julilili42/papers huggingface dataset:
Differential effects of clinically used derivatives and metabolites of artemisinin in the activation of constitutive androstane receptor isoforms
2012-05-11

BACKGROUND AND PURPOSE Widespread resistance to antimalarial drugs requires combination therapies with increasing risk of pharmacokinetic drug–drug interactions. Here, we explore the capacity of antimalarial drugs to induce drug metabolism via activation of constitutive androstane receptors (CAR) by ligand binding. EXPERIMENTAL APPROACH A total of 21 selected antimalarials and 11 major metabolites were screened for binding to CAR isoforms using cellular and in vitro CAR‐coactivator interaction assays, combined with in silico molecular docking. Identified ligands were further characterized by cell‐based assays and primary human hepatocytes were used to elucidate induction of gene expression. KEY RESULTS Only two artemisinin derivatives arteether and artemether, the metabolite deoxyartemisinin and artemisinin itself demonstrated agonist binding to the major isoforms CAR1 and CAR3, while arteether and artemether were also inverse agonists of CAR2. Dihydroartemisinin and artesunate acted as weak inverse agonists of CAR1. While arteether showed the highest activities in vitro , it was less active than artemisinin in inducing hepatic CYP3A4 gene expression in hepatocytes. CONCLUSIONS AND IMPLICATIONS Artemisinin derivatives and metabolites differentially affect the activities of CAR isoforms and of the pregnane X receptor (PXR). This negates a common effect of these drugs on CAR/PXR‐dependent induction of drug metabolism and further provides an explanation for artemisinin consistently inducing cytochrome P450 genes in vivo , whereas arteether and artemether do not. All these drugs are metabolized very rapidly, but only artemisinin is converted to an enzyme‐inducing metabolite. For better understanding of pharmacokinetic drug–drug interaction possibilities, the inducing properties of artemisinin metabolites should be considered.
Bird and mammal frugivores ofEuterpe edulisat Santa Catarina island monitored by camera traps
2012-05-11

From July to October 2009, the frugivorous fauna associated with palmito palms (Euterpe edulis) was studied to identify possible seed dispersers in Atlantic forest remnants on Santa Catarina Island, southern Brazil. The animals approaching or feeding on fruits were recorded by camera traps directed towards infructescences bearing ripe fruits and towards fruit patches on the ground. In a total sampling effort of 165 trap-days, 48 feeding events were recorded. Three birds, the Channel-billed Toucan (Ramphastos vitellinus), Speckled Chachalaca (Ortalis guttata) and White-necked Thrush (Turdus albicollis), and four mammal species, the coati (Nasua nasua), russet rice rat (Euryoryzomys russatus), South American water rat (Nectomys squamipes) and the tayra (Eira barbara) were identified. The highest number of feeding events was recorded for O. guttata, followed by R. vitellinus and E. russatus. Although the number of detected species was low, seed dispersal of E. edulis fruits on Santa Catarina Island is likely still performed by birds and small mammals.
Factor XIII Val34Leu polymorphism is associated with increased factor XIII activation and decreased transcutaneous oxygen readings in patients with diabetic foot ulcers
2012-05-11

Diabet. Med. 29, 1596–1599 (2012) Abstract Aim To investigate the relationship between the factor XIII Val34Leu polymorphism, plasma factor XIII activation and transcutaneous oxygen readings in patients with diabetic foot ulcers. Methods Ninety‐two consecutive patients with Type 2 diabetes and active foot ulcers were investigated. Plasma factor XIII activation was assessed by ELISA. Genetic polymorphism was detected using the ABI PRISM® SNaPshotTM Multiplex Kit. Results are expressed as median (minimum–maximum). Differences between groups were calculated by Mann–Whitney U ‐test or χ 2 ‐test where appropriate. A P ‐value &lt; 0.05 was considered significant. Results The Val34Leu polymorphism was found in 50 subjects (54%) with 42 being heterozygous (Val/Leu) and eight being homozygous (Leu/Leu). The rate of plasma factor XIII activation was increased in patients with Val/Leu or Leu/Leu [Val/Leu or Leu/Leu 152 (55–283) % vs. Val/Val 103 (33–282) %; P &lt; 0.0001]. Transcutaneous oxygen readings were lower in the Val/Leu or Leu/Leu group [Val/Leu or Leu/Leu 16 (0–58) mmHg vs. Val/Val 35 (1–65) mmHg; P = 0.008]. Similarly, plasma factor XIII activation negatively correlated with transcutaneous oxygen readings ( r 2 = −0.314; P = 0.014). Conclusions Val34Leu polymorphism is associated with increased plasma factor XIII activation and seems to be linked with impaired cutaneous microcirculation in patients with diabetic foot ulcers.
Ex vivo pharmacology of surgical samples of the uterosacral ligament. Part I: Effects of carbachol and oxytocin on smooth muscle
2012-05-11

Abstract Aims In a previous study we observed impaired smooth muscle in the uterosacral ligament (USL) of patients with pelvic organ prolapse. The aims of the study were to describe the method of the novel microperfusion system and to determine normal function and pharmacology of smooth muscle in the USL. Methods Samples from the USL were obtained during hysterectomy for benign reasons. Small stretches of connective tissue were mounted in a perfusion chamber under the stereomicroscope. Isotonic contractions of smooth muscle were monitored by digital time‐lapse video and quantified by image processing. Results Constant perfusion with carbachol elicited tonic and pulse stimulation with carbachol and oxytocin rhythmic contractions of smooth muscle in the ground reticulum. Under constant perfusion with relaxin the tonic contraction after carbachol was abolished. Conclusions With the novel microperfusion system, isotonic contractions of smooth muscle in the USL can be recorded and quantified in the tissue microenvironment on the microscopic level. The USL smooth muscle is cholinergic, stimulated by oxytocin and modulated by relaxin. Neurourol. Urodynam. 31:1294–1299, 2012. © 2012 Wiley Periodicals, Inc.
Genome‐wide binding‐site analysis of REVOLUTA reveals a link between leaf patterning and light‐mediated growth responses
2012-05-12

Summary Unlike the situation in animals, the final morphology of the plant body is highly modulated by the environment. During Arabidopsis development, intrinsic factors provide the framework for basic patterning processes. CLASS III HOMEODOMAIN LEUCINE ZIPPER (HD‐ZIPIII) transcription factors are involved in embryo, shoot and root patterning. During vegetative growth HD‐ZIPIII proteins control several polarity set‐up processes such as in leaves and the vascular system. We have identified several direct target genes of the HD‐ZIPIII transcription factor REVOLUTA (REV) using a chromatin immunoprecipitation/DNA sequencing (ChIP‐Seq) approach. This analysis revealed that REV acts upstream of auxin biosynthesis and affects directly the expression of several class II HD‐ZIP transcription factors that have been shown to act in the shade‐avoidance response pathway. We show that, as well as involvement in basic patterning, HD‐ZIPIII transcription factors have a critical role in the control of the elongation growth that is induced when plants experience shade. Leaf polarity is established by the opposed actions of HD‐ZIPIII and KANADI transcription factors. Finally, our study reveals that the module that consists of HD‐ZIPIII/KANADI transcription factors controls shade growth antagonistically and that this antagonism is manifested in the opposed regulation of shared target genes.
Indirect coating of RGD peptides using a poly‐L‐lysine spacer enhances jaw periosteal cell adhesion, proliferation, and differentiation into osteogenic tissue
2012-05-12

Abstract The aim of our study was to generate a biofunctionalized, three‐dimensional (3D) biomaterial to enhance jaw periosteal cell (JPC) adhesion and differentiation into osteogenic tissue. Therefore, open‐cell polylactic acid (OPLA) scaffolds were coated covalently with different RGD peptides (a conserved recognition sequence of the most ECM proteins—arginine‐glycine‐asparagine) and different coating variants. The linear and cyclic RGD peptides were either applied directly or indirectly via a poly‐ L ‐lysine (PLL) spacer. JPCs were analyzed on coated constructs in 2D and 3D cultures and showed enhanced rates for indirectly coated scaffolds using the PLL spacer. By gene expression, we detected significantly increased levels of osteogenic marker genes, such as alkaline phosphatase, RUNX2, and AMELY in JPCs seeded onto PLL/linear RGD constructs compared to the otherwise‐coated constructs. An analysis of the JPC mineralization capacity revealed the highest amounts of calcium–phosphate precipitates in cells growing within the PLL/linear scaffolds. Additionally, the JPC adhesion behavior on OPLA scaffolds seems to be mediated by ITGB3, ITGB1, and ITGAV, as shown by blocking assays. We concluded that coating of OPLA constructs with linear RGD peptides via PLL represents a suitable approach for functionalizing the polymer surface and enhancing adhesion, proliferation, and mineralization of JPCs. © 2012 Wiley Periodicals, Inc. J Biomed Mater Res Part A, 2012.
A FUZZY RULE BASE APPROACH FOR DEVELOPING A SOIL PROTECTION INDEX MAP: A CASE STUDY in the UPPER AWASH BASIN, ETHIOPIAN HIGHLANDS
2012-05-12

ABSTRACT Land use practices and vegetation cover distribution are considered to be the most important dynamic factors that influence the land degradation or the soil erosion of a region. In this study, a Soil Protection Index (SPI) is defined as a function of land use practices and intensity of vegetation cover. This index is used to map the relative degree of protection of topsoil from being eroded by external effects such as rainfall and overland flow. A fuzzy rule‐based model integrated within ArcGIS® has been set‐up and tested with the aim to develop SPI maps. The amount of vegetation cover distribution, that is, Normalized Difference Vegetation Index as proxy parameter and Land Use–Land Cover map are chosen as fuzzy input parameters for the SPI as the desired system output. The approach was tested in the Upper Awash basin in Ethiopia. The output SPI map was qualitatively evaluated against the expert‐defined land degradation risk class, and it was found that locations that are mapped with ‘low and very low’ SPI classes at different time periods of the year have a high potential land degradation risk. Furthermore, socio‐economic data (‘population and livestock densities’) and environmental parameters (‘altitude and soil erodibility’) for the region are used to correlate with the SPI map as an indirect method of evaluation. It is found that population and livestock density explained 68 per cent of the spatial distribution pattern of predicted SPI and an adjusted R ‐squared value of 0·681 ( p &lt; 0·05) was obtained. It was also found that the SPI distribution over the region for two different time periods, that is, January and July 2001, correlated positively ( R 2 = 0·41 and R 2 = 0·51) with the soil erodibility of the region. The transferability and applicability of the model for different environmental settings or landscapes were tested by mapping the SPI of Italy. This SPI map of Italy was compared with the soil erosion map of Italy produced by the European Soil Bureau. It can be concluded that the SPI map reflects the potential land degradation risk distribution of the case‐study region. Results show that a fuzzy rule‐based model can provide useful preliminary information even without detailed and precise data information for developing appropriate strategies for land degradation assessment vital for sustainable land use management. Copyright © 2012 John Wiley &amp; Sons, Ltd.
Alpha-synuclein aggregation involves a bafilomycin A1-sensitive autophagy pathway
2012-05-13

Synucleinopathies like Parkinson disease and dementia with Lewy bodies (DLB) are characterized by α-synuclein aggregates within neurons (Lewy bodies) and their processes (Lewy neurites). Whereas α-synuclein has been genetically linked to the disease process, the pathological relevance of α-synuclein aggregates is still debated. Impaired degradation is considered to result in aggregation of α-synuclein. In addition to the ubiquitin-proteasome degradation, the autophagy-lysosomal pathway (ALP) is involved in intracellular degradation processes for α-synuclein. Here, we asked if modulation of ALP affects α-synuclein aggregation and toxicity. We have identified an induction of the ALP markers LAMP-2A and LC3-II in human brain tissue from DLB patients, in a transgenic mouse model of synucleinopathy, and in a cell culture model for α-synuclein aggregation. ALP inhibition using bafilomycin A 1 (BafA1) significantly potentiates toxicity of aggregated α-synuclein species in transgenic mice and in cell culture. Surprisingly, increased toxicity is paralleled by reduced aggregation in both in vivo and in vitro models. The dichotomy of effects on aggregating and nonaggregating species of α-synuclein was specifically sensitive to BafA1 and could not be reproduced by other ALP inhibitors. The present study expands on the accumulating evidence regarding the function of ALP for α-synuclein degradation by isolating an aggregation specific, BafA1-sensitive, ALP-related pathway. Our data also suggest that protein aggregation may represent a detoxifying event rather than being causal for cellular toxicity.
Candida albicans-Epithelial Interactions: Dissecting the Roles of Active Penetration, Induced Endocytosis and Host Factors on the Infection Process
2012-05-14

Candida albicans frequently causes superficial infections by invading and damaging epithelial cells, but may also cause systemic infections by penetrating through epithelial barriers. C. albicans is a remarkable pathogen because it can invade epithelial cells via two distinct mechanisms: induced endocytosis, analogous to facultative intracellular enteropathogenic bacteria, and active penetration, similar to plant pathogenic fungi. Here we investigated the contributions of the two invasion routes of C. albicans to epithelial invasion. Using selective cellular inhibition approaches and differential fluorescence microscopy, we demonstrate that induced endocytosis contributes considerably to the early time points of invasion, while active penetration represents the dominant epithelial invasion route. Although induced endocytosis depends mainly on Als3-E-cadherin interactions, we observed E-cadherin independent induced endocytosis. Finally, we provide evidence of a protective role for serum factors in oral infection: human serum strongly inhibited C. albicans adhesion to, invasion and damage of oral epithelial cells.
Functional Network Connectivity Underlying Food Processing: Disturbed Salience and Visual Processing in Overweight and Obese Adults
2012-05-14

In order to adequately explore the neurobiological basis of eating behavior of humans and their changes with body weight, interactions between brain areas or networks need to be investigated. In the current functional magnetic resonance imaging study, we examined the modulating effects of stimulus category (food vs. nonfood), caloric content of food, and body weight on the time course and functional connectivity of 5 brain networks by means of independent component analysis in healthy lean and overweight/obese adults. These functional networks included motor sensory, default-mode, extrastriate visual, temporal visual association, and salience networks. We found an extensive modulation elicited by food stimuli in the 2 visual and salience networks, with a dissociable pattern in the time course and functional connectivity between lean and overweight/obese subjects. Specifically, only in lean subjects, the temporal visual association network was modulated by the stimulus category and the salience network by caloric content, whereas overweight and obese subjects showed a generalized augmented response in the salience network. Furthermore, overweight/obese subjects showed changes in functional connectivity in networks important for object recognition, motivational salience, and executive control. These alterations could potentially lead to top-down deficiencies driving the overconsumption of food in the obese population.
PKCα is genetically linked to memory capacity in healthy subjects and to risk for posttraumatic stress disorder in genocide survivors
2012-05-14

Strong memory of a traumatic event is thought to contribute to the development and symptoms of posttraumatic stress disorder (PTSD). Therefore, a genetic predisposition to build strong memories could lead to increased risk for PTSD after a traumatic event. Here we show that genetic variability of the gene encoding PKCα ( PRKCA ) was associated with memory capacity—including aversive memory—in nontraumatized subjects of European descent. This finding was replicated in an independent sample of nontraumatized subjects, who additionally underwent functional magnetic resonance imaging (fMRI). fMRI analysis revealed PRKCA genotype-dependent brain activation differences during successful encoding of aversive information. Further, the identified genetic variant was also related to traumatic memory and to the risk for PTSD in heavily traumatized survivors of the Rwandan genocide. Our results indicate a role for PKCα in memory and suggest a genetic link between memory and the risk for PTSD.
Nuclear factor of activated T cells (NFATc4) is required for BDNF-dependent survival of adult-born neurons and spatial memory formation in the hippocampus
2012-05-14

New neurons generated in the adult dentate gyrus are constantly integrated into the hippocampal circuitry and activated during encoding and recall of new memories. Despite identification of extracellular signals that regulate survival and integration of adult-born neurons such as neurotrophins and neurotransmitters, the nature of the intracellular modulators required to transduce those signals remains elusive. Here, we provide evidence of the expression and transcriptional activity of nuclear factor of activated T cell c4 (NFATc4) in hippocampal progenitor cells. We show that NFATc4 calcineurin-dependent activity is required selectively for survival of adult-born neurons in response to BDNF signaling. Indeed, cyclosporin A injection and stereotaxic delivery of the BDNF scavenger TrkB-Fc in the mouse dentate gyrus reduce the survival of hippocampal adult-born neurons in wild-type but not in NFATc4 −/− mice and do not affect the net rate of neural precursor proliferation and their fate commitment. Furthermore, associated with the reduced survival of adult-born neurons, the absence of NFATc4 leads to selective defects in LTP and in the encoding of hippocampal-dependent spatial memories. Thus, our data demonstrate that NFATc4 is essential in the regulation of adult hippocampal neurogenesis and identify NFATc4 as a central player of BDNF–driven prosurvival signaling in hippocampal adult-born neurons.
Relevance of Deterministic Structures for Modeling of Transport: The Lauswiesen Case Study
2012-05-14

Knowledge of site‐specific contaminant transport processes is an essential requirement for performing various tasks concerning the protection and management of groundwater resources. However, prediction of their behavior is often difficult, especially in heterogeneous aquifers because of the lack of information about flow‐ and transport‐governing subsurface structures and parameters. Hence, stochastic approaches have been developed and frequently used. However, extensive modeling studies on sedimentary structures have shown that consideration of hydrogeological subunits and their distribution can be essential for transport modeling. A case study from the intensely investigated Lauswiesen site is used to demonstrate that more accurate predictions are possible with improved knowledge of deterministic structures. Results of this case study using direct‐push injection logging (DPIL) provide a more reliable characterization of hydraulic conductivity than sieve and flow meter data.
Surgical management of stem cell transplantation‐related complications in children
2012-05-14

Lieber J, Hauch H, Lang P, Handgretinger R, Blumenstock G, Seitz G, Warmann SW, Fuchs J. Surgical management of stem cell transplantation‐related complications in children. Abstract: HSCT is an established treatment option for some children with life‐threatening diseases, but complications remain a major cause of morbidity and mortality. This retrospective data analysis addresses the surgical issues of children with HSCT‐related complications. Between 2002 and 2008, HSCT was performed in 240 children for leukemias/lymphomas (n=135), solid tumors (n=59), immunodeficiencies (n=20), lipid storage diseases (n=10), autoimmune diseases (n=9), and others (n=7). HSCT‐related complications requiring surgery occurred in 24 cases (10%) and most often in the leukemias/lymphomas group (18/24 cases): HC (cystoscopic irrigation, n=7), pulmonary aspergilloses (resection, n=7), bone necroses (core decompression, n=3), GvHD bowel (colostomy/PEG, n=2), ICH (drainage, n=2), bilateral kidney abscess (nephrectomies/renal transplantation, n=1), aspergillosis of the maxillary sinus (decompression, n=1), and post‐traumatic wound healing disorder (meshed skin transplantation, n=1). Survival was 50% in the group with surgery and 62% in the group without (p=0.275). Even though this difference was not statistically significant, surgical intervention should be encouraged in all cases to achieve favorable results.
Crenic habitats, hotspots for freshwater biodiversity conservation: toward an understanding of their ecology
2012-05-15

Springs are unique aquatic habitats that contribute significantly to local and regional biodiversity because of their high habitat complexity and the large number of different spring types. Many springs are small, but they are numerous and often of high water quality, and thus, provide habitats for species that are rare elsewhere because of their sensitivity to anthropogenic impacts (least-impaired habitat relicts). Springs are often species-rich and contain a larger number of Red List taxa than other aquatic habitats. Hydrological factors, particularly flow permanence, water chemistry, and temperature are important ecological factors determining species distribution and community composition. Despite their importance for biodiversity and water quality, springs are much less studied than other aquatic ecosystems. They also are insufficiently covered by protective legislation, often resulting in the destruction of their natural habitat. The authors of papers in this special issue describe specific spring biota, including multitaxon studies, and discuss the role of environmental factors, habitat variability at different spatial and temporal scales, and the importance of natural and anthropogenic disturbance in spring habitats. They suggest directions for future research, including defining reference conditions for springs and their role in long-term ecological research, the development of quality-assessment methods, and their more sustainable use as freshwater resources. © 2012 The Society for Freshwater Science.
Dexamethasone Levels and Base-to-Apex Concentration Gradients in the Scala Tympani Perilymph After Intracochlear Delivery in the Guinea Pig
2012-05-15

With significantly higher, less variable drug levels and smaller base-to-apex concentration gradients, intracochlear applications have advantages to intratympanic injections. For further development of this technique, it is of importance to control leaks of perilymph and drug from the injection site and to evaluate its clinical feasibility and associated risks.