The Promenades of Paris. Alphand and the Urbanization of Garden Art, 1852-1871

This study investigates a formative episode in the history of modern landscape architecture and public space design: the rapid creation of public parks, squares, and tree-lined thoroughfares in Paris between 1852 and 1870, the period of the French Second Empire, to form a series of interconnecting “promenades.” It seeks to identify continuities and innovations with respect to traditions of garden art, urban art, and engineering in France. It asks how a multi-disciplinary team of public servants, led by the engineer Alphand, responded to the simultaneous demands of cultural and utilitarian necessities, and how the public received the new gardens. The research method consists primarily in interpretive analysis of archival and historic texts, design drawings, popular media accounts, art and literature, and physical landscapes. Of particular interest is Alphand’s treatise, Les Promenades de Paris (1867-73), which points back to a lineage of earlier texts, but also forward to an age in which environment and infrastructure are fundamental to the urban landscape. The record shows that Parisians had mixed reactions to the growth of the city and to the new vegetated spaces that would supposedly improve public health via fresh air. The promenades of Paris also show an intriguing ambiguity in defining the public good as collective health and/or collective pleasure. Alphand and his collaborators in the Service des Promenades et Plantations, or parks department—including Barillet-Deschamps, Davioud, Belgrand, Darcel, and André—forged a systematic approach that accommodated practical necessities, difficult sites, and a wide range of scales. Their work was bound by an ethics of purposefulness and respect for the limits of a given situation. Nonetheless they pursued an artistic and decorative agenda, reflecting a desire to ennoble the public sphere. The landscapes that they designed are marked by a frequent divergence between visible and invisible elements, the latter encompassing both buried infrastructures and intangible metaphors. Categories of true and false natures gave way to questions of what urban landscapes do, in relation to their surroundings, and what people do in them

Isosterism and Bioisosterism Case Studies with Muscarinic Agonists

The synthesis and activity of enantiomerically pure analogues of pilocarpine and muscarinic agonists with the azabicyclo[2.2.1]heptane skeleton is described. Structure-activity relationships support a flexible model in which a coulombic interaction as well as two H-bonding interactions with the receptor are necessary for potent muscarinic agonist activity. In this context, a critical appraisal of the concepts of isosterism and bioisosterism is put forward, isosterism is redefined, and bioisosterism is discarded in favor of the new concept of bioanalogy

Amplification of multiple genomic loci from single cells isolated by laser micro-dissection of tissues

<p>Abstract</p> <p>Background</p> <p>Whole genome amplification (WGA) and laser assisted micro-dissection represent two recently developed technologies that can greatly advance biological and medical research. WGA allows the analysis of multiple genomic loci from a single genome and has been performed on single cells from cell suspensions and from enzymatically-digested tissues. Laser micro-dissection makes it possible to isolate specific single cells from heterogeneous tissues.</p> <p>Results</p> <p>Here we applied for the first time WGA on laser micro-dissected single cells from stained tissue sections, and developed a protocol for sequentially performing the two procedures. The combined procedure allows correlating the cell's genome with its natural morphology and precise anatomical position. From each cell we amplified 122 genomic and mitochondrial loci. In cells obtained from fresh tissue sections, 64.5% of alleles successfully amplified to ~700000 copies each, and mitochondrial DNA was amplified successfully in all cells. Multiplex PCR amplification and analysis of cells from pre-stored sections yielded significantly poorer results. Sequencing and capillary electrophoresis of WGA products allowed detection of slippage mutations in microsatellites (MS), and point mutations in P53.</p> <p>Conclusion</p> <p>Comprehensive genomic analysis of single cells from stained tissue sections opens new research opportunities for cell lineage and depth analyses, genome-wide mutation surveys, and other single cell assays.</p

Cholestenoic acid, an endogenous cholesterol metabolite, is a potent γ-secretase modulator.

BackgroundAmyloid-β (Aβ) 42 has been implicated as the initiating molecule in the pathogenesis of Alzheimer's disease (AD); thus, therapeutic strategies that target Aβ42 are of great interest. γ-Secretase modulators (GSMs) are small molecules that selectively decrease Aβ42. We have previously reported that many acidic steroids are GSMs with potencies ranging in the low to mid micromolar concentration with 5β-cholanic acid being the most potent steroid identified GSM with half maximal effective concentration (EC50) of 5.7 μM.ResultsWe find that the endogenous cholesterol metabolite, 3β-hydroxy-5-cholestenoic acid (CA), is a steroid GSM with enhanced potency (EC50 of 250 nM) relative to 5β-cholanic acid. CA i) is found in human plasma at ~100-300 nM concentrations ii) has the typical acidic GSM signature of decreasing Aβ42 and increasing Aβ38 levels iii) is active in in vitro γ-secretase assay iv) is made in the brain. To test if CA acts as an endogenous GSM, we used Cyp27a1 knockout (Cyp27a1-/-) and Cyp7b1 knockout (Cyp7b1-/-) mice to investigate if manipulation of cholesterol metabolism pathways relevant to CA formation would affect brain Aβ42 levels. Our data show that Cyp27a1-/- had increased brain Aβ42, whereas Cyp7b1-/- mice had decreased brain Aβ42 levels; however, peripheral dosing of up to 100 mg/kg CA did not affect brain Aβ levels. Structure-activity relationship (SAR) studies with multiple known and novel CA analogs studies failed to reveal CA analogs with increased potency.ConclusionThese data suggest that CA may act as an endogenous GSM within the brain. Although it is conceptually attractive to try and increase the levels of CA in the brain for prevention of AD, our data suggest that this will not be easily accomplished

A randomized, placebo-controlled, phase II study of obeticholic acid for primary sclerosing cholangitis

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Efficacy of Obeticholic Acid in Patients With Primary Biliary Cirrhosis and Inadequate Response to Ursodeoxycholic Acid

Background & AimsWe evaluated the efficacy and safety of obeticholic acid (OCA, α-ethylchenodeoxycholic acid) in a randomized controlled trial of patients with primary biliary cirrhosis who had an inadequate response to ursodeoxycholic acid therapy.MethodsWe performed a double-blind study of 165 patients with primary biliary cirrhosis (95% women) and levels of alkaline phosphatase (ALP) 1.5- to 10-fold the upper limit of normal. Patients were randomly assigned to groups given 10 mg, 25 mg, or 50 mg doses of OCA or placebo, once daily for 3 months. Patients maintained their existing dose of ursodeoxycholic acid throughout the study. The primary outcome was change in level of ALP from baseline (day 0) until the end of the study (day 85 or early termination). We also performed an open-label extension of the trial in which 78 patients were enrolled and 61 completed the first year.ResultsOCA was superior to placebo in achieving the primary end point. Subjects given OCA had statistically significant relative reductions in mean ALP from baseline to the end of the study (P < .0001 all OCA groups vs placebo). Levels of ALP decreased 21%–25% on average from baseline in the OCA groups and 3% in the placebo group. Sixty-nine percent (68 of 99) of patients given OCA had at least a 20% reduction in ALP compared with 8% (3 of 37) of patients given placebo (P < .0003). Among secondary end points, levels of γ-glutamyl transpeptidase decreased 48%–63%, on average, among subjects given OCA, vs a 7% decrease in the group given placebo; levels of alanine aminotransferase decreased 21%–35% on average among subjects given OCA vs none of the patients given placebo. Pruritus was the principal adverse event; incidence values in the OCA 10 mg, 25 mg, and 50 mg groups were 47% (not significantly different), 87% (P < .0003), and 80% (P < .006), respectively, vs 50% in the placebo group. In the extension study, levels of ALP continued to decrease to a mean level of 202 ± 11 U/L after 12 months vs 285 ± 15 U/L at baseline.ConclusionsDaily doses of OCA, ranging from 10 to 50 mg, significantly reduced levels of ALP, γ-glutamyl transpeptidase, and alanine aminotransferase, compared with placebo, in patients with primary biliary cirrhosis who had inadequate responses to ursodeoxycholic acid. The incidence and severity of pruritus were lowest among patients who received 10 mg/d OCA. Biochemical responses to OCA were maintained in a 12-month open-label extension trial. ClinicalTrials.gov ID: NCT00550862

Diversity in a honey bee pathogen: first report of a third master variant of the Deformed Wing Virus quasispecies

Treatment of emerging RNA viruses is hampered by the high mutation and replication rates that enable these viruses to operate as a quasispecies. Declining honey bee populations have been attributed to the ectoparasitic mite Varroa destructor and its affiliation with Deformed Wing Virus (DWV). In the current study we use next-generation sequencing to investigate the DWV quasispecies in an apiary known to suffer from overwintering colony losses. We show that the DWV species complex is made up of three master variants. Our results indicate that a new DWV Type C variant is distinct from the previously described types A and B, but together they form a distinct clade compared with other members of the Iflaviridae. The molecular clock estimation predicts that Type C diverged from the other variants ~319 years ago. The discovery of a new master variant of DWV has important implications for the positive identification of the true pathogen within global honey bee populations

Comparison of Two Quantitative Methods of Discerning Airspace Enlargement in Smoke-Exposed Mice

In this work, we compare two methods for evaluating and quantifying pulmonary airspace enlargement in a mouse model of chronic cigarette smoke exposure. Standard stereological sample preparation, sectioning, and imaging of mouse lung tissues were performed for semi-automated acquisition of mean linear intercept (Lm) data. After completion of the Lm measurements, D2, a metric of airspace enlargement, was measured in a blinded manner on the same lung images using a fully automated technique developed in-house. An analysis of variance (ANOVA) shows that although Lm was able to separate the smoke-exposed and control groups with statistical significance (p = 0.034), D2 was better able to differentiate the groups (p<0.001) and did so without any overlap between the control and smoke-exposed individual animal data. In addition, the fully automated implementation of D2 represented a time savings of at least 24x over semi-automated Lm measurements. Although D2 does not provide 3D stereological metrics of airspace dimensions as Lm does, results show that it has higher sensitivity and specificity for detecting the subtle airspace enlargement one would expect to find in mild or early stage emphysema. Therefore, D2 may serve as a more accurate screening measure for detecting early lung disease than Lm

Embryonic Pig Pancreatic Tissue Transplantation for the Treatment of Diabetes

BACKGROUND: Transplantation of embryonic pig pancreatic tissue as a source of insulin has been suggested for the cure of diabetes. However, previous limited clinical trials failed in their attempts to treat diabetic patients by transplantation of advanced gestational age porcine embryonic pancreas. In the present study we examined growth potential, functionality, and immunogenicity of pig embryonic pancreatic tissue harvested at different gestational ages. METHODS AND FINDINGS: Implantation of embryonic pig pancreatic tissues of different gestational ages in SCID mice reveals that embryonic day 42 (E42) pig pancreas can enable a massive growth of pig islets for prolonged periods and restore normoglycemia in diabetic mice. Furthermore, both direct and indirect T cell rejection responses to the xenogeneic tissue demonstrated that E42 tissue, in comparison to E56 or later embryonic tissues, exhibits markedly reduced immunogenicity. Finally, fully immunocompetent diabetic mice grafted with the E42 pig pancreatic tissue and treated with an immunosuppression protocol comprising CTLA4-Ig and anti–CD40 ligand (anti-CD40L) attained normal blood glucose levels, eliminating the need for insulin. CONCLUSIONS: These results emphasize the importance of selecting embryonic tissue of the correct gestational age for optimal growth and function and for reduced immunogenicity, and provide a proof of principle for the therapeutic potential of E42 embryonic pig pancreatic tissue transplantation in diabetes