bluuebunny/crossref_metadata_2025_split huggingface dataset:
Combined Chemical, Biological and Theoretical DFT‐QTAIM Study of Potent Glycosidase Inhibitors Based on Quaternary Indolizinium Salts
Authors: Šafář Peter , Žúžiová Jozefína , Marchalín Štefan , Prónayová Nadežda , Švorc Ľubomír , Vrábel Viktor , Šesták Sergej , Rendić Dubravko , Tognetti Vincent , Joubert Laurent , Daïch Adam 
Published: August 2012

AbstractSix novel enantiopure epimeric indolizidinediols have been easily prepared in high yields by an effective and well‐established regioselective THF ring‐opening reaction as a key step. Quarternization of these species was also studied and comparison was made to the quaternizations of other substituted indolizidines. Importantly, a combined theoretical DFT‐QTAIM study has cast light on the various factors that explain the observed conformational selectivity. The inhibitory properties of the six synthesized indolizidines were then investigated against the recombinant Golgi α‐mannosidase‐IIb (dGMIIb) and lysosomal α‐mannosidase (dLM408), human homologues of Drosophila melanogaster. Among the tested compounds, two of them, 4a and 4b, exhibited a pH‐dependent inhibition of dGMIIb at the milimolar level (IC50 = 3.5 or 1.7 mM at pH 5.8 or 6.5, respectively) without affecting the activity of dLM408.
Chiral NHC Ligands for the Copper‐Catalyzed Asymmetric Conjugate Addition of Grignard Reagents
Authors: Germain Nicolas , Magrez Magaly , Kehrli Stefan , Mauduit Marc , Alexakis Alexandre 
Published: August 2012

AbstractIn this paper, we disclose our recent advances in the copper‐catalyzed enantioselective conjugate addition of Grignard reagents to 3‐substituted cyclic enones. Several new N‐heterocyclic carbene (NHC) ligands have been synthesized in high yields by starting from inexpensive materials. These new NHCs were evaluated as ligands for copper, for the Michaeladdition of ethylmagnesium bromide leading to chiral 3,3‐disubstituted cyclohexanones (up to 93 % ee). The best ligand was then engaged in conjugate additions of various Grignard reagents, allowing the formation of quaternary centers with high levels of regio‐ and enantioselectivity with only 0.75 mol‐% catalyst loading. The reaction is also robust to scale‐up. The addition of ethylmagnesium bromide for the construction of a 3,3‐disubstituted cyclopentanone (up to 86 % ee), a synthetically useful chiral synthon, is noteworthy. A tentative mechanism for the catalytic cycle is also discussed.
Controlled Switching of Multicomponent Heterocyclizations of 5‐Amino‐N‐arylpyrazole‐4‐carboxamides, 1,3‐Cyclohexanediones, and Aldehydes
Authors: Chebanov Valentin A. , Saraev Vyacheslav E. , Shishkina Svetlana V. , Shishkin Oleg V. , Musatov Vladimir I. , Desenko Sergey M. 
Published: August 2012

AbstractMulticomponent heterocyclization of 5‐amino‐N‐arylpyrazole‐4‐carboxamides, 1,3‐cyclohexanediones, and aromatic aldehydes was studied, and reaction conditions allowing selective switching between two directions were found. When the reaction was carried out under thermal heating or ultrasonication at room temperature, formation of linear pyrazoloquinoline‐3‐carboxamides was observed. Isomeric angular heterocycles were obtained by ultrasonic‐assisted synthesis at ambient temperature in the presence of HCl catalyst. Treatment with 2 equiv. of 1,3‐diketone in boiling N,N‐dimethylformamide/HCl gave a mixture of pyrazoloquinoline‐3‐carboxamides and unusual acridin‐10‐yl‐pyrazole‐4‐carboxamides, which showed hindered rotation of the pyrazole fragment around the C–N bond.
Characteristics‐based boundary conditions for the Euler adjoint problem
Authors: Hayashi Marcelo , Ceze Marco , Volpe Ernani 
Published: August 2012

SUMMARYOver the last decade, the adjoint method has been consolidated as one of the most versatile and successful tools for aerodynamic design. It has become a research area on its own, spawning a large variety of applications and a prolific literature. Yet, some relevant aspects of the method remain relatively less explored in the literature. Such is the case with the adjoint boundary problem. In particular for Euler flows, both fluid dynamic and adjoint equations entail complementary Riemann problems, and these yield boundary conditions that are fully consistent with well‐posedness. In the literature, this approach has been pursued solely in terms of Riemann variables. This work formulates the adjoint boundary problem so as to correspond precisely to that imposed on the flow, as it is given in terms of primitive variables. Test results have shown to be in agreement with the traditional approach for external flow problems. Copyright © 2012 John Wiley & Sons, Ltd.
Determination of Picogram Amounts of Dihydroxybenzenes in Water Samples with Luminol–lysozyme Chemiluminescence System
Authors: Haixiang Zhao , Xijuan Tan , Zhenghua Song 
Published: August 2012

AbstractAn ultrasensitive method for the determination of dihydroxybenzens by flow injection (FI) chemiluminescence (CL) analysis was proposed for the first time. It was found that the CL intensity of luminol–lysozyme system could be significantly inhibited by dihydroxybenzens. The CL intensity decrements were linear with the logarithm of dihydroxybenzens concentrations over the ranges of 1.0 ∼ 700 pg mL‐1 for hydroquinone (HQ), 5.0 ∼ 700 pg mL‐1 for catechol (CT) and 10 ∼ 7000 pg mL‐1 for resorcinol (RS), with the corresponding limits of detection of 0.7, 3.0 and 7.0 pg mL‐1, respectively. The proposed method was successfully applied to the determination of CT in tap water, rain water, river water and HQ in waste photographic developer samples, with recoveries from 93.5 to 105.8% and relative standard deviations (RSDs) less than 4.0% (n = 5). The possible interaction mechanism of lysozyme with dihydroxybenzens was discussed, and CT to lysozyme's binding constant and the thermodynamic parameters were given by the homemade FI–CL model. The results shown that the binding of dihydroxybenzens to lysozyme was spontaneous with the hydrophobic force.
Nanocomposite Silica Aerogel Activated Carbon: Preparation, Characterization and Application to Remove Lead(II) from Aqueous Solutions
Authors: Fariba Tadayon , Mina Hosseini , Shiva Motahar 
Published: August 2012

AbstractAnovel nanocomposite adsorbent, Silica aerogel activated carbon (SA‐AC) has been prepared for the purpose of removing lead ions from aqueous solution in batch process. The nanocomposite was characterized by Fourier transform infrared spectra (FTIR) and scanning electron microscope (SEM). In the present investigation, Pb(II) adsorption experiments on nanocomposite were conducted on aqueous solution at different initial Pb(II) concentration, pH of the solution, adsorption temperature, adsorbent dosage and contact time. Optimum pH for the adsorption was found to be 6 with corresponding adsorbent dosage level of 0.5 g and 60 °C temperature. The equilibriumwas achieved within 30 min of contact time. It is remarkable that using the developed nanocomposite absorbent, more than 90% of Pb(II) can be removed under desirable experimental conditions. The efficiency of the ions adsorption was determined using atomic absorption spectroscopy. Langmuir and Freundlich isotherm models were applied to analyze the experimental data. The best interpretation for the experimental data was given by the Freundlich isotherm equation. Desorption experiments by elution of the adsorbent with nitric acid show that the nanocomposite could be reused without significant losses of its initial properties.
An Efficient, Mild and Scalable Synthesis of Bioactive Compounds Containing the Angelicin Scaffold
Authors: Hui‐Yi Shiao , Ching‐Chuan Kuo , Jim‐Tong Horng , Shin‐Ru Shih , Sui‐Yuan Chang , Chun‐Chen Liao , John T.‐A. Hsu , Prashanth Kumar Amancha , Yu‐Sheng Chao , Hsing‐Pang Hsieh 
Published: August 2012

AbstractAn efficient, mild and scalable synthesis of angelicin scaffold based compounds was developed. Particularly, the new synthetic route described here circumvents the need for the previously reported key Fries rearrangement step, which uses impractically harsh conditions. The new methodology is applied to the synthesis of several, previously reported analogs of angelicin which have potent anti‐influenza and anti‐cancer activities.
Changes in daily extreme temperatures in the extra‐Carpathians regions of Romania
Authors: Croitoru Adina‐Eliza , Piticar Adrian 
Published: August 2012

AbstractChanges in daily extreme temperatures have been identified in many studies conducted at local, regional or global scales. For Romanian territory, only little research on this issue was done. In this article, the extra‐Carpathians regions of Romania located southward and eastward from the Carpathians Chain were considered. This study is focused on analyzing daily extreme temperature trends at a regional scale (eastern, southern and southeastern regions of Romania) across 50 years (1961–2010). Data sets of daily minimum and maximum temperature recorded in 14 weather stations were analyzed. The main goal was to find changes in extreme daily temperatures using a set of 20 indices adopted from the core indices developed by ETCCDMI with appropriate modifications to suit to the analyzed territory. The main results suggest that regional temperature trends at the scale of extra‐Carpathians areas of Romania are similar to those calculated for global and European continental scales; the climate has become warmer during the last decades. It has been identified that both extreme daily maximum and minimum temperatures have increased in the analyzed areas. For all the indices related to hot temperature most trends are significantly positive. The strongest increase was detected for hot related extremes such as summer days and tropical nights as well as for maximum values of maximum and minimum daily temperatures. For indices related to cold there are different sign slopes, but negative slopes prevail, especially for number of days under a defined threshold. This is also an evidence of the important warming in the area. Generally, it was found that the daily maximum temperature is getting more extreme, whereas the minimum is getting less extreme. Copyright © 2012 Royal Meteorological Society
A daytime over land algorithm for computing AVHRR convective cloud climatologies for the Iberian Peninsula and the Balearic Islands
Authors: Azorin‐Molina Cesar , Baena‐Calatrava Rafael , Echave‐Calvo Imanol , Connell Bernadette H. , Vicente‐Serrano Sergio M. , López‐Moreno Juan I. 
Published: August 2012

ABSTRACTA daytime over land multispectral cloud detection algorithm is presented to derive accurate convective cloud climatologies with high spatial resolution (1.1 km) over the Iberian Peninsula (IP) and the Balearic Islands (BI). The cloud detection scheme was designed to process Advanced Very High Resolution Radiometer (AVHRR) HRPT data and is tested here on NOAA‐17 morning (0900–1200 UTC) and NOAA‐16 afternoon (1200–1500 UTC) overpasses for the warm 6‐month study period May–October. The algorithm consists of four spectral threshold tests applied to each pixel. Test 1 corresponds to the snow‐ice removal, test 2 is the thermal infrared test, test 3 is the albedo or visible test and test 4 is the ratio between near‐infrared and visible channels. The algorithm discretizes all AVHRR data into four groups called cloud‐filled, cloud‐free, snow‐ice and snow‐free radiances. The high‐resolution convective cloud masks are obtained by subtracting snow‐ice pixels from cloudy ones. In this article, a detailed description of the convective cloud detection scheme and the sources of error detected for each test are given, and the first seasonal and monthly regional convective cloud frequency composites are presented. Future applications of the newly proposed threshold algorithm in climate and meteorology are also discussed in this article, particularly the production of convective cloud composites for climate monitoring of storms over the IP and BI.
An activator for pyruvoyl‐dependent l‐aspartate α‐decarboxylase is conserved in a small group of the γ‐proteobacteria including Escherichia coli
Authors: Nozaki Shingo , Webb Michael E. , Niki Hironori 
Published: August 2012

AbstractIn bacteria, β‐alanine is formed via the action of l‐aspartate α‐decarboxylase (PanD) which is one of the small class of pyruvoyl‐dependent enzymes. The pyruvoyl cofactor in these enzymes is formed via the intramolecular rearrangement of a serine residue in the peptide backbone leading to chain cleavage and formation of the covalently‐bound cofactor from the serine residue. This reaction was previously thought to be uncatalysed. Here we show that in Escherichia coli, PanD is activated by the putative acetyltransferase YhhK, subsequently termed PanZ. Activation of PanD both in vivo and in vitro is PanZ‐dependent. PanZ binds to PanD, and we demonstrate that a PanZ(N45A) site‐directed mutant is unable to enhance cleavage of the proenzyme PanD despite retaining affinity for PanD. This suggests that the putative acetyltransferases domain of PanZ may be responsible for activation to enhance the processing of PanD. Although panD is conserved among most bacteria, the panZ gene is conserved only in E. coli‐related enterobacterial species including Shigella, Salmonella, Klebsiella and Yersinia. These bacteria are found predominantly in the gut flora where pantothenate is abundant and regulation of PanD by PanZ allows these organisms to closely regulate production of β‐alanine and hence pantothenate in response to metabolic demand.
Molecular dynamics simulation of the last step of a catalytic cycle: Product release from the active site of the enzyme chorismate mutase from Mycobacterium tuberculosis
Authors: Choutko Alexandra , van Gunsteren Wilfred F. 
Published: August 2012

AbstractThe protein chorismate mutase MtCM from Mycobacterium tuberculosis catalyzes one of the few pericyclic reactions known in biology: the transformation of chorismate to prephenate. Chorismate mutases have been widely studied experimentally and computationally to elucidate the transition state of the enzyme catalyzed reaction and the origin of the high catalytic rate. However, studies about substrate entry and product exit to and from the highly occluded active site of the enzyme have to our knowledge not been performed on this enzyme. Crystallographic data suggest a possible substrate entry gate, that involves a slight opening of the enzyme for the substrate to access the active site. Using multiple molecular dynamics simulations, we investigate the natural dynamic process of the product exiting from the binding pocket of MtCM. We identify a dominant exit pathway, which is in agreement with the gate proposed from the available crystallographic data. Helices H2 and H4 move apart from each other which enables the product to exit from the active site. Interestingly, in almost all exit trajectories, two residues arginine 72 and arginine 134, which participate in the burying of the active site, are accompanying the product on its exit journey from the catalytic site.
Bacterial collagen‐binding domain targets undertwisted regions of collagen
Authors: Philominathan Sagaya Theresa Leena , Koide Takaki , Matsushita Osamu , Sakon Joshua 
Published: August 2012

AbstractClostridium histolyticum collagenase causes extensive degradation of collagen in connective tissue that results in gas gangrene. The C‐terminal collagen‐binding domain (CBD) of these enzymes is the minimal segment required to bind to a collagen fibril. CBD binds unidirectionally to the undertwisted C‐terminus of triple helical collagen. Here, we examine whether CBD could also target undertwisted regions even in the middle of the triple helix. Collageneous peptides with an additional undertwisted region were synthesized by introducing a Gly → Ala substitution [(POG)xPOA(POG)y]3, where x + y = 9 and x > 3). 1H–15N heteronuclear single quantum coherence nuclear magnetic resonance (HSQC NMR) titration studies with 15N‐labeled CBD demonstrated that the minicollagen binds to a 10 Å wide 25 Å long cleft. Six collagenous peptides each labeled with a nitroxide radical were then titrated with 15N‐labeled CBD. CBD binds to either the Gly → Ala substitution site or to the C‐terminus of each minicollagen. Small‐angle X‐ray scattering measurements revealed that CBD prefers to bind the Gly → Ala site to the C‐terminus. The HSQC NMR spectra of 15N‐labeled minicollagen and minicollagen with undertwisted regions were unaffected by the titration of unlabeled CBD. The results imply that CBD binds to the undertwisted region of the minicollagen but does not actively unwind the triple helix.
Asenapine (Sycrest): sublingual antipsychotic for acute mania
Authors: Chaplin Steve , Smith Daniel 
Published: August 2012

AbstractAsenapine (Sycrest) is an antipsychotic taken sub ‐ lingually for the treatment of moderate to severe manic episodes in bipolar disorder. In our New products review, Steve Chaplin presents the clinical data relating to its efficacy and adverse events and Dr Daniel Smith discusses its place in therapy. Copyright © 2012 Wiley Interface Ltd
Resolution of sharp fronts in the presence of model error in variational data assimilation
Authors: Freitag M. A. , Nichols N. K. , Budd C. J. 
Published: August 2012

AbstractWe show that the four‐dimensional variational data assimilation method (4DVar) can be interpreted as a form of Tikhonov regularization, a very familiar method for solving ill‐posed inverse problems. It is known from image restoration problems thatL1‐norm penalty regularization recovers sharp edges in the image more accurately than Tikhonov, orL2‐norm, penalty regularization. We apply this idea from stationary inverse problems to 4DVar, a dynamical inverse problem, and give examples for anL1‐norm penalty approach and a mixed total variation (TV)L1–L2‐norm penalty approach. For problems with model error where sharp fronts are present and the background and observation error covariances are known, the mixed TVL1–L2‐norm penalty performs better than either theL1‐norm method or the strong‐constraint 4DVar (L2‐norm) method. A strength of the mixed TVL1–L2‐norm regularization is that in the case where a simplified form of the background error covariance matrix is used it produces a much more accurate analysis than 4DVar. The method thus has the potential in numerical weather prediction to overcome operational problems with poorly tuned background error covariance matrices. Copyright © 2012 Royal Meteorological Society
Post‐translational modification: nature's escape from genetic imprisonment and the basis for dynamic information encoding
Authors: Prabakaran Sudhakaran , Lippens Guy , Steen Hanno , Gunawardena Jeremy 
Published: August 2012

AbstractWe discuss protein post‐translational modification (PTM) from an information processing perspective. PTM at multiple sites on a protein creates a combinatorial explosion in the number of potential ‘mod‐forms’, or global patterns of modification. Distinct mod‐forms can elicit distinct downstream responses, so that the overall response depends partly on the effectiveness of a particular mod‐form to elicit a response and partly on the stoichiometry of that mod‐form in the molecular population. We introduce the ‘mod‐form distribution’—the relative stoichiometries of each mod‐form—as the most informative measure of a protein's state. Distinct mod‐form distributions may summarize information about distinct cellular and physiological conditions and allow downstream processes to interpret this information accordingly. Such information ‘encoding’ by PTMs may facilitate evolution by weakening the need to directly link upstream conditions to downstream responses. Mod‐form distributions provide a quantitative framework in which to interpret ideas of ‘PTM codes’ that are emerging in several areas of biology, as we show by reviewing examples of ion channels, GPCRs, microtubules, and transcriptional co‐regulators. We focus particularly on examples other than the well‐known ‘histone code’, to emphasize the pervasive use of information encoding in molecular biology. Finally, we touch briefly on new methods for measuring mod‐form distributions. WIREs Syst Biol Med 2012, 4:565–583. doi: 10.1002/wsbm.1185This article is categorized under:

Models of Systems Properties and Processes > Mechanistic Models
Laboratory Methods and Technologies > Proteomics Methods
Biological Mechanisms > Regulatory Biology
Population pharmacokinetic modeling of Sepantronium bromide (YM155), a small molecule survivin suppressant, in patients with non-small cell lung cancer, hormone refractory prostate cancer, or unresectable stage III or IV melanoma
Authors: Aoyama Yumiko , Kaibara Atsunori , Takada Akitsugu , Nishimura Tetsuya , Katashima Masataka , Sawamoto Taiji 
Published: August 2012

Summary
Purpose Population pharmacokinetics (PK) of sepantronium bromide (YM155) was characterized in patients with non-small cell lung cancer, hormone refractory prostate cancer, or unresectable stage III or IV melanoma and enrolled in one of three phase 2 studies conducted in Europe or the U.S. Method Sepantronium was administered as a continuous intravenous infusion (CIVI) at 4.8 mg/m2/day over 7 days every 21 days. Population PK analysis was performed using a linear one-compartment model involving total body clearance (CL) and volume of distribution with an inter-individual random effect on CL and a proportional residual errors to describe 578 plasma sepantronium concentrations obtained from a total of 96 patients by NONMEM Version VI. The first-order conditional estimation method with interaction was applied. Results The one-compartment model with one random effect on CL and two different proportional error models provided an adequate description of the data. Creatinine clearance (CLCR), cancer type, and alanine aminotransferase (ALT) were recognized as significant covariates of CL. CLCR was the most influential covariate on sepantronium exposure and predicted to contribute to a 25 % decrease in CL for patients with moderately impaired renal function (CLCR = 40 mL/min) compared to patients with normal CLCR. Cancer type and ALT had a smaller but nonetheless significant contribution. Other patient characteristics such as age, gender, and race were not considered as significant covariates of CL. Conclusions The results provide the important information for optimizing the therapeutic efficacy and minimizing the toxicity for sepantronium in cancer therapy.
Unintended Diagnosis of Von Hippel Lindau Syndrome Using Array Comparative Genomic Hybridization (CGH): Counseling Challenges Arising from Unexpected Information
Authors: Hogan Jennifer , Turner A. , Tucker K. , Warwick L. 
Published: August 2012

AbstractArray Comparative Genomic Hybridization (array CGH) is a powerful tool for identifying genomic imbalances and providing a diagnosis in individuals with a normal karyotype. It has been particularly useful in the investigation of individuals with developmental delay +/−, dysmorphic features and/or multiple congenital abnormalities. However, this non‐targeted method of scanning the whole genome can reveal unexpected information. We present a case where array CGH identified the cause of a proband's moderate mental retardation by discovery of a de novo deletion of chromosome 3p25.3. This deletion was shown to contain at least 25 genes including the VHL gene, the deletion or mutation of which leads to Von Hippel Lindau (VHL) syndrome. Presymptomatic testing for VHL is usually offered after appropriate genetic counseling about the implications of this condition. Therefore, scanning the genome by array CGH presents a number of challenges for the genetic counselor. We suggest that further understanding of the psychosocial effects of array CGH is needed in order for appropriate pre‐ and post‐test counseling to be provided.