Bitter Taste Receptors and Endocrine Disruptors: Cellular and Molecular Insights from an In Vitro Model of Human Granulosa Cells

Endocrine disrupting chemicals (EDCs) are compounds that interfere with the synthesis, transport and binding action of hormones responsible for reproduction and homeostasis. Some EDCs compounds are activators of Taste bitter Receptors, a subclass of taste receptors expressed in many extraoral locations, including sperm and follicular somatic cells. This makes TAS2Rs attractive molecules to study and investigate to shed light on the effect of EDCs on female reproduction and fertility. This study aims to assess the effect of selected EDCs [namely Biochanin A (BCA), caffeine, Daidzein, Genistein and Isoflavone] on hGL5, an immortalized cell line exhibiting characteristics coherent with primary follicular granulosa cells. After demonstrating that this model expresses all the TAS2Rs (TAS2R3, TAS2R4, TAS2R14, TAS2R19, TAS2R43) specifically expressed by the primary human granulosa cells, we demonstrated that BCA and caffeine significantly affect mitochondrial footprint and intracellular lipid content, indicating their contribution in steroidogenesis. Our results showed that bitter taste receptors may be involved in steroidogenesis, thus suggesting an appealing mechanism by which these compounds affect the female reproductive system

The Impact of Repeated Abutment Changes on Peri-implant Tissue Stability: Five-year Post-loading Results From a Multicentre Randomised Controlled Trial

PURPOSE. To evaluate the impact of at least three abutment disconnections on hard and soft tissues around conventionally loaded implants versus definitive immediately non-oc-clusally loaded abutments in implants. A secondary aim was to evaluate whether the presence of less than 2 mm of keratinised mucosa is associated with increased soft tissue recession and/or peri-implant marginal bone loss. MATERIALS AND METHODS. Eighty patients requiring one single crown or one fixed partial prosthesis supported by a maximum of three implants were randomised, after implant placement at greater than 35 Ncm, according to a parallel-group design to receive either definitive immediately loaded abutments (definitive abutment or immediate loading group) or transmucosal abutments which were loaded after a delay of 3 months and removed at least three times. Patients were treated in four centres, and each patient contributed to the study with only one prosthesis, which was followed up for 5 years after initial loading. Outcome measures were: prosthesis failures, implant failures, complica-tions, pink aesthetic score (PES), buccal recessions, patient satisfaction, peri-implant marginal bone-level changes and height of the keratinised mucosa. RESULTS. Forty patients were randomly allocated to each group according to a paral-lel-group design. Seven patients from the definitive abutment group versus six from the repeated disconnection group dropped out or died. No patient from the definitive group had implant failures versus three patients who lost five implants in the repeated disconnection group (difference = 9.1%; CI95%:-0.7% to 18.9% to; P = 0.227). Nine patients from the repeated disconnection group lost or had to have their prosthesis remade (four provisional and five definitive prostheses) versus one provisional prosthesis failure in the definitive abutment group; this difference was statistically significant (difference = 23.5%; CI95%: 7.6% to 39.4%; P = 0.017), but was due to the erroneous use of non-indexed abutments in indexed implants in patients from the repeated disconnection group alone. Seven patients from the definitive abutment group versus nine patients from the repeated disconnection group were affected by complications (difference =-5.9%; CI95%:-26.0% to 14.2%; P = 0.775), the difference being not statistically significant. PES scores assessed at 5 years post-loading were 12.1±1.8 for the definitive abutment group and 11.9±1.7 for the repeated abutment changes group (difference = 0.2; CI95%:-0.7 to 1.1; P = 0.615); however, there was a statistically significant difference of 0.20 out of a maximum score of 2 in favour of the definitive abutment group for soft tissue contour alone (P = 0.045). Buccal recessions at 5 years post-loading amounted to-0.19±0.77 mm for the definitive abutment group and-0.07±1.24 mm for the repeated abutment changes group (difference = 0.12 mm CI95%:-0.42 to 0.66; P = 0.662). All patients declared being very satisfied or sati-sfied with the function and aesthetics of their prosthesis and would undergo the same procedure again. Mean peri-implant marginal bone loss 5 years after loading was 0.11±0.30 mm for the definitive abutment group and 0.48±0.73 mm for the repeated abutment change group (difference =-0.37 [SE=0.14] mm; CI95%:-0.66 to-0.09; P = 0.012), the difference being statistically significant. The height of keratinised mucosa at 5 years post-loading was 2.81±1.46 mm in the definitive abutment group and 2.83±1.84 mm in the repeated abutment change group (difference =-0.02 mm; CI95%:-0.85 to 0.80; P = 0.956), and there were no significant differences in marginal bone loss (difference = 0.00 mm; CI95%:-0.32 to 0.32, P = 0.990) or buccal recession (difference = 0.05 mm, CI95%:-0.43 to 0.54, P = 0.826) at implants having less than 2 mm of keratinised mucosa at loading compared to those having more than 2 mm of keratinised mucosa. CONCLUSIONS. Five-year post-loading data show that at least three repeated abutment disconnections significantly increased bone loss by 0.37 mm when compared to no di-sconnection, but this difference may not be clinically significant. While it might be advi-sable to avoid unnecessary abutment disconnection whenever possible, if disconnections are required, no clinically significant side effects may be expected. Immediately non-oc-clusally loaded dental implants are a viable alternative to conventional loading, and no increased bone loss or buccal recessions were noted even at implants with less than 2 mm of keratinised mucosa

Two-to-one resonant multi-modal dynamics of horizontal/inclined cables. Part I : theoretical formulation and model validation

This paper is first of the two papers dealingwith analytical investigation of resonant multimodal dynamics due to 2:1 internal resonances in the finite-amplitude free vibrations of horizontal/inclined cables. Part I deals with theoretical formulation and validation of the general cable model. Approximate nonlinear partial differential equations of 3-D coupled motion of small sagged cables - which account for both spatio-temporal variation of nonlinear dynamic tension and system asymmetry due to inclined sagged configurations - are presented. A multidimensional Galerkin expansion of the solution ofnonplanar/planar motion is performed, yielding a complete set of system quadratic/cubic coefficients. With the aim of parametrically studying the behavior of horizontal/inclined cables in Part II [25], a second-order asymptotic analysis under planar 2:1 resonance is accomplished by the method of multiple scales. On accounting for higher-order effectsof quadratic/cubic nonlinearities, approximate closed form solutions of nonlinear amplitudes, frequencies and dynamic configurations of resonant nonlinear normal modes reveal the dependence of cable response on resonant/nonresonant modal contributions. Depending on simplifying kinematic modeling and assigned system parameters, approximate horizontal/inclined cable models are thoroughly validated by numerically evaluating statics and non-planar/planar linear/non-linear dynamics against those of the exact model. Moreover, the modal coupling role and contribution of system longitudinal dynamics are discussed for horizontal cables, showing some meaningful effects due to kinematic condensation

A novel phytocannabinoid isolated from Cannabis sativa L. with an in vivo cannabimimetic activity higher than \u3949-tetrahydrocannabinol: \u3949-Tetrahydrocannabiphorol

(-)-Trans-Delta(9)-tetrahydrocannabinol (Delta(9)-THC) is the main compound responsible for the intoxicant activity of Cannabis sativa L. The length of the side alkyl chain influences the biological activity of this cannabinoid. In particular, synthetic analogues of Delta(9)-THC with a longer side chain have shown cannabimimetic properties far higher than Delta(9)-THC itself. In the attempt to define the phytocannabinoids profile that characterizes a medicinal cannabis variety, a new phytocannabinoid with the same structure of Delta(9)-THC but with a seven-term alkyl side chain was identified. The natural compound was isolated and fully characterized and its stereochemical configuration was assigned by match with the same compound obtained by a stereoselective synthesis. This new phytocannabinoid has been called (-)-trans-Delta(9)-tetrahydrocannabiphorol (Delta(9)-THCP). Along with Delta(9)-THCP, the corresponding cannabidiol (CBD) homolog with seven-term side alkyl chain (CBDP) was also isolated and unambiguously identified by match with its synthetic counterpart. The binding activity of Delta(9)-THCP against human CB1 receptor in vitro (K-i = 1.2 nM) resulted similar to that of CP55940 (K-i = 0.9 nM), a potent full CB1 agonist. In the cannabinoid tetrad pharmacological test, Delta(9)-THCP induced hypomotility, analgesia, catalepsy and decreased rectal temperature indicating a THC-like cannabimimetic activity. The presence of this new phytocannabinoid could account for the pharmacological properties of some cannabis varieties difficult to explain by the presence of the sole Delta(9)-THC

Volcanic spreading of Vesuvius, a new paradigm for interpreting its volcanic activity

We integrate geologic, structural, leveling and Differential SAR Interferometry data to show that Vesuvius began to spread onto its sedimentary substratum about 3,600 years ago. Moreover, we model the detected deformation with a solution of the lubrication approximation of the Navier-Stokes equations to show that spreading may continue for about 7,200 years more. Correlation of volcanic spreading with phases of the eruptive activity suggests that Plinian eruptions, which are thought to pose the major hazard, are less likely to occur in the near future.Published1-4partially_ope

Gas dependent hysteresis in MoS2_2 field effect transistors

We study the effect of electric stress, gas pressure and gas type on the hysteresis in the transfer characteristics of monolayer molybdenum disulfide (MoS2) field effect transistors. The presence of defects and point vacancies in the MoS2 crystal structure facilitates the adsorption of oxygen, nitrogen, hydrogen or methane, which strongly affect the transistor electrical characteristics. Although the gas adsorption does not modify the conduction type, we demonstrate a correlation between hysteresis width and adsorption energy onto the MoS2 surface. We show that hysteresis is controllable by pressure and/or gas type. Hysteresis features two well-separated current levels, especially when gases are stably adsorbed on the channel, which can be exploited in memory devices.Comment: 8 pages, 5 figure

Grape pomace polyphenols improve insulin response to a standard meal in healthy individuals: A pilot study

Dietary polyphenols have beneficial effects on glucose/lipid metabolism in subjects at high risk to develop type 2 diabetes; however, the underlying mechanisms are not clear. We aimed to evaluate: 1) the acute effects of the consumption of a drink rich in polyphenols from red grape pomace (RGPD) on glucose/insulin and triglyceride responses to a standard meal in healthy individuals, and, 2) the relationship between plasma levels of phenolic metabolites and metabolic parameters

Scale-Free model for governing universe dynamics

We investigate the effects of scale-free model on cosmology, providing, in this way, a statistical background in the framework of general relativity. In order to discuss properties and time evolution of some relevant universe dynamical parameters (cosmographic parameters), such as $H(t)$ (Hubble parameter), $q(t)$ (deceleration parameter), $j(t)$ (jerk parameter) and $s(t)$ (snap parameter), which are well re-defined in the framework of scale-free model, we analyze a comparison between WMAP data. Hence the basic purpose of the work is to consider this statistical interpretation of mass distribution of universe, in order to have a mass density $\rho$ dynamics, not inferred from Friedmann equations, via scale factor $a(t)$. This model, indeed, has been used also to explain a possible origin and a viable explanation of cosmological constant, which assumes a statistical interpretation without the presence of extended theories of gravity; hence the problem of dark energy could be revisited in the context of a classical probability distribution of mass, which is, in particular, for the scale-free model, $P(k)\sim k^{-\gamma}$, with $2<\gamma<3$. The $\Lambda$CDM model becomes, with these considerations, a consequence of the particular statistics together with the use of general relativity.Comment: 7 pages, 4 figure

One-step in vitro generation of ETV2-null pig embryos

Each year, tens of thousands of people worldwide die of end-stage organ failure due to the limited availability of organs for use in transplantation. To meet this clinical demand, one of the last frontiers of regenerative medicine is the generation of humanized organs in pigs from pluripotent stem cells (PSCs) via blastocyst complementation. For this, organ-disabled pig models are needed. As endothelial cells (ECs) play a critical role in xenotransplantation rejection in every organ, we aimed to produce hematoendothelial-disabled pig embryos targeting the master transcription factor ETV2 via CRISPR-Cas9-mediated genome modification. In this study, we designed five different guide RNAs (gRNAs) against the DNA-binding domain of the porcine ETV2 gene, which were tested on porcine fibroblasts in vitro. Four out of five guides showed cleavage capacity and, subsequently, these four guides were microinjected individually as ribonucleoprotein complexes (RNPs) into one-cell-stage porcine embryos. Next, we combined the two gRNAs that showed the highest targeting efficiency and microinjected them at higher concentrations. Under these conditions, we significantly improved the rate of biallelic mutation. Hence, here, we describe an efficient one-step method for the generation of hematoendothelial-disabled pig embryos via CRISPR-Cas9 microinjection in zygotes. This model could be used in experimentation related to the in vivo generation of humanized organs