gebhart/patrepeval huggingface dataset:
Ethanol Extract of Bupleurum falcatum Improves Functional Recovery by Inhibiting Matrix Metalloproteinases-2 and -9 Activation and Inflammation after Spinal Cord Injury (2010)

Matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases that degrade the extracellular matrix and other extracellular proteins. Upregulation of MMPs activity is known to be required for the inflammatory cell infiltration after spinal cord injury (SCI) and most likely contributes to early blood spinal barrier disruption and inflammation, thereby leading to the impairment of functional recovery. Here, we examined the effect of ethanol extract of Bupleurum falcatum (BF) on functional recovery by inhibiting MMP-2 and -9 activation and inflammation after SCI. Rats received a moderate, weight-drop contusion injury to spinal cord were administered orally with BF at a dose of 100 mg/kg for 14 d and functional recovery was measured by Basso-Beattie-Bresnahan locomotor open field behavioral rating test, inclined plane test and foot print analysis. To examine the neuroprotective effect of BF, TUNEL staining and counting were also performed. In addition, the expression and/or activation of MMP-2, MMP-9 and inflammatory mediators such as TNF-α, IL-1β, COX-2, and iNOS were examined by RT-PCR and gelatin zymography using spinal cord tissue from 1 d after injury. Our data showed that BF significantly inhibited the expression and activation of both MMP-2 and MMP-9 after SCI. The mRNA expressions of TNF-α, IL-1β, COX-2, and iNOS were also significantly attenuated by BF. Furthermore, BF reduced apoptotic cell death at 1 d after injury, thereby significantly reduced lesion volume and improved functional recovery. Taken together, these results suggest that BF can be used as a potential therapeutic agent for treating acute spinal injury.
In vivo liposomal delivery of PPARα/γ dual agonist tesaglitazar in a model of obesity enriches macrophage targeting and limits liver and kidney drug effects (2019)

Macrophages are important regulators of obesity-associated inflammation and PPARα and -γ agonism in macrophages has anti-inflammatory effects. In this study, we tested the efficacy with which liposomal delivery could target the PPARα/γ dual agonist tesaglitazar to macrophages while reducing drug action in common sites of drug toxicity: the liver and kidney, and whether tesaglitazar had anti-inflammatory effects in an <i>in vivo</i> model of obesity-associated dysmetabolism. <b>Methods</b>: Male leptin-deficient (<i>ob/ob</i>) mice were administered tesaglitazar or vehicle for one week in a standard oral formulation or encapsulated in liposomes. Following the end of treatment, circulating metabolic parameters were measured and pro-inflammatory adipose tissue macrophage populations were quantified by flow cytometry. Cellular uptake of liposomes in tissues was assessed using immunofluorescence and a broad panel of cell subset markers by flow cytometry. Finally, PPARα/γ gene target expression levels in the liver, kidney, and sorted macrophages were quantified to determine levels of drug targeting to and drug action in these tissues and cells. <b>Results</b>: Administration of a standard oral formulation of tesaglitazar effectively treated symptoms of obesity-associated dysmetabolism and reduced the number of pro-inflammatory adipose tissue macrophages. Macrophages are the major cell type that took up liposomes with many other immune and stromal cell types taking up liposomes to a lesser extent. Liposome delivery of tesaglitazar did not have effects on inflammatory macrophages nor did it improve metabolic parameters to the extent of a standard oral formulation. Liposomal delivery did, however, attenuate effects on liver weight and liver and kidney expression of PPARα and -γ gene targets compared to oral delivery. <b>Conclusions</b>: These findings reveal for the first time that tesaglitazar has anti-inflammatory effects on adipose tissue macrophage populations <i>in vivo</i>. These data also suggest that while nanoparticle delivery reduced off-target effects, yet the lack of tesaglitazar actions in non-targeted cells such (as hepatocytes and adipocytes) and the uptake of drug-loaded liposomes in many other cell types, albeit to a lesser extent, may have impacted overall therapeutic efficacy. This fulsome analysis of cellular uptake of tesaglitazar-loaded liposomes provides important lessons for future studies of liposome drug delivery.
Kinetic Mechanism of Blebbistatin Inhibition of Nonmuscle Myosin IIB (2004)

We examined the effect of blebbistatin on the kinetic properties of nonmuscle myosin IIB subfragment 1 (NMIIB S1). Blebbistatin is a small molecule that affects cell blebbing during the process of cell division, which has been shown to decrease the myosin ATPase activity of a number of myosins [Straight et al. (2003) Science 299, 1743-1747]. The steady-state actin-activated ATPase activity of NMIIB S1 was decreased approximately 90% at 40 microM actin in the presence of blebbistatin. Stopped-flow techniques were employed to elucidate the effect of blebbistatin on the various steps of the NMIIB S1 cross-bridge cycle. Blebbistatin did not affect ATP binding and hydrolysis. Binding to actin in the presence of ADP (0.57 +/-0.08 microM(-1) s(-1)) was reduced slightly in the presence of blebbistatin (0.38 +/- 0.03 microM(-1) s(-1)), while mantADP dissociation from acto-NMIIB S1 was reduced (approximately 30%). P(i) release was blocked in the presence of blebbistatin. Accordingly, the apparent affinity of NMIIB S1 for actin in the presence of ATP was greatly reduced. Based on the above data, we surmise that blebbistatin inhibits the ATPase activity of NMIIB S1 primarily by blocking entry into the strong binding state; secondarily, it reduces the rate of ADP release. These effects are likely mediated by binding of blebbistatin within the myosin cleft that progressively closes in forming the acto-myosin rigor state.
Vancomycin-induced deletion of the methicillin resistance gene mecA in Staphylococcus aureus (2004)

Acquisition of vancomycin resistance in one MRSA strain triggered mecA deletion suggesting that this deletion, coupled to other rearrangements and/or mutations, may be responsible for the increased vancomycin resistance phenotype.
Ru(bpy)32+ derivatized polystyrenes constructed by nitroxide-mediated radical polymerization. Relationship between polymer chain length, structure and photophysical properties (2015)

A series of polystyrene-based light harvesting polymers featuring pendant polypyridyl ruthenium complexes has been synthesized.
Lyotropic Liquid-Crystalline Behavior in Disc-Shaped Compounds Incorporating the 3,3′-Di(acylamino)-2,2′-bipyridine Unit (1998)

An extended-core liquid crystal (LC) based on the 3,3′-di(acylamino)-2,2′-bipyridine unit is investigated with respect to its behavior in alkane solvents. It is demonstrated that the lyotropic mesomorphism observed in dodecane can be tuned by varying the concentration of the sample, and the columns can be switched in an electric field. The Figure shows the structure of the columnar nematic phase present in dodecane containing 15.7 wt.-% LC.
Design and Demonstration of a Wound Field Synchronous Machine for Electric Vehicle Traction With Brushless Capacitive Field Excitation (2017)

This paper describes the modeling, optimization, mechanical design, and experimental characterization of a high power density wound field synchronous machine (WFSM) for electric vehicle traction applications. The WFSM is designed for brushless rotor field excitation using an axial flux hydrodynamic capacitive power coupler (CPC). The flexible design environment, which was used for large-scale multiobjective optimization of the WFSM, is described. A prototype WFSM, spray cooled with automatic transmission fluid, with an 80-kW output at a base speed of 4000 r/min has been tested. The prototyped WFSM achieves volumetric torque and power densities of 17.22 N·m/L and 7.19 kW/L referred to the envelope cylindrical volume of the active materials plus spray cooling rings. The specific torque and power densities are 4.69 N·m/kg and 1.95 kW/kg referred to the mass of the active materials and the shaft. The prototyped CPC provided up to 1-kW excitation power with a mass 600 g and volume of 0.271 L.
Self-Consistent Model of Concentration and Temperature Dependence of Permeability in Rubbery Polymers (2005)

A model describing the concentration and temperature dependences of gas and vapor permeability in rubbery polymers is presented. The solubility and permeability of propane in poly(dimethylsiloxane) (PDMS), a commercially used vapor separation membrane material, were determined over a wide range of temperatures and pressures to test the model. The model describes propane permeability in PDMS with an average error of 8.2%. The model also accurately predicts a decrease in propane permeability in PDMS with decreasing permeate pressure at fixed feed pressure. The model has also been tested satisfactorily using literature data for transport of condensable penetrants in PDMS and poly(ethylene).
Capillary zone electrophoresis for analysis of complex proteomes using an electrokinetically pumped sheath flow nanospray interface (2013)

The vast majority of proteomic studies employ RP-HPLC coupled with MS/MS for analysis of the tryptic digest of a cellular lysate. This technology is quite mature, and typically provides identification of hundreds to thousands of peptides, which is used to infer the identity of hundreds to thousands of proteins. These studies usually require milligrams to micrograms of starting material. CZE provides an interesting alternative separation method based on a different separation mechanism than HPLC. CE received some attention for protein analysis beginning 25 years ago. Those efforts stalled because of the limited performance of the electrospray interfaces and the limited speed and sensitivity of mass spectrometers of that era. This review considers a new electrospray interface design coupled with Orbitrap Velos and linear Q-trap mass spectrometers. CZE coupled with this interface and these detectors provides single shot detection of >1250 peptides from an Escherichia coli digest in less than 1 h, identification of nearly 5000 peptides from analysis of seven fractions produced by SPE of the E. coli digest in a 6 h total analysis time, low attomole detection limits for peptides generated from standard proteins, and high zeptomole detection limits for selected ion monitoring of peptides. Incorporation of an integrated on-line immobilized trypsin microreactor allows digestion and analysis of picogram amounts of a complex eukaryotic proteome.
The safety, tolerability and efficacy of LP-10 in subjects with refractory moderate to severe hemorrhagic cystitis: Phase 2a multicenter dose escalation clinical trial. (2023)

e24064 Background: Hemorrhagic Cystitis (HC), a rare but highly morbid disease for which there are currently no FDA approved treatments, can occur in cancer survivors including patients with prostate cancer, cervical/uterine cancer and colon cancer. Lipella Pharmaceuticals received orphan disease designation for HC, and recently completed a phase 2a clinical trial of LP-10 (intravesical tacrolimus) for the treatment of HC. Methods: The LP-10 Phase 2a clinical trial was a multi-center, dose-escalation study (clinicaltrials.gov: NCT01393223). The study recruited subjects with moderate to severe refractory HC. These subjects were treated with up to two courses of LP-10 intravesical bladder instillations (liposomal formulation of tacrolimus at 2 mg, 4 mg and 8 mg). Results: Fifteen subjects were screened (14 male and 1 female) and 13 enrolled. All enrolled subjects were male with mean age 67 (range 25-89 years old) with a history of prostate cancer (n = 9), bladder cancer (n = 2) and lymphoma (n = 2). Mean duration of HC was 4 years and ranged from 1-14 years. No subject discontinued treatment or were lost to follow-up. All subjects tolerated LP-10 instillations and completed the study without report of product related serious adverse events. 12 AEs were reported in 6 subjects. Pharmacokinetic analysis demonstrated short duration of low systemic uptake of tacrolimus. A dose response was noted with higher efficacy at both the 4mg and 8 mg dose groups. After LP-10 treatment, the number of cystoscopic bleeding sites and bladder ulcerations decreased and patients’ urinary symptoms improved. Conclusions: This first phase 2a study demonstrated safety and a signal of efficacy at intravesical tacrolimus (LP-10) doses of 4 mg and 8 mg for the treatment for HC, a rare and serious disease. Clinical trial information: NCT01393223 . [Table: see text]
Design of Amphoteric Bifunctional Ligands: Application to the Enantioselective Simmons-Smith Cyclopropanation of Allylic Alcohols (1994)

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTDesign of Amphoteric Bifunctional Ligands: Application to the Enantioselective Simmons-Smith Cyclopropanation of Allylic AlcoholsAndre B. Charette and Helene JuteauCite this: J. Am. Chem. Soc. 1994, 116, 6, 2651–2652Publication Date (Print):March 1, 1994Publication History Published online1 May 2002Published inissue 1 March 1994https://pubs.acs.org/doi/10.1021/ja00085a068https://doi.org/10.1021/ja00085a068research-articleACS PublicationsRequest reuse permissionsArticle Views3276Altmetric-Citations187LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-AlertscloseSupporting Info (2)»Supporting Information Supporting Information Get e-Alerts
Withania Somnifera (Ashwagandha) and Withaferin A: Potential in Integrative Oncology (2019)

Ashwagandha (<i>Withania Somnifera, WS)</i>, belonging to the family Solanaceae, is an Ayurvedic herb known worldwide for its numerous beneficial health activities since ancient times. This medicinal plant provides benefits against many human illnesses such as epilepsy, depression, arthritis, diabetes, and palliative effects such as analgesic, rejuvenating, regenerating, and growth-promoting effects. Several clinical trials of the different parts of the herb have demonstrated safety in patients suffering from these diseases. In the last two decades, an active component of Withaferin A (WFA) has shown tremendous cytotoxic activity suggesting its potential as an anti-carcinogenic agent in treatment of several cancers. In spite of enormous progress, a thorough elaboration of the proposed mechanism and mode of action is absent. Herein, we provide a comprehensive review of the properties of <i>WS</i> extracts (<i>WS</i>E) containing complex mixtures of diverse components including WFA, which have shown inhibitory properties against many cancers, (breast, colon, prostate, colon, ovarian, lung, brain), along with their mechanism of actions and pathways involved.
Reconstruction of discrete resistivity targets using coupled artificial neural networks and watershed algorithms (2013)

ABSTRACT Estimating the dimensions (defined here as width, height and depth of burial) of discrete targets within resistivity models produced as a result of applying smoothness constraints in most inversion algorithms is difficult, especially when targets are closely spaced. Here we couple an image processing technique (watershed algorithm) with a trained Artificial Neural Network (ANN) model to arrive at predictions of the geometry and resistivity of discrete targets from an initial smoothness constraint resistivity model. These predictions are compared with those obtained from (1) applying the watershed algorithm alone, (2) inversion using the regular L1 norm and (3) when a smoothing disconnect is defined using image processing with data subsequently reinverted to arrive at a revised model estimate. Synthetic studies were conducted on a single cavity model, a model for two widely spaced cavities (spacing &gt;&gt; unit electrode spacing), a model for two closely spaced cavities (spacing &lt; unit electrode spacing) and a model for three closely spaced cavities (spacing &lt; unit electrode spacing). In all model scenarios, the average root mean square (RMS) model error using our ANN approach is below 1 whilst the average combined RMS model error when including target resistivity is 35 for the single cavity, 30 for widely spaced targets and 75 for the closely spaced targets. Despite the higher errors in the closely spaced cavity models, application of the algorithm confirms the presence of multiple features, which is not ascertainable from the smooth inversion, or even when using a disconnect constraint. The ANN derived model significantly reduces the RMS misfit between synthetic and inverted models. We demonstrate the approach using field measurements collected over a precisely known void and also apply the method to smooth resistivity images obtained from measurements collected over an archaeological site at Qurnet Murai, Luxor city, Egypt.
Abstract 19056: Discovery of Potent and Selective Neprilysin Inhibitors Exhibiting Sustained Pharmacodynamic Activity and Non-renal Elimination in Rats (2015)

Introduction: Neprilysin (NEP) inhibitors in combination with angiotensin-II receptor antagonists (ARNIs) have demonstrated benefits in patients with hypertension and chronic heart failure (CHF). A significant population of patients with cardiorenal diseases (e.g., CHF, chronic kidney disease and diabetic nephropathy) exhibit moderate to severe levels of renal impairment. Sacubitril (NEP inhibitor component of LCZ696) is extensively cleared by the kidney and systemic exposures are increased in patients with renal dysfunction thus potentially limiting its therapeutic utility. We aimed to identify potent and selective NEP inhibitors that exhibit non-renal excretion in order to discover agents that may provide optimal therapy in patients with renal dysfunction. Methods: In vitro enzyme activity assays at human NEP were used to assess inhibitory potencies and half-lives of the enzyme-inhibitor complexes. In vivo potentiation of ANP-induced plasma cGMP was evaluated after PO dosing in Sprague Dawley rats. Blood pressure was monitored in conscious Dahl Salt-Sensitive (Dahl/SS) hypertensive rats surgically implanted with telemetry transmitters. Urinary and biliary excretion was evaluated in bile-duct cannulated rats. Results: Selective NEP inhibitors (THRX-213068, THRX-134025, and THRX-124283) were identified with increased potency relative to LBQ657 (active moiety of sacubitril) at NEP (pKi 9.4, 9.3, 9.3 versus 8.2) and displayed longer enzyme residence time (T1/2 = 25, 145, and 190 versus 3 min). All three NEP inhibitors potentiated cGMP to a greater extent than LBQ657 in rat plasma after PO dosing (10 mg/kg). Sustained lowering of mean arterial pressure also was observed in Dahl/SS rats after PO dosing (24 hr average change -17 to -45 mm Hg). Negligible renal excretion was observed for all NEP inhibitors in rats after IV or PO dosing [&lt; 5% of dose relative to 40% (IV) for LBQ657]. Conclusions: Novel, potent, and selective NEP inhibitors were identified that exhibit sustained potentiation of cGMP and BP-lowering in rodent models. Negligible levels of renal excretion were observed in rats suggesting the possibility of providing consistent dosing in patients with cardiorenal diseases across various levels of renal dysfunction.
The crystal structure of WCl6 (1968)

During the examination of a commercial~ preparation of supposed WCIs, the material was submitted for X-ray analysis to verify the compound designation. Chemical analyses were inconclusive in determining the W:CI ratio because of difficulties with the reactivity of the compound. With the Debye-Scherrer techniques used, the pattern proved unidentifiable with any other tungsten-chlorine compound previously described (Reick, 1967). Other physical property measurements such as color and boiling point implied that the compound should be WCI6. The Debye-Scherrer pattern, however, did not conform to that of WCI6 described by Ketelaar & Oosterhout (1943). Needle-shaped single crystals of the unknown were examined on a Buerger precession camera. The diffraction symbol proved to be 3m P with cell constants a0= 10.511+0.003, c0=5.757+0.001 A (refined values from Debye-Scherrer pattern). The only systematic reflection condition was hk. 0 present only with h k = 3n. This condition must be structural because it does not conform to any conditions established by any of the allowable space groups. Structures of similar 1:6 compounds were examined with the aid of Donnay, Donnay, Cox, Kennard & King (1963) and Wyckoff (1967). The similarity of the unit cell to that of UCI6 reported by Zachariasen (1948) suggested a similar structure type. To test this hypothesis, powder pattern intensities were calculated using the POWD2 program of Smith (1967), with Zachariasen's UCI6 atomic position coordinates. This calculated pattern agrees very well with the measured pattern as shown in Table 1. This agreement suggests that the unknown is isostructural with UC16 (space group PSml) and is thus a new polymorph of WCI6. It can be noted that the calculated intensities also satisfy the hk. 0 condition described.
Quantification of multi-organ iron overload using R2* mapping in patients with transfusion-dependent diseases (2023)

We used R2* mapping to assess iron overload in multiple organs of patients with transfusion-dependent diseases and related the R2* values to transfusion volumes and serum ferritin (SF) levels. The organs assessed included the liver, spleen, pancreas, vertebral bone marrow, and myocardium. The results showed a correlation between the R2* values of multiple organs and between the R2* values of some organs and transfusion volumes. This study revealed differences in the distribution of iron overload in various organs and suggested that transfusion volumes could be used to predict the degree of liver iron overload in patients with transfusion-dependent diseases.