Deletion of the gabra2 gene results in hypersensitivity to the acute effects of ethanol but does not alter ethanol self administration

Human genetic studies have suggested that polymorphisms of the GABRA2 gene encoding the GABA(A) α2-subunit are associated with ethanol dependence. Variations in this gene also convey sensitivity to the subjective effects of ethanol, indicating a role in mediating ethanol-related behaviours. We therefore investigated the consequences of deleting the α2-subunit on the ataxic and rewarding properties of ethanol in mice. Ataxic and sedative effects of ethanol were explored in GABA(A) α2-subunit wildtype (WT) and knockout (KO) mice using a Rotarod apparatus, wire hang and the duration of loss of righting reflex. Following training, KO mice showed shorter latencies to fall than WT littermates under ethanol (2 g/kg i.p.) in both Rotarod and wire hang tests. After administration of ethanol (3.5 g/kg i.p.), KO mice took longer to regain the righting reflex than WT mice. To ensure the acute effects are not due to the gabra2 deletion affecting pharmacokinetics, blood ethanol concentrations were measured at 20 minute intervals after acute administration (2 g/kg i.p.), and did not differ between genotypes. To investigate ethanol's rewarding properties, WT and KO mice were trained to lever press to receive increasing concentrations of ethanol on an FR4 schedule of reinforcement. Both WT and KO mice self-administered ethanol at similar rates, with no differences in the numbers of reinforcers earned. These data indicate a protective role for α2-subunits, against the acute sedative and ataxic effects of ethanol. However, no change was observed in ethanol self administration, suggesting the rewarding effects of ethanol remain unchange

Diversity of universes created by pure gravity

We show that a number of problems of modern cosmology may be solved in the framework of multidimensional gravity with high-order curvature invariants, without invoking other fields. We use a method employing a slow-change approximation, able to work with rather a general form of the gravitational action, and consider Kaluza-Klein type space-times with one or several extra factor spaces. A vast choice of effective theories suggested by the present framework may be stressed: even if the initial Lagrangian is entirely fixed, one obtains quite different models for different numbers, dimensions and topologies of the extra factor spaces. As examples of problems addressed we consider (i) explanation of the present accelerated expansion of the Universe, with a reasonably small cosmological constant, and the problem of its fine tuning is considered from a new point of view; (ii) the mechanism of closed wall production in the early Universe; such walls are necessary for massive primordial black hole formation which is an important stage in some scenarios of cosmic structure formation; (iii) sufficient particle production rate at the end of inflation; (iv) it is shown that our Universe may contain spatial domains with a macroscopic size of extra dimensions. We also discuss chaotic attractors appearing at possible nodes of the kinetic term of the effective scalar field Lagrangian.Comment: 14 pages, 8 figures, revtex4. Final version, some considerations added in response to referee remark

Does backreaction enforce the averaged null energy condition in semiclassical gravity?

The expected stress-energy tensor of quantum fields generically violates the local positive energy conditions of general relativity. However, may satisfy some nonlocal conditions such as the averaged null energy condition (ANEC), which would rule out traversable wormholes. Although ANEC holds in Minkowski spacetime, it can be violated in curved spacetimes if one is allowed to choose the spacetime and quantum state arbitrarily, without imposition of the semiclassical Einstein equation G_{ab} = 8 \pi . In this paper we investigate whether ANEC holds for solutions to this equation, by studying a free, massless scalar field with arbitrary curvature coupling in perturbation theory to second order about the flat spacetime/vacuum solution. We "reduce the order" of the perturbation equations to eliminate spurious solutions, and consider the limit in which the lengthscales determined by the incoming state are much larger than the Planck length. We also need to assume that incoming classical gravitational radiation does not dominate the first order metric perturbation. We find that although the ANEC integral can be negative, if we average the ANEC integral transverse to the geodesic with a suitable Planck scale smearing function, then a strictly positive result is obtained in all cases except for the flat spacetime/vacuum solution. This result suggests --- in agreement with conclusions drawn by Ford and Roman from entirely independent arguments --- that if traversable wormholes do exist as solutions to the semiclassical equations, they cannot be macroscopic but must be ``Planck scale''. A large portion of our paper is devoted to the analysis of general issues concerning the nature of the semiclassical Einstein equation and of prescriptions for extracting physically relevant solutions.Comment: 54 pages, 3 figures, uses revtex macros and epsf.tex, to appear in Phys Rev D. A new appendix has been added showing consistency of our results with recent results of Visser [gr-qc/9604008]. Some corrections were made to Appendix A, and several other minor changes to the body of the paper also were mad

Statistical characteristics of formation and evolution of structure in the universe

An approximate statistical description of the formation and evolution of structure of the universe based on the Zel'dovich theory of gravitational instability is proposed. It is found that the evolution of DM structure shows features of self-similarity and the main structure characteristics can be expressed through the parameters of initial power spectrum and cosmological model. For the CDM-like power spectrum and suitable parameters of the cosmological model the effective matter compression reaches the observed scales $R_{wall}\sim$20 -- 25$h^{-1}$Mpc with the typical mean separation of wall-like elements $D_{SLSS}\sim$50 -- 70$h^{-1}$Mpc. This description can be directly applied to the deep pencil beam galactic surveys and absorption spectra of quasars. For larger 3D catalogs and simulations it can be applied to results obtained with the core-sampling analysis. It is shown that the interaction of large and small scale perturbations modulates the creation rate of early Zel'dovich pancakes and generates bias on the SLSS scale. For suitable parameters of the cosmological model and reheating process this bias can essentially improve the characteristics of simulated structure of the universe. The models with $0.3\leq \Omega_m \leq 0.5$ give the best description of the observed structure parameters. The influence of low mass "warm" dark matter particles, such as a massive neutrino, will extend the acceptable range of $\Omega_m$ and $h$.Comment: 20pages, 7 figures, MNRAS in pres

Design, synthesis, cytotoxic activity and molecular docking studies of new 20(S)-sulfonylamidine camptothecin derivatives

20(S)-Sulfonylamidine CPT-derivatives were prepared and tested for cytotoxicity.Several analogs showed superior cytotoxic activity compared to irinotecan.Key structural features related to cytotoxicity were identified by SAR analysis.Compounds 9 and 15c interacted with Topo I-DNA by a different binding mode from CPT.These compounds are new generation CPT-derived antitumor agents.In an ongoing investigation of 20-sulfonylamidine derivatives (9, YQL-9a) of camptothecin (1) as potential anticancer agents directly and selectively inhibiting topoisomerase (Topo) I, the sulfonylamidine pharmacophore was held constant, and a camptothecin derivatives with various substitution patterns were synthesized. The new compounds were evaluated for antiproliferative activity against three human tumor cell lines, A-549, KB, and multidrug resistant (MDR) KB subline (KBvin). Several analogs showed comparable or superior antiproliferative activity compared to the clinically prescribed 1 and irinotecan (3). Significantly, the 20-sulfonylamidine derivatives exhibited comparable cytotoxicity against KBvin, while 1 and 3 were less active against this cell line. Among them, compound 15c displayed much better cytotoxic activity than the controls 1, 3, and 9. Novel key structural features related to the antiproliferative activities were identified by structure–activity relationship (SAR) analysis. In a molecular docking model, compounds 9 and 15c interacted with Topo I-DNA through a different binding mode from 1 and 3. The sulfonylamidine side chains of 9 and 15c could likely form direct hydrogen bonds with Topo I, while hydrophobic interaction with Topo I and π–π stacking with double strand DNA were also confirmed as binding driving forces. The results from docking models were consistent with the SAR conclusions. The introduction of bulky substituents at the 20-position contributed to the altered binding mode of the compound by allowing them to form new interactions with Topo I residues. The information obtained in this study will be helpful for the design of new derivatives of 1 with most promising anticancer activity.CPT (green), 9 (magenta), and 15c (blue) in the binding site of DNA-Topo-I

中正嶺學報 第三十五卷 第一期 民國95.11

ABSTRACT The regression curve, obtained for project control of large-scale or small-scale engineering, is smoothly connected by a Takagi-Sugeno fuzzy model. A sample of data taken from Department of Rapid Transit Systems, Taipei City Government is used to demonstrate the concept of the proposed regression model using statistical method. This developed S-curve equation could be used in a variety of applications related to project control in the working capital management of construction firms

A ferritin-based COVID-19 nanoparticle vaccine that elicits robust, durable, broad-spectrum neutralizing antisera in non-human primates

While the rapid development of COVID-19 vaccines has been a scientific triumph, the need remains for a globally available vaccine that provides longer-lasting immunity against present and future SARS-CoV-2 variants of concern (VOCs). Here, we describe DCFHP, a ferritin-based, protein-nanoparticle vaccine candidate that, when formulated with aluminum hydroxide as the sole adjuvant (DCFHP-alum), elicits potent and durable neutralizing antisera in non-human primates against known VOCs, including Omicron BQ.1, as well as against SARS-CoV-1. Following a booster ~one year after the initial immunization, DCFHP-alum elicits a robust anamnestic response. To enable global accessibility, we generated a cell line that can enable production of thousands of vaccine doses per liter of cell culture and show that DCFHP-alum maintains potency for at least 14 days at temperatures exceeding standard room temperature. DCFHP-alum has potential as a once-yearly (or less frequent) booster vaccine, and as a primary vaccine for pediatric use including in infants

Effects of work-related factors on the breastfeeding behavior of working mothers in a Taiwanese semiconductor manufacturer: a cross-sectional survey

BACKGROUND: In recent years, the creation of supportive environments for encouraging mothers to breastfeed their children has emerged as a key health issue for women and children. The provision of lactation rooms and breast pumping breaks have helped mothers to continue breastfeeding after returning to work, but their effectiveness is uncertain. The aim of this study was to assess the effects of worksite breastfeeding-friendly policies and work-related factors on the behaviour of working mothers. METHODS: This study was conducted at a large Taiwanese semiconductor manufacturer in August-September 2003. Questionnaires were used to collect data on female employees' breastfeeding behaviour, child rearing and work status when raising their most recently born child. A total of 998 valid questionnaires were collected, giving a response rate of 75.3%. RESULTS: The results showed that 66.9% of survey respondents breastfed initially during their maternity leave, which averaged 56 days. Despite the provision of lactation rooms and breast pumping breaks, only 10.6% mothers continued to breastfeed after returning to work, primarily office workers and those who were aware of their company's breastfeeding-friendly policies. CONCLUSION: In conclusion, breastfeeding-friendly policies can significantly affect breastfeeding behaviour. However, an unfavourable working environment, especially for fab workers, can make it difficult to implement breastfeeding measures. With health professionals emphasizing that the importance of breastfeeding for infant health, and as only females can perform lactation, it is vital that women's work "productive role" and family "reproductive role" be respected and accommodated by society