Atropisomerism in Hindered Naphthyl Sulfoxides: Structure, Stereodynamics, and Chiral Resolution.

Barriers for the EZ interconversion of atropisomers of 1-naphthyl sulfoxides (ArSOR) having a methyl group at position 2 of the naphthalene moiety were measured by variable-temperature NMR. Their values were found to cover the range 10.6-18.4 kcal mol-1, the extreme values corresponding to derivatives 1 (R = Me) and 4 (R = Bu(t)), respectively. NOE and LIS measurements indicated that the Z atropisomer is more stable than the E but that the absence of the methyl group at position 2 of the naphthalene moiety reverses this trend, rendering E more stable than Z. Solid-state NMR and X-ray diffraction of 4 established that only the more stable atropisomer (Z) is present in the crystalline state. Molecular mechanics calculations suggest that the Z,E interconversion process might occur by a rotation pathway having an opposite direction in the case of the more hindered derivatives 3 and 4 (R = Pr(i) and Bu(t), respectively) with respect to the less hindered 1 and 2 (R = Me and Et, respectively). The enantiomers, which are due to the presence of the asymmetric sulfur atom, were resolved on a chiral stationary phase (DACH-DNB) having an SS configuration. Asymmetric oxidation reactions were employed to assign the absolute R configuration to the more retained enantiomers of alkyl aryl sulfoxides. The opposite trend (S being retained longer) was observed for diaryl sulfoxides such as 5 (R = Ph). In the case of the derivative with the largest interconversion barrier, sulfoxide 4, it was also possible to resolve (at -35-degrees-C) the two enantiomeric forms and their associated atropisomers. The use of on-line CD detection and the knowledge of the NMR assignments allowed us to unambiguously assign the elution order of the four species as ES, ER, ZS, ZR

Metasomatism induced by alkaline magma in the upper mantle of northern Victoria Land (Antarctica): an experimental approach

Magma generation in the Ross Sea system is related to partial melting of strongly metasomatised mantle sources where amphibole most probably plays a crucial role. In this context, metasomatism induced by a mela-nephelinite melt in lithospheric mantle of the Mt. Melbourne Volcanic Province (northern Victoria Land – NVL, Antarctica) was investigated experimentally studying the effects of melt interaction with lherzolite at 1.5-2.0 GPa and T=975-1300°C, and wehrlite at 1.0 GPa and T=1050-1250°C. The experiments were designed to induce melt infiltration into the ultramafic rocks. The observed modifications in minerals are compared with those found in mantle xenoliths from NVL. The effects of metasomatic modifications are evaluated on the basis of run temperature, distance from the infiltrating melt and on the diffusion rates of chemical components. Both in lherzolite and wehrlite, clinopyroxene exhibits large compositional variations ranging from primary diopside to high Mg-Cr-(Na) augitic and omphacitic clinopyroxenes in lherzolite, and to low Mg and high Ti-Al-Fe-Na augites in wehrlite. Olivine (in wehrlite) and spinel (in lherzolite) also result compositionally modified, the former shows enrichments in Fe, the latter displays a higher Cr/(Cr+Al) ratio. The systematic variations in mineral compositions imply modifications of the chemistry of the infiltrating melt as recorded by the glass veinlets and patches observed in some charges. In experiments involving wehrlite paragenesis, the glass composition approaches that of melt patches associated to both amphibole-free and amphibole-bearing natural samples, and is related to olivine+clinopyroxene crystallisation coupled with primary clinopyroxene dissolution at the contact between the metasomatising melt and the solid matrix. Even if amphibole crystallisation was not attained in the experiments, we were able to explain the occurrence of amphibole in the natural system considering that in this case a hot metasomatising melt infiltrates a cooler matrix

A general viscosity model of Campi Flegrei (Italy) melts

Viscosities of shoshonitic and latitic melts, relevant to the Campi Flegrei caldera magmas, have been experimentally determined at atmospheric pressure and 0.5 GPa, temperatures between 840 K and 1870 K, and H2O contents from 0.02 to 3.30 wt%. The concentric cylinder technique was employed at atmospheric pressure to determine viscosity of nominally anhydrous melts in the viscosity range of 101.5 - 103 Pa·s. The micropenetration technique was used to determine the viscosity of hydrous and anhydrous melts at atmospheric pressure in the high viscosity range (1010 Pa·s). Falling sphere experiments were performed at 0.5 GPa in the low viscosity range (from 100.35 to 102.79 Pa·s) in order to obtain viscosity data of anhydrous and hydrous melts. The combination of data obtained from the three different techniques adopted permits a general description of viscosity as a function of temperature and water content using the following modified VFT equation: where η is the viscosity in Pa·s, T the temperature in K, w the H2O content in wt%, and a, b, c, d, e, g are the VFT parameters. This model reproduces the experimental data (95 measurements) with a 1σ standard deviation of 0.19 and 0.22 log units for shoshonite and latite, respectively. The proposed model has been applied also to a more evolved composition (trachyte) from the same area in order to create a general model applicable to the whole compositional range of Campi Flegrei products. Moreover, speed data have been used to constrain the ascent velocity of latitic, shoshonitic, and trachytic melts within dikes. Using petrological data and volcanological information (geometrical parameters of the eruptive fissure and depth of magma storage), we estimate a time scale for the ascent of melt from 9 km to 4 km depth (where deep and shallow reservoirs, respectively, are located) in the order of few minutes. Such a rapid ascent should be taken into account for the hazard assessment in the Campi Flegrei area

Estrogen-dependent dynamic profile of eNOS-DNA associations in prostate cancer

In previous work we have documented the nuclear translocation of endothelial NOS (eNOS) and its participation in combinatorial complexes with Estrogen Receptor Beta (ERβ) and Hypoxia Inducible Factors (HIFs) that determine localized chromatin remodeling in response to estrogen (E2) and hypoxia stimuli, resulting in transcriptional regulation of genes associated with adverse prognosis in prostate cancer (PCa). To explore the role of nuclear eNOS in the acquisition of aggressive phenotype in PCa, we performed ChIP-Sequencing on chromatin-associated eNOS from cells from a primary tumor with poor outcome and from metastatic LNCaP cells. We found that: 1. the eNOS-bound regions (peaks) are widely distributed across the genome encompassing multiple transcription factors binding sites, including Estrogen Response Elements. 2. E2 increased the number of peaks, indicating hormone-dependent eNOS re-localization. 3. Peak distribution was similar with/without E2 with ≈ 55% of them in extragenic DNA regions and an intriguing involvement of the 5′ domain of several miRs deregulated in PCa. Numerous potentially novel eNOS-targeted genes have been identified suggesting that eNOS participates in the regulation of large gene sets. The parallel finding of downregulation of a cluster of miRs, including miR-34a, in PCa cells associated with poor outcome led us to unveil a molecular link between eNOS and SIRT1, an epigenetic regulator of aging and tumorigenicity, negatively regulated by miR-34a and in turn activating eNOS. E2 potentiates miR-34a downregulation thus enhancing SIRT1 expression, depicting a novel eNOS/SIRT1 interplay fine-tuned by E2-activated ER signaling, and suggesting that eNOS may play an important role in aggressive PCa

Thyroid Hormone T3 Counteracts STZ Induced Diabetes in Mouse

This study intended to demonstrate that the thyroid hormone T3 counteracts the onset of a Streptozotocin (STZ) induced diabetes in wild type mice. To test our hypothesis diabetes has been induced in Balb/c male mice by multiple low dose Streptozotocin injection; and a group of mice was contemporaneously injected with T3. After 48 h mice were tested for glucose tolerance test, insulin serum levels and then sacrified. Whole pancreata were utilized for morphological and biochemical analyses, while protein extracts and RNA were utilized for expression analyses of specific molecules. The results showed that islets from T3 treated mice were comparable to age- and sex-matched control, untreated mice in number, shape, dimension, consistency, ultrastructure, insulin and glucagon levels, Tunel positivity and caspases activation, while all the cited parameters and molecules were altered by STZ alone. The T3-induced pro survival effect was associated with a strong increase in phosphorylated Akt. Moreover, T3 administration prevented the STZ-dependent alterations in glucose blood level, both during fasting and after glucose challenge, as well as in insulin serum level. In conclusion we demonstrated that T3 could act as a protective factor against STZ induced diabetes

Telomerase activity, estrogen receptors (α, β), Bcl-2 expression in human breast cancer and treatment response

BACKGROUND: The mechanism for maintaining telomere integrity is controlled by telomerase, a ribonucleoprotein enzyme that specifically restores telomere sequences, lost during replication by means of an intrinsic RNA component as a template for polymerization. Among the telomerase subunits, hTERT (human telomerase reverse transcriptase) is expressed concomitantly with the activation of telomerase. The role of estrogens and their receptors in the transcriptional regulation of hTERT has been demonstrated. The current study determines the possible association between telomerase activity, the expression of both molecular forms of estrogen receptor (ERα and ERβ) and the protein bcl-2, and their relative associations with clinical parameters. METHODS: Tissue samples from 44 patients with breast cancer were used to assess telomerase activity using the TRAP method and the expression of ERα, ERβ and bcl-2 by means of immunocytochemical techniques. RESULTS: Telomerase activity was detected in 59% of the 44 breast tumors examined. Telomerase activity ranged from 0 to 49.93 units of total product generated (TPG). A correlation was found between telomerase activity and differentiation grade (p = 0.03). The only significant independent marker of response to treatment was clinical stage. We found differences between the frequency of expression of ERα (88%) and ERβ (36%) (p = 0.007); bcl-2 was expressed in 79.5% of invasive breast carcinomas. We also found a significant correlation between low levels of telomerase activity and a lack of ERβ expression (p = 0.03). CONCLUSION: Lower telomerase activity was found among tumors that did not express estrogen receptor beta. This is the first published study demonstrating that the absence of expression of ERβ is associated with low levels of telomerase activity

Effectiveness of student response systems in terms of learning environment, attitudes and achievement

In order to investigate the effectiveness of using Student Response Systems (SRS) among grade 7 and 8 science students in New York, the How Do You Feel About This Class? (HDYFATC) questionnaire was administered to 1097 students (532 students did use SRS and 565 students who did not use SRS). Data analyses attested to the sound factorial validity and internal consistency reliability of the HDYFATC, as well as its ability to differentiate between the perceptions of students in different classrooms. Very large differences between users and non-users of SRS, ranging from 1.17 to 2.45 standard deviations for various learning environment scales, attitudes and achievement, supported the efficacy of using SRS

Estrogenic Plant Extracts Reverse Weight Gain and Fat Accumulation without Causing Mammary Gland or Uterine Proliferation

Long-term estrogen deficiency increases the risk of obesity, diabetes and metabolic syndrome in postmenopausal women. Menopausal hormone therapy containing estrogens might prevent these conditions, but its prolonged use increases the risk of breast cancer, as wells as endometrial cancer if used without progestins. Animal studies indicate that beneficial effects of estrogens in adipose tissue and adverse effects on mammary gland and uterus are mediated by estrogen receptor alpha (ERα). One strategy to improve the safety of estrogens to prevent/treat obesity, diabetes and metabolic syndrome is to develop estrogens that act as agonists in adipose tissue, but not in mammary gland and uterus. We considered plant extracts, which have been the source of many pharmaceuticals, as a source of tissue selective estrogens. Extracts from two plants, Glycyrrhiza uralensis (RG) and Pueraria montana var. lobata (RP) bound to ERα, activated ERα responsive reporters, and reversed weight gain and fat accumulation comparable to estradiol in ovariectomized obese mice maintained on a high fat diet. Unlike estradiol, RG and RP did not induce proliferative effects on mammary gland and uterus. Gene expression profiling demonstrated that RG and RP induced estradiol-like regulation of genes in abdominal fat, but not in mammary gland and uterus. The compounds in extracts from RG and RP might constitute a new class of tissue selective estrogens to reverse weight gain, fat accumulation and metabolic syndrome in postmenopausal women

Advances in estrogen receptor biology: prospects for improvements in targeted breast cancer therapy

Estrogen receptor (ER) has a crucial role in normal breast development and is expressed in the most common breast cancer subtypes. Importantly, its expression is very highly predictive for response to endocrine therapy. Current endocrine therapies for ER-positive breast cancers target ER function at multiple levels. These include targeting the level of estrogen, blocking estrogen action at the ER, and decreasing ER levels. However, the ultimate effectiveness of therapy is limited by either intrinsic or acquired resistance. Identifying the factors and pathways responsible for sensitivity and resistance remains a challenge in improving the treatment of breast cancer. With a better understanding of coordinated action of ER, its coregulatory factors, and the influence of other intracellular signaling cascades, improvements in breast cancer therapy are emerging