Miracle-dz/UniFAR-FTUs huggingface dataset:
Eects of the Aconitum alkaloid mesaconitine in rat hippocampal slices and the involvement of a- and b-adrenoceptors

1 The eects of mesaconitine, the main alkaloid contained in Aconiti tuber, were investigated by use of extracellular recordings of stimulus-evoked population spikes and ®eld excitatory postsynaptic potentials (e.p.s.ps) in the CA1 region of rat hippocampal slices. 2 At a concentration of 10 nM, mesaconitine evoked excitations, which were manifested as an increase in the amplitude of the orthodromic spike and the appearance of multiple spikes following the ®rst postsynaptic spike, without aecting the magnitude of paired-pulse facilitation. The increase in spike amplitude was persistent and was not reversed by up to 90 min of washout. At concentrations of 30 and 100 nM, the alkaloid produced a biphasic eect, that is an excitation followed by an inhibition without having any eect upon the ®eld e.p.s.p. At concentrations above 100 nM, mesaconitine suppressed the orthodromic population spike and the ®eld e.p.s.p. 3 The excitatory eect was also observed when electrical stimulation was stopped completely during the application of mesaconitine (10 nM) and during the ®rst 15 min of washout. 4 The enhancement of the population spike and the appearance of multiple spikes induced by mesaconitine (10 ± 100 nM) were blocked by pretreatment with the b-adrenoceptor antagonists propranolol (1 mM) and timolol (1 mM), whereas the inhibitory eect was blocked by the a-adrenoceptor antagonists yohimbine (1 mM) and phentolamine (10 mM). However, when the b-adrenoceptor antagonist timolol was added 10 min after the application of mesaconitine, it failed to block the long-lasting enhancement of the spike amplitude and the appearance of multiple population spikes. 5 Application of the selective b-adrenoceptor agonist isoprenaline (500 nM) to the hippocampal slices induced an increase in the amplitude of the orthodromic population spike and elicited 2 ± 3 additional spikes. Mesaconitine (10 nM) did not further potentiate this enhancement of the spike amplitude when added after a 15 min pretreatment with isoprenaline. 6 Perfusion of forskolin, which directly activates adenylate cyclase, enhanced the population spike. Mesaconitine had no additional eect when applied after pretreatment with forskolin. 7 It is concluded that the excitatory eects evoked by lower concentrations of the plant alkaloid mesaconitine are mediated by stimulation of b-adrenoceptors and the consequent activation of intracellular processes which lead to the long-lasting changes in excitability.
Sorting out the functional role(s) of peroxisome proliferator- activated receptor-β/δ (PPARβ/δ) in cell proliferation and cancer

Peroxisome proliferator-activated receptor-β/δ (PPARβ/δ) has many beneficial physiological functions ranging from enhancing fatty acid catabolism, improving insulin sensitivity, inhibiting inflammation and increasing oxidative myofibers allowing for improved athletic performance. Thus, given the potential for targeting PPARβ/δ for the prevention and/or treatment of diseases including diabetes, dyslipidemias, metabolic syndrome and cancer, it is critical to clarify the functional role of PPARβ/δ in cell proliferation and associated disorders such as cancer. However, there is considerable controversy whether PPARβ/δ stimulates or inhibits cell proliferation. This review summarizes the literature describing the influence of PPARβ/δ on cell proliferation, with an emphasis toward dissecting the data that give rise to opposing hypotheses. Suggestions are offered to standardize measurements associated with these studies so that interlaboratory comparisons can be accurately assessed.
Changes in Diet after Introduction of a Full Service Supermarket in a Food Desert

Tamara Dubowitz1, Madhumita Ghosh-Dastidar1, Deborah A. Cohen1, Robin Beckman1, Elizabeth D. Steiner1, Gerald P. Hunter1, Karen R. Flórez1, Christina Huang1, Christine A. Vaughan1, Jennifer C. Sloan1, Shannon N. Zenk2, Steven Cummins3, and Rebecca L. Collins1 Tamara Dubowitz: dubowitz@rand.org 1senior policy researcher at the RAND Corporation in Pittsburgh, Pennsylvania. 1senior statistician at RAND in Arlington, Virginia. 1senior natural scientist at RAND in Santa Monica, California. 1research programmer at RAND in Santa Monica. 1project associate at RAND in Pittsburgh. 1research programmer at RAND in Pittsburgh. 1associate social scientist at RAND in Santa Monica. 1doctoral fellow at the Pardee RAND Graduate School and an assistant policy analyst at RAND, both in Santa Monica.
Expression of β-subunit of human chorionic gonadotropin genes during the normal and failed pregnancy

BACKGROUND—One of the first proteins synthesized by a conceptus, is human chorionic gonadotropin (hCG). The receptor-binding β-subunit of hCG (hCGβ) is encoded by highly homologous CGB, CGB5, CGB7 and CGB8 genes. The function of two additional gene copies, CGB1 and CGB2, is still unknown. AIM—We aimed to compare the expression of individual CGB genes during the normal pregnancy and in cases of recurrent miscarriages (RM) and ectopic pregnancy (EP) METHODS—A semi-quantitative RT-PCR with fluorescent-labeled primers coupled with the gene-specific restriction and quantification was used. RESULTS—The summarized expression of hCGβ genes was high throughout the pregnancy, and moderately correlated with hCG in serum. In cases of RM, reduced hormone values were consistent with low mRNA levels, whereas for EP no reduction in transcriptional activity was detected. CGB1 and CGB2 showed a considerable expressional peak during the first trimester, both in normal and ectopic pregnancy, but not for RM. CONCLUSIONS—In case of RM, low hCG could result from expressional failure of hCGβ genes, whereas in EP the problems other than the transcriptional failure contribute to reduced hormone levels. The expression patterns of CGB1 and CGB2 suggest their putative role in the implantation stage.
Smoking-Cue Induced Brain Activation In Adolescent Light Smokers

Purpose—Using fMRI, we examined whether or not adolescents with low levels of nicotine exposure (light smokers) display neural activation in areas shown to be involved with addiction in response to smoking-related stimuli. Design/Setting/Participants—Twelve adolescent light smokers (aged 13 to17, smoked 1 to 5 cigarettes per day) and 12 non-smokers (ages 13 to 17, never smoked a cigarette) from the San Francisco Bay Area underwent fMRI scanning. During scanning they viewed blocks of photographic smoking and control cues. Smoking cues consisted of pictures of people smoking cigarettes and smoking-related objects such as lighters and ashtrays. Neutral cues consisted of everyday objects and people engaged in everyday activities. Findings—For smokers, smoking cues elicited greater activation than neutral cues in the mesolimbic reward circuit (left anterior cingulate (T=7.88, p<.001), right hippocampus (T=6.62, p<.001) and right parahippocampal gyrus (T=4.70, p<.001)). We found activation from smoking cues versus neutral cues within both the left and right frontal medial orbital regions (T=5.09, p<. 001 and T=3.94, p=.001 respectively), which may be unique to adolescents. Non-smokers showed no significant difference in activation between smoking-related cues and neutral cues. Conclusions—Our finding that smoking cues produced activation in adolescent light smokers in brain regions seen in adult and heavy teen smokers suggests that even at low levels of smoking, adolescents exhibit heightened reactivity to smoking cues. This paper adds to the existing literature suggesting that nicotine dependence may begin with exposure to low levels of nicotine, underscoring the need for early intervention among adolescent smokers.
Involvement of Integrin v 3 and Cell Adhesion Molecule L1 in Transendothelial Migration of Melanoma Cells

Tumor metastasis involves many stage-specific adhesive interactions. The expression of several cell adhesion molecules, notably the integrin v 3, has been associated with the metastatic potential of tumor cells. In this study, we used a novel in vitro assay to examine the role of v 3 in the transmigration of melanoma cells through a monolayer of human lung microvascular endothelial cells. Confocal microscopy revealed the presence of the integrin v 3 on melanoma membrane protrusions and pseudopods penetrating the endothelial junction. v 3 was also enriched in heterotypic contacts between endothelial cells and melanoma cells. Transendothelial migration of melanoma cells was inhibited by either a cyclic Arg-Gly-Asp peptide or the antiv 3 monoclonal antibody LM609. Although both platelet endothelial cell adhesion molecule-1 and L1 are known to bind integrin v 3, only L1 serves as a potential ligand for v 3 during melanoma transendothelial migration. Also, polyclonal antibodies against L1 partially inhibited the transendothelial migration of melanoma cells. However, addition of both L1 and v 3 antibodies did not show additive effects, suggesting that they are components of the same adhesion system. Together, the data suggest that interactions between the integrin v 3 on melanoma cells and L1 on endothelial cells play an important role in the transendothelial migration of melanoma cells.
TRANSLATIONAL REVIEW Noninvasive Imaging of Experimental Lung Fibrosis

Small animal models of lung fibrosis are essential for unraveling the molecular mechanisms underlying human fibrotic lung diseases; additionally, they are useful for preclinical testing of candidate antifibrotic agents. The current end-point measures of experimental lung fibrosis involve labor-intensive histological and biochemical analyses. These measures fail to account for dynamic changes in the disease process in individual animals and are limited by the need for large numbers of animals for longitudinal studies. The emergence of noninvasive imaging technologies provides exciting opportunities to image lung fibrosis in live animals as often as needed and to longitudinally track the efficacy of novel antifibrotic compounds. Data obtained by noninvasive imaging provide complementary information to histological and biochemical measurements. In addition, the use of noninvasive imaging in animal studies reduces animal usage, thus satisfying animal welfare concerns. In this article, we review these new imaging modalities with the potential for evaluation of lung fibrosis in small animal models. Such techniques include micro-computed tomography (micro-CT), magnetic resonance imaging, positron emission tomography (PET), single photon emission computed tomography (SPECT), and multimodal imaging systems including PET/CT and SPECT/CT. It is anticipated that noninvasive imaging will be increasingly used in animal models of fibrosis to gain insights into disease pathogenesis and as preclinical tools to assess drug efficacy.
Identification of the Mitochondrial ATP-Mg/P i Transporter BACTERIAL EXPRESSION, RECONSTITUTION, FUNCTIONAL CHARACTERIZATION, AND TISSUE DISTRIBUTION*

The mitochondrial carriers are a family of transport proteins that, with a few exceptions, are found in the inner membranes of mitochondria. They shuttle metab-olites, nucleotides, and cofactors through this membrane and thereby connect and/or regulate cytoplasm and matrix functions. ATP-Mg is transported in exchange for phosphate, but no protein has ever been associated with this activity. We have isolated three human cDNAs that encode proteins of 458, 468, and 489 amino acids with 66–75% similarity and with the characteristic features of the mitochondrial carrier family in their C-terminal domains and three EF-hand Ca 2 (cid:1) -bind-ing motifs in their N-terminal domains. These proteins have been overexpressed in Escherichia coli and reconstituted into phospholipid vesicles. Their transport properties and their targeting to mitochondria demonstrate that they are isoforms of the ATP-Mg/P i carrier described in the past in whole mitochondria. The tissue specificity of the three isoforms shows that at least one isoform was present in all of the tissues investigated. Because phosphate recycles via the phosphate carrier in mitochondria, the three isoforms of the ATP-Mg/P i car- rier are most likely responsible for the
Brief Reports Initial Experience with ‘‘Honoring Choices Wisconsin’’: Implementation of an Advance Care Planning Pilot in a Tertiary Care Setting

Background: Although previous research on advance care planning (ACP) has associated ACP with improved quality of care at the end of life, the appropriate use of ACP remains limited. Objective: To evaluate the impact of a pilot program using the ‘‘Honoring Choices Wisconsin’’ (HCW) model for ACP in a tertiary care setting, and to understand barriers to system-wide implementation. Design: Retrospective review of prospectively collected data. Setting/Subjects: Patients who received medical or surgical oncology care at Froedtert and the Medical College of Wisconsin. Measurements: Patient demographics, disease characteristics, patient satisfaction, and clinical outcomes. Results: Data from 69 patients who died following the implementation of the HCW program were reviewed; 24 patients were enrolled in the HCW program while 45 were not. Patients enrolled in HCW were proportionally less likely to be admitted to the ICU (12.5% vs. 17.8%) and were more likely to be ‘‘do not resuscitate’’ (87.5% vs. 80.0%), as well as have a completed ACP (83.3% vs. 79.1%). Furthermore, admission to a hospice was also higher among patients who were enrolled in the HCW program (79.2% vs. 25.6%), with patients enrolled in HCW more likely to die in hospice (70.8% vs. 53.3%). The HCW program was favorably viewed by patients, patient caregivers, and healthcare providers. Conclusions: Implementation of a facilitator-based ACP care model was associated with fewer ICU admissions, and a higher use of hospice care. System-level changes are required to overcome barriers to ACP that limit patients from receiving end-of-life care in accordance with their preferences.
Inhibition of NF- B Signaling Reduces Virus Load and Gammaherpesvirus-Induced Pulmonary Fibrosis

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive lung disorder of unknown etiology. Several studies have demonstrated an association between pulmonary infection with a herpesvirus and IPF. Based on those observations, we have developed a mouse model in which interferon (IFN) R / mice infected intranasally with murine gammaherpesvirus 68 (MHV68) develop lung fibrosis. We hypothesize that viral load was a critical factor for the development of fibrosis. Because nuclear factor (NF)B signaling is required to efficiently establish gammaherpesvirus, latency we infected IFN R / mice with a MHV68 virus that expresses a mutant dominant inhibitor of the NFB signaling pathway, called I B M. Striking differences were observed at the onset of the chronic infection, which correlated with a decreased virus load in mice infected with MHV68-I B M compared with mice infected with control MHV68 (MHV68-MR). IFN R / mice infected with MHV68-I B M lacked vasculitis and fibrosis 15 to 120 days post infection. Inhibition of NFB in MHV68-infected cells of the lungs diminished the expression of the fibrocyte recruiting chemokines monocyte chemoattractant protein 1 (MCP-1) and CXCL12, ameliorated macrophage expression of markers of alternative activation, and failed to increase expression of the integrin v 6, which is implicated in the activation of the profibrotic factor TGF. Thus, the inhibition of NFB signaling in the infected lung cells of IFN R / mice reduces virus persistence and ameliorates profibrotic events. Host determinants of latency might therefore represent new therapeutic targets for gammaherpesvirus-associated pulmonary fibrosis. (Am J Pathol 2010, 177:608–621; DOI: 10.2353/ajpath.2010.091122)
Risk factors for reading disability in rolandic epilepsy families

OBJECTIVE—The high prevalence and impact of neurodevelopmental comorbidities in childhood epilepsy are now well known, as are the increased risks and familial aggregation of reading disability (RD) and speech sound disorder (SSD) in rolandic epilepsy (RE). The risk factors for RD in the general population include male sex, SSD and ADHD but it is not known if these are the same in RE or whether there is a contributory role of seizure and treatment related variables. METHODS—An observational study of 108 RE probands (age range 3.6–22 years) and their 159 siblings (age range 1–29 years; 83 with EEG data) singly ascertained in the US or UK through an affected RE proband. We used a nested case-control design, multiple logistic regression and generalized estimating equations to test the hypothesis of association between RD and seizure variables or antiepileptic drug treatment in RE; we also assessed an association between EEG focal sharp waves and RD in siblings. RESULTS—RD was reported in 42% of probands and 22% of siblings. Among probands, RD was strongly associated with a history of SSD (OR 9.64, 95% CI: 2.45–37.21), ADHD symptoms (OR 10.31, 95% CI: 2.15–49.44), and male sex (OR 3.62, 95% CI: 1.11–11.75), but not with seizure or treatment variables. Among siblings, RD was independently associated only with SSD (OR 4.30, 95%CI: 1.42–13.0) and not with the presence of interictal EEG focal sharp waves. SIGNIFICANCE—The principal risk factors for RD in RE are SSD, ADHD and male sex, the same risk factors as for RD without epilepsy. Seizure or treatment variables do not appear to be important risk factors for RD in RE probands, and there was no evidence to support interictal EEG focal sharp waves as a risk factor for RD in siblings. Future studies should focus on the precise neuropsychological characterisation of RD in RE families, and on the effectiveness of standard oral-language and reading interventions.
Cause of Rubinstein- Taybi Syndrome: Clinical Aspects

In the accompanying paper, a chromosomal localization of the Rubinstein-Taybi syndrome by cytogenetic investigations with fluorescence in situ hybridization techniques at chromosome 16pl3.3 is described. We investigated 19 of these patients and their parents (a) to ascertain the parental origin of the chromosome with the deletion in families where such a deletion was detected, (b) to disclose whether uniparental disomy plays a role in etiology, and (c) to compare clinical features in patients with a deletion to those in individuals in whom deletions were not detectable. Molecular studies showed a copy of chromosome 16 from each parent in all 19 patients. Uniparental disomy was also excluded for five other chromosome arms known to be imprinted in mice. None of the probes used for determining the origin of the deleted chromosome proved to be informative. The clinical features were essentially the same in patients with and without visible deletion, with a possible exception for the incidence of microcephaly, angulation of thumbs and halluces, and partial duplication of the halluces. A small deletion at 16pi3.3 may be found in some patients with Rubinstein-Taybi syndrome. Cytogenetically undetectable deletions, point mutations, mosaicism, heterogeneity, or phenocopy by a nongenetic cause are the
Implementation as more than installation: a case study of the challenges in implementing green infrastructure projects in two Australian primary schools

ABSTRACT Green infrastructure delivers a range of benefits for urban water management, amenity, human well-being, and ecosystem health. However, the implementation of green urban infrastructure can be challenging, whether in private or public spaces. In Australia and elsewhere, there is increasing investment in green infrastructure projects in schools. To date, the implementation issues experienced in schools have not been investigated. This article reports on a case study of the range of factors influencing implementation of green infrastructure projects in two primary schools in Melbourne, Australia. Interviews with diverse stakeholders in these projects revealed four key areas of concern for implementation: 1) professional roles and relationships; 2) planning and design; 3) value to the school community; and 4) engagement of the broader community. We conclude that successful implementation is not simply the installation of well-functioning green infrastructure; rather, it is an ongoing achievement that is as social as it is technical.
Dexamethasone-Induced Ocular Hypertension in Mice

opyright a 2017 American Society for Inve ttp://dx.doi. org/10.1016/j.ajpath. 2016.12. 003 Glucocorticoid (GC)-induced ocular hypertension (OHT) is a serious adverse effect of prolonged GC therapy that can lead to iatrogenic glaucoma and permanent vision loss. An appropriate mouse model can help us understand precise molecular mechanisms and etiology of GC-induced OHT. We therefore developed a novel, simple, and reproducible mouse model of GC-induced OHT. GC-induced myocilin expression in the trabecular meshwork (TM) has been suggested to play an important role in GC-induced OHT. We further determined whether myocilin contributes to GC-OHT. C57BL/6J mice received weekly periocular conjunctival fornix injections of a dexamethasone-21-acetate (DEX-Ac) formulation. Intraocular pressure (IOP) elevation was relatively rapid and significant, and correlated with reduced conventional outflow facility. Nighttime IOPs were higher in ocular hypertensive eyes compared to daytime IOPs. DEX-Ac treatment led to increased expression of fibronectin, collagen I, and a-smooth muscle actin in the TM in mouse eyes. No changes in body weight indicated no systemic toxicity associated with DEX-Ac treatment. Wild-type mice showed increased myocilin expression in the TM on DEX-Ac treatment. Both wild-type and Myoc / mice had equivalent and significantly elevated IOP with DEX-Ac treatment every week. In conclusion, our mouse model mimics many aspects of GC-induced OHT in humans, and we further demonstrate that myocilin does not play a major role in DEX-induced OHT in mice. (Am J Pathol 2017, 187: 713e723; http://dx.doi.org/10.1016/j.ajpath.2016.12.003)
Rat Following Vasectomy

Endogenous cyclic AMP levels and the activities of adenylate cyclase, cyclic AMP-dependent and independent protein kinases were examined in testes of mature rats bilaterally vasectomized for one, three and seven months. Although no significant alteration in testicular cyclic AMP was detected one month following vasectomy, marked decreases (by 55% and 32%, respectively) were seen three and seven months postvasectomy. Likewise, vasectomy also resulted in a significant decrease (by 25%) in the activity of testicular adenylate cyclase three and seven months after vasectomy. Although soluble cyclic AMP-dependent protein kinase activity remained unaffected three months postvasectomy, the activity of the cyclic nucleotide-dependent enzyme was significantly increased (by 21%) when compared to the sham-operated controls. Furthermore, while the protein kinase ratio (-cyclic AMP/+cyclic AMP) was decreased in animals vasectomized for three months, the ability of the enzyme to bind (3H) cyclic AMP in vitro was significantly enhanced (18%). Rats vasectomized for seven months showed similar biochemical alterations but the effects of this procedure were more pronounced. Moreover, while short-term vasectomy increased the responsiveness of seminiferous tubular adenylate cyclase to in vitro stimulation by follicle stimulating hormone, the activity of the enzyme was also increased (by 100%) in the presence of luteinizing hormone in vasectomized rats. These data raise the possibility that changes in testicular function seen following vasectomy may be related to the alterations in cyclic AMP metabolism as well as *Department of Pharmacology, Faculty of Medicine, University of Ottawa, Ottawa, Ontario KIN 9A9. Correspondence to R. L. Singhal. Submitted January 24, 1978. in the sensitivity of testicular adenylate cyclase to regulation by gonadotropins.