Miracle-dz/UniFAR-FTUs huggingface dataset:
Tripartite motif 8 (TRIM8) modulates TNFα- and IL-1β–triggered NF-κB activation by targeting TAK1 for K63-linked polyubiquitination

The tripartite motif (TRIM)-containing proteins are a family of proteins that have been known to be involved in divergent biological processes, including important roles in immune responses through regulating various signaling pathways. In this study, we identified a member of the TRIM family, TRIM8, as a positive regulator of tumor necrosis factor-α (TNFα) and interleukin-1β (IL-1β)–triggered NF-κB activation. Overexpression of TRIM8 activated NF-κB and potentiated TNFα- and IL-1β–induced activation of NF-κB, whereas knockdown of TRIM8 had opposite effects. Coimmunoprecipitations indicated that TRIM8 interacted with TGFβ activated kinase 1 (TAK1), a serine/threonine kinase essential for TNFα- and IL-β–induced NF-κB activation. Furthermore, we found that TRIM8 mediated K63-linked polyubiquitination of TAK1 triggered by TNFα and IL-1β. Our findings demonstrate that TRIM8 serves as a critical regulator of TNFα- and IL-1β–induced NF-κB activation by mediating K63-linked polyubiquitination of TAK1.
Proteolytic Activation of Monocyte Chemoattractant Protein-1 by Plasmin Underlies Excitotoxic Neurodegeneration in Mice

Exposure of neurons to high concentrations of excitatory neurotransmitters causes them to undergo excitotoxic death via multiple synergistic injury mechanisms. One of these mechanisms involves actions undertaken locally by microglia, the CNS-resident macrophages. Mice deficient in the serine protease plasmin exhibit decreased microglial migration to the site of excitatory neurotransmitter release and are resistant to excitotoxic neurodegeneration. Microglial chemotaxis can be signaled by the chemokine monocyte chemoattractant protein-1 (MCP-1)/CCL2 (CC chemokine ligand 2). We show here that mice genetically deficient for MCP-1 phenocopy plasminogen deficiency by displaying decreased microglial recruitment and resisting excitotoxic neurodegeneration. Connecting these pathways, we demonstrate that MCP-1 undergoes a proteolytic processing step mediated by plasmin. The processing, which consists of removal of the C terminus of MCP-1, enhances the potency of MCP-1 in in vitro migration assays. Finally, we show that infusion of the cleaved form of MCP-1 into the CNS restores microglial recruitment and excitotoxicity in plasminogen-deficient mice. These findings identify MCP-1 as a key downstream effector in the excitotoxic pathway triggered by plasmin and identify plasmin as an extracellular chemokine activator. Finally, our results provide a mechanism that explains the resistance of plasminogen-deficient mice to excitotoxicity.
Trypanosomes, fleas and field voles: ecological dynamics of a host-vector–parasite interaction

To investigate the prevalence of a flea-borne protozoan (Trypanosoma (Herpetosoma) microti) in its field vole (Microtus agrestis) host, we monitored over a 2-year period a range of intrinsic and extrinsic parameters pertaining to host demographics, infection status and vector (flea) prevalence. Generalized Linear Mixed Modelling was used to analyse patterns of both flea and trypanosome occurrence. Overall, males of all sizes and ages were more likely to be infested with fleas than their female counterparts. Flea prevalence also showed direct density dependence during the winter, but patterns of density dependence varied amongst body mass (age) classes during the summer. Trypanosome prevalence did not vary between the sexes but was positively related to past flea prevalence with a lag of 3 months, with the highest levels occurring during the autumn season. A convex age-prevalence distribution was observed, suggesting that individuals develop a degree of immunity to trypanosome infection with age and exposure. An interaction between age and whether the individual was new or recaptured suggested that infected animals are less likely to become territory holders than their uninfected counterparts.
Reducing 4D CT artifacts using optimized sorting based on anatomic similarity.

PURPOSE Four-dimensional (4D) computed tomography (CT) has been widely used as a tool to characterize respiratory motion in radiotherapy. The two most commonly used 4D CT algorithms sort images by the associated respiratory phase or displacement into a predefined number of bins, and are prone to image artifacts at transitions between bed positions. The purpose of this work is to demonstrate a method of reducing motion artifacts in 4D CT by incorporating anatomic similarity into phase or displacement based sorting protocols. METHODS Ten patient datasets were retrospectively sorted using both the displacement and phase based sorting algorithms. Conventional sorting methods allow selection of only the nearest-neighbor image in time or displacement within each bin. In our method, for each bed position either the displacement or the phase defines the center of a bin range about which several candidate images are selected. The two dimensional correlation coefficients between slices bordering the interface between adjacent couch positions are then calculated for all candidate pairings. Two slices have a high correlation if they are anatomically similar. Candidates from each bin are then selected to maximize the slice correlation over the entire data set using the Dijkstra's shortest path algorithm. To assess the reduction of artifacts, two thoracic radiation oncologists independently compared the resorted 4D datasets pairwise with conventionally sorted datasets, blinded to the sorting method, to choose which had the least motion artifacts. Agreement between reviewers was evaluated using the weighted kappa score. RESULTS Anatomically based image selection resulted in 4D CT datasets with significantly reduced motion artifacts with both displacement (P = 0.0063) and phase sorting (P = 0.00022). There was good agreement between the two reviewers, with complete agreement 34 times and complete disagreement 6 times. CONCLUSIONS Optimized sorting using anatomic similarity significantly reduces 4D CT motion artifacts compared to conventional phase or displacement based sorting. This improved sorting algorithm is a straightforward extension of the two most common 4D CT sorting algorithms.
Best Practice Guidelines for the Use of Next‐Generation Sequencing Applications in Genome Diagnostics: A National Collaborative Study of Dutch Genome Diagnostic Laboratories

Next‐generation sequencing (NGS) methods are being adopted by genome diagnostics laboratories worldwide. However, implementing NGS‐based tests according to diagnostic standards is a challenge for individual laboratories. To facilitate the implementation of NGS in Dutch laboratories, the Dutch Society for Clinical Genetic Laboratory Diagnostics (VKGL) set up a working group in 2012. The results of their discussions are presented here. We provide best practice guidelines and criteria for implementing and validating NGS applications in a clinical setting. We introduce the concept of “diagnostic yield” as the main performance characteristic for evaluating diagnostic tests. We recommend that the laboratory procedures, including the tested genes, should be recorded in a publicly available document describing the complete “diagnostic routing. ” We also propose that laboratories should use a list of “core disease genes” for specific genetic diseases. This core list contains the essential genes for each disease, and they should all be included in a diagnostic test to establish a reliable and accurate molecular diagnosis. The guidelines will ensure a clear and standardized quality of care provided by genetic diagnostic laboratories. The best practice guidelines and criteria that are presented here were adopted by the VKGL in January 2013.
Cortical inhibition at rest and under a focused attention challenge in adults with migraine with and without aura

Objectives: We aimed to further elucidate the functional and attentional regulation of cortical excitability in migraine patients. Methods: We investigated the cortical silent period (CSP) after transcranial magnetic stimulation as a measure of cortical inhibition under three conditions: resting condition, cortical preactivation during reaction preparation, and during the post-processing of a motor response using a visual contingent negative variation paradigm in adults with migraine with aura, migraine without aura and healthy controls. Results: CSP was reduced in individuals with migraine with aura and unaffected in those with migraine without aura under resting conditions. Along with the intensity of transcranial magnetic stimulation, CSP increased equally in all groups (equal slopes). Furthermore, the functional challenge by a contingent negative variation task requiring focused sustained attention led to a comparable reduction of CSP duration in all groups. Discussion: Our data provide further hints towards the conclusion that a specific cortical inhibition deficit in migraine with aura but not migraine without aura is due to a tonic imbalance and not related to increased reactions to phasic stressors. Given that CSP at rest is related to GABA-ergic inhibition whereas the CSP reduction during late contingent negative variation is thought to be related to dopaminergic disinhibition in the basal ganglia, our results point towards reduced GABA-ergic cortical inhibition related to dysfunctional thalamo-cortical loops, especially in migraine with aura.
E-learners Kansei experience towards expert-like virtual agent: A case study

The rapid growth of Internet users and diverse Web 5.0 technologies has made the research scholars and educators to think of intelligent tools such as; expert-like virtual agents as an effective e-learning tool. The success of an e-learning tool relies primarily on the level of acceptance of the tool by the e-learners and their state of emotion while using the tool. Therefore, addressing e-learner's emotional competences is important to understand the implicit emotion of the young minds. In this context, virtual agents are expected to play the role of instructors in a virtual learning environment. This paper aims to study the affective design of the Virtual Agent in terms of attractiveness and realism that adopts Kansei Engineering, an emerging technology used to explore and validate the emotion structure defined as a complex state of feelings that can result in the changes of human behaviour and thoughts of e-learners. Adding on, the paper also highlights and validates the six universal emotions such as anger, happiness, surprise, disgust, sadness and fear. The findings suggest that the most attractive and realistic virtual agents have higher Kansei value. Some implications of the findings in relation to expert-like virtual agent design and Kansei are discussed in this paper.
Microtubule arrays in differentiated cells contain elevated levels of a post-translationally modified form of tubulin.

Tyrosinated (Tyr) and detyrosinated (Glu) alpha-tubulins are post-translationally modified species that differ by a single amino acid at their respective C-termini. We have examined the distribution of these two species by immunofluorescence in proliferating and differentiated cells using antisera specifically reactive with each of the forms. In proliferating PtK1 cells, Tyr tubulin was the predominant form in almost every cytoplasmic microtubule (MT); only a few MTs contained detectable Glu tubulin. In contrast, staining of centrioles and primary cilia of PtK1 cells suggested that Glu tubulin was the predominant form in these stable assemblies of MTs. An examination of the distribution (by immunofluorescence) and relative amount (by immunoblot analysis) of the two forms of tubulin in the stable assemblies of MTs present in cultured neuronal cells (neurites), sperm and tracheal cells (axonemes and basal bodies), and platelets and erythrocytes (marginal bands) revealed that, in general, the MTs in these arrays contained substantially elevated levels of Glu tubulin in comparison with the levels in MTs of cultured cells. The one exception, the marginal band of toad erythrocytes, which contained only Tyr tubulin, demonstrates that an elevated level of Glu tubulin is not an obligate feature of a stable array of MTs. Nonetheless, an elevated level of Glu tubulin may be a useful indicator of stable MTs in differentiated cells. It is important to note that commonly used sources of tubulin (e.g., brain or flagella) necessarily yield tubulin that differs strikingly from tubulin of proliferating cells in its content of Glu tubulin. (ABSTRACT TRUNCATED AT 250 WORDS)
Studies on cell-cycle synchronization in the asexual erythrocytic stages of Plasmodium falciparum

Multiplication of Plasmodium parasites within human erythrocytes is essential to malarial disease. The cell-division cycle of this organism, however, is still poorly understood. In other eukaryotes, various techniques for (apparent) cell-cycle synchronization have been used to shed light on the mechanisms involved in cell division and its control. Thus far there is no technique for cell-cycle synchronization (as opposed to selection of parasites of a limited age-range) in Plasmodium. We therefore investigated the possibility that inhibitors of DNA synthesis, the mitotic spindle, or cell-cycle control elements (such as cyclin-dependent kinases) could be used to synchronize P. falciparum cultures to a particular cell-cycle phase. Surprisingly, most of these compounds did not cause a block at a specific phase. Three compounds, Hoechst 33342, roscovitine and L-mimosine, did block development at the trophozoite–schizont transition (S or G2 phase). The block caused by the latter 2 inhibitors was reversible, suggesting that they might be used as synchronizing agents. However, a consideration of the perturbing effects of inhibitors and problems with ‘batch’ synchronization techniques in general lead us to believe that any results obtained using roscovitine- or L-mimosine-treated parasites may not be reflective of the normal cell cycle.
Soil carbon stock change following afforestation in Northern Europe: a meta‐analysis

Northern Europe supports large soil organic carbon (SOC) pools and has been subjected to high frequency of land‐use changes during the past decades. However, this region has not been well represented in previous large‐scale syntheses of land‐use change effects on SOC, especially regarding effects of afforestation. Therefore, we conducted a meta‐analysis of SOC stock change following afforestation in Northern Europe. Response ratios were calculated for forest floors and mineral soils (0–10 cm and 0–20/30 cm layers) based on paired control (former land use) and afforested plots. We analyzed the influence of forest age, former land‐use, forest type, and soil textural class. Three major improvements were incorporated in the meta‐analysis: analysis of major interaction groups, evaluation of the influence of nonindependence between samples according to study design, and mass correction. Former land use was a major factor contributing to changes in SOC after afforestation. In former croplands, SOC change differed between soil layers and was significantly positive (20%) in the 0–10 cm layer. Afforestation of former grasslands had a small negative (nonsignificant) effect indicating limited SOC change following this land‐use change within the region. Forest floors enhanced the positive effects of afforestation on SOC, especially with conifers. Meta‐estimates calculated for the periods <30 years and >30 years since afforestation revealed a shift from initial loss to later gain of SOC. The interaction group analysis indicated that meta‐estimates in former land‐use, forest type, and soil textural class alone were either offset or enhanced when confounding effects among variable classes were considered. Furthermore, effect sizes were slightly overestimated if sample dependence was not accounted for and if no mass correction was performed. We conclude that significant SOC sequestration in Northern Europe occurs after afforestation of croplands and not grasslands, and changes are small within a 30‐year perspective.
Highly active anti‐retroviral therapy (HAART)‐induced maintenance of adaptive but not innate immune parameters is associated with protection from HIV‐induced mortality

Immunosuppression induced by the human immunodeficiency virus (HIV‐1) increases the risk of death. We measured the influence of immunological and virological factors and the type of highly active anti‐retroviral therapy (HAART) on this risk. Adaptive (lymphocyte) and innate (natural killer) immune correlates and maximum HIV viral loads were assessed for association with mortality using univariate and multivariate analyses. The protective effect of HAART regimens, containing protease inhibitors (PI) and/or non‐nucleoside reverse transcriptase inhibitors (NNRTI) on mortality were also examined in a prospectively recorded cohort of 9621 HIV‐infected individuals. From this entire cohort, 5873 HIV infected individuals (61%) have been followed‐up in the HAART era and of these 499 (8·5%) have died. In multivariate analyses, CD4 counts below the 50th centile and CD8 and CD19 counts below the 25th centile were significantly associated with mortality, as was increased age (P < 0·001). Innate immune subset levels had no effect on mortality. A maximum HIV viral load greater than the 75th centile was also associated independently with mortality (P < 0·035). Exposure to either a PI or an NNRTI‐containing HAART regimen, or both together, was protective against death compared with no anti‐retrovirals (P < 0·001). Effective HAART‐induced maintenance of the adaptive immune system (CD4, CD8 and CD19 counts) protects from HIV‐related mortality.
Microparticles, Vascular Function, and Atherothrombosis

Membrane-shed submicron microparticles (MPs) are released after cell activation or apoptosis. High levels of MPs circulate in the blood of patients with atherothrombotic diseases, where they could serve as a useful biomarker of vascular injury and a potential predictor of cardiovascular mortality and major adverse cardiovascular events. Atherosclerotic lesions also accumulate large numbers of MPs of leukocyte, smooth muscle cell, endothelial, and erythrocyte origin. A large body of evidence supports the role of MPs at different steps of atherosclerosis development, progression, and complications. Circulating MPs impair the atheroprotective function of the vascular endothelium, at least partly, by decreased nitric oxide synthesis. Plaque MPs favor local inflammation by augmenting the expression of adhesion molecule, such as intercellular adhesion molecule -1 at the surface of endothelial cell, and monocyte recruitment within the lesion. In addition, plaque MPs stimulate angiogenesis, a key event in the transition from stable to unstable lesions. MPs also may promote local cell apoptosis, leading to the release and accumulation of new MPs, and thus creating a vicious circle. Furthermore, highly thrombogenic plaque MPs could increase thrombus formation at the time of rupture, together with circulating MPs released in this context by activated platelets and leukocytes. Finally, MPs also could participate in repairing the consequences of arterial occlusion and tissue ischemia by promoting postischemic neovascularization.
Argininosuccinate lyase deficiency—Argininosuccinic aciduria and beyond

The urea cycle consists of six consecutive enzymatic reactions that convert waste nitrogen into urea. Deficiencies of any of these enzymes of the cycle result in urea cycle disorders (UCD), a group of inborn errors of hepatic metabolism that often result in life threatening hyperammonemia. Argininosuccinate lyase (ASL) is a cytosolic enzyme which catalyzes the fourth reaction in the cycle and the first degradative step, that is, the breakdown of argininosuccinic acid to arginine and fumarate. Deficiency of ASL results in an accumulation of argininosuccinic acid in tissues, and excretion of argininosuccinic acid in urine leading to the condition argininosuccinic aciduria (ASA). ASA is an autosomal recessive disorder and is the second most common UCD. In addition to the accumulation of argininosuccinic acid, ASL deficiency results in decreased synthesis of arginine, a feature common to all UCDs except argininemia. Arginine is not only the precursor for the synthesis of urea and ornithine as part of the urea cycle but it is also the substrate for the synthesis of nitric oxide, polyamines, proline, glutamate, creatine, and agmatine. Hence, while ASL is the only enzyme in the body able to generate arginine, at least four enzymes use arginine as substrate: arginine decarboxylase, arginase, nitric oxide synthetase (NOS) and arginine/glycine aminotransferase. In the liver, the main function of ASL is ureagenesis, and hence, there is no net synthesis of arginine. In contrast, in most other tissues, its role is to generate arginine that is designated for the specific cell's needs. While patients with ASA share the acute clinical phenotype of hyperammonemia, encephalopathy, and respiratory alkalosis common to other UCD, they also present with unique chronic complications most probably caused by a combination of tissue specific deficiency of arginine and/or elevation of argininosuccinic acid. This review article summarizes the clinical characterization, biochemical, enzymatic, and molecular features of this disorder. Current treatment, prenatal diagnosis, diagnosis through the newborn screening as well as hypothesis driven future treatment modalities are discussed. © 2011 Wiley‐Liss, Inc.
Improvement of sequential-test-based cooperative spectrum sensing systems in band limited control channels

In a cooperative spectrum sensing system, many nodes perform spectrum sensing and report their decisions to one fusion center via control channels. This paper considers efficient use of the frequency band for the control channels. For this purpose, sequential-test is introduced for the local decision at each node. With this scheme, the transmission timing of the reports from the nodes becomes at random and necessary maximum bandwidth for the control channels decreases. Numberical results show that this sequential-test-base-scheme not only decrease the number of simultaneous reports but also improves sensing reliability. For further improvement, this paper also introduces a decision scheme at the fusion center based on probabilistic features of the reports from the nodes.