+e−(γ)] with the Dalitz decay final state using tagged photon energies in the range of Eγ = 1.275–5.425 GeV. The complete angular distribution of the final state π0, for the entire photon energy range up to large values of t and u, has been measured for the first time. The data obtained show that the cross section dσ/dt, at mid to large angles, decreases with energy as s−6.89±0.26. This is in agreement with the perturbative QCD quark counting rule prediction of s−7. Paradoxically, the size of angular distribution of measured cross sections is greatly underestimated by the QCD-based generalized parton distribution mechanism at highest available invariant energy s = 11 GeV2. At the same time, the Regge-exchange-based models for π0 photoproduction are more consistent with experimental data

Measurement of the Helicity Asymmetry \u3cem\u3eE\u3c/em\u3e in \u3cem\u3eω\u3c/em\u3e → \u3cem\u3eπ\u3c/em\u3e\u3csup\u3e+\u3c/sup\u3e\u3cem\u3eπ\u3c/em\u3e\u3csup\u3e−\u3c/sup\u3e\u3cem\u3eπ\u3c/em\u3e\u3csup\u3e0\u3c/sup\u3e Photoproduction

The double-polarization observable E was studied for the reaction γp → pω using the CEBAF Large Acceptance Spectrometer (CLAS) in Hall B at the Thomas Jefferson National Accelerator Facility and the longitudinally polarized frozen-spin target (FROST). The observable was measured from the charged decay mode of the meson, ω → π+π−π0, using a circularly polarized tagged-photon beam with energies ranging from the ω threshold at 1.1 to 2.3 GeV. A partial-wave analysis within the Bonn-Gatchina framework found dominant contributions from the 3/2+ partial wave near threshold, which is identified with the subthreshold N(1720)3/2+ nucleon resonance. To describe the entire data set, which consisted of ω differential cross sections and a large variety of polarization observables, further contributions from other nucleon resonances were found to be necessary. With respect to nonresonant mechanisms, π exchange in the t channel was found to remain small across the analyzed energy range, while Pomeron t-channel exchange gradually grew from the reaction threshold to dominate all other contributions above W ≈ 2 GeV