Mechanism of Hydroxylation of Steroids. Hydroxylation of 16a-Methyl-4-pregnene-21-ol-3,20- dione Acetate with Mucor Griseo-Cyanus

Mucor griseo-cyanus, which introduces an hydroxyl group in the 14-position of several steroids, converts 16a-methyl-4-pregnene- 21-ol-3,20-dione acetate (I) into a monohydrox:yderiva1Jive for which the structure 16a-methyl-4-pregnene-7a,21-diol-3,20-dione (III) has been determined. 16a-Methyl-4-pregnene-21-ol-3,20-dione acetate (I) and 16a- methyl-4-pregnene-7a,21-diol-3,20-dione (III) are transformed by Mucor griseo-cyanus, with a long time of incubation, into a dihydroxyderivative for which the structure 16a-methyl-4-pregnene- 7a,12~,21-triol-3,20-dione triacetate (VI) has been determined. The, 16a-methyl group in compound I inhibits the 14n-hydroxylase of Mucor griseo-cyanus by steric hindrance

Epithelial to mesenchymal transition in the liver field: the double face of Everolimus in vitro.

Everolimus (EVE), a mammalian target of rapamycin inhibitor, has been proposed as liver transplant immunosuppressive drug, gaining wide interest also for the treatment of cancer. Although an appropriate tolerance, it may induce several adverse effects, such as fibro-interstitial pneumonitis due to the acquisition of activated myofibroblasts. The exact molecular mechanism associated with epithelial to mesenchymal transition (EMT) may be crucial also in the liver context. This work examines the role and the molecular mediators of EMT in hepatic stellate cell (HSC) and human liver cancer cells (HepG2) and the potential role of EVE to maintain the epithelial phenotype rather than to act as a potential initiators of EMT.Real time-PCR and western blot have been used to assess the capability of EVE at low-therapeutic (10 nM) and high (100 nM) dose to induce an in vitro EMT in HSC and HepG2.Biomolecular experiments demonstrated that low concentration of EVE (10 nM) did not modify the gene expression of alpha-smooth muscle actin (α-SMA), Vimentin (VIM), Fibronectin (FN) in both HSC and HepG2 cells, whereas EVE at 100 nM induced a significant over-expression of all the three above-mentioned genes and an increment of α-SMA and FN protein levels. Additionally, 100 nM of EVE induced a significant phosphorylation of AKT and an up-regulation of TGF-β expression in HSC and HepG2 cells.Our data, although obtained in an in vitro model, revealed, for the first time, that high concentration of EVE may induce EMT in liver cells confirming previous published evidences obtained in renal cells. Additionally, they suggested that mTOR-I should be administered at the lowest dose able to maximize their important and specific therapeutic properties minimizing or avoiding fibrosis-related adverse effects.In summary, if confirmed by additional studies, our results could be useful for researchers to standardize new therapeutic immunosuppressive and anticancer drugs protocols

Paired comparisons of carbon exchange between undisturbed and regenerating stands in four managed forests in Europe

The effects of harvest on European forest net ecosystem exchange (NEE) of carbon and its photosynthetic and respiratory components (GPP (gross primary production) and TER (total ecosystem respiration)) were examined by comparing four pairs of mature/harvested sites in Europe via a combination of eddy covariance measurements and empirical modeling. Three of the comparisons represented high coniferous forestry (spruce in Britain, and pines in Finland and France), while a coppice-with-standard oak plantation was examined in Italy. While every comparison revealed that harvesting converted a mature forest carbon sink into a carbon source of similar magnitude, the mechanisms by which this occurred were very different according to species or management practice. In Britain, Finland, and France the annual sink (source) strength for mature (clear-cut) stands was estimated at 496 (112), 138 (239), and 222 (225) g C m−2, respectively, with 381 (427) g C m−2 for the mature (coppiced) stand in Italy. In all three cases of high forestry in Britain, Finland, and France, clear-cutting crippled the photosynthetic capacity of the ecosystem – with mature (clear-cut) GPP of 1970 (988), 1010 (363), and 1600 (602) g C m−2– and also reduced ecosystem respiration to a lesser degree – TER of 1385 (1100), 839 (603), and 1415 (878) g C m−2, respectively. By contrast, harvesting of the coppice oak system provoked a burst in respiration – with mature (clear-cut) TER estimated at 1160 (2220) gC m−2– which endured for the 3 years sampled postharvest. The harvest disturbance also reduced GPP in the coppice system – with mature (clear-cut) GPP of 1600 (1420) g C m−2– but to a lesser extent than in the coniferous forests, and with near-complete recovery within a few years. Understanding the effects of harvest on the carbon balance of European forest systems is a necessary step towards characterizing carbon exchange for timberlands on large scales

Risk Factors for Microvascular Atherosclerotic Changes in Patients with Type 2 Diabetes Mellitus

A B S T R A C T Diabetes mellitus is a metabolic disorder primarily characterized by elevated blood glucose levels and by microvas

Delayed Denosumab Injections and Bone Mineral Density Response: An Electronic Health Record-based Study.

CONTEXT: Discontinuation of denosumab leads to a rapid reversal of its therapeutic effect. However, there are no data regarding how unintended delays or missed injections of denosumab impact bone mineral density (BMD) response. OBJECTIVE: We examined the association of delays in injections of denosumab with BMD change. DESIGN:We used electronic medical records from two academic hospitals from 2010 to 2017. PARTICIPANTS: Patients over 45 years of age and used at least two doses of 60mg denosumab. Denosumab adherence was evaluated by the medication coverage ratio (MCR). Good adherence corresponds to a dosing interval ≤7 months (defined by MCR ≥93%), moderate adherence corresponds to an interval of 7-10 months (MCR 75-93%), and poor adherence corresponds to an interval ≥10 months (MCR ≤74%). OUTCOME MEASURES: Annualized percent BMD change from baseline at the lumbar spine, total hip, and femoral neck. RESULTS:We identified 938 denosumab injections among 151 patients; the mean (SD) age was 69 (10) years, and 95% were female. Patients with good adherence had an annualized BMD increase of 3.9% at the lumbar spine, compared with patients with moderate (3.0%) or poor adherence (1.4%, p for trend 0.002). Patients with good adherence had an annualized BMD increase of 2.1% at the total hip, compared with patients with moderate (1.3%) or poor adherence (0.6%, p for trend 0.002). CONCLUSIONS: A longer interval between denosumab injections is associated with suboptimal BMD response at both spine and total hip. Strategies to improve the timely administration of denosumab in real-world settings are needed

Measurements of 12C(→γ,pp) photon asymmetries for Eγ= 200–450 MeV

The 12C (→γ ,pp) reaction has been studied in the photon energy range 200-450 MeV at the Mainz microtron MAMI-C, where linearly polarised photons were energy-tagged using the Glasgow-Mainz Tagged Photon Spectrometer and protons were detected in the Crystal Ball detector. The photon asymmetry Σ has been measured over a wider Eγ range than previous measurements. The strongest asymmetries were found at low missing energies where direct emission of nucleon pairs is expected. Cuts on the difference in azimuthal angles of the two ejected protons increased the magnitude of the observed asymmetries. At low missing energies the Σ data exhibit a strong angular dependence, similar to deuteron photodisintegration

Observation of an Exotic S=+1S=+1 Baryon in Exclusive Photoproduction from the Deuteron

In an exclusive measurement of the reaction $\gamma d \to K^+ K^- p n$, a narrow peak that can be attributed to an exotic baryon with strangeness $S=+1$ is seen in the $K^+n$ invariant mass spectrum. The peak is at $1.542\pm 0.005$ GeV/c$^2$ with a measured width of 0.021 GeV/c$^2$ FWHM, which is largely determined by experimental mass resolution. The statistical significance of the peak is $5.2 \pm 0.6 \sigma$. The mass and width of the observed peak are consistent with recent reports of a narrow $S=+1$ baryon by other experimental groups.Comment: 5 pages, 5 figure

Electron Scattering From High-Momentum Neutrons in Deuterium

We report results from an experiment measuring the semi-inclusive reaction $d(e,e'p_s)$ where the proton $p_s$ is moving at a large angle relative to the momentum transfer. If we assume that the proton was a spectator to the reaction taking place on the neutron in deuterium, the initial state of that neutron can be inferred. This method, known as spectator tagging, can be used to study electron scattering from high-momentum (off-shell) neutrons in deuterium. The data were taken with a 5.765 GeV electron beam on a deuterium target in Jefferson Laboratory's Hall B, using the CLAS detector. A reduced cross section was extracted for different values of final-state missing mass $W^{*}$, backward proton momentum $\vec{p}_{s}$ and momentum transfer $Q^{2}$. The data are compared to a simple PWIA spectator model. A strong enhancement in the data observed at transverse kinematics is not reproduced by the PWIA model. This enhancement can likely be associated with the contribution of final state interactions (FSI) that were not incorporated into the model. A ``bound neutron structure function'' $F_{2n}^{eff}$ was extracted as a function of $W^{*}$ and the scaling variable $x^{*}$ at extreme backward kinematics, where effects of FSI appear to be smaller. For $p_{s}>400$ MeV/c, where the neutron is far off-shell, the model overestimates the value of $F_{2n}^{eff}$ in the region of $x^{*}$ between 0.25 and 0.6. A modification of the bound neutron structure function is one of possible effects that can cause the observed deviation.Comment: 33 pages RevTeX, 9 figures, to be submitted to Phys. Rev. C. Fixed 1 Referenc