Synthesis and in vivo evaluation of non-hepatotoxic acetaminophen analogs

A series of acetaminophen (APAP) analogs, 2-(1,1-dioxido-3-oxo-1,2-benzisothiazol-2(3H)-yl)-N-(4-hydroxyphenyl)alkanecarboxamides, bearing a heterocyclic moiety linked to the p-acylaminophenol fragment, were prepared in a general project to develop APAP analogs with modulated pharmacokinetic profiles. Unexpectedly, the products described maintained the in vivo analgesic profile, while the characteristic hepatotoxicity of APAP was consistently reduced. One of the products, 5a, was studied in vivo in comparison with APAP. Compound 5a displayed an analgesic efficacy comparable to that of APAP. A relatively high acute oral dose of 5a (6 mmol/kg) produced no measurable toxicity, whereas the equimolar dose of APAP increased transaminase activity, depleted hepatic and renal glutathione, and resulted in mortality. In human hepatocytes (HEPG-2) and in human primary cultures of normal liver cells, APAP, but not 5a, was associated with apoptotic cell death, Fas-ligand up-regulation, and CAR (constitutive androstane receptor) activation, contributing to a favorable safety profile of 5a as an orally delivered analgesic.MDA972-03-C-010 (Defense Advanced Research Programs Agency-DARPA)Neurobiotechnology Program of Louisian

Differential impact of LPG-and PG-deficient Leishmania major mutants on the immune response of human dendritic cells

<div><p>Background</p><p><i>Leishmania major</i> infection induces robust interleukin-12 (IL12) production in human dendritic cells (hDC), ultimately resulting in Th1-mediated immunity and clinical resolution. The surface of <i>Leishmania</i> parasites is covered in a dense glycocalyx consisting of primarily lipophosphoglycan (LPG) and other phosphoglycan-containing molecules (PGs), making these glycoconjugates the likely pathogen-associated molecular patterns (PAMPS) responsible for IL12 induction.</p><p>Methodology/Principal Findings</p><p>Here we explored the role of parasite glycoconjugates on the hDC IL12 response by generating <i>L</i>. <i>major</i> Friedlin V1 mutants defective in LPG alone, (FV1 <i>lpg1-</i>), or generally deficient for all PGs, (FV1 <i>lpg2-</i>). Infection with metacyclic, infective stage, <i>L</i>. <i>major</i> or purified LPG induced high levels of <i>IL12B</i> subunit gene transcripts in hDCs, which was abrogated with FV1 <i>lpg1-</i> infections. In contrast, hDC infections with FV1 <i>lpg2-</i> displayed increased <i>IL12B</i> expression, suggesting other PG-related/<i>LPG2</i> dependent molecules may act to dampen the immune response. Global transcriptional profiling comparing WT, FV1 <i>lpg1-</i>, FV1 <i>lpg2-</i> infections revealed that FV1 <i>lpg1-</i> mutants entered hDCs in a silent fashion as indicated by repression of gene expression. Transcription factor binding site analysis suggests that LPG recognition by hDCs induces IL-12 in a signaling cascade resulting in Nuclear Factor κ B (NFκB) and Interferon Regulatory Factor (IRF) mediated transcription.</p><p>Conclusions/Significance</p><p>These data suggest that <i>L</i>. <i>major</i> LPG is a major PAMP recognized by hDC to induce IL12-mediated protective immunity and that there is a complex interplay between PG-baring <i>Leishmania</i> surface glycoconjugates that result in modulation of host cellular IL12.</p></div

Magnetic Excitations in Ferromagnetically Coupled Spin-1 Nanographenes

In the quest for high-spin building blocks to form covalently bonded 1D or 2D materials with controlled magnetic interactions, $\pi$-electron magnetism provides an ideal framework to engineer large ferromagnetic interactions between nanographenes. As a first step in this direction, we investigate the spin properties of ferromagnetically coupled triangulenes, triangular nanographenes with spin $S = 1$. Combining in-solution synthesis of rationally designed molecular precursors and on-surface synthesis, we achieve covalently bonded $S = 2$ triangulene dimers and $S = 3$ trimers on Au(111). Starting from the triangulene dimer, we thoroughly characterize its low-energy magnetic excitations using inelastic electron tunneling spectroscopy (IETS). IETS reveals conductance steps identified as a quintet to triplet excitation, and a zero-bias peak stemming from higher-order spin-spin scattering of the 5-fold degenerate ferromagnetic ground state. The Heisenberg picture captures the relevant parameters of inter-triangulene ferromagnetic exchange, and its successful extension to the larger $S = 3$ system confirms the model's accuracy. We expect that the addition of ferromagnetically coupled building blocks to the toolbox of magnetic nanographenes opens new opportunities to design carbon materials with complex magnetic ground states.Comment: 38 pages, 5 Figure

When serving customers includes correcting them : understanding the ambivalent effects of enforcing service rules

Service employees frequently must enforce rules upon their customers to mitigate dysfunctional customer behavior and ensure proper service delivery (e.g., enforce “fasten seatbelt” signs on flights). However, the consequences of enforcing service rules (ESR) are not well understood. To elucidate the effect of ESR, the authors present seven studies involving > 6800 customers and consisting of cross-sectional and longitudinal data from customer surveys and company records as well as experiments. The results indicate that ESR exerts ambivalent effects: customers who experience ESR directed at other customers perceive service employees as more competent, which increases customer loyalty. However, if ESR is directed at customers themselves, they perceive a self-concept threat, leading them to devalue service employees' warmth and competence and to become less loyal. The effects of ESR hinge on a number of factors, including the harm that dysfunctional behavior potentially causes, the way ESR is communicated, and customers' experience with the service situation. Furthermore, the authors show that service employees can alleviate the negative effects of ESR by communicating service rules in advance and justifying ESR appropriately

A prospective evaluation of the safety and efficacy of the TAXUS Element paclitaxel-eluting coronary stent system for the treatment of de novo coronary artery lesions: Design and statistical methods of the PERSEUS clinical program

<p>Abstract</p> <p>Background</p> <p>Paclitaxel-eluting stents decrease angiographic and clinical restenosis following percutaneous coronary intervention compared to bare metal stents. TAXUS Element is a third-generation paclitaxel-eluting stent which incorporates a novel, thinner-strut, platinum-enriched metal alloy platform. The stent is intended to have enhanced radiopacity and improved deliverability compared to other paclitaxel-eluting stents. The safety and efficacy of the TAXUS Element stent are being evaluated in the pivotal PERSEUS clinical trials.</p> <p>Methods/Design</p> <p>The PERSEUS trials include two parallel studies of the TAXUS Element stent in single, de novo coronary atherosclerotic lesions. The PERSEUS Workhorse study is a prospective, randomized (3:1), single-blind, non-inferiority trial in subjects with lesion length ≤28 mm and vessel diameter ≥2.75 mm to ≤4.0 mm which compares TAXUS Element to the TAXUS Express²paclitaxel-eluting stent system. The Workhorse study employs a novel Bayesian statistical approach that uses prior information to limit the number of study subjects exposed to the investigational device and thus provide a safer and more efficient analysis of the TAXUS Element stent. PERSEUS Small Vessel is a prospective, single-arm, superiority trial in subjects with lesion length ≤20 mm and vessel diameter ≥2.25 mm to <2.75 mm that compares TAXUS Element with a matched historical bare metal Express stent control.</p> <p>Discussion</p> <p>The TAXUS PERSEUS clinical trial program uses a novel statistical approach to evaluate whether design and metal alloy iterations in the TAXUS Element stent platform provide comparable safety and improved procedural performance compared to the previous generation Express stent. PERSEUS trial enrollment is complete and primary endpoint data are expected in 2010. PERSEUS Workhorse and Small Vessel are registered at <url>http://www.clinicaltrials.gov</url>, identification numbers NCT00484315 and NCT00489541.</p

Exacerbated fires in Mediterranean Europe due to anthropogenic warming projected with non-stationary climate-fire models

The observed trend towards warmer and drier conditions in southern Europe is projected to continue in the next decades, possibly leading to increased risk of large fires. However, an assessment of climate change impacts on fires at and above the 1.5 °C Paris target is still missing. Here, we estimate future summer burned area in Mediterranean Europe under 1.5, 2, and 3 °C global warming scenarios, accounting for possible modifications of climate-fire relationships under changed climatic conditions owing to productivity alterations. We found that such modifications could be beneficial, roughly halving the fire-intensifying signals. In any case, the burned area is robustly projected to increase. The higher the warming level is, the larger is the increase of burned area, ranging from ~40% to ~100% across the scenarios. Our results indicate that significant benefits would be obtained if warming were limited to well below 2 °C

Magnetic Excitations in Ferromagnetically Coupled Spin‐1 Nanographenes

In the pursuit of high-spin building blocks for the formation of covalently bonded 1D or 2D materials with controlled magnetic interactions, mathematical equation π-electron magnetism offers an ideal framework to engineer ferromagnetic interactions between nanographenes. As a first step in this direction, we explore the spin properties of ferromagnetically coupled triangulenes—triangular nanographenes with spin S = 1 . By combining in-solution synthesis of rationally designed molecular precursors with on-surface synthesis, we successfully achieve covalently bonded S = 2 triangulene dimers and S = 3 trimers on Au(111). Starting with the triangulene dimer, we meticulously characterize its low-energy magnetic excitations using inelastic electron tunneling spectroscopy (IETS). IETS reveals conductance steps corresponding to a quintet-to-triplet excitation, and a zero-bias peak resulting from higher-order spin-spin scattering of the five-fold degenerate ferromagnetic ground state. The Heisenberg model captures the key parameters of inter-triangulene ferromagnetic exchange, and its successful extension to the larger S = 3 system validates the model's accuracy. We anticipate that incorporating ferromagnetically coupled building blocks into the repertoire of magnetic nanographenes will unlock new possibilities for designing carbon nanomaterials with complex magnetic ground states

Docosahexaenoic Acid Therapy of Experimental Ischemic Stroke

We examined the neuroprotective efficacy of docosahexaenoic acid (DHA), an omega-3 essential fatty acid family member, in acute ischemic stroke; studied the therapeutic window; and investigated whether DHA administration after an ischemic stroke is able to salvage the penumbra. In each series described below, SD rats underwent 2 h of middle cerebral artery occlusion (MCAo). In series 1, DHA or saline was administered i.v. at 3, 4, 5, or 6 h after stroke. In series 2, MRI was conducted on days 1, 3 and 7. In series 3, DHA or saline was administered at 3 h, and lipidomic analysis was conducted on day 3. Treatment with DHA significantly improved behavior and reduced total infarct volume by a mean of 40% when administered at 3 h, by 66% at 4 h, and by 59% at 5 h. Total lesion volumes computed from T2-weighted images were reduced in the DHA group at all time points. Lipidomic analysis showed that DHA treatment potentiates neuroprotectin D1 (NPD1) synthesis in the penumbra 3 days after MCAo. DHA administration provides neurobehavioral recovery, reduces brain infarction and edema, and activates NPD1 synthesis in the penumbra when administered up to 5 h after focal cerebral ischemia in rats