julilili42/papers huggingface dataset:
Role of Polymeric Excipients in the Stabilization of Olanzapine when Exposed to Aqueous Environments
2015-12-12

Hydrate formation is a phase transition which can occur during manufacturing processes involving water. This work considers the prevention of hydration of anhydrous olanzapine and hydrate conversions in the presence of water and polymers (polyethyleneglycol; hydroxypropylcellulose; polyvinylpyrrolidone) in forming pellets by wet extrusion and spheronisation. Anhydrous olanzapine was added to water with or without those polymers prior to extrusion with microcrystalline cellulose. Assessment of olanzapine conversion was made by XRP-Diffraction; FTIR spectroscopy; calorimetry (DSC) and microscopy (SEM for crystal size and shape). The addition of water converted the anhydrous form into dihydrate B and higher hydrate; whereas polyethyleneglycol promoted a selective hydrate conversion into the higher hydrate olanzapine form. Both polyvinylpyrrolidone and hydroxypropylcellulose prevented the hydrate transformations of the anhydrous drug; the latter even in the presence of hydrate seeds. This may be explained by the higher H-bond ability; higher network association and higher hydrophobicity of hydroxypropylcellulose by comparison with polyethyleneglycol and polyvinylpyrrolidone; which could contribute to its higher affinity to the crystal surfaces of the hydrate nuclei/initial crystals and promoting steric hindrance to the incorporation of other drug molecules into the crystal lattice; thus, preventing the crystal growth. The addition of microcrystalline cellulose needed for the pellets production (final product) did not eliminate the protector effect of both hydroxypropylcellulose and polyvinylpyrrolidone during pellets’ processing and dissolution evaluation.
Helical Flow and Transient Solute Dilution in Porous Media
2015-12-12

Helical flow can occur in porous media if the hydraulic conductivity tensor is anisotropic. We study the structure of steady-state flow fields in three-dimensional anisotropic porous media formed by two homogeneous layers, one of which is anisotropic. We simulate transient transport of a conservative scalar in such flow fields by a hybrid streamline/smoothed particle hydrodynamics method and analyze dilution. We use stretching and folding metrics to characterize the flow field and the dilution index of a conservative scalar divided by the volume of the domain to quantify plume dilution. Based on the results of detailed numerical simulations, we conclude that nonlinear deformation triggers dilution and that plume dilution is controlled by two parameters: the contrast between the principal directions of the anisotropic layer, and the orientation of the hydraulic conductivity tensor with respect to the main flow direction. Furthermore, we show that in this kind of flow fields transverse dispersion is responsible for an increase in plume dilution, while the effect of longitudinal dispersion is negligible.
Early Clinical and Radiological Course, Management, and Outcome of Intracerebral Hemorrhage Related to New Oral Anticoagulants
2015-12-14

Non-vitamin K antagonist oral anticoagulant-associated ICH has a high mortality and an unfavorable outcome, and hematoma expansion is frequent. Larger-scale prospective studies are needed to determine whether the early administration of specific antidotes can improve the poor prognosis of NOAC-associated ICH.
Metabotropic glutamate receptor 5 couples cellular prion protein to intracellular signalling in Alzheimer’s disease
2015-12-14

Alzheimer's disease-related phenotypes in mice can be rescued by blockade of either cellular prion protein or metabotropic glutamate receptor 5. We sought genetic and biochemical evidence that these proteins function cooperatively as an obligate complex in the brain. We show that cellular prion protein associates via transmembrane metabotropic glutamate receptor 5 with the intracellular protein mediators Homer1b/c, calcium/calmodulin-dependent protein kinase II, and the Alzheimer's disease risk gene product protein tyrosine kinase 2 beta. Coupling of cellular prion protein to these intracellular proteins is modified by soluble amyloid-β oligomers, by mouse brain Alzheimer's disease transgenes or by human Alzheimer's disease pathology. Amyloid-β oligomer-triggered phosphorylation of intracellular protein mediators and impairment of synaptic plasticity in vitro requires Prnp-Grm5 genetic interaction, being absent in transheterozygous loss-of-function, but present in either single heterozygote. Importantly, genetic coupling between Prnp and Grm5 is also responsible for signalling, for survival and for synapse loss in Alzheimer's disease transgenic model mice. Thus, the interaction between metabotropic glutamate receptor 5 and cellular prion protein has a central role in Alzheimer's disease pathogenesis, and the complex is a potential target for disease-modifying intervention.
Improving Motor Corticothalamic Communication After Stroke Using Real-Time fMRI Connectivity-Based Neurofeedback
2015-12-14

Background. Two thirds of stroke survivors experience motor impairment resulting in long-term disability. The anatomical substrate is often the disruption of cortico-subcortical pathways. It has been proposed that reestablishment of cortico-subcortical communication relates to functional recovery. Objective. In this study, we applied a novel training protocol to augment ipsilesional cortico-subcortical connectivity after stroke. Chronic stroke patients with severe motor impairment were provided online feedback of blood-oxygenation level dependent signal connectivity between cortical and subcortical regions critical for motor function using real-time functional magnetic resonance imaging neurofeedback. Results. In this proof of principle study, 3 out of 4 patients learned to voluntarily modulate cortico-subcortical connectivity as intended. Conclusions. Our results document for the first time the feasibility and safety for patients with chronic stroke and severe motor impairment to self-regulate and augment ipsilesional cortico-subcortical connectivity through neurofeedback using real-time functional magnetic resonance imaging.
Fragmentation functions at next-to-next-to-leading order accuracy
2015-12-14

We present a first analysis of parton-to-pion fragmentation functions at next-to-next-to-leading order accuracy in QCD based on single-inclusive pion production in electron-positron annihilation. Special emphasis is put on the technical details necessary to perform the QCD scale evolution and cross section calculation in Mellin moment space. Lastly, we demonstrate how the description of the data and the theoretical uncertainties are improved when next-to-next-to-leading order QCD corrections are included.
Diversity of ABBA Prenyltransferases in Marine Streptomyces sp. CNQ-509: Promiscuous Enzymes for the Biosynthesis of Mixed Terpenoid Compounds
2015-12-14

Terpenoids are arguably the largest and most diverse family of natural products, featuring prominently in e.g. signalling, self-defence, UV-protection and electron transfer. Prenyltransferases are essential players in terpenoid and hybrid isoprenoid biosynthesis that install isoprene units on target molecules and thereby often modulate their bioactivity. In our search for new prenyltransferase biocatalysts we focused on the marine-derived Streptomyces sp. CNQ-509, a particularly rich source of meroterpenoid chemistry. Sequencing and analysis of the genome of Streptomyces sp. CNQ-509 revealed seven putative phenol/phenazine-specific ABBA prenyltransferases, and one putative indole-specific ABBA prenyltransferase. To elucidate the substrate specificity of the ABBA prenyltransferases and to learn about their role in secondary metabolism, CnqP1 -CnqP8 were produced in Escherichia coli and incubated with various aromatic and isoprenoid substrates. Five of the eight prenyltransferases displayed enzymatic activity. The efficient conversion of dihydroxynaphthalene derivatives by CnqP3 (encoded by AA958_24325) and the co-location of AA958_24325 with genes characteristic for the biosynthesis of THN (tetrahydroxynaphthalene)-derived natural products indicates that the enzyme is involved in the formation of debromomarinone or other naphthoquinone-derived meroterpenoids. Moreover, CnqP3 showed high flexibility towards a range of aromatic and isoprenoid substrates and thus represents an interesting new tool for biocatalytic applications.
Interrogating Substrate Selectivity and Composition of Endogenous Histone Deacetylase Complexes with Chemical Probes
2015-12-14

Abstract Histone deacetylases (HDACs) regulate the function and activity of numerous cellular proteins by removing acetylation marks from regulatory lysine residues. We have developed peptide‐based HDAC probes that contain hydroxamate amino acids of various lengths to replace modified lysine residues in the context of known acetylation sites. The interaction profiles of all human HDACs were studied with three sets of probes, which derived from different acetylation sites, and sequence context was found to have a strong impact on substrate recognition and composition of HDAC complexes. By investigating K382 acetylation of the tumor suppressor p53 as an example, we further demonstrate that the interaction profiles reflect the catalytic activities of respective HDACs. These results underline the utility of the newly established probes for deciphering not only activity, but also substrate selectivity and composition of endogenous HDAC complexes, which can hardly be achieved otherwise.
Shotgun proteomics of bacterial pathogens: advances, challenges and clinical implications
2015-12-14

Mass spectrometry-based proteomics is increasingly used in analysis of bacterial pathogens. Simple experimental set-ups based on high accuracy mass spectrometry and powerful biochemical and bioinformatics tools are capable of reliably quantifying levels of several thousand bacterial proteins in a single experiment, reaching the analytical capacity to completely map whole proteomes. Here the authors present the state-of-the-art in bacterial pathogen proteomics and discuss challenges that the field is facing, especially in analysis of low abundant, modified proteins from organisms that are difficult to culture. Constant improvements in speed and sensitivity of mass spectrometers, as well as in bioinformatic and biochemical workflows will soon allow for comprehensive analysis of regulatory mechanisms of pathogenicity and enable routine application of proteomics in the clinical setting.
Response profiles of murine spiral ganglion neurons on multi-electrode arrays
2015-12-14

This study is the first to show electrical activity of SGNs on MEAs. Our findings may help to improve stimulation by and to reduce energy consumption of CIs and thereby contribute to the development of fully implantable devices with better auditory resolution in the future.
Whole Exome Sequencing Identifies Rare Protein‐Coding Variants in Behçet's Disease
2015-12-14

Objective Behçet's disease (BD) is a systemic inflammatory disease with an incompletely understood etiology. Despite the identification of multiple common genetic variants associated with BD, rare genetic variants have been less explored. We undertook this study to investigate the role of rare variants in BD by performing whole exome sequencing in BD patients of European descent. Methods Whole exome sequencing was performed in a discovery set comprising 14 German BD patients of European descent. For replication and validation, Sanger sequencing and Sequenom genotyping were performed in the discovery set and in 2 additional independent sets of 49 German BD patients and 129 Italian BD patients of European descent. Genetic association analysis was then performed in BD patients and 503 controls of European descent. Functional effects of associated genetic variants were assessed using bioinformatic approaches. Results Using whole exome sequencing, we identified 77 rare variants (in 74 genes) with predicted protein‐damaging effects in BD. These variants were genotyped in 2 additional patient sets and then analyzed to reveal significant associations with BD at 2 genetic variants detected in all 3 patient sets that remained significant after Bonferroni correction. We detected genetic association between BD and LIMK2 (rs149034313), involved in regulating cytoskeletal reorganization, and between BD and NEIL1 (rs5745908), involved in base excision DNA repair ( P = 3.22 × 10 −4 and P = 5.16 × 10 −4 , respectively). The LIMK2 association is a missense variant with predicted protein damage that may influence functional interactions with proteins involved in cytoskeletal regulation by Rho GTPase, inflammation mediated by chemokine and cytokine signaling pathways, T cell activation, and angiogenesis (Bonferroni‐corrected P = 5.63 × 10 −14 , P = 7.29 × 10 −6 , P = 1.15 × 10 −5 , and P = 6.40 × 10 −3 , respectively). The genetic association in NEIL1 is a predicted splice donor variant that may introduce a deleterious intron retention and result in a noncoding transcript variant. Conclusion We used whole exome sequencing in BD for the first time and identified 2 rare putative protein‐damaging genetic variants associated with this disease. These genetic variants might influence cytoskeletal regulation and DNA repair mechanisms in BD and might provide further insight into increased leukocyte tissue infiltration and the role of oxidative stress in BD.
Transcriptional regulatory networks governing stem cell differentiation into hepatocytes in vitro
2015-12-14

The differentiation of embryonic stem cells (ESC) to hepatocytes offers the possibility of unlimited supply of human hepatocytes for cell therapy and biomedical research. However, current protocols achieve only a partial hepatocyte differentiation. This is largely due to our poor understanding of the transcriptional regulatory networks (TRN) governing stem cell and hepatocyte plasticity.
IFN-mediated cytokine induction is associated with sustained virological response in chronic HCV infection
2015-12-14

Hepatitis C virus (HCV) infection is a major cause of chronic liver disease and associated complications such as liver cirrhosis and hepatocellular carcinoma. Interferons (IFNs) are crucial for HCV clearance and a sustained virological response (SVR). There is evidence that an appropriate endogenous IFN response is also required for an efficient final virus clearance by novel directly acting antiviral agents. Understanding the molecular mechanisms of IFN response for the treatment outcome remains therefore important.
Population Pharmacokinetics of Pyronaridine in Pediatric Malaria Patients
2015-12-15

ABSTRACT Pyramax is a pyronaridine (PYR)-artesunate (PA) combination for the treatment of uncomplicated malaria in adult and pediatric patients. A granule formulation of this combination is being developed for treatment of uncomplicated P. falciparum and P. vivax malaria in pediatric patients. The aims of this study were to describe the pharmacokinetics of PYR using a total of 1,085 blood PYR concentrations available from 349 malaria patients younger than 16 years of age with mild to moderate uncomplicated malaria and to confirm the dosing regimen for the pediatric granule formulation. Nonlinear mixed-effects modeling using NONMEM software was used to obtain the pharmacokinetic and inter- and intraindividual variability parameter estimates. The population pharmacokinetics of PYR were described by a two-compartment model with first-order absorption and elimination. Allometric scaling was implemented to address the effect of body weight on clearance and volume parameters. The final parameter estimates of PYR apparent clearance (CL/ F ), central volume of distribution ( V 2 / F ), peripheral volume of distribution ( V 3 / F ), intercompartmental clearance ( Q / F ), and absorption rate constant ( K a ) were 377 liters/day, 2,230 liters, 3,230 liters, 804 liters/day and 17.9 day −1 , respectively. Covariate model building conducted using forward addition ( P &lt; 0.05) followed by backward elimination ( P &lt; 0.001) yielded two significant covariate-parameter relationships, i.e., age on V 2 / F and formulation on K a . Evaluation of bootstrapping, visual predictive check, and condition number indicated that the final model displayed satisfactory robustness, predictive power, and stability. Simulations of PYR concentration-time profiles generated from the final model show similar exposures across pediatric weight ranges, supporting the proposed labeling for weight-based dosing of Pyramax granules. (These studies have been registered at ClinicalTrials.gov under registration no. NCT00331136 [phase II study] and NCT00541385, NCT00403260, NCT00422084, and NCT00440999 [phase III studies]. The most recent phase III study was registered at pactr.org under registration no. PACTR201105000286876.)
Conserved and unique features of the homeologous maize Aux/IAA proteins ROOTLESS WITH UNDETECTABLE MERISTEM 1 and RUM1-like 1
2015-12-15

The maize (Zea mays L.) Aux/IAA protein RUM1 (ROOTLESS WITH UNDETECTABLE MERISTEM 1) is a key regulator of lateral and seminal root formation. An ancient maize genome duplication resulted in the emergence of its homeolog rum1-like1 (rul1), which displays 92% amino acid sequence identity with RUM1. Both, RUL1 and RUM1 exhibit the canonical four domain structure of Aux/IAA proteins. Moreover, both are localized to the nucleus, are instable and have similar short half-lives of ~23min. Moreover, RUL1 and RUM1 can be stabilized by specific mutations in the five amino acid degron sequence of domain II. In addition, proteins encoded by both genes interact in vivo with auxin response factors (ARFs) such as ZmARF25 and ZmARF34 in protoplasts. Although it was demonstrated that RUL1 and RUM1 can homo and heterodimerize in vivo, rul1 expression is independent of rum1. Moreover, on average rul1 expression is ~84-fold higher than rum1 in the 12 tested tissues and developmental stages, although the relative expression levels in different root tissues are very similar. While RUM1 and RUL1 display conserved biochemical properties, yeast-two-hybrid in combination with BiFC experiments identified a RUM1-associated protein 1 (RAP1) that specifically interacts with RUM1 but not with RUL1. This suggests that RUM1 and RUL1 are at least in part interwoven into different molecular networks.
Targeting hedgehog signalling by arsenic trioxide reduces cell growth and induces apoptosis in rhabdomyosarcoma
2015-12-15

Rhabdomyosarcomas (RMS) are soft tissue tumours treated with a combination of surgery and chemotherapy. However, mortality rates remain high in case of recurrences and metastatic disease due to drug resistance and failure to undergo apoptosis. Therefore, innovative approaches targeting specific signalling pathways are urgently needed. We analysed the impact of different hedgehog (Hh) pathway inhibitors on growth and survival of six RMS cell lines using MTS assay, colony formation assay, 3D spheroid cultures, flow cytometry and western blotting. Especially the glioma-associated oncogene family (GLI) inhibitor arsenic trioxide (ATO) effectively reduced viability as well as clonal growth and induced cell death in RMS cell lines of embryonal, alveolar and sclerosing, spindle cell subtype, whereas normal skeletal muscle cells were hardly compromised by ATO. Combination of ATO with itraconazole potentiated the reduction of colony formation and spheroid size. These results show that ATO is a promising substance for treatment of relapsed and refractory RMS by directly targeting GLI transcription factors. The combination with itraconazole or other chemotherapeutic drugs has the opportunity to enforce the treatment efficiency of resistant and recurrent RMS.
Ln(II)/Pb(II)–Ln(III)/Pb(0) Redox Approach toward Rare-Earth-Metal Half-Sandwich Complexes
2015-12-15

The divalent bis(trimethylsilyl)amide complexes Ln[N(SiMe3)2]2(THF)2 (Ln = Sm, Yb) react with 0.5 equiv of lead(II) pentamethylcyclopentadienide, Cp*2Pb (Cp* = C5Me5), in n-hexane to form the half-sandwich complexes Cp*Ln[N(SiMe3)2]2 (Ln = Sm, Yb) in almost quantitative yield. The same reaction performed with Eu[N(SiMe3)2]2(THF)2 resulted in the cocrystallization of the sandwich complex Cp*2Eu[N(SiMe3)2] and homoleptic Eu[N(SiMe3)2]3. The divalent bis(dimethylsilyl)amide complexes Ln{[μ-N(SiHMe2)2]2Ln[N(SiHMe2)2](THF)}2 (Ln = Sm, Yb) react with 1.5 equiv of Cp*2Pb in n-hexane/THF to form the half-sandwich complexes Cp*Ln[N(SiHMe2)2]2(THF) (Ln = Sm, Yb). The corresponding europium reaction did not provide any crystalline material. Treatment of divalent Eu[N(SiMe3)2]2(THF)2 with 2 equiv of 3-tert-butyl-5-methylpyrazole (HpztBu,Me) in THF generates [(pztBu,Me)Eu(μ-pztBu,Me)(THF)2]2. Oxidation of the europium(II) pyrazolate complex with 1 equiv of Cp*2Pb in THF afforded Cp*Eu(μ-pztBu,Me)2(THF)2. The tetramethylaluminate compounds {Ln(AlMe4)2}n (Ln = Sm, Yb) react with 0.5 equiv of PbCp*2 in n-hexane to produce mixtures of half-sandwich and metallocene complexes Cp*Ln(AlMe4)2 and [Cp*2Ln(μ-AlMe4)]2, respectively. The attempted oxidation of {Eu(AlMe4)2}n led to the formation of {Cp*Eu(AlMe4)}, which could be crystallized from THF to give polymeric {Cp*Eu(μ-AlMe4)(THF)3}n. The reaction of "chloro-contaminated" {Sm(AlMe4)2}n with 2 equiv of HCp* performed in THF led to the isolation of the unexpected mixed chloride methylidene complex [Cp*3Sm3(μ2-Cl)3(μ3-Cl)(μ3-CH2)(THF)3]. Reacting {Yb(AlEt4)2}n with 0.5 equiv of Cp*2Pb in n-hexane gave a mixture of products, from which Cp*2Yb(AlEt4) was identified. Performing the same reaction in toluene in the presence of diethyl ether resulted in the formation of the divalent metathesis product Cp*Yb(AlEt4)(Et2O)2.
LEARNER CORPORA AND THEIR POTENTIAL FOR MULTILINGUAL TEACHING
2015-12-15

This article primarily deals with building and using a type of language corpus -the learner corpus -for multilingual teaching.It describes all relevant aspects of the conceptualization, motivation and construction of learner corpora including the case example of the German learner corpus FALKO (Fehlerannotiertes Lernerkorpus 'error annotated learner corpus').In addition we discuss the possibility of a learner corpus for the Georgian language using examples from real Georgian language courses at Goethe University Frankfurt and Tbilisi State University.The article stresses the potential of learner corpora for multilingual teaching and multilingual teacher education.