Cannabinoid/Endocannabinoid signaling impact on early pregnancy events.
It has been known for decades that marijuana and its major psychoactive component Δ⁹-tetrahydrocannabinol (THC) alter both male and female reproductive functions in humans and laboratory animals. The discovery of cannabinoid-like molecules (endocannabinoids), anandamide (AEA) and 2-arachidonylglycerol (2AG), as well as G-protein-coupled cannabinoid/endocannabinoid receptors CB₁ and CB₂, created an opportunity to study the adverse and beneficial effects of cannabinoids/endocannabinoids on fertility using molecular, physiological and genetic approaches. In fact, studies to explore the significance of cannabinoid/endocannabinoid signaling in reproduction have revealed some intriguing physiological roles in early pregnant events. This review summarizes some aspects of these signaling molecules in preimplantation and implantation biology utilizing genetically engineered mouse models.

title: Aspects of endocannabinoid signaling in periimplantation biology
abstract: Physiological roles of endocannabinoids, a group of endogenously produced cannabinoid-like lipid molecules that activate G protein-coupled cannabinoid receptors, are being increasingly appreciated in female reproduction. Adverse effects of cannabinoids on female fertility have been suspected for decades; however, underlying molecular and genetic bases by which they exert these effects were not clearly understood. The discovery of cannabinoid receptors (CB1 and CB2), endocannabinoid ligands (anandamide and 2-acylglycerol) as well as their key synthetic and hydrolytic pathways has helped to better understand the roles of cannabinoid/endocannabinoid signaling in preimplantation embryo development, oviductal embryo transport, embryo implantation and postimplantation embryonic growth. This review focuses on various aspects of the endocannabinoid system in female fertility based on studies that used knockout mouse models. The information generated from studies in mice is likely to shed deeper insight into fertility regulation in women.

title: [Isolation of a metsulfuron-methyl-resistant bacteria and cloning and expression of the acetohydroxyacid synthase genes ilvlH].
abstract: Acetohydroxyacid synthase (EC 4.1.3.18) is the enzyme that catalyses the first step in the synthesis of the branched-chain amino acids valine, leucine and isoleucine in plant, fungi and bacteria, and also is target of the sulfonylurea, imidazolinone, triazolopyrimidine and other acetohydroxyacid synthase inhibitor herbicides.



The purpose of this study is to get the resistant gene, prepare a functional bacteria with acetohydroxyacid synthase, and investigate the relationship between the mutation sites of the acetohydroxyacid synthase and the herbicides-resistant.



A metsulfuron-methyl-resistant bacterium Lm10 was isolated from metsulfuron-methyl contaminated soil. Acetohydroxyacid synthase genes ilvIH was amplified from the genome DNA of strains Lm10 by PCR. The ilvI and ilvH were cloned into the bacterial expression vector pET29a(+) respectively.



Strain Lm10 was identified preliminarily as Pseudomonas sp.. It can endure 14000 micromol/L metsulfuron-methyl and showed cross resistance to diffenent acetohydroxyacid synthase inhibitor herbicids, such as chlorsulfuron, imazethapyr, flumetsulam and penoxsulam. The alignment result of the ilvIH amino acid sequence showed that ilvI of strains Lm10 differed from that of strain KT2440 by 6 sites, While the ilvH of the two strains were the same. The gene ilvI and ilvH were functional expressed in the Escherichia coli strain BL21(DE3) respectively. The expressed production pET-I displayed acetohydroxyacid synthase activity and showed resistance to high concentration of metsulfuron-methyl.



The ilvI displayed acetohydroxyacid synthase activity. The 6 different sites in ilvI of strains Lml0 probably led to herbicids resistance.

title: Kruppel-like factor 5 (KLF5) is critical for conferring uterine receptivity to implantation
abstract: A blastocyst will implant only when the uterus becomes receptive. Following attachment, luminal epithelial cells undergo degeneration at the site of the blastocyst. Although many genes critical for uterine receptivity are primarily regulated by ovarian hormones, Kruppel-like factor 5 (KLF5), a zinc finger-containing transcription factor, is persistently expressed in epithelial cells independently of ovarian hormones. Loss of uterine Klf5 causes female infertility due to defective implantation. Cox2 is normally expressed in the luminal epithelium and stroma at the site of blastocyst attachment, but luminal epithelial COX2 expression is absent with loss of Klf5. This is associated with the retention of the epithelium around the implantation chamber with arrested embryonic growth. These results suggest that Klf5 is indispensable for normal implantation.

title: Endocannabinoid signaling in female reproduction.
abstract: Marijuana is a preparation of the flower, as well as the leaves and seeds, of the plant Cannabis sativa. Marijuana has been used for medicinal and recreational purposes for thousands of years due to its psychoactive effects including euphoria, sedation, and analgesia. Although it has been suspected for decades that marijuana has adverse effects on female fertility, the underlying molecular mechanism was not clear. The discovery of cannabinoid receptors and endocannabinoids has advanced studies if cannabinoid signaling. Since then, numerous studies have been published on cannabinoid signaling in female reproductive events, including preimplantation embryo development, oviductal embryo transport, embryo implantation, placentation, and parturition. This review focuses on various aspects of endocannabinoid signaling in female fertility.

title: Uterine deletion of Gp130 or Stat3 shows implantation failure with increased estrogenic responses.
abstract: Leukemia inhibitory factor (LIF), a downstream target of estrogen, is essential for implantation in mice. LIF function is thought to be mediated by its binding to LIF receptor (LIFR) and recruitment of coreceptor GP130 (glycoprotein 130), and this receptor complex then activates signal transducer and activator of transcription (STAT)1/3. However, the importance of LIFR and GP130 acting via STAT3 in implantation remains uncertain, because constitutive inactivation of Lifr, Gp130, or Stat3 shows embryonic lethality in mice. To address this issue, we generated mice with conditional deletion of uterine Gp130 or Stat3 and show that both GP130 and STAT3 are critical for uterine receptivity and implantation. Implantation failure in these deleted mice is associated with higher uterine estrogenic responses prior to the time of implantation. These heightened estrogenic responses are not due to changes in ovarian hormone levels or expression of their nuclear receptors. In the deleted mice, estrogen-responsive gene, Lactoferrin (Ltf), and Mucin 1 protein, were up-regulated in the uterus. In addition, progesterone-responsive genes, Hoxa10 and Indian hedgehog (Ihh), were markedly down-regulated in STAT3-inactivated uteri. These changes in uteri of deleted mice were reflected by the failure of differentiation of the luminal epithelium, which is essential for blastocyst attachment.

title: Up-regulation of survivin by AKT and hypoxia-inducible factor 1α contributes to cisplatin resistance in gastric cancer.
abstract: This study investigated the contribution of survivin and its upstream regulators, AKT and hypoxia-inducible factor 1α (HIF-1α), to the resistance of gastric cancer cells to cisplatin (CDDP). We found that over-expression of survivin increased the resistance of SGC7901 and BGC823 gastric cancer cells to CDDP. Its over-expression abrogated CDDP-induced inhibition of cell proliferation and CDDP-induced cell apoptosis. In contrast, down-regulation of survivin expression using small hairpin RNA (shRNA) vectors and the small-molecule inhibitor YM155, or inhibition of survivin function using a recombinant cell-permeable dominant-negative survivin protein (dNSur9), promoted CDDP-induced apoptosis. CDDP-resistant sub-lines generated from the parental SGC7901 and BGC823 cells by exposure to increasing concentrations of CDDP expressed higher levels of HIF-1α and survivin in response to hypoxia, and higher levels of phosphorylated AKT (pAKT). Specific inhibition of AKT reduced the expression of HIF-1α and survivin, whereas specific inhibition or depletion of HIF-1α reduced survivin expression but had no effect on the expression of phosphorylated AKT. The expression levels of survivin affected the therapeutic efficacy of CDDP in treating gastric tumors in mice. Specific inhibition of survivin, AKT and HIF-1α enhanced the sensitivity of CDDP-resistant cells to CDDP. Specific inhibition of survivin, AKT and HIF-1α synergized with CDDP to suppress the growth of gastric tumors that had been engineered to overexpress survivin. In summary, the results provide evidence that up-regulation of survivin by AKT and HIF-1α contributes to CDDP resistance, indicating that inhibition of these pathways may be a potential strategy for overcoming CDDP resistance in the treatment of gastric cancer.

title: Subgroup Analysis of Trials Is Rarely Easy (SATIRE): a study protocol for a systematic review to characterize the analysis, reporting, and claim of subgroup effects in randomized trials
abstract: BackgroundSubgroup analyses in randomized trials examine whether effects of interventions differ between subgroups of study populations according to characteristics of patients or interventions. However, findings from subgroup analyses may be misleading, potentially resulting in suboptimal clinical and health decision making. Few studies have investigated the reporting and conduct of subgroup analyses and a number of important questions remain unanswered. The objectives of this study are: 1) to describe the reporting of subgroup analyses and claims of subgroup effects in randomized controlled trials, 2) to assess study characteristics associated with reporting of subgroup analyses and with claims of subgroup effects, and 3) to examine the analysis, and interpretation of subgroup effects for each study's primary outcome.MethodsWe will conduct a systematic review of 464 randomized controlled human trials published in 2007 in the 118 Core Clinical Journals defined by the National Library of Medicine. We will randomly select journal articles, stratified in a 1:1 ratio by higher impact versus lower impact journals. According to 2007 ISI total citations, we consider the New England Journal of Medicine, JAMA, Lancet, Annals of Internal Medicine, and BMJ as higher impact journals. Teams of two reviewers will independently screen full texts of reports for eligibility, and abstract data, using standardized, pilot-tested extraction forms. We will conduct univariable and multivariable logistic regression analyses to examine the association of pre-specified study characteristics with reporting of subgroup analyses and with claims of subgroup effects for the primary and any other outcomes.DiscussionA clear understanding of subgroup analyses, as currently conducted and reported in published randomized controlled trials, will reveal both strengths and weaknesses of this practice. Our findings will contribute to a set of recommendations to optimize the conduct and reporting of subgroup analyses, and claim and interpretation of subgroup effects in randomized trials.

title: Surface-emitting circular DFB, disk- and ring- Bragg resonator lasers with chirped gratings: a unified theory and comparative study.
abstract: We have developed a theory that unifies the analysis of the modal properties of surface-emitting chirped circular grating lasers. This theory is based on solving the resonance conditions which involve two types of reflectivities of chirped circular gratings. This approach is shown to be in agreement with previous derivations which use the characteristic equations. Utilizing this unified analysis, we obtain the modal properties of circular DFB, disk-, and ring- Bragg resonator lasers. We also compare the threshold gain, single mode range, quality factor, emission efficiency, and modal area of these types of circular grating lasers. It is demonstrated that, under similar conditions, disk Bragg resonator lasers have the highest quality factor, the highest emission efficiency, and the smallest modal area, indicating their suitability in low-threshold, high-efficiency, ultracompact laser design, while ring Bragg resonator lasers have a large single mode range, high emission efficiency, and large modal area, indicating their suitability for high-efficiency, large-area, high-power applications.

title: Multifarious Roles of Intrinsic Disorder in Proteins Illustrate Its Broad Impact on Plant Biology
abstract: Intrinsically disordered proteins (IDPs) are highly abundant in eukaryotic proteomes. Plant IDPs play critical roles in plant biology and often act as integrators of signals from multiple plant regulatory and environmental inputs. Binding promiscuity and plasticity allow IDPs to interact with multiple partners in protein interaction networks and provide important functional advantages in molecular recognition through transient protein–protein interactions. Short interaction-prone segments within IDPs, termed molecular recognition features, represent potential binding sites that can undergo disorder-to-order transition upon binding to their partners. In this review, we summarize the evidence for the importance of IDPs in plant biology and evaluate the functions associated with intrinsic disorder in five different types of plant protein families experimentally confirmed as IDPs. Functional studies of these proteins illustrate the broad impact of disorder on many areas of plant biology, including abiotic stress, transcriptional regulation, light perception, and development. Based on the roles of disorder in the protein–protein interactions, we propose various modes of action for plant IDPs that may provide insight for future experimental approaches aimed at understanding the molecular basis of protein function within important plant pathways.

title: Angiostatin enhances B7.1-mediated cancer immunotherapy independently of effects on vascular endothelial growth factor expression
abstract: Tumors must develop an adequate vascular network to meet their increasing demands for nutrition and oxygen. Angiostatin, a multiple kringle (1–4)–containing fragment of plasminogen, is an effective natural inhibitor of tumor angiogenesis. Here we show that gene transfer of angiostatin into small (0.1 cm in diameter) solid EL-4 lymphomas established in syngeneic C57BL/6 mice led to reduced tumor angiogenesis and weak inhibition of tumor growth. In contrast, when angiostatin gene therapy was preceded by in situ gene transfer of the T-cell costimulator B7.1, large (0.4 cm in diameter) tumors were rapidly and completely eradicated, whereas B7.1 and angiostatin monotherapies were ineffective. Combined gene transfer of B7.1 and angiostatin generated potent systemic antitumor immunity that was effective in eradicating a systemic challenge of 107 EL-4 cells. Gene transfer of angiostatin expression plasmids led to overexpression of angiostatin in tumors, increased apoptosis of tumor cells, and decreased density of tumor blood vessels, which may allow the immune system to overcome tumor immune resistance. The latter effects were not the result of a decrease in vascular endothelial growth factor expression, as tumoral vascular endothelial growth factor expression increased slightly after angiostatin gene transfer, presumably in response to increasing hypoxia. These results suggest that combining immunogene therapy with a vascular attack by angiostatin is a particularly effective approach for eliciting antitumor immunity. Cancer Gene Therapy (2001) 8, 719–727