Miracle-dz/UniFAR-FTUs huggingface dataset:
Pharmacodynamic Monitoring of RO5459072, a Small Molecule Inhibitor of Cathepsin S

Major histocompatibility complex class II (MHCII)-restricted antigen priming of CD4+ T cells is both involved in adaptive immune responses and the pathogenesis of autoimmune diseases. Degradation of invariant chain Ii, a protein that prevents premature peptide loading, is a prerequisite for nascent MHCII–peptide complex formation. A key proteolytic step in this process is mediated by cathepsin S. Inhibition of this cysteine protease is known to result in the intracellular accumulation of Lip10 in B cells. Here, we describe the development and application of a neoepitope-based flow cytometry assay measuring accumulation of Lip10. This novel method enabled the investigation of cathepsin S-dependent MHCII maturation in professional antigen-presenting cell (APC) subsets. Inhibition of cathepsin S by a specific inhibitor, RO5459072, in human PBMC ex vivo resulted in accumulation of Lip10 in B cells and myeloid dendritic cells, but not in plasmacytoid dendritic cells and only to a minor degree in monocytes. We qualified Lip10 as a pharmacodynamic biomarker by showing the cathepsin S inhibitor-dependent accumulation of Lip10 in vivo in cynomolgus monkeys treated with RO5459072. Finally, dosing of RO5459072 in a first-in-human clinical study (www.ClinicalTrials.gov, identifier NCT02295332) exhibited a dose-dependent increase in Lip10, confirming target engagement and demonstrating desired pharmacologic inhibition in vivo. The degree of cathepsin S antagonist-induced maximum Lip10 accumulation in APCs varied significantly between individuals both in vitro and in vivo. This finding has not been reported previously using alternative, less sensitive methods and demands further investigation as to the potential of this biomarker to predict response to treatment. These results will help guide subsequent clinical studies investigating the pharmacokinetic and pharmacodynamic relationship of cathepsin S inhibitor RO5459072 after multiple dosing.
Test-Enhanced E-Learning Strategies in Postgraduate Medical Education: A Randomized Cohort Study

Background The optimal design of pedagogical strategies for e-learning in graduate and postgraduate medical education remains to be determined. Video-based e-learning use is increasing, with initial research suggesting that taking short breaks while watching videos (independent of answering test questions) may improve learning by focusing attention on the content presented. Interspersed test questions may also improve knowledge acquisition and retention. Objective To examine the effect of interspersed test questions and periodic breaks on immediate knowledge acquisition and retention at 6 months by pediatric residents engaged in video-based e-learning. Methods First- and second-year pediatric residents were randomized to 1 of the following 3 groups: viewing the complete video uninterrupted (full video), viewing the video interrupted with unrelated logic puzzles (logic puzzles), or viewing the video interrupted with brief comprehension test questions (short answer questions). Residents answered pre- and post-tests before and after video viewing, followed by a retention test at 6 months. Primary outcome included comparison of the change in test scores between groups. Results A total of 49 residents completed the initial testing session. All 3 learning groups had comparable mean increases in immediate knowledge gain, but with no significant differences between groups (F2,46=0.35, P=.71). Thirty-five residents completed retention testing with comparable degrees of knowledge retention in the full video and short answer test questions groups (P<.001), but no significant change in the logic puzzles group (F1,32=2.44, P=.13). Conclusions Improved knowledge gain was not demonstrated among residents answering interspersed questions or completing logic puzzles during interrupted online video viewing when compared with residents viewing uninterrupted video content. However, residents who either participated in uninterrupted video viewing or answered interspersed questions during interrupted video viewing demonstrated significant knowledge retention at 6 months.
Assessment of sulphates effect on pH and pozzolanic reactions of soil–lime–natural pozzolana mixtures

ABSTRACT The geotechnical properties of subgrade soils may need to be enhanced for appropriateness in pavement construction using mineral additives such as cement, lime (L) and fly ash. An experimental investigation was undertaken to study the effects of sodium (Na2SO4) and calcium (CaSO4·2H2O) sulphates on pH and pozzolanic reactions of soil–lime–natural pozzolana (soil–L–NP) mixtures in order to choose an adequate mixture for pavement subgrade soil stabilisation. The pH was measured for different curing periods with and without sulphates. The results showed that increases and decreases in pH values depend on the type of additive and its amount, type of sulphate and its content, mineralogical composition of stabilised soil and curing period. In addition, the pH parameter can be used as an indicator to track the pozzolanic reactions process. On the other hand, clayey subgrade soils can be stabilised with Lime–Natural Pozzolana (L–NP) mixtures containing any amounts of CaSO4·2H2O which is highly recommended. However, Na2SO4 with a low content has a better effect on the behaviour of these soils but become deleterious when its content is greater than 2%. In general, the addition of sulphates accelerates both the pozzolanic reactions and NP dissolution.
Volley: Automated Data Placement for Geo-Distributed Cloud Services

As cloud services grow to span more and more globally distributed datacenters, there is an increasingly urgent need for automated mechanisms to place application data across these datacenters. This placement must deal with business constraints such as WAN bandwidth costs and datacenter capacity limits, while also minimizing user-perceived latency. The task of placement is further complicated by the issues of shared data, data inter-dependencies, application changes and user mobility. We document these challenges by analyzing month-long traces from Microsoft's Live Messenger and Live Mesh, two large-scale commercial cloud services. We present Volley, a system that addresses these challenges. Cloud services make use of Volley by submitting logs of datacenter requests. Volley analyzes the logs using an iterative optimization algorithm based on data access patterns and client locations, and outputs migration recommendations back to the cloud service. To scale to the data volumes of cloud service logs, Volley is designed to work in SCOPE [5], a scalable MapReduce-style platform; this allows Volley to perform over 400 machine-hours worth of computation in less than a day. We evaluate Volley on the month-long Live Mesh trace, and we find that, compared to a state-of-the-art heuristic that places data closest to the primary IP address that accesses it, Volley simultaneously reduces datacenter capacity skew by over 2×, reduces inter-datacenter traffic by over 1.8× and reduces 75th percentile user-latency by over 30%.
Arguments Reinforcing the Three-Domain View of Diversified Cellular Life

The archaeal ancestor scenario (AAS) for the origin of eukaryotes implies the emergence of a new kind of organism from the fusion of ancestral archaeal and bacterial cells. Equipped with this “chimeric” molecular arsenal, the resulting cell would gradually accumulate unique genes and develop the complex molecular machineries and cellular compartments that are hallmarks of modern eukaryotes. In this regard, proteins related to phagocytosis and cell movement should be present in the archaeal ancestor, thus identifying the recently described candidate archaeal phylum “Lokiarchaeota” as resembling a possible candidate ancestor of eukaryotes. Despite its appeal, AAS seems incompatible with the genomic, molecular, and biochemical differences that exist between Archaea and Eukarya. In particular, the distribution of conserved protein domain structures in the proteomes of cellular organisms and viruses appears hard to reconcile with the AAS. In addition, concerns related to taxon and character sampling, presupposing bacterial outgroups in phylogenies, and nonuniform effects of protein domain structure rearrangement and gain/loss in concatenated alignments of protein sequences cast further doubt on AAS-supporting phylogenies. Here, we evaluate AAS against the traditional “three-domain” world of cellular organisms and propose that the discovery of Lokiarchaeota could be better reconciled under the latter view, especially in light of several additional biological and technical considerations.
A Simple State-Determined Model Reproduces Entrainment and Phase-Locking of Human Walking

Theoretical studies and robotic experiments have shown that asymptotically stable periodic walking may emerge from nonlinear limit-cycle oscillators in the neuro-mechanical periphery. We recently reported entrainment of human gait to periodic mechanical perturbations with two essential features: 1) entrainment occurred only when the perturbation period was close to the original (preferred) walking period, and 2) entrainment was always accompanied by phase locking so that the perturbation occurred at the end of the double-stance phase. In this study, we show that a highly-simplified state-determined walking model can reproduce several salient nonlinear limit-cycle behaviors of human walking: 1) periodic gait that is 2) asymptotically stable; 3) entrainment to periodic mechanical perturbations only when the perturbation period is close to the model's unperturbed period; and 4) phase-locking to locate the perturbation at the end of double stance. Importantly, this model requires neither supra-spinal control nor an intrinsic self-sustaining neural oscillator such as a rhythmic central pattern generator. Our results suggest that several prominent limit-cycle features of human walking may stem from simple afferent feedback processes without significant involvement of supra-spinal control or a self-sustaining oscillatory neural network.
Mesenchymal Stem Cells in Perichondrium Express Activated Leukocyte Cell Adhesion Molecule and Participate in Bone Marrow Formation

Perichondrium in fetal limb is composed of undifferentiated mesenchymal cells. However, the multipotency of cells in this region and the role of perichondrium in bone marrow formation are not well understood. In this report, we purified and characterized perichondrial cells using a monoclonal antibody against activated leukocyte cell adhesion molecule (ALCAM) and investigated the role of perichondrial cells in hematopoietic bone marrow formation. ALCAM is expressed on hematopoietic cells, endothelial cells, bone marrow stromal cells, and mesenchymal stem cells and mediates homophilic (ALCAM–ALCAM)/heterophilic (ALCAM-CD6) cell adhesion. Here we show by immunohistochemical staining that ALCAM is expressed in perichondrium. ALCAM+ perichondrial cells isolated by FACS® exhibit the characteristics of mesenchymal stem cells. ALCAM+ cells can differentiate into osteoblasts, adipocytes, chondrocytes, and stromal cells, which can support osteoclastogenesis, hematopoiesis, and angiogenesis. Furthermore, the addition of ALCAM-Fc or CD6-Fc to the metatarsal culture, the invasion of the blood vessels to a cartilage was inhibited. Our findings indicate that ALCAM+ perichondrial cells participate in vascular invasion by recruiting osteoclasts and vessels. These findings suggest that perichondrium might serve as a stem cell reservoir and play an important role in the early development of a bone and bone marrow.
Effects of Subchronic Exposures to Concentrated Ambient Particles (CAPs) in Mice: V. CAPs Exacerbate Aortic Plaque Development in Hyperlipidemic Mice

Abstract Recent epidemiological studies suggest that long-term exposure to particulate matter (PM) causes chronic effects on the cardiovascular system that result in cumulative increases cardiovascular morbidity and mortality. Since atherosclerosis is a progressive irreversible condition and an underlying cause of many cardiovascular diseases, we hypothesized that long-term exposure to PM causes adverse cardiovascular effects by exacerbating atherosclerosis. In this study, we exposed C57- and ApoE-deficient (ApoE−/−) and ApoE, LDLr (DK)-deficient mice to concentrated ambient PM2.5 for 6 h/day, 5 days/wk, for up to 5 mo. The overall mean exposure concentration for these groups of animals was 110 μ g/m3. The cross-sectional area of the aorta root of DK mice was examined morphologically using confocal microscopy for the severity of lesion, extent of cellularity, and lipid contents. Aortas from the arch to the iliac bifurcations were also sectioned longitudinally and lesion areas were stained with Sudan IV. All DK mice regardless of exposure had developed extensive lesions in the aortic sinus regions, with lesion areas that covered more than 79% of the total area. In male DK mice, the lesion areas in the aortic sinus regions appeared to be enhanced by concentrated ambient particles (CAPs), with changes approaching statistical significance (p = .06). In addition, plaque cellularity was increased by 28% (p = .014, combined), whereas there were no CAPs-associated changes in the lipid content in these mice. When examining the entire aorta opened longitudinally, both the ApoE−/− and DK mice had prominent areas of severe atherosclerosis covering 40% or more of the lumenal surface. Visual examination of all images suggested that plaques tend to form in clusters concentrating near the aortic arch and the iliac bifurcations. Quantitative measurements showed that CAPs exposure increased the percentage of aortic intimal surface covered by grossly discernible atherosclerotic lesion by 57% in the ApoE−/− mice (p = .03). Changes produced by CAPs in male (10% increase) or female DK mice (8% decrease) were not statistically significant. In this study, we have demonstrated that subchronic exposure to CAPs in mice prone to develop atherosclerotic lesions had a significant impact on the size, severity, and composition of aortic plaque.
Methodological Development of a Clonogenic Assay to Determine Endothelial Progenitor Cell Potential

The precise and conceptual insight of circulating endothelial progenitor cell (EPC) kinetics is hampered by the absence of an assay system capable of evaluating the EPC differentiation cascade. An assay system for EPC colony formation was developed to delineate circulating EPC differentiation. EPC colony-forming assay using semisolid medium and single or bulk CD133+ cells from umbilical cord blood exhibited the formation of two types of attaching cell colonies made of small or large cells featuring endothelial lineage potential and properties, termed small EPC colony-forming units and large EPC colony-forming units, respectively. In vitro and in vivo assays of each EPC colony-forming unit cell revealed a differentiation hierarchy from small EPC to large EPC colonies, indicating a primitive EPC stage with highly proliferative activity and a definitive EPC stage with vasculogenic properties, respectively. Experimental comparison with a conventional EPC culture assay system disclosed EPC colony-forming unit cells differentiate into noncolony-forming early EPC. The fate analysis of single CD133+ cells into the endothelial and hematopoietic lineage was achieved by combining this assay system with a hematopoietic progenitor assay and demonstrated the development of colony-forming EPC and hematopoietic progenitor cells from a single hematopoietic stem cell. EPC colony-forming assay permits the determination of circulating EPC kinetics from single or bulk cells, based on the evaluation of hierarchical EPC colony formation. This assay further enables a proper exploration of possible links between the origin of EPC and hematopoietic stem cells, representing a novel and powerful tool to investigate the molecular signaling pathways involved in EPC biology.
Aggregation and deposition of engineered TiO2 nanoparticles in natural fresh and brackish waters

The use and thus environmental release potential of metal-based nanoparticles have rapidly increased. Due to their size-dependent new properties, the fate and effect of nanomaterial may differ from those of the conventional form of corresponding material. The agglomeration and sedimentation were studied by spiking the TiO2-P25 particles in natural fresh and brackish water samples. The natural waters were determined for conductivity, pH, salinity, total organic carbon, turbidity, common nutrients and trace elements. The hydrodynamic diameter and concentration of TiO2-P25 particle dispersions were monitored by using a dynamic light scattering and a spectrophotometer, respectively. The experiments were performed at two particle concentrations 100 mg/l and 1 mg/l (10 mg/l for deposition studies). The aggregation rates in brackish waters were clearly higher in higher initial concentration and the sedimentation of aggregates decreased the TiO2 concentration down to 20% and 80% of initial higher and lower concentrations, respectively. One fresh water sample favoured the destabilisation of TiO2-P25 particles whereas another fresh water sample stabilised the TiO2 particle dispersion. The aggregation had a strong dependence on the particle concentration. High ionic content of brackish water probably explains the formation of aggregates, whereas organic substances and pH may account for the different agglomeration behaviour in fresh waters.
Defacing the Map: Cartographic Vandalism in the Digital Commons

Abstract This article addresses the emergent phenomenon of carto-vandalism, the intentional defacement of collaborative cartographic digital artefacts in the context of volunteered geographic information. Through a qualitative analysis of reported incidents in WikiMapia and OpenStreetMap, a typology of this kind of vandalism is outlined, including play, ideological, fantasy, artistic and industrial carto-vandalism, as well as carto-spam. Two families of counter-strategies deployed in amateur mapping communities are discussed. First, the contributors organize forms of policing, based on volunteered community involvement, patrolling the maps and reporting incidents. Second, the detection of carto-vandalism can be supported by automated tools, based either on explicit rules or on machine learning.
Herbal medication: potential for adverse interactions with analgesic drugs

The use of herbal supplements in the US has increased dramatically in recent years. These products are not regulated by the Food and Drug Administration (FDA) with the same scrutiny as conventional drugs. Patients who use herbal supplements often do so in conjunction with conventional drugs. This article is a review of potential adverse interactions between some of the commonly used herbal supplements and analgesic drugs. Non‐steroidal anti‐inflammatory drugs (NSAIDs), particularly aspirin, have the potential to interact with herbal supplements that are known to possess antiplatelet activity (ginkgo, garlic, ginger, bilberry, dong quai, feverfew, ginseng, turmeric, meadowsweet and willow), with those containing coumarin (chamomile, motherworth, horse chestnut, fenugreek and red clover) and with tamarind, enhancing the risk of bleeding. Acetaminophen may also interact with ginkgo and possibly with at least some of the above herbs to increase the risk of bleeding. Further, the incidences of hepatotoxicity and nephrotoxicity may be augmented by acetaminophen when concomitantly used with the potentially hepatotoxic herbs Echinacea and kava, and with herbs containing salicylate (willow, meadowsweet), respectively. The concomitant use of opioid analgesics with the sedative herbal supplements, valerian, kava and chamomile, may lead to increased central nervous system (CNS) depression. The analgesic effect of opioids may also be inhibited by ginseng. It is suggested that health‐care professionals should be more aware of the potential adverse interactions between herbal supplements and analgesic drugs, and take appropriate precautionary measures to avoid their possible occurrences. However, as most of the interaction information available is based on individual case reports, animal studies and in vitro data, further research is needed to confirm and assess the clinical significance of these potential interactions.
Dynamical Tangles in Third-Order Oscillator with Single Jump Function

This contribution brings a deep and detailed study of the dynamical behavior associated with nonlinear oscillator described by a single third-order differential equation with scalar jump nonlinearity. The relative primitive geometry of the vector field allows making an exhaustive numerical analysis of its possible solutions, visualizations of the invariant manifolds, and basins of attraction as well as proving the existence of chaotic motion by using the concept of both Shilnikov theorems. The aim of this paper is also to complete, carry out and link the previous works on simple Newtonian dynamics, and answer the question how individual types of the phenomenon evolve with time via understandable notes.
Laser Powder Bed Fusion – Materials Issues and Optimized Processing Parameters for Tool steels, AlSiMg‐ and CuCrZr‐Alloys  

Laser Powder Bed Fusion (L‐PBF) is the main technology for additive manufacturing of metallic components and is primarily used for rapid prototyping and tooling in cases with very complex geometry or lightweight design and small quantities. There are manifold influencing parameters, which need to be optimized in order to build components with suitable properties. The paper deals with three distinct application fields, like the development of new tool steel grades for injection molds, light weight design using aluminum alloys with optimized post‐weld heat treatment as well as production of copper alloys without porosity. The most sensitive process parameters are displayed and the multi‐layered components are characterized using light and high‐resolution microscopy as well as mechanical testing.
Optimizing Cutoff Scores for the Barthel Index and the Modified Rankin Scale for Defining Outcome in Acute Stroke Trials

Background and Purpose— There is little agreement on how to assess outcome in acute stroke trials. Cutoff scores for the Barthel Index (BI) and modified Rankin Scale (mRS) are frequently arbitrarily chosen to dichotomize favorable and unfavorable outcome. We investigated sensitivity and specificity of BI cutoff scores in relation to the mRS to obtain the optimal corresponding BI and mRS scores. Methods— BI and mRS scores were collected from 1034 ischemic stroke patients. Sensitivity and specificity were calculated for BI cutoff scores from 45 to 100 in mRS score 1, 2, and 3 and were plotted in receiver operator characteristic (ROC) curves. Results— The cutoff scores for the BI with the highest sum of sensitivity and specificity were 95 (sensitivity 85.6%; specificity 91.7%), 90 (sensitivity 90.7%; specificity 88.1%), and 75 (sensitivity 95.7%; specificity, 88.5%) for, respectively, mRS 1, 2, and 3. The area under the ROC curve was 0.933 in mRS 1, 0.960 in mRS 2, and 0.979 in mRS 3. Conclusions— The optimal cutoff scores for the BI were 95 for mRS 1, 90 for mRS 2, and 75 for mRS 3. For future acute stroke trials that assess stroke outcome with the BI and mRS, we recommend the use of these BI cutoff score(s) with the corresponding mRS cutoff score(s), to ensure the use of consistent and uniform end points.