julilili42/papers huggingface dataset:
Human Cep192 and Cep152 cooperate in Plk4 recruitment and centriole duplication
2013-01-01

Polo-like kinase 4 (Plk4) is a key regulator of centriole duplication, but the mechanism underlying its recruitment to mammalian centrioles is not understood. In flies, Plk4 recruitment depends on Asterless, whereas nematodes rely on a distinct protein, Spd-2. Here, we have explored the roles of two homologous mammalian proteins, Cep152 and Cep192, respectively, in the centriole recruitment of human Plk4. We demonstrate that Cep192 plays a key role in centrosome recruitment of both Cep152 and Plk4. Double-depletion of Cep192 and Cep152 completely abolishes Plk4 binding to centrioles as well as centriole duplication, indicating that the two proteins cooperate. Most importantly, we show that Cep192 binds Plk4 through an N-terminal extension that is specific to the largest isoform. The Plk4 binding regions of Cep192 and Cep152 (residues 190–240 and 1–46, respectively) are rich in negatively charged amino acids, suggesting that Plk4 localization to centrioles depends on electrostatic interactions with the positively charged polo-box domain. We conclude that cooperation between Cep192 and Cep152 is crucial for centriole recruitment of Plk4 and centriole duplication during the cell cycle.
Interconnections between apoptotic, autophagic and necrotic pathways: implications for cancer therapy development
2013-01-01

Summary The rapid accumulation of knowledge on apoptosis regulation in the 1990s was followed by the development of several experimental anticancer‐ and anti‐ischaemia (stroke or myocardial infarction) drugs. Activation of apoptotic pathways or the removal of cellular apoptotic inhibitors has been suggested to aid cancer therapy and the inhibition of apoptosis was thought to limit ischaemia‐induced damage. However, initial clinical studies on apoptosis‐modulating drugs led to unexpected results in different clinical conditions and this may have been due to co‐effects on non‐apoptotic interconnected cell death mechanisms and the ‘yin‐yang’ role of autophagy in survival versus cell death. In this review, we extend the analysis of cell death beyond apoptosis. Upon introduction of molecular pathways governing autophagy and necrosis (also called necroptosis or programmed necrosis), we focus on the interconnected character of cell death signals and on the shared cell death processes involving mitochondria ( e.g . mitophagy and mitoptosis) and molecular signals playing prominent roles in multiple pathways ( e.g . Bcl2‐family members and p53). We also briefly highlight stress‐induced cell senescence that plays a role not only in organismal ageing but also offers the development of novel anticancer strategies. Finally, we briefly illustrate the interconnected character of cell death forms in clinical settings while discussing irradiation‐induced mitotic catastrophe. The signalling pathways are discussed in their relation to cancer biology and treatment approaches.
Coordinated Computer-Supported Collaborative Learning: Awareness and Awareness Tools
2013-01-01

Traditionally, research on awareness during online collaboration focused on topics such as the effects of spatial information about group members’ activities on the collaborative process. When the concept of awareness was introduced to computer-supported collaborative learning, this focus shifted to cognitive group awareness (e.g., information about group members’ knowledge and expertise) and social group awareness (e.g., information about group members’ contributions to the group process). In this article, we show how both cognitive and social group awareness affect coordination of collaborative activities in the content (e.g., cognitive learning activities) and relational space (e.g., maintaining a positive group climate) of collaboration. Furthermore, we describe how cognitive and social group awareness tools (i.e., tools designed to enhance cognitive or social group awareness) may help learners coordinate their activities in both spaces. We present a conceptual framework that shows how group awareness affects coordination in both dialogical spaces and the effectiveness of collaboration.
Dissociating neuronal gamma-band activity from cranial and ocular muscle activity in EEG
2013-01-01

EEG is the most common technique for studying neuronal dynamics of the human brain. However, electromyogenic artifacts from cranial muscles and ocular muscles executing involuntary microsaccades compromise estimates of neuronal activity in the gamma band (>30 Hz). Yet, the relative contributions and practical consequences of these artifacts remain unclear. Here, we systematically dissected the effects of these different artifacts on studying visual gamma-band activity with EEG on the sensor and source level, and show strategies to cope with these confounds. We found that cranial muscle activity prevented a direct investigation of neuronal gamma-band activity at the sensor level. Furthermore, we found prolonged microsaccade-related artifacts beyond the well-known transient EEG confounds. We then show that if electromyogenic artifacts are carefully accounted for, the EEG nonetheless allows for studying visual gamma-band activity even at the sensor level. Furthermore, we found that source analysis based on spatial filtering does not only map the EEG signals to the cortical space of interest, but also efficiently accounts for cranial and ocular muscle artifacts. Together, our results clarify the relative contributions and characteristics of myogenic artifacts confounding visual gamma-band activity in EEG, and provide practical guidelines for future experiments.
Pharmacogenomics of Cytochrome P450 3A4: Recent Progress Toward the “Missing Heritability” Problem
2013-01-01

CYP3A4 is the most important drug metabolizing enzyme in adult humans because of its prominent expression in liver and gut and because of its broad substrate specificity, which includes drugs from most therapeutic categories and many endogenous substances. Expression and function of CYP3A4 vary extensively both intra- and interindividually thus contributing to unpredictable drug response and toxicity. A multitude of environmental, genetic, and physiological factors are known to influence CYP3A4 expression and activity. Among the best predictable sources of variation are drug-drug interactions, which are either caused by pregnane X-receptor (PXR), constitutive androstane receptor (CAR) mediated gene induction, or by inhibition through coadministered drugs or other chemicals, including also plant and food ingredients. Among physiological and pathophysiological factors are hormonal status, age, and gender, the latter of which was shown to result in higher levels in females compared to males, as well as inflammatory processes that downregulate CYP3A4 transcription. Despite the influence of these non-genetic factors, the genetic influence on CYP3A4 activity was estimated in previous twin studies and using information on repeated drug administration to account for 66% up to 88% of the interindividual variation. Although many single nucleotide polymorphisms (SNPs) within the CYP3A locus have been identified, genetic association studies have so far failed to explain a major part of the phenotypic variability. The term "missing heritability" has been used to denominate the gap between expected and known genetic contribution, e.g., for complex diseases, and is also used here in analogy. In this review we summarize CYP3A4 pharmacogenetics/genomics from the early inheritance estimations up to the most recent genetic and clinical studies, including new findings about SNPs in CYP3A4 (*22) and other genes (P450 oxidoreductase (POR), peroxisome proliferator-activated receptor alpha (PPARA)) with possible contribution to CYP3A4 variable expression.
Randomized Response Estimates for the 12‐Month Prevalence of Cognitive‐Enhancing Drug Use in University Students
2013-01-01

Study Objective To estimate the 12‐month prevalence of cognitive‐enhancing drug use. Design Paper‐and‐pencil questionnaire that used the randomized response technique. Setting University in Mainz, Germany. Participants A total of 2569 university students who completed the questionnaire. Measurements and Main Results An anonymous, specialized questionnaire that used the randomized response technique was distributed to students at the beginning of classes and was collected afterward. From the responses, we calculated the prevalence of students taking drugs only to improve their cognitive performance and not to treat underlying mental disorders such as attention‐deficit–hyperactivity disorder, depression, and sleep disorders. The estimated 12‐month prevalence of using cognitive‐enhancing drugs was 20%. Prevalence varied by sex (male 23.7%, female 17.0%), field of study (highest in students studying sports‐related fields, 25.4%), and semester (first semester 24.3%, beyond first semester 16.7%). To our knowledge, this is the first time that the randomized response technique has been used to survey students about cognitive‐enhancing drug use. Conclusion Using the randomized response technique, our questionnaire provided data that showed a high 12‐month prevalence of cognitive‐enhancing drug use in German university students. Our study suggests that other direct survey techniques have underestimated the use of these drugs. Drug prevention programs need to be established at universities to address this issue.
The Uremic Toxin Acrolein Promotes Suicidal Erythrocyte Death
2013-01-01

&lt;b&gt;&lt;i&gt;Background: &lt;/i&gt;&lt;/b&gt;Anemia is a major complication of end stage renal disease. The anemia is mainly the result of impaired formation of erythrocytes due to lack of erythropoietin and iron deficiency. Compelling evidence, however, points to the contribution of accelerated erythrocyte death, which decreases the life span of circulating erythrocytes. Erythrocytes may enter suicidal death or eryptosis, which is characterized by cell shrinkage and by cell membrane scrambling with phosphatidylserine-exposure at the erythrocyte surface. Triggers of eryptosis include increase of cytosolic Ca&lt;sup&gt;2+&lt;/sup&gt;-activity ([Ca&lt;sup&gt;2+&lt;/sup&gt;]&lt;sub&gt;i&lt;/sub&gt;). Erythrocytes could be sensitized to cytosolic Ca&lt;sup&gt;2+&lt;/sup&gt; by ceramide. In end stage renal disease, eryptosis may possibly be stimulated by uremic toxins. The present study explored, whether the uremic toxin acrolein could trigger eryptosis. &lt;b&gt;&lt;i&gt;Methods: &lt;/i&gt;&lt;/b&gt;Cell volume was estimated from forward scatter, phosphatidylserine-exposure from annexin-V-binding, hemolysis from hemoglobin release, [Ca&lt;sup&gt;2+&lt;/sup&gt;]&lt;sub&gt;i&lt;/sub&gt; from Fluo3-fluorescence, and ceramide from fluorescent antibodies. &lt;b&gt;&lt;i&gt;Results: &lt;/i&gt;&lt;/b&gt;A 48 h exposure to acrolein (30 - 50 μM) did not significantly modify [Ca&lt;sup&gt;2+&lt;/sup&gt;]&lt;sub&gt;i&lt;/sub&gt; but significantly decreased forward scatter and increased annexin-V-binding. Acrolein further triggered slight, but significant hemolysis and increased ceramide formation in erythrocytes. Acrolein (50 μM) induced annexin-V-binding was significantly blunted in the nominal absence of extracellular Ca&lt;sup&gt;2+&lt;/sup&gt;. Acrolein augmented the annexin-V-binding following treatment with Ca&lt;sup&gt;2+&lt;/sup&gt; ionophore ionomycin (1 μM). &lt;b&gt;&lt;i&gt;Conclusion: &lt;/i&gt;&lt;/b&gt;Acrolein stimulates suicidal erythrocyte death or eryptosis, an effect at least in part due to stimulation of ceramide formation with subsequent sensitisation of the erythrocytes to cytosolic Ca&lt;sup&gt;2+&lt;/sup&gt;.
Detection of Malicious PDF Files Based on Hierarchical Document Structure.
2013-01-01

Malicious PDF files remain a real threat, in practice, to masses of computer users, even after several high-profile security incidents. In spite of a series of a security patches issued by Adobe and other vendors, many users still have vulnerable client software installed on their computers. The expressiveness of the PDF format, furthermore, enables attackers to evade detection with little effort. Apart from traditional antivirus products, which are always a step behind attackers, few methods are known that can be deployed for protection of end-user systems. In this paper, we propose a highly performant static method for detection of malicious PDF documents which, instead of analyzing JavaScript or any other content, makes use of essential differences in the structural properties of malicious and benign PDF files. We demonstrate its effectiveness on a data corpus containing about 660,000 real-world malicious and benign PDF files, both in laboratory conditions and during a 10-week operational deployment with weekly retraining. Additionally, we present the first comparative evaluation of several learning setups with regard to resistance against adversarial evasion and show that our method is reasonably resistant to sophisticated attack scenarios.
What is Bottom-Up and What is Top-Down in Predictive Coding?
2013-01-01

Everyone knows what bottom-up is, and how it is different from top-down. At least one is tempted to think so, given that both terms are ubiquitously used, but only rarely defined in the psychology and neuroscience literature. In this review, we highlight the problems and limitations of our current understanding of bottom-up and top-down processes, and we propose a reformulation of this distinction in terms of predictive coding.
Challenges in international survey research: a review with illustrations and suggested solutions for best practice
2013-01-01

When conducting international research projects, scholars face a myriad of challenges that reach beyond those encountered in domestic research. In this paper, we explore the specific issues related to international survey research, focusing on the different stages of the research process that include defining the study population and gaining data access, survey development, data collection, data analysis, and finally publication of the results. For each stage, we review the pertinent literature, provide illustrations based on examples from our own research projects, and offer possible solutions to address the inherent challenges by formulating suggestions for improving the quality of international survey research.
Cell Transplantation for Spinal Cord Injury: A Systematic Review
2013-01-01

Cell transplantation, as a therapeutic intervention for spinal cord injury (SCI), has been extensively studied by researchers in recent years. A number of different kinds of stem cells, neural progenitors, and glial cells have been tested in basic research, and most have been excluded from clinical studies because of a variety of reasons, including safety and efficacy. The signaling pathways, protein interactions, cellular behavior, and the differentiated fates of experimental cells have been studied in vitro in detail. Furthermore, the survival, proliferation, differentiation, and effects on promoting functional recovery of transplanted cells have also been examined in different animal SCI models. However, despite significant progress, a “bench to bedside” gap still exists. In this paper, we comprehensively cover publications in the field from the last years. The most commonly utilized cell lineages were covered in this paper and specific areas covered include survival of grafted cells, axonal regeneration and remyelination, sensory and motor functional recovery, and electrophysiological improvements. Finally we also review the literature on the in vivo tracking techniques for transplanted cells.
Flagellin Induces Myeloid-Derived Suppressor Cells: Implications for Pseudomonas aeruginosa Infection in Cystic Fibrosis Lung Disease
2013-01-01

Abstract Pseudomonas aeruginosa persists in patients with cystic fibrosis (CF) and drives CF lung disease progression. P. aeruginosa potently activates the innate immune system, mainly mediated through pathogen-associated molecular patterns, such as flagellin. However, the host is unable to eradicate this flagellated bacterium efficiently. The underlying immunological mechanisms are incompletely understood. Myeloid-derived suppressor cells (MDSCs) are innate immune cells generated in cancer and proinflammatory microenvironments and are capable of suppressing T cell responses. We hypothesized that P. aeruginosa induces MDSCs to escape T cell immunity. In this article, we demonstrate that granulocytic MDSCs accumulate in CF patients chronically infected with P. aeruginosa and correlate with CF lung disease activity. Flagellated P. aeruginosa culture supernatants induced the generation of MDSCs, an effect that was 1) dose-dependently mimicked by purified flagellin protein, 2) significantly reduced using flagellin-deficient P. aeruginosa bacteria, and 3) corresponded to TLR5 expression on MDSCs in vitro and in vivo. Both purified flagellin and flagellated P. aeruginosa induced an MDSC phenotype distinct from that of the previously described MDSC-inducing cytokine GM-CSF, characterized by an upregulation of the chemokine receptor CXCR4 on the surface of MDSCs. Functionally, P. aeruginosa–infected CF patient ex vivo–isolated as well as flagellin or P. aeruginosa in vitro–generated MDSCs efficiently suppressed polyclonal T cell proliferation in a dose-dependent manner and modulated Th17 responses. These studies demonstrate that flagellin induces the generation of MDSCs and suggest that P. aeruginosa uses this mechanism to undermine T cell–mediated host defense in CF and other P. aeruginosa–associated chronic lung diseases.
Stimulation of Suicidal Erythrocyte Death by Increased Extracellular Phosphate Concentrations
2013-01-01

&lt;b&gt;&lt;i&gt;Background/Aim&lt;/i&gt;&lt;/b&gt;&lt;i&gt;: &lt;/i&gt;Anemia in renal insufficiency results in part from impaired erythrocyte formation due to erythropoietin and iron deficiency. Beyond that, renal insufficiency enhances eryptosis, the suicidal erythrocyte death characterized by phosphatidylserine-exposure at the erythrocyte surface. Eryptosis may be stimulated by increase of cytosolic Ca&lt;sup&gt;2+&lt;/sup&gt;-activity ([Ca&lt;sup&gt;2+&lt;/sup&gt;]&lt;sub&gt;i&lt;/sub&gt;). Several uremic toxins have previously been shown to stimulate eryptosis. Renal insufficiency is further paralleled by increase of plasma phosphate concentration. The present study thus explored the effect of phosphate on erythrocyte death. &lt;b&gt;&lt;i&gt;Methods: &lt;/i&gt;&lt;/b&gt;Cell volume was estimated from forward scatter, phosphatidylserine-exposure from annexin V binding, and [Ca&lt;sup&gt;2+&lt;/sup&gt;]&lt;sub&gt;i&lt;/sub&gt; from Fluo3-fluorescence. &lt;b&gt;&lt;i&gt;Results: &lt;/i&gt;&lt;/b&gt;Following a 48 hours incubation, the percentage of phosphatidylserine exposing erythrocytes markedly increased as a function of extracellular phosphate concentration (from 0-5 mM). The exposure to 2 mM or 5 mM phosphate was followed by slight but significant hemolysis. [Ca&lt;sup&gt;2+&lt;/sup&gt;]&lt;sub&gt;i&lt;/sub&gt; did not change significantly up to 2 mM phosphate but significantly decreased at 5 mM phosphate. The effect of 2 mM phosphate on phosphatidylserine exposure was significantly augmented by increase of extracellular Ca&lt;sup&gt;2+&lt;/sup&gt; to 1.7 mM, and significantly blunted by nominal absence of extracellular Ca&lt;sup&gt;2+&lt;/sup&gt;, by additional presence of pyrophosphate as well as by presence of p38 inhibitor SB203580. &lt;b&gt;&lt;i&gt;Conclusion&lt;/i&gt;&lt;/b&gt;&lt;i&gt;: &lt;/i&gt;Increasing phosphate concentration stimulates erythrocyte membrane scrambling, an effect depending on extracellular but not intracellular Ca&lt;sup&gt;2+&lt;/sup&gt; concentration. It is hypothesized that suicidal erythrocyte death is triggered by complexed CaHPO&lt;sub&gt;4&lt;/sub&gt;.
Sensitization of Erythrocytes to Suicidal Erythrocyte Death Following Water Deprivation
2013-01-01

&lt;b&gt;&lt;i&gt;Background/Aims&lt;/i&gt;&lt;/b&gt;: Klotho deficiency results in excessive formation of 1,25(OH)&lt;sub&gt;2&lt;/sub&gt;D&lt;sub&gt;3&lt;/sub&gt;, accelerated ageing and early death. Moreover, klotho deficiency enhances eryptosis, the suicidal erythrocyte death characterized by phosphatidylserine exposure at the erythrocyte surface. Triggers of eryptosis include increase of cytosolic Ca&lt;sup&gt;2+&lt;/sup&gt;-activity ([Ca&lt;sup&gt;2+&lt;/sup&gt;]&lt;sub&gt;i&lt;/sub&gt;), glucose depletion, hyperosmotic shock and oxidative stress. Klotho expression is decreased and 1,25(OH)&lt;sub&gt;2&lt;/sub&gt;D&lt;sub&gt;3&lt;/sub&gt;-formation enhanced by dehydration. The present study thus explored whether dehydration influences eryptosis. &lt;b&gt;&lt;i&gt;Methods&lt;/i&gt;&lt;/b&gt;: Blood was drawn from hydrated or 36h dehydrated mice. Plasma osmolarity was determined by vapour pressure method, plasma 1,25(OH)&lt;sub&gt;2&lt;/sub&gt;D&lt;sub&gt;3&lt;/sub&gt; and aldosterone concentrations using ELISA, and plasma Ca&lt;sup&gt;2+&lt;/sup&gt;-concentration utilizing photometry. Erythrocytes were exposed to Ca&lt;sup&gt;2+&lt;/sup&gt;-ionophore ionomycin (1 μM, 30 min), energy depletion (12 h glucose removal), hyperosmotic shock (500 mM sucrose added, 2 h) and oxidative stress (100 μM tert-butyl-hydroperoxide, 30 min) and phosphatidylserine exposure at the erythrocyte surface estimated from annexin V binding. &lt;b&gt;&lt;i&gt;Results&lt;/i&gt;&lt;/b&gt;: Dehydration increased plasma osmolarity and plasma 1,25(OH)&lt;sub&gt;2&lt;/sub&gt;D&lt;sub&gt;3&lt;/sub&gt; and aldosterone concentrations. Dehydration did not significantly modify phosphatidylserine-exposure of freshly drawn erythrocytes but significantly enhanced the increase of phosphatidylserine-exposure under control conditions and following treatment with ionomycin, glucose-deprivation, hyperosmolarity or tert-butyl-hydroperoxide. &lt;b&gt;&lt;i&gt;Conclusions&lt;/i&gt;&lt;/b&gt;: Dehydration sensitizes the erythrocytes to spontaneous eryptosis and to the triggering of eryptosis by excessive Ca&lt;sup&gt;2+&lt;/sup&gt;-entry, energy depletion, hyperosmotic shock and oxidative stress.
Neurophysiology of Robot-Mediated Training and Therapy: A Perspective for Future Use in Clinical Populations
2013-01-01

The recovery of functional movements following injury to the central nervous system (CNS) is multifaceted and is accompanied by processes occurring in the injured and non-injured hemispheres of the brain or above/below a spinal cord lesion. The changes in the CNS are the consequence of functional and structural processes collectively termed neuroplasticity and these may occur spontaneously and/or be induced by movement practice. The neurophysiological mechanisms underlying such brain plasticity may take different forms in different types of injury, for example stroke vs. spinal cord injury (SCI). Recovery of movement can be enhanced by intensive, repetitive, variable, and rewarding motor practice. To this end, robots that enable or facilitate repetitive movements have been developed to assist recovery and rehabilitation. Here, we suggest that some elements of robot-mediated training such as assistance and perturbation may have the potential to enhance neuroplasticity. Together the elemental components for developing integrated robot-mediated training protocols may form part of a neurorehabilitation framework alongside those methods already employed by therapists. Robots could thus open up a wider choice of options for delivering movement rehabilitation grounded on the principles underpinning neuroplasticity in the human CNS.