High affinity binding of hydrophobic and autoantigenic regions of proinsulin to the 70 kDa chaperone DnaK

BACKGROUND: Chaperones facilitate proper folding of peptides and bind to misfolded proteins as occurring during periods of cell stress. Complexes of peptides with chaperones induce peptide-directed immunity. Here we analyzed the interaction of (pre)proinsulin with the best characterized chaperone of the hsp70 family, bacterial DnaK. RESULTS: Of a set of overlapping 13-mer peptides of human preproinsulin high affinity binding to DnaK was found for the signal peptide and one further region in each proinsulin domain (A- and B-chain, C-peptide). Among the latter, peptides covering most of the B-chain region B11-23 exhibited strongest binding, which was in the range of known high-affinity DnaK ligands, dissociation equilibrium constant (K'd) of 2.2 ± 0.4 μM. The B-chain region B11-23 is located at the interface between two insulin molecules and not accessible in insulin oligomers. Indeed, native insulin oligomers showed very low DnaK affinity (K'd 67.8 ± 20.8 μM) whereas a proinsulin molecule modified to prevent oligomerization showed good binding affinity (K'd 11.3 ± 7.8 μM). CONCLUSIONS: Intact insulin only weakly interacts with the hsp70 chaperone DnaK whereas monomeric proinsulin and peptides from 3 distinct proinsulin regions show substantial chaperone binding. Strongest binding was seen for the B-chain peptide B 11-23. Interestingly, peptide B11-23 represents a dominant autoantigen in type 1 diabetes

Heat shock protein 60: Identification of specific epitopes for binding to primary macrophages

AbstractIn the present study, we characterized regions of human heat shock protein (HSP) 60 responsible for binding to primary macrophages. Studies using 20-mer peptides of the HSP60 sequence to compete with HSP60-binding to macrophages from C57BL/6J mice showed that regions aa241–260, aa391–410 and aa461–480 are involved in surface-binding. HSP60 mutants, lacking the N-terminal 137, 243 or 359 amino acids, inhibited HSP60-binding to primary macrophages to different degrees, demonstrating that all three regions are required for optimal binding. Analysis of different pro- and eukaryotic HSP60 species indicated that phylogenetically separate HSP60 species use different binding sites on primary macrophages

Improved Preservation of Residual Beta Cell Function by Atorvastatin in Patients with Recent Onset Type 1 Diabetes and High CRP Levels (DIATOR Trial)

A recent randomized placebo-controlled trial of the effect of atorvastatin treatment on the progression of newly diagnosed type 1 diabetes suggested a slower decline of residual beta cell function with statin treatment. Aim of this secondary analysis was to identify patient subgroups which differ in the decline of beta cell function during treatment with atorvastatin.The randomized placebo-controlled Diabetes and Atorvastatin (DIATOR) Trial included 89 patients with newly diagnosed type 1 diabetes and detectable islet autoantibodies (mean age 30 years, 40% females), in 12 centers in Germany. Patients received placebo or 80 mg/d atorvastatin for 18 months. As primary outcome stimulated serum C-peptide levels were determined 90 min after a standardized liquid mixed meal. For this secondary analysis patients were stratified by single baseline characteristics which were considered to possibly be modified by atorvastatin treatment. Subgroups defined by age, sex or by baseline metabolic parameters like body mass index (BMI), total serum cholesterol or fasting C-peptide did not differ in C-peptide outcome after atorvastatin treatment. However, the subgroup defined by high (above median) baseline C-reactive protein (CRP) concentrations exhibited higher stimulated C-peptide secretion after statin treatment (p = 0.044). Individual baseline CRP levels correlated with C-peptide outcome in the statin group (r(2) = 0.3079, p<0.004). The subgroup with baseline CRP concentrations above median differed from the corresponding subgroup with lower CRP levels by higher median values of BMI, IL-6, IL-1RA, sICAM-1 and E-selectin.Atorvastatin treatment may be effective in slowing the decline of beta cell function in a patient subgroup defined by above median levels of CRP and other inflammation associated immune mediators.ClinicalTrials.gov NCT00974740

Anatomy of an evolving island arc : tectonic and eustatic control in the south Central American fore-arc area

The southern part of the Central American isthmus is the product of an island arc. It evolved initially as a ridge of primitive island-arc tholeiites at a collision zone between the Farallon plate and proto-Caribbean crust (Albian-Santonian). During the Campanian, a major tectonic event (most probably subduction reversal) caused décollement of different units of the former plate margin. The resulting structural high was covered by a carbonate platform. From Maastrichtian to Eocenc times continuous subduction produced a stable morphotectonic configuration (trench-slope-outer-arc-fore-arccalcalkaline-arc). Fore-arc sedimentation was controlled by volcaniclastic input and tectonic activity along the outer arc's inner margin. Eustatic control is essentially recognized through lowstand signals such as extensive turbidite sand lobes. Steady accretionary uplift of the outer arc gradually closed the bypasses between forc-arc and trench slope. Eustatic control is verified by lowstand signals (sands) on the trench slope and highstand signals on the outer arc (carbonate ramps). During the Oligocene another major tectonic event affected the entire system: accretion ceased, segments decoupled, and regional compression resulted in general uplift and erosion. From latest Oligocene to Pliocene times, three episodes of tilting created a series of fault-angle depressions. Subsidence varies enormously among these basins. but sedimentation is largely shallow marine. Facies architecture reflects complex interactions between tectonic processes, changes in volcaniclastic sediment supply, and eustasy. Subsequently. very strong explosive volcanic activity resulted in excessive sediment input that overfilled most basins. The history of the island arc shows that tectonic processes largely controlled composition, distribution and geometry of the major sedimentary units. Eustatic signals do indeed occur when they are expected, but may be considered as an overprint rather than a dominating factor

Infrared wavefront sensing for adaptive optics assisted Galactic Center observations with the VLT interferometer and GRAVITY: operation and results

This article describes the operation of the near-infrared wavefront sensing based Adaptive Optics (AO) system CIAO. The Coud\'e Infrared Adaptive Optics (CIAO) system is a central auxiliary component of the Very Large Telescope (VLT) interferometer (VLTI). It enables in particular the observations of the Galactic Center (GC) using the GRAVITY instrument. GRAVITY is a highly specialized beam combiner, a device that coherently combines the light of the four 8-m telescopes and finally records interferometric measurements in the K-band on 6 baselines simultaneously. CIAO compensates for phase disturbances caused by atmospheric turbulence, which all four 8 m Unit Telescopes (UT) experience during observation. Each of the four CIAO units generates an almost diffraction-limited image quality at its UT, which ensures that maximum flux of the observed stellar object enters the fibers of the GRAVITY beam combiner. We present CIAO performance data obtained in the first 3 years of operation as a function of weather conditions. We describe how CIAO is configured and used for observations with GRAVITY. In addition, we focus on the outstanding features of the near-infrared sensitive Saphira detector, which is used for the first time on Paranal, and show how it works as a wavefront sensor detector.Comment: 12 pages, 8 figures, accepted for publication in Instruments (open access journal from mdpi

Dietary factors and low-grade inflammation in relation to overweight and obesity

Low-grade inflammation is a characteristic of the obese state, and adipose tissue releases many inflammatory mediators. The source of these mediators within adipose tissue is not clear, but infiltrating macrophages seem to be especially important, although adipocytes themselves play a role. Obese people have higher circulating concentrations of many inflammatory markers than lean people do, and these are believed to play a role in causing insulin resistance and other metabolic disturbances. Blood concentrations of inflammatory markers are lowered following weight loss. In the hours following the consumption of a meal, there is an elevation in the concentrations of inflammatory mediators in the bloodstream, which is exaggerated in obese subjects and in type 2 diabetics. Both high-glucose and high-fat meals may induce postprandial inflammation, and this is exaggerated by a high meal content of advanced glycation end products (AGE) and partly ablated by inclusion of certain antioxidants or antioxidant-containing foods within the meal. Healthy eating patterns are associated with lower circulating concentrations of inflammatory markers. Among the components of a healthy diet, whole grains, vegetables and fruits, and fish are all associated with lower inflammation. AGE are associated with enhanced oxidative stress and inflammation. SFA and trans-MUFA are pro-inflammatory, while PUFA, especially long-chain n-3 PUFA, are anti-inflammatory. Hyperglycaemia induces both postprandial and chronic low-grade inflammation. Vitamin C, vitamin E and carotenoids decrease the circulating concentrations of inflammatory markers. Potential mechanisms are described and research gaps, which limit our understanding of the interaction between diet and postprandial and chronic low-grade inflammation, are identifie

Usages des modèles spatiaux pour la prospective

International audienceCet article théorique a pour objectif de faire un état de l'art sur l'usage des modèles spatiaux pour la prospective. Dans un premier temps, il présente un bref historique de la convergence implicite entre prospective et géographie. Dans un second temps, il aborde la question du choix du modèle en présentant les critères à prendre en compte. Dans un troisième temps, il présente la validation des modèles comme un moyen d'améliorer la plausibilité des scénarios à travers la combinaison de méthodes d'évaluation. Enfin, si on constate un usage de plus en plus important de modèles spatiaux en prospective, les méthodes évoquées sont loin d'être exhaustives et replacent la géoprospective comme une simple communauté de pratiques et de méthodes ayant un objectif commun : mieux explorer les futurs pour éclairer l'action présente. Au final, il apporte un éclairage sur l'apport des modèles aux démarches prospectives et vise à aider les géographes, les modélisateurs et/ou les prospectivistes à choisir un modèle approprié à leur problématique et à leurs objectifs afin de tirer parti de tous les avantages qu'ils offrent. Il tente également de clarifier certaines confusions sémantiques qui existent autour de l'usage des modèles couplés à des scénarios

Ex vivo drug response profiling for response and outcome prediction in hematologic malignancies: the prospective non-interventional SMARTrial

Ex vivo drug response profiling is a powerful tool to study genotype-drug response associations and is being explored as a tool set for precision medicine in cancer. Here we conducted a prospective non-interventional trial to investigate feasibility of ex vivo drug response profiling for treatment guidance in hematologic malignancies (SMARTrial, NCT03488641 ). The primary endpoint to provide drug response profiling reports within 7 d was met in 91% of all study participants (N = 80). Secondary endpoint analysis revealed that ex vivo resistance to chemotherapeutic drugs predicted chemotherapy treatment failure in vivo. We confirmed the predictive value of ex vivo response to chemotherapy in a validation cohort of 95 individuals with acute myeloid leukemia treated with daunorubicin and cytarabine. Ex vivo drug response profiles improved ELN-22 risk stratification in individuals with adverse risk. We conclude that ex vivo drug response profiling is clinically feasible and has the potential to predict chemotherapy response in individuals with hematologic malignancies beyond clinically established genetic markers

First direct detection of an exoplanet by optical interferometry; Astrometry and K-band spectroscopy of HR8799 e

To date, infrared interferometry at best achieved contrast ratios of a few times $10^{-4}$ on bright targets. GRAVITY, with its dual-field mode, is now capable of high contrast observations, enabling the direct observation of exoplanets. We demonstrate the technique on HR8799, a young planetary system composed of four known giant exoplanets. We used the GRAVITY fringe tracker to lock the fringes on the central star, and integrated off-axis on the HR8799e planet situated at 390 mas from the star. Data reduction included post-processing to remove the flux leaking from the central star and to extract the coherent flux of the planet. The inferred K band spectrum of the planet has a spectral resolution of 500. We also derive the astrometric position of the planet relative to the star with a precision on the order of 100$\,\mu$as. The GRAVITY astrometric measurement disfavors perfectly coplanar stable orbital solutions. A small adjustment of a few degrees to the orbital inclination of HR 8799 e can resolve the tension, implying that the orbits are close to, but not strictly coplanar. The spectrum, with a signal-to-noise ratio of $\approx 5$ per spectral channel, is compatible with a late-type L brown dwarf. Using Exo-REM synthetic spectra, we derive a temperature of $1150\pm50$\,K and a surface gravity of $10^{4.3\pm0.3}\,$cm/s$^{2}$. This corresponds to a radius of $1.17^{+0.13}_{-0.11}\,R_{\rm Jup}$ and a mass of $10^{+7}_{-4}\,M_{\rm Jup}$, which is an independent confirmation of mass estimates from evolutionary models. Our results demonstrate the power of interferometry for the direct detection and spectroscopic study of exoplanets at close angular separations from their stars.Comment: published in A&

Accretion-ejection morphology of the microquasar SS 433 resolved at sub-au scale

This is the author accepted manuscript. the final version is available from EDP Sciences via the DOI in this recordWe present the first optical observation of the microquasar SS 433 at sub-milliarcsecond (mas) scale obtained with the GRAVITY instrument on the Very Large Telescope interferometer (VLTI). The 3.5-h exposure reveals a rich K-band spectrum dominated by hydrogen Brγand He i lines, as well as (red-shifted)emission lines coming from the jets. The K-band-continuum-emitting region is dominated by a marginally resolved point source (<1 mas) embedded inside a diffuse background accounting for 10% of the total flux. The jet line positions agree well with the ones expected from the jet kinematic model, an interpretation also supported by the consistent sign (i.e., negative/positive for the receding/approaching jet component) of the phase shifts observed in the lines. The significant visibility drop across the jet lines, together with the small and nearly identical phases for all baselines, point toward a jet that is offset by less than 0.5 mas from the continuum source and resolved in the direction of propagation, with a typical size of 2 mas. The jet position angle of ~80° is consistent with the expected one at the observation date. Jet emission so close to the central binary system would suggest that line locking, if relevant to explain the amplitude and stability of the 0.26c jet velocity, operates on elements heavier than hydrogen. The Brγprofile is broad and double peaked. It is better resolved than the continuum and the change of the phase signal sign across the line on all baselines suggests an East-West-oriented geometry similar to the jet direction and supporting a (polar) disk wind origin.Centre National d’Etudes Spatiales (CNES)Programme National Hautes Energies (PNHE)Humboldt FoundationNAS