In the framework of VIGOR Project, a national project coordinated by the Institute of Geosciences and Earth Resources (CNR-IGG) and sponsored by the Ministry of Economic Development (MiSE), dedicated ...to the evaluation of geothermal potential in the regions of the Convergence Objective in Italy (Puglia, Calabria, Campania and Sicily), is expected to evaluate the ability of the territory to heat exchange with the ground for air conditioning of buildings. To identify the conditions for the development of low enthalpy geothermal systems collected and organized on a regional scale geological and stratigraphic data useful for the preparation of a specific thematic mapping, able to represent in a synergistic and simplified way the physical parameters (geological, lithostratigraphic, hydrogeological, thermodynamic) that most influence the subsoil behavior for thermal exchange. The litho-stratigraphic and hydrogeological database created for every region led to the production of different cartographic thematic maps, such as the thermal conductivity (lithological and stratigraphical), the surface geothermal flux, the average annual temperature of air, the climate zoning, the areas of hydrogeological restrictions. To obtain a single representation of the geo-exchange potential of the region, the different thematic maps described must be combined together by means of an algorithm, defined on the basis of the SINTACS methodology. The purpose is to weigh the contributions of the involved parameters and to produce a preliminary synthesis map able to identify the territorial use of geothermal heat pump systems, based on the geological characteristics and in agreement with the existing regulatory constraints.
Recently we reported the pharmacological characterization of the 9,10-dihydropyrrolo1,3benzothiazepine derivative (S)-(+)-8 as a novel atypical antipsychotic agent. This compound had an optimum pK(i) ...5-HT(2A)/D(2) ratio of 1.21 (pK(i) 5-HT(2A) = 8.83; pK(i) D(2) = 7.79). The lower D(2) receptor affinity of (S)-(+)-8 compared to its enantiomer was explained by the difficulty in reaching the conformation required to optimally fulfill the D(2) pharmacophore. With the aim of finding novel atypical antipsychotics we further investigated the core structure of (S)-(+)-8, synthesizing analogues with specific substituents; the structure-activity relationship (SAR) study was also expanded with the design and synthesis of other analogues characterized by a pyrrolo2,1-b1,3benzothiazepine skeleton, substituted on the benzo-fused ring or on the pyrrole system. On the 9,10-dihydro analogues the substituents introduced on the pyrrole ring were detrimental to affinity for dopamine and for 5-HT(2A) receptors, but the introduction of a double bond at C-9/10 on the structure of (S)-(+)-8 led to a potent D(2)/5-HT(2A) receptor ligand with a typical binding profile (9f, pK(i) 5-HT(2A)/D(2) ratio of 1.01, log Y = 8.43). Then, to reduce D(2) receptor affinity and restore atypicality on unsaturated analogues, we exploited the effect of specific substitutions on the tricyclic system of 9f. Through a molecular modeling approach we generated a novel series of potential atypical antipsychotic agents, with optimized 5HT(2A)/D(2) receptor affinity ratios and that were easier to synthesize and purify than the reference compound (S)-(+)-8. A number of SAR trends were identified, and among the analogues synthesized and tested in binding assays, 9d and 9m were identified as the most interesting, giving atypical log Y scores respectively 4.98 and 3.18 (pK(i) 5-HT(2A)/D(2) ratios of 1.20 and 1.30, respectively). They had a multireceptor affinity profile and could be promising atypical agents. Compound 9d, whose synthesis is easier and whose binding profile is atypical (log Y score similar to that of olanzapine, 3.89), was selected for further biological investigation. Pharmacological and biochemical studies confirmed an atypical antipsychotic profile in vivo. The compound was active on conditioned avoidance response at 1.1 mg/kg, a dose 100-times lower than that required to cause catalepsy (ED(50) >90 mg/kg), it induced a negligible increase of prolactin serum levels after single and multiple doses, and antagonized the cognitive impairment induced by phencyclidine. In conclusion, the pharmacological profile of 9d proved better than clozapine and olanzapine, making this compound a potential clinical candidate.
Normal brain tissue from 28 individuals and 50 glioma samples were analyzed by real-time Quantitative Methylation-Specific PCR (QMSP). Data from this analysis were compared with results obtained on ...the same samples by MSP. QMSP analysis demonstrated a statistically significant difference in both methylation level (P=.000009 Mann Whitney Test) and frequencies (P=.0000007, Z-test) in tumour samples as compared with normal brain tissues. Although QMSP and MSP showed similar sensitivity, the specificity of QMSP analysis was significantly higher (93%; CI95%: 84%–100%) as compared with MSP (64%; 95%CI: 46%–82%). Our results suggest that QMSP analysis may represent a powerful tool to identify glioma patients that will benefit from alkylating agents chemotherapy.
FADD protein is a critical mediator of signal transduction pathways activated by several members of the TNF-receptor gene superfamily. Recently, an
induced proximity model has been proposed to ...interpret FADD-mediated signaling events. According to this model, FADD facilitates signaling by inducing clusters of effector molecules in proximity of the activated receptor complex. An important corollary of the induced-proximity model is that FADD protein should not form oligomers in the absence of receptor stimulation. Here we show that, in the absence of death receptor stimulation, FADD is found associated to the α chain of the nascent polypeptide-associated complex (NAC). Exposure to TNF results in disruption of FADD/NAC complex. Expression of NAC regulates formation of FADD oligomers and modulates FADD-mediated signaling. Thus, our observation indicates that NAC may serve as an intracellular regulator of FADD function.
CARMA proteins are scaffold molecules that contain a caspase recruitment domain and a membrane-associated guanylate kinase-like domain. CARMA1 plays a critical role in mediating activation of the ...NFkappaB transcription factor following antigen receptor stimulation of both B and T lymphocytes. However, the biochemical mechanism by which CARMA1 regulates activation of NFkappaB remains to be determined. Here we have shown that CARMA1 and CARMA3 physically associate with Ikappa kinase gamma/NFkappaB essential modulator (IkappaKgamma-NEMO) in lymphoid and non-lymphoid cells. CARMA1 participates to an inducible large molecular complex that contains IkappaKgamma/NEMO, Bcl10, and IkappaKalpha/beta kinases. Expression of the NEMO-binding region of CARMA3 exerts a dominant negative effect on Bcl10-mediated activation of NFkappaB. Thus, our results provide direct evidence for physical and functional interaction between CARMA and the IkappaK complex and offer a biochemical framework to understand the molecular activities controlled by CARMA-1, -2, and -3 and Bcl10.
The prototypical dopamine and serotonin antagonist (+/-)-7-chloro-9-(4-methylpiperazin-1-yl)-9,10-dihydropyrrolo2,1-b1,3benzothiazepine (5) was resolved into its R and S enantiomers via ...crystallization of the diastereomeric tartaric acid salts. Binding studies confirmed that the (R)-(-)-enantiomer is a more potent D(2) receptor antagonist than the (S)-(+)-enantiomer, with almost identical affinity at the 5-HT(2) receptor ((S)-(+)-5, log Y = 4.7; (R)-(-)-5, log Y = 7.4). These data demonstrated a significant stereoselective interaction of 5 at D(2) receptors. Furthermore, enantiomer (S)-(+)-5 (ST1460) was tested on a panel of receptors; this compound showed an intriguing binding profile characterized by high affinity for H(1) and the alpha(1) receptor, a moderate affinity for alpha(2) and D(3) receptors, and low affinity for muscarinic receptors. Pharmacological and biochemical investigation confirmed an atypical pharmacological profile for (S)-(+)-5. This atypical antipsychotic lead has low propensity to induce catalepsy in rat. It has minimal effect on serum prolactin levels, and it has been selected for further pharmacological studies. (S)-(+)-5 increases the extracellular levels of dopamine in the rat striatum after subcutaneous administration. By use of 5 as the lead compound, a novel series of potential atypical antipsychotics has been developed, some of them being characterized by a stereoselective interaction at D(2) receptors. A number of structure-activity relationships trends have been identified, and a possible explanation is advanced in order to account for the observed stereoselectivity of the enantiomer of (+/-)-5 for D(2) receptors. The molecular structure determination of the enantiomers of 5 by X-ray diffraction and molecular modeling is reported.
Proteins containing the caspase recruiting domain (CARD) have emerged as critical regulators of different signal transduction pathways, including those controlling apoptosis and activation of ...necrosis factor (NF)-kappaB transcription factor. TUCAN/CARDINAL is a recently identified CARD-containing protein involved in regulation of caspases and NF-kappaB activation. We find that TUCAN/CARDINAL associates with DRAL, a p53-responsive gene implicated in induction of apoptosis. We also show that, whereas TUCAN/CARDINAL exerts a suppressive effect on NF-kappaB activity, expression of DRAL results in enhancement of NF-kappaB activation. Thus, our observations suggest that DRAL and TUCAN/CARDINAL may participate in a regulatory mechanism that coordinates cellular responses controlled by NF-kappaB transcription factor.
PDF
![Pyrrolo[1,3]benzothiazepine...](http://api.summon.serialssolutions.com/2.0.0/image/issn/XR4PS5YY4K/0022-2623/small "Pyrrolo[1,3]benzothiazepine-based serotonin and dopamine receptor antagonists. Molecular modeling, further structure-activity relationship studies, and identification of novel atypical antipsychotic agents")
