Genetic analysis of maximum cigarette-use phenotypes

BACKGROUND: Using the Framingham Heart Study data set provided for Genetic Analysis Workshop 13, we defined the cigarette-use phenotype M for smokers to be the maximum number of cigarettes-per-day (MAXCIG) reported over the longitudinal course of the study. Adjustments were made for the significant covariates of gender and year of birth, and sib-pair based linkage analysis was performed. RESULTS: The primary analyses, in which individuals with MAXCIG = 0 were considered to have missing phenotype, resulted in modest linkage evidence, with LOD scores over 1 on chromosomes 5, 9, 13, 14, and 22. CONCLUSIONS: While the results reported here do not indicate definitive evidence for linkage to specific chromosomal regions, future studies may find it useful to include direct assessments of maximum and quantitative cigarette use. In defining and analyzing quantitative or "maximum use" phenotypes, the choice of how to handle individuals with MAXCIG = 0, or alternatively, individuals who are substance-naive, is a crucial one for genetic studies of nicotine and other substance use. In this study, the linkage results vary greatly depending on whether or not these "unexposed" individuals are included in the analyses

Genetic analysis of the maximum drinks phenotype

Using data provided by the Collaborative Study on the Genetics of Alcoholism we studied the genetics of a quantitative trait: the maximum number of drinks consumed in a 24-hour period. A two-stage method was used. First, linkage analysis was performed, followed by association analysis in regions where linkage was detected. Additionally, the extent of linkage disequilibrium among single-nucleotide polymorphisms (SNP) associated with the phenotype was assessed. Linkage to chromosomes 2 and 7 was detected, and follow-up association analysis found multiple trait-associated SNPs in the chromosome 7 linkage region. Chromosome 4, which has been implicated in previous studies of the maximum drinks phenotype, did not pass our threshold for linkage evidence in stage 1, but secondary analyses of this chromosome indicated modest evidence for both linkage and association. The evidence suggests that chromosome 7 may harbor an additional locus influencing the maximum drinks consumption phenotype

Halogen bonding stabilizes a cis-azobenzene derivative in the solid state: A crystallographic study

Crystals of trans- and cis-isomers of a fluorinated azobenzene derivative have been prepared and characterized by single-crystal X-ray diffraction. The presence of F atoms on the aromatic core of the azobenzene increases the lifetime of the metastable cis-isomer, allowing single crystals of the cis-azobenzene to be grown. Structural analysis on the cis-azobenzene, complemented with density functional theory calculations, highlights the active role of the halogen-bond contact (N...I synthon) in promoting the stabilization of the cis-isomer. The presence of a long aliphatic chain on the azobenzene unit induces a phase segregation that stabilizes the molecular arrangement for both the trans- and cis-isomers. Due to the rarity of cis-azobenzene crystal structures in the literature, our paper makes a step towards understanding the role of non-covalent interactions in driving the packing of metastable azobenzene isomers. This is expected to be important in the future rational design of solid-state, photoresponsive materials based on halogen bonding. We show by single-crystal X-ray diffraction studies and computational analysis that halogen bonding can stabilize a metastable cis-azobenzene derivative in the solid state

Coordination networks incorporating halogen-bond donor sites and azobenzene groups

Two Zn coordination networks, [Zn(1)(Py)2]2(2-propanol)n (3) and [Zn(1)2(Bipy)2](DMF)2n (4), incorporating halogen-bond (XB) donor sites and azobenzene groups have been synthesized and fully characterized. Obtaining 3 and 4 confirms that it is possible to use a ligand wherein its coordination bond acceptor sites and XB donor sites are on the same molecular scaffold (i.e., an aromatic ring) without interfering with each other. We demonstrate that XBs play a fundamental role in the architectures and properties of the obtained coordination networks. In 3, XBs promote the formation of 2D supramolecular layers, which, by overlapping each other, allow the incorporation of 2-propanol as a guest molecule. In 4, XBs support the connection of the layers and are essential to firmly pin DMF solvent molecules through I⋯O contacts, thus increasing the stability of the solvated systems

CELL-BASED BIOASSAYS FOR TESTING BIOACTIVE COMPOUNDS IN FARM ANIMALS

Cell-based assays can be adopted as in vitro method to evaluate the bioavailability and functionality of different nutraceutical and bioactive compounds, particularly in view of the need to use alternatives to animal studies. The interest in these bioactive compounds in animal sciences is not only related to medical research. It also represents an enormous benefit for health food companies and the animal produce sector in general. The general aim of my PhD study was to study nutraceutical effects at a cellular level in response to different stress challenges. In the first section of my thesis, the protective role of \u3b1-tocopherol in counteracting the cytotoxicity and DNA damage induced by Ochratoxin A (OTA) in primary porcine fibroblast cell cultures (ear and embryo), was determined by using the MTT assay, LDH release, DNA fragmentation, and TUNEL stain. The aim of the second section was to evaluate the protective role of bovine Lactoferrin (bLf), added to the culture medium, against lipopolysaccharide (LPS) cytotoxicity using the established bovine mammary epithelial cell line BME-UV1 as an in vitro model of the bovine mammary epithelium. In addition, we assessed whether BME-UV1 cells were able to express endogenous bLf after in vitro exposure to LPS. A further objective of my thesis work was to use cell-based bioassays to investigate the plasmin-plasminogen system. This system plays a key role in cellular responses, and is involved both in physiological and in pathological conditions in the mammary gland. The aim of the third section was to determine the effect of growth factors (IGF-1 and EGF) and three hormones (insulin, dexamethasone, and prolactin) on the expression of plasminogen activator (PA)-related genes (u-PA, u-PAR, PAI-1, PAI-2) and BME-UV1 cell proliferation. In addition we investigated the effects of E. coli LPS on cell viability, the modulation of cell-associated u-PA activity and the regulation of u-PA and u-PAR RNA expression in BME-UV1 cells. Below are more details on what each section covers: The first section reports how the role of \u3b1-tocopherol in counteracting OTA toxicity was evaluated in various experimental conditions using primary porcine fibroblasts. Cells showed a dose-, time- and origin-dependent (ear vs. embryo) sensitivity to ochratoxin A. Pre-incubation for 3 h with 1 nM \u3b1-tocopherol significantly (P < 0.01) reduced OTA cytotoxicity, lactate dehydrogenase release and DNA damage in both fibroblast cultures. These findings indicate that \u3b1-tocopherol administration may counteract short-term OTA toxicity, thus supporting its defensive role at a cell membrane level. The second section describes how BME-UV1 was used as an in vitro model to evaluate the protective role of exogenous bovine Lf (bLf) against the cytotoxic damage induced by bacterial lipopolysaccharides (LPS). Exogenous bLf showed a protective effect against endotoxin cytotoxicity, which could be mediated by the LPS-neutralizing capability of bLf. In addition, in BME-UV1 cells the response to LPS exposure did not involve endogenous bLf mRNA expression, suggesting that this cell line lacks functional LPS-responsive elements. The third section details how cell proliferation was measured using the MTT assay and direct cell enumeration on BME-UV1 treated with physiological stimuli. Results showed that both IGF-1 and EGF increased cell proliferation. Neither of the growth factors had any effect on the expression of PAI-1 and PAI-2. In line with changes in gene expression, EGF and IGF-1 up regulated total cell-associated, membrane-bound and secreted u-PA activity. Dexamethasone alone and when combined with insulin or prolactin up regulated the gene expression of both PAI- and PAI-2, but not that of u-PA and u-PAR without affecting cell proliferation. Total decreased cell-associated, membrane-bound and secreted u-PA activity was detected in cells cultured in the presence of dexamethasone when combined with insulin or prolactin. However no such effect was observed in the presence of dexamethasone alone. This thus suggests that when dexamethasone acts synergistically with prolactin or insulin it inhibits the activation of the plasmin-plasminogen system, but this inhibition is not correlated with any changes in cell proliferation. In addition, the plasmin-plasminogen system was examined, using the BME-UV1 cell model, in order to evaluate the effects of Escherichia coli LPS on cell viability, the modulation of cell-associated u-PA activity, and the regulation of u-PA and u-PA receptor (u-PAR) RNA expression. LPS did not affect cell viability, but led to an increase in u-PA activity, with the maximum response after 6 h of incubation. In addition, u-PA and u-PAR mRNA expression were both up-regulated in BME-UV1 cells after 3 h of incubation with LPS. These data indicated that E. coli LPS increased u-PA activity and RNA expression of u-PA and u-PAR in BME-UV1 cells, thus strengthening the role of the PA system during pathological processes. In conclusion, the application of appropriate in vitro models represents a fundamental requirement for the study of cellular responses to different stimuli as in the case covered in my thesis regarding nutraceutical compounds. Cell-based assays are a valuable tool for assessing fundamental regulatory mechanisms at a cellular level, such as the plasmin-plasminogen system. Cell-based assays allow both the functionality of nutraceutical and cellular response mechanisms to be evaluated reducing use animal models in the preliminary study phase. Obviously, data obtained in cell culture models must be interpreted carefully, since this system represents a simplification of the intricacies of the numerous reactions and interactions that occur in vivo

Early amniotomy after cervical ripening for induction of labor: a systematic review and meta-analysis of randomized controlled trials

OBJECTIVE DATA: Timing of artificial rupture of membranes (ie, amniotomy) in induction of labor is controversial, because it has been associated not only with shorter labors, but also with fetal nonreassuring testing, at times necessitating cesarean delivery. The aim of this systematic review and metaanalysis of randomized trials was to evaluate the effectiveness of early amniotomy vs late amniotomy or spontaneous rupture of membranes after cervical ripening. STUDY: The search was conducted with the use of electronic databases from inception of each database through February 2019. Review of articles included the abstracts of all references that were retrieved from the search. STUDY APPRAISAL AND SYNTHESIS METHODS: Selection criteria included randomized clinical trials that compared early amniotomy vs control (ie, late amniotomy or spontaneous rupture of membranes) after cervical ripening with either Foley catheter or prostaglandins at any dose. The primary outcome was the incidence of cesarean delivery. The summary measures were reported as summary relative risk with 95% of confidence interval with the use of the random effects model of DerSimonian and Laird. RESULTS: Four trials that included 1273 women who underwent cervical ripening with either Foley catheter or prostaglandins and then were assigned randomly to either early amniotomy, late amniotomy, or spontaneous rupture of membranes (control subjects) were included in the review. Women who were assigned randomly to early amniotomy had a similar risk of cesarean delivery (31.1% vs 30.9%; relative risk, 1.05; 95% confidence interval, 0.71-1.56) compared with control subjects and had a shorter interval from induction to delivery of approximately 5 hours (mean difference, -4.95 hours; 95% confidence interval, -8.12 to -1.78). Spontaneous vaginal delivery was also reduced in the early amniotomy group, but only 1 of the included trials reported this outcome (67.5% vs 69.1%; relative risk, 0.78; 95% confidence interval, 0.66-0.93). No between-group differences were reported in the other obstetrics or perinatal outcomes. CONCLUSION: After cervical ripening, routine early amniotomy does not increase the risk of cesarean delivery and reduces the interval from induction to delivery

Halogen Bonding beyond Crystals in Materials Science

Halogen bonding has recently gained well deserved attention in present-day research for its importance in many fields of supramolecular science and crystal engineering. Although generally overlooked in comprehensive studies in the past, halogen bonding has become an important tool also in the field of materials science. An increased number of scientific reports are published every year where halogen bonding is exploited in soft materials rather than in crystal engineering. Here, we focus on a description of the most exciting contemporary developments in the field of halogen-bonded functional soft materials, assembled using the guiding principles of crystal engineering. We give a particular emphasis to those published in the past few years

Efficient light-induced phase transitions in halogen-bonded liquid crystals

Here, we present a new family of light-responsive, fluorinated supramolecular liquid crystals (LCs) showing efficient and reversible light-induced LC-to-isotropic phase transitions. Our materials design is based on fluorinated azobenzenes, where the fluorination serves to strengthen the noncovalent interaction with bond-accepting stilbazole molecules, and increase the lifetime of the cis-form of the azobenzene units. The halogen-bonded LCs were characterized by means of X-ray diffraction, hot-stage polarized optical microscopy, and differential scanning calorimetry. Simultaneous analysis of light-induced changes in birefringence, absorption, and optical scattering allowed us to estimate that &lt;4% of the mesogenic units in the cis-form suffices to trigger the full LC-to-isotropic phase transition. We also report a light-induced and reversible crystal-to-isotropic phase transition, which has not been previously observed in supramolecular complexes. In addition to fundamental understanding of light-responsive supramolecular complexes, we foresee this study to be important in the development of bistable photonic devices and supramolecular actuators