Terpyridyl Complexes as Antimalarial Agents

Anumber of transition metals and their terpyridyl complexes have been evaluated for antimalarial activity on the strain 3D7. The metals, ligands and complexes were each in turn investigated for their efficacy. All activities were in the sub-micromolar range (0.1–1 μM). Their modes of action were compared with that of chloroquine to discover whether or not they were capable of inhibiting haemozoin formation. The data indicate that efficacy could be a result of several mechanisms and that speciation of the metal complex and the manner in which the agents are added to the parasitic broth have a profound effect on the activity of the agents. We believe that our study offers a template by which other researchers should approach their experiments using transition metal complex agents.KEYWORDS Antimalarial agents, terpyridyl and transition metals

Understanding State Preferences With Text As Data: Introducing the UN General Debate Corpus

Every year at the United Nations, member states deliver statements during the General Debate discussing major issues in world politics. These speeches provide invaluable information on governments’ perspectives and preferences on a wide range of issues, but have largely been overlooked in the study of international politics. This paper introduces a new dataset consisting of over 7,300 country statements from 1970-2014. We demonstrate how the UN General Debate Corpus (UNGDC) can be used to derive country positions on different policy dimensions using text analytic methods. The paper provides applications of these estimates, demonstrating the contribution the UNGDC can make to the study of international politics

Fingerprinting and tracing the sources of soils and sediments: Earth and ocean science, geoarchaeological, forensic, and human health applications

publisher: Elsevier articletitle: Fingerprinting and tracing the sources of soils and sediments: Earth and ocean science, geoarchaeological, forensic, and human health applications journaltitle: Earth-Science Reviews articlelink: http://dx.doi.org/10.1016/j.earscirev.2016.08.012 content_type: article copyright: © 2016 Elsevier B.V. All rights reserved

Content, cost and context: a framework for understanding human signaling systems

Humans frequently perform extravagant and seemingly costly behaviors, such as widely sharing hunted resources, erecting conspicuous monumental structures, and performing dramatic acts of religious devotion. Evolutionary anthropologists and archeologists have used signaling theory to explain the function of such displays, drawing inspiration from behavioral ecology, economics, and the social sciences. While signaling theory is broadly aimed at explaining honest communication, it has come to be strongly associated with the handicap principle, which proposes that such costly extravagance is in fact an adaptation for signal reliability. Most empirical studies of signaling theory have focused on obviously costly acts, and consequently anthropologists have likely overlooked a wide range of signals that also promote reliable communication. Here, we build on recent developments in signaling theory and animal communication, developing an updated framework that highlights the diversity of signal contents, costs, contexts, and reliability mechanisms present within human signaling systems. By broadening the perspective of signaling theory in human systems, we strive to identify promising areas for further empirical and theoretical work

Movement variability in stroke patients and controls performing two upper limb functional tasks: a new assessment methodology

Background: In the evaluation of upper limb impairment post stroke there remains a gap between detailed kinematic analyses with expensive motion capturing systems and common clinical assessment tests. In particular, although many clinical tests evaluate the performance of functional tasks, metrics to characterise upper limb kinematics are generally not applicable to such tasks and very limited in scope. This paper reports on a novel, user-friendly methodology that allows for the assessment of both signal magnitude and timing variability in upper limb movement trajectories during functional task performance. In order to demonstrate the technique, we report on a study in which the variability in timing and signal magnitude of data collected during the performance of two functional tasks is compared between a group of subjects with stroke and a group of individually matched control subjects. Methods: We employ dynamic time warping for curve registration to quantify two aspects of movement variability: 1) variability of the timing of the accelerometer signals' characteristics and 2) variability of the signals' magnitude. Six stroke patients and six matched controls performed several trials of a unilateral ('drinking') and a bilateral ('moving a plate') functional task on two different days, approximately 1 month apart. Group differences for the two variability metrics were investigated on both days. Results: For 'drinking from a glass' significant group differences were obtained on both days for the timing variability of the acceleration signals' characteristics (p = 0.002 and p = 0.008 for test and retest, respectively); all stroke patients showed increased signal timing variability as compared to their corresponding control subject. 'Moving a plate' provided less distinct group differences. Conclusion: This initial application establishes that movement variability metrics, as determined by our methodology, appear different in stroke patients as compared to matched controls during unilateral task performance ('drinking'). Use of a user-friendly, inexpensive accelerometer makes this methodology feasible for routine clinical evaluations. We are encouraged to perform larger studies to further investigate the metrics' usefulness when quantifying levels of impairment

Neural correlates of heterotopic facilitation induced after high frequency electrical stimulation of nociceptive pathways

<p>Abstract</p> <p>Background</p> <p>High frequency electrical stimulation (HFS) of primary nociceptive afferents in humans induce a heightened sensitivity in the surrounding non-stimulated skin area. Several studies suggest that this heterotopic effect is the result of central (spinal) plasticity. The aim of this study is to investigate HFS-induced central plasticity of sensory processing at the level of the brain using the electroencephalogram (EEG). To this end we measured evoked potentials in response to noxious electrical pinprick-like stimuli applied in the heterotopic skin area before, directly after and 30 minutes after HFS.</p> <p>Results</p> <p>We observed potential cortical electrophysiological correlates of heterotopic facilitation. Two different cortical correlates were found; the first one was a lateralized effect, i.e. a larger N100 amplitude on the conditioned arm than the control arm 30 minutes after end of HFS. This was comparable with the observed lateralized effect of visual analogue scale (VAS) scores as response to the mechanical punctate stimuli. The second correlate seems to be a more general (non-lateralized) effect, because the result affects both arms. On average for both arms the P200 amplitude increased significantly 30 minutes after end of HFS with respect to baseline.</p> <p>Conclusions</p> <p>We suggest that for studying heterotopic nociceptive facilitation the evoked brain response is suitable and relevant for investigating plasticity at the level of the brain and is perhaps a more sensitive and reliable marker than the perceived pain intensity (e.g. VAS).</p

The PERK Inhibitor GSK2606414 Enhances Reovirus Infection in Head and Neck Squamous Cell Carcinoma via an ATF4-Dependent Mechanism.

Reovirus type 3 Dearing (reovirus) is a tumor-selective oncolytic virus currently under evaluation in clinical trials. Here, we report that the therapeutic efficacy of reovirus in head and neck squamous cell cancer can be enhanced by targeting the unfolded protein response (UPR) kinase, protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK). PERK inhibition by GSK2606414 increased reovirus efficacy in both 2D and 3D models in vitro, while perturbing the normal host cell response to reovirus-induced endoplasmic reticulum (ER) stress. UPR reporter constructs were used for live-cell 3D spheroid imaging. Profiling of eIF2a-ATF4, IRE1a-XBP1, and ATF6 pathway activity revealed a context-dependent increase in eIF2a-ATF4 signaling due to GSK2606414. GSK2606414 blocked eIF2a-ATF4 signaling because of the canonical ER stress agent thapsigargin. In the context of reovirus infection, GSK2606414 induced eIF2a-ATF4 signaling. Knockdown of eIF2a kinases PERK, GCN2, and PKR revealed eIF2a-ATF4 reporter activity was dependent on either PERK or GCN2. Knockdown of ATF4 abrogated the GSK2606414-induced increase in reovirus protein levels, confirming eIF2a-ATF signaling as key to the observed phenotype. Our work identifies a novel approach to enhance the efficacy and replication of reovirus in a therapeutic setting

Make Better Choices (MBC): Study design of a randomized controlled trial testing optimal technology-supported change in multiple diet and physical activity risk behaviors

<p>Abstract</p> <p>Background</p> <p>Suboptimal diet and physical inactivity are prevalent, co-occurring chronic disease risk factors, yet little is known about how to maximize multiple risk behavior change. Make Better Choices, a randomized controlled trial, tests competing hypotheses about the optimal way to promote healthy change in four bundled risk behaviors: high saturated fat intake, low fruit and vegetable intake, low physical activity, and high sedentary leisure screen time. The study aim is to determine which combination of two behavior change goals - one dietary, one activity - yields greatest overall healthy lifestyle change.</p> <p>Methods/Design</p> <p>Adults (n = 200) with poor quality diet and sedentary lifestyle will be recruited and screened for study eligibility. Participants will be trained to record their diet and activities onto a personal data assistant, and use it to complete two weeks of baseline. Those who continue to show all four risk behaviors after baseline recording will be randomized to one of four behavior change prescriptions: 1) increase fruits and vegetables and increase physical activity, 2) decrease saturated fat and increase physical activity, 3) increase fruits and vegetable and decrease saturated fat, or 4) decrease saturated fat and decrease sedentary activity. They will use decision support feedback on the personal digital assistant and receive counseling from a coach to alter their diet and activity during a 3-week prescription period when payment is contingent upon meeting behavior change goals. They will continue recording on an intermittent schedule during a 4.5-month maintenance period when payment is not contingent upon goal attainment. The primary outcome is overall healthy lifestyle change, aggregated across all four risk behaviors.</p> <p>Discussion</p> <p>The Make Better Choices trial tests a disseminable lifestyle intervention supported by handheld technology. Findings will fill a gap in knowledge about optimal goal prescription to facilitate simultaneous diet and activity change. Results will shed light on which goal prescription maximizes healthful lifestyle change.</p> <p>Trial Registration</p> <p>Clinical Trials Gov. Identifier NCT00113672</p