julilili42/papers huggingface dataset:
Homo‐ and heterodimerization of ROCO kinases: LRRK2 kinase inhibition by the LRRK2 ROCO fragment
2009-08-27

Abstract Mutations in the gene encoding leucine‐rich repeat kinase 2 (LRRK2) are the most common cause of autosomal‐dominant familial and late‐onset sporadic Parkinson’s disease (PD). LRRK2 is a large multi‐domain protein featuring a GTP‐binding C‐terminal of Ras of complex proteins (ROC) (ROCO) domain combination unique for the ROCO protein family, directly followed by a kinase domain. Dimerization is a well‐established phenomenon among protein kinases. Here, we confirm LRRK2 self‐interaction, and provide evidence for general homo‐ and heterodimerization potential among the ROCO kinase family (LRRK2, LRRK1, and death‐associated protein kinase 1). The ROCO domain was critically, though not exclusively involved in dimerization, as a LRRK2 deletion mutant lacking the ROCO domain retained dimeric properties. GTP binding did not appear to influence ROCO LRRK2 self‐interaction. Interestingly, ROCO LRRK2 fragments exerted an inhibitory effect on both wild‐type and the elevated G2019S LRRK2 autophosphorylation activity. Insertion of PD mutations into ROCO LRRK2 reduced self‐interaction and led to a reduction of LRRK2 kinase inhibition. Collectively, these results suggest a functional link between ROCO interactions and kinase activity of wild‐type and mutant LRRK2. Importantly, our finding of ROCO LRRK2 fragment‐mediated LRRK2 kinase inhibition offers a novel lead for drug design and thus might have important implications for new therapeutic avenues in PD.
A novel algorithm for detecting differentially regulated paths based on gene set enrichment analysis
2009-08-27

Abstract Motivation: Deregulated signaling cascades are known to play a crucial role in many pathogenic processes, among them are tumor initiation and progression. In the recent past, modern experimental techniques that allow for measuring the amount of mRNA transcripts of almost all known human genes in a tissue or even in a single cell have opened new avenues for studying the activity of the signaling cascades and for understanding the information flow in the networks. Results: We present a novel dynamic programming algorithm for detecting deregulated signaling cascades. The so-called FiDePa (Finding Deregulated Paths) algorithm interprets differences in the expression profiles of tumor and normal tissues. It relies on the well-known gene set enrichment analysis (GSEA) and efficiently detects all paths in a given regulatory or signaling network that are significantly enriched with differentially expressed genes or proteins. Since our algorithm allows for comparing a single tumor expression profile with the control group, it facilitates the detection of specific regulatory features of a tumor that may help to optimize tumor therapy. To demonstrate the capabilities of our algorithm, we analyzed a glioma expression dataset with respect to a directed graph that combined the regulatory networks of the KEGG and TRANSPATH database. The resulting glioma consensus network that encompasses all detected deregulated paths contained many genes and pathways that are known to be key players in glioma or cancer-related pathogenic processes. Moreover, we were able to correlate clinically relevant features like necrosis or metastasis with the detected paths. Availability: C++ source code is freely available, BiNA can be downloaded from http://www.bnplusplus.org/. Contact: ack@bioinf.uni-sb.de Supplementary information: Supplementary data are available at Bioinformatics online.
Neutron Reflectometry Study of Swelling of Polyelectrolyte Multilayers in Water Vapors: Influence of Charge Density of the Polycation
2009-08-27

We studied the swelling of polyelectrolyte (PE) multilayers (PEM) in water (H2O) vapors. The PEM were made from polyanion poly(styrene sulfonate) (PSS) and polycation poly(diallyldimethylammonium chloride)-N-methyl-N-vinylacetamide (pDADMAC-NMVA). While PSS is a fully charged polyanion, pDADMAC-NMVA is a random copolymer made of charged pDADMAC and uncharged NMVA monomer units. Variation of the relative amount of these two units allows for controlling the charge density of pDADMAC-NMVA. The degree of swelling was studied as a function of the relative humidity in the experimental chamber (respectively water concentration in the gas phase) for PEM prepared from PSS and pDADMAC-NMVA with their different charge densities--100%, 89% and 75%. The films were prepared by means of spraying technique and consisted of six PE couples-PSS/pDADMAC-NMVA. Neutron reflectometry was applied as main tool to observe the swelling process. The technique allows to obtain in a single experiment information about film thickness and amount of water in the film. The experiments were complemented with AFM measurements to obtain the thickness of the films. It was found that the film thickness increases when the charge density of the polycation decreases. The swelling of the PEM increases with the relative humidity and it depends on the charge density of pDADMAC-NMVA. The swelling behavior is 2-fold, splitting up in a charge dependent mode with relatively little volume increase, and a second mode with high volume expansion, which is independent from charge density of PEM. The "swelling transition" occurs for all samples at a relative humidity about 60% and a volume increase of ca. 20%. The results were interpreted according to the Flory-Huggins theory which assumes a phase separation in PEM network at higher water contents.
Topical 3.0% diclofenac in 2.5% hyaluronic acid gel induces regression of cancerous transformation in actinic keratoses
2009-08-27

Abstract Background Actinic keratoses (AKs) are frequently diagnosed in dermatological patients. As they represent in situ carcinomas, effective treatment is required. Objectives We investigated the effect of topical 3.0% diclofenac in 2.5% hyaluronic acid gel on AK. Methods Sixty‐five patients with AKs were clinically evaluated before and after 3 months’ treatment with topical 3.0% diclofenac in 2.5% hyaluronic gel. Biopsy specimens were taken and stained with haematoxylin‐eosin and immunohistological markers. Specimens were evaluated for histological type of AKs using the AK classification scheme suggested by Röwert‐Huber et al. [(early) in situ squamous cell carcinoma type AK Grade I–III], number of mitoses per high‐power field and expression of immunohistological markers. Results Complete clinical resolution was observed in 11 patients (16.9%). A significant ( P &lt; 0.001) downgrading of AK grade was observed. Complete histological resolution was achieved in 15 patients (23.1%). The number of mitoses per high‐power field was reduced significantly ( P &lt; 0.001). The expression of anti‐p53‐antibody decreased significantly ( P = 0.009), as did the expression of anti‐MiB‐1 antibody ( P = 0.021). Conclusions 3.0% diclofenac in 2.5% hyaluronic acid gel causes regression of signs of cancerous transformation after 3 months’ therapy.
Continuous monitoring of pulse period variations in Hercules X-1 usingSwift/BAT
2009-08-27

Context: Monitoring of pulse period variations in accreting binary pulsars is\\nan important tool to study the interaction between the magnetosphere of the\\nneutron star and the accretion disk. While the X-ray flux of the brightest\\nX-ray pulsars have been successfully monitored over many years (e.g. with\\nRXTE/ASM, CGRO/BATSE, Swift/BAT), the possibility to monitor their pulse timing\\nproperties continuously has so far been very limited. Aims: In our work we show\\nthat the Swift/BAT observations can be used to monitor coherent pulsations of\\nbright X-ray sources and use the Swift archival data to study one of the most\\nenigmatic X-ray pulsars, Hercules X-1. A quasi-continuous monitoring of the\\npulse period and the pulse period derivative of an X-ray pulsar, here Her X-1,\\nis achieved over a long time (&lt;~ 4 yrs). We compare our observational results\\nwith predictions of accretion theory and use them to test different aspects of\\nthe physical model of the system. Methods: In our analysis we use the data\\naccumulated with Swift/BAT starting from the beginning of 2005 (shortly after\\nlaunch) until the present time. To search for pulsations and for their\\nsubsequent analysis we used the count rate measured by the BAT detector in the\\nentire field of view. Results: The slope of the correlation between the locally\\ndetermined spin-up rate and the X-ray luminosity is measured for Her X-1 and\\nfound to be in agreement with predictions of basic accretion torque theory. The\\nobserved behaviour of the pulse period together with the previously measured\\nsecular decrease of the system's orbital period is discussed in the frame of a\\nmodel assuming ejection of matter close to the inner boundary of the accretion\\ndisk.\\n
Efficacy of Various Durations ofIn VitroPredegeneration on the Cell Count and Purity of Rat Schwann-Cell Cultures
2009-08-27

The efficacy of Schwann-cell cultivation can be enhanced by in vitro predegeneration of the harvested cells compared to immediate culture. The aim of this study was to improve Schwann-cell culture efficacy by comparing three different durations of predegeneration. The sciatic and median nerves of 6-8-week-old Lewis rats were harvested and subjected to either 2-day, 7-day, or 14-day predegeneration in Dulbecco's Modified Eagle's Medium supplemented with 10% fetal calf serum and 1% Penicillin/Streptomycin. Afterward, tissue was enzymatically dissociated and placed in a modified melanocyte growth medium. The cell count was determined immediately after dissociation while the cell purity was determined one subculture/trypsinization cycle later after cell attachment to the culture plate by means of optical microscopy and immunocytochemistry. Particular attention was then paid to the Schwann-cell-to-fibroblast relation. The cumulative cell count in the culture was 5.8 x 10(5) for 2-day, 1.12 x 10(6) for 7-day, and 1.48 x 10(6) for 14-day predegeneration. The culture purity was approximately equal for 2- and 7-day predegeneration (88% Schwann cells, 12% fibroblasts after 2 days; 85% Schwann cells, 15% fibroblasts after 7 days). After 14 days, however, cell cultures were significantly debased by fibroblast proliferation (57% Schwann cells, 43% fibroblasts). In vitro predegeneration is a particularly suitable procedural method to increase the cultural Schwann-cell yield. The number of cultivated rat Schwann cells is doubled by 7-day in vitro predegeneration in comparison to 2-day predegeneration. After 14-day predegeneration, however, the culture is significantly debased by fibroblasts. Therefore, 7-day in vitro predegeneration is an advisable predegeneration period.
Epinephrine‐induced hyperpolarization of pancreatic islet cells is sensitive to PI3K–PDK1 signaling
2009-08-27

Epinephrine inhibits insulin release by activation of K + channels and subsequent hyperpolarization of pancreatic beta cells. The present study explored whether epinephrine‐induced hyperpolarization is modified by phosphatidylinositol 3‐kinase (PI3K) and phosphatidylinositide‐dependent kinase PDK1. Perforated patch‐clamp was performed in islet cells isolated from PDK1 hypomorphic mice ( pdk1 fl/fl ), expressing only 20% of PDK1, and in their wild‐type littermates. At 16.8 mM glucose, the cell membrane was hyperpolarized by epinephrine (1 μM), an effect significantly blunted in pdk1 fl/fl and abrogated in wild‐type cells by inhibition of PI3K with wortmannin (100 nM) or LY294002 (10 μM). The hyperpolarizing effect of epinephrine in pancreatic islet cells is thus sensitive to PI3K and PDK1.
Climate Signatures in the Morphological Differentiation of Worldwide Modern Human Populations
2009-08-28

Abstract The ability of cranial morphology to reflect population/phylogenetic history, and the degree to which it might be influenced by environmental factors and selection pressures have been widely discussed. Recent consensus views cranial morphology as largely indicative of population history in humans, with some anatomical cranial regions/measurements being more informative on population history, while others being under selection pressure. We test earlier findings using the largest and most diverse cranial dataset available as yet: 7,423 male specimens from 135 geographic human population samples represented by 33 standard craniometric linear measurements. We calculated Mahalanobis D 2 for three datasets: complete cranial dataset; facial measurement dataset; and neurocranial measurement dataset; these morphological distance matrices were then compared to matrices of geographic distances as well as of several climatic variables. Additionally, we calculated Fst values for our cranial measurements and compared the results to the expected Fst values for neutral genetic loci. Our findings support the hypothesis that cranial, and especially neurocranial morphology, is phylogenetically informative, and that aspects of the face and cranium are subject to selection related to climatic factors. The Fst analysis suggest that selection to climate is largely restricted to groups living in extremely cold environments, including Northeast Asia, North America, and Northern Europe, though each of these regions appears to have arrived at their morphology through distinct adaptive pathways. Anat Rec, 2009. © 2009 Wiley‐Liss, Inc.
Towardsin silicodesign of epitope-based vaccines
2009-08-28

State-of-the-art in silico approaches to MHC binding prediction yield high accuracies. However, a more thorough understanding of the underlying biological processes and significant amounts of experimental data will be required for the validation and improvement of in silico approaches to the remaining aspects of EV design.
High Baseline Vitamin C Levels Do Not Prevent a Positive Outcome of a Lifestyle Intervention
2009-08-28

Reactive oxygen species (ROS) generated by oxidative stress induced by physical activity are important mediators responsible for adaptive processes in skeletal muscle (1). ROS induce the production of myokines (muscle-derived cytokines) that mediate systemic metabolic effects (1) and induce an increase in the expression of genes involved in mitochondrial biogenesis (2). Therefore, the oxidative stress induced by exercise may play an important role in the cellular responses occurring within skeletal muscle after training. Supplementation with the antioxidant vitamin C pharmacologically inhibits positive effects of exercise on the parameters of glucose metabolism (3). However, these data conflict with the finding that high levels of vitamin C also reduce the risk of type 2 diabetes (4). Therefore, we ...
Small-Colony Variant Selection as a Survival Strategy for Staphylococcus aureus in the Presence of Pseudomonas aeruginosa
2009-08-29

ABSTRACT Previously it has been demonstrated that Staphylococcus aureus is sensitive toward Pseudomonas -secreted exotoxins, which preferentially target the electron transport chain in staphylococci. Here it is shown that a subpopulation of S. aureus survives these respiratory toxins of P seudomonas aeruginosa by selection of the small-colony variant (SCV) phenotype. Purified pyocyanin alone causes the same effect. A hem B mutant of S. aureus survives cocultivation with P. aeruginosa without a decrease in CFU.
Use of Multiple Metabolic and Genetic Markers to Improve the Prediction of Type 2 Diabetes: the EPIC-Potsdam Study
2009-08-31

OBJECTIVE We investigated whether metabolic biomarkers and single nucleotide polymorphisms (SNPs) improve diabetes prediction beyond age, anthropometry, and lifestyle risk factors. RESEARCH DESIGN AND METHODS A case-cohort study within a prospective study was designed. We randomly selected a subcohort (n = 2,500) from 26,444 participants, of whom 1,962 were diabetes free at baseline. Of the 801 incident type 2 diabetes cases identified in the cohort during 7 years of follow-up, 579 remained for analyses after exclusions. Prediction models were compared by receiver operatoring characteristic (ROC) curve and integrated discrimination improvement. RESULTS Case-control discrimination by the lifestyle characteristics (ROC-AUC: 0.8465) improved with plasma glucose (ROC-AUC: 0.8672, P &amp;lt; 0.001) and A1C (ROC-AUC: 0.8859, P &amp;lt; 0.001). ROC-AUC further improved with HDL cholesterol, triglycerides, γ-glutamyltransferase, and alanine aminotransferase (0.9000, P = 0.002). Twenty SNPs did not improve discrimination beyond these characteristics (P = 0.69). CONCLUSIONS Metabolic markers, but not genotyping for 20 diabetogenic SNPs, improve discrimination of incident type 2 diabetes beyond lifestyle risk factors.
Rotation of the swing plane of Foucault's pendulum and Thomas spin precession: two sides of one coin
2009-08-31

Using elementary geometric tools, we apply essentially the same methods to\\nderive expressions for the rotation angle of the swing plane of Foucault's\\npendulum and the rotation angle of the spin of a relativistic particle moving\\nin a circular orbit (Thomas precession effect).\\n
Posttraumatic stress reactions and HPA system regulation in patients with acute spinal cord injury: a repeated measures approach
2009-08-31

Objective: Research results over the past years have provided evidence for acute and chronic alterations of the endocrinological stress system in posttraumatic stress disorder (PTSD). However, the underlying pathogenesis and the chronological sequence of alterations in hypothalamic-pituitary-adrenal (HPA) activity still remain unclear. Heterogenous sample protocols and differing assessment methods complicate the interpretation of the existing data. Most studies examining basal HPA activity were conducted on patients with chronic PTSD like war veterans. Hence, it is unclear at which point of the pathogenesis the alterations of the HPA axis occur. Longitudinal, prospective studies on homogenous samples of patients with acute traumatization are necessary in order to draw valid conclusions about the process of HPA axis alteration. Methods: Two months post-accident, patients (N=15) with an acute spinal cord injury were recruited in two regional trauma centers. Urinary cortisol and dehydroepiandrosterone (DHEA) were assessed weekly over a period of six weeks. To assess the psychological state and control for potentially confounding variables during the urine collection, an accompanying questionnaire was employed. Results: Preliminary data of the six-week endocrine assessment and its interaction with the psychopathological status will be presented at the conference.
Are treatment preferences relevant for response to serotonergic antidepressants and cognitive-behavioural therapy in depressed primary care patients? Results from a randomized controlled trial including a patient choice arm
2009-08-31

Little is known about the influence on treatment outcome of patients' preferences and expectations about offered treatments for depression. We investigated in primary care depressed patients whether or not receiving the preferred treatment is associated with a better clinical outcome. Within a randomized, placebo-controlled, single-centre, 10-week trial with five arms (sertraline; placebo; cognitive-behavioural group therapy (CBT); nonspecific supportive group treatment control; treatment with sertraline or CBT according to patients' choice), 146 primary care patients with mild-to-moderate depressive disorders (acc. to DSM-IV) were investigated. Drug confidence was assessed at patients' screening using an illness-concept scale and attitudes towards psychotherapy by an inventory to measure psychotherapy motivation. To assess outcome, the post-baseline sum scores of the Hamilton Depression Rating Scale (HAMD-17) were used. Depressed patients receiving their preferred treatment (sertraline or CBT) (N=91) responded significantly better than those who did not (N=55) (p=0.011). The difference in outcome between both groups was clinically relevant for both pharmacotherapy and psychotherapy. Thus, patients' preference for pharmaco- versus psychotherapy should be considered when offering a treatment because receiving the preferred treatment conveys an additional and clinically relevant benefit (HAMD-17: + 4 points for drugs; + 2 points for CBT) in outcome.
MultiLoc2: integrating phylogeny and Gene Ontology terms improves subcellular protein localization prediction
2009-09-01

MultiLoc2 is an extensive high-performance subcellular protein localization prediction system. By incorporating phylogenetic profiles and Gene Ontology terms MultiLoc2 yields higher accuracies compared to its previous version. Moreover, it outperforms other prediction systems in two benchmarks studies. MultiLoc2 is available as user-friendly and free web-service, available at: http://www-bs.informatik.uni-tuebingen.de/Services/MultiLoc2.
Hematopoietic Development from Human Induced Pluripotent Stem Cells
2009-09-01

A decade of research on human embryonic stem cells (ESC) has paved the way for the discovery of alternative approaches to generating pluripotent stem cells. Combinatorial overexpression of a limited number of proteins linked to pluripotency in ESC was recently found to reprogram differentiated somatic cells back to a pluripotent state, enabling the derivation of isogenic (patient‐specific) pluripotent stem cell lines. Current research is focusing on improving reprogramming protocols (e.g., circumventing the use of retroviral technology and oncoproteins), and on methods for differentiation into transplantable tissues of interest. In mouse ESC, we have previously shown that the embryonic morphogens BMP4 and Wnt3a direct blood formation via activation of Cdx and Hox genes. Ectopic expression of Cdx4 and HoxB4 enables the generation of mouse ESC‐derived hematopoietic stem cells (HSC) capable of multilineage reconstitution of lethally irradiated adult mice. Here, we explore hematopoietic development from human induced pluripotent stem (iPS) cells generated in our laboratory. Our data show robust differentiation of iPS cells to mesoderm and to blood lineages, as shown by generation of CD34 + CD45 + cells, hematopoietic colony activity, and gene expression data, and suggest conservation of blood patterning pathways between mouse and human hematopoietic development.
Participation of leukotriene C(4) in the regulation of suicidal erythrocyte death.
2009-09-01

Eryptosis, the suicidal death of erythrocytes, is characterized by cell shrinkage and cell membrane scrambling with phosphatidylserine exposure at the erythrocyte surface. Eryptosis is triggered by increase in cytosolic Ca(2+) concentration upon energy depletion. The present study explored the involvement of leukotrienes. Western blotting was employed to detect the cysteinyl-leukotriene receptor cysLT1, competitive immune assay to determine leukotriene release from erythrocytes, Fluo3 fluorescence to estimate cytosolic Ca(2+) concentration, forward scatter to analyse cell volume and annexin V-binding to disclose phosphatidylserine exposure. As a result, erythrocytes expressed the leukotriene receptor CysLT1. Glucose depletion (24 hours) significantly increased the formation of the cysteinyl-leukotrienes C(4)/D(4)/E(4). Leukotriene C(4) (10 nM) increased Ca(2+) entry, decreased forward scatter, activated caspases 3 and 8, and stimulated annexin V-binding. Glucose depletion similarly increased annexin V-binding, an effect significantly blunted in the presence of the leukotriene receptor antagonist cinalukast (1 microM) or the 5-lipoxygenase inhibitor BW B70C (1 microM). In conclusion, upon energy depletion erythrocytes form leukotrienes, which in turn activate cation channels, leading to Ca(2+) entry, cell shrinkage and cell membrane scrambling. Cysteinyl-leukotrienes thus participate in the signaling of eryptosis during energy depletion.