In Silico Mining for Antimalarial Structure-Activity Knowledge and Discovery of Novel Antimalarial Curcuminoids.

Malaria is a parasitic tropical disease that kills around 600,000 patients every year. The emergence of resistant Plasmodium falciparum parasites to artemisinin-based combination therapies (ACTs) represents a significant public health threat, indicating the urgent need for new effective compounds to reverse ACT resistance and cure the disease. For this, extensive curation and homogenization of experimental anti-Plasmodium screening data from both in-house and ChEMBL sources were conducted. As a result, a coherent strategy was established that allowed compiling coherent training sets that associate compound structures to the respective antimalarial activity measurements. Seventeen of these training sets led to the successful generation of classification models discriminating whether a compound has a significant probability to be active under the specific conditions of the antimalarial test associated with each set. These models were used in consensus prediction of the most likely active from a series of curcuminoids available in-house. Positive predictions together with a few predicted as inactive were then submitted to experimental in vitro antimalarial testing. A large majority from predicted compounds showed antimalarial activity, but not those predicted as inactive, thus experimentally validating the in silico screening approach. The herein proposed consensus machine learning approach showed its potential to reduce the cost and duration of antimalarial drug discovery

Analytical and numerical study on grating depth effects in grating coupled waveguide sensors

The in-coupling process for grating-coupled planar optical waveguide sensors is investigated in the case of TE waves. A simple analytical model based on the Rayleigh-Fourier-Kiselev method is applied to take into account the depth of the grating coupler, which is usually neglected in the modeling. Analytical expressions are derived both for the position and width of the in-coupling peaks to illustrate the effects of grating depth on the guided mode resonances in grating coupled waveguide sensors. Numerical computations verify the model for shallow gratings both in terms of peak shape and position and provide the limitations for the analytical formulas

Guidance for the design and reporting of studies evaluating the clinical performance of tests for present or past SARS-CoV-2 infection

Testing for SARS-CoV-2 infection is key in managing the current pandemic. More than 1700 preprints and peer reviewed journal articles evaluating tests for SARS-CoV-2 infection have been published as of January 2021. However, evaluations of these studies have identified many methodological issues, leading to a high risk of bias and difficulties applying the results in practice. Better guidance is urgently needed on the conduct and interpretation of these studies. This article outlines the principles for defining the intended purpose of the test; study population selection; reference standard, test timing; and other critical considerations for the design, reporting, and interpretation of diagnostic accuracy studies. The implementation and accuracy of SARS-CoV-2 tests have major implications for individuals and communities, balancing the potential consequences of continued infection against the need for public health measures, such as the restriction of movements and social activities. Decision making in the current pandemic requires a clear understanding of the clinical performance and limitations of testing. This article provides guidance to assist researchers design robust diagnostic accuracy studies, assist publishers and peer reviewers to assess such studies, and support clinicians and policy makers in their evaluation of the evidence on SARS-CoV-2 testing for clinical and public health decisions. The guidance aims to ensure that studies evaluating the diagnostic accuracy of SARS-CoV-2 tests are conducted as rigorously as possible, in an efficient and timely way

Exhaled carbon monoxide in asthmatics: a meta-analysis

<p>Abstract</p> <p>Background</p> <p>The non-invasive assessment of airway inflammation is potentially advantageous in asthma management. Exhaled carbon monoxide (eCO) measurement is cheap and has been proposed to reflect airway inflammation and oxidative stress but current data are conflicting. The purpose of this meta-analysis is to determine whether eCO is elevated in asthmatics, is regulated by steroid treatment and reflects disease severity and control.</p> <p>Methods</p> <p>A systematic search for English language articles published between 1997 and 2009 was performed using Medline, Embase and Cochrane databases. Observational studies comparing eCO in non-smoking asthmatics and healthy subjects or asthmatics before and after steroid treatment were included. Data were independently extracted by two investigators and analyzed to generate weighted mean differences using either a fixed or random effects meta-analysis depending upon the degree of heterogeneity.</p> <p>Results</p> <p>18 studies were included in the meta-analysis. The eCO level was significantly higher in asthmatics as compared to healthy subjects and in intermittent asthma as compared to persistent asthma. However, eCO could not distinguish between steroid-treated asthmatics and steroid-free patients nor separate controlled and partly-controlled asthma from uncontrolled asthma in cross-sectional studies. In contrast, eCO was significantly reduced following a course of corticosteroid treatment.</p> <p>Conclusions</p> <p>eCO is elevated in asthmatics but levels only partially reflect disease severity and control. eCO might be a potentially useful non-invasive biomarker of airway inflammation and oxidative stress in nonsmoking asthmatics.</p

X-ray emission from isolated neutron stars

X-ray emission is a common feature of all varieties of isolated neutron stars (INS) and, thanks to the advent of sensitive instruments with good spectroscopic, timing, and imaging capabilities, X-ray observations have become an essential tool in the study of these objects. Non-thermal X-rays from young, energetic radio pulsars have been detected since the beginning of X-ray astronomy, and the long-sought thermal emission from cooling neutron star's surfaces can now be studied in detail in many pulsars spanning different ages, magnetic fields, and, possibly, surface compositions. In addition, other different manifestations of INS have been discovered with X-ray observations. These new classes of high-energy sources, comprising the nearby X-ray Dim Isolated Neutron Stars, the Central Compact Objects in supernova remnants, the Anomalous X-ray Pulsars, and the Soft Gamma-ray Repeaters, now add up to several tens of confirmed members, plus many candidates, and allow us to study a variety of phenomena unobservable in "standard'' radio pulsars.Comment: Chapter to be published in the book of proceedings of the 1st Sant Cugat Forum on Astrophysics, "ICREA Workshop on the high-energy emission from pulsars and their systems", held in April, 201

Motivational interviewing for low mood and adjustment early after stroke: a feasibility randomised trial

Background Management of psychological adjustment and low mood after stroke can result in positive health outcomes. We have adapted a talk-based therapy, motivational interviewing (MI), and shown it to be potentially effective for managing low mood and supporting psychological adjustment post-stroke in a single-centre trial. In the current study, we aimed to explore the feasibility of delivering MI using clinical stroke team members, and using an attention control (AC), to inform the protocol for a future definitive trial. Methods This parallel two-arm feasibility trial took place in north-west England. Recruitment occurred between December 2012 and November 2013. Participants were stroke patients aged 18 years or over, who were medically stable, had no severe communication problems, and were residents of the hospital catchment. Randomisation was to MI or AC, and was conducted by a researcher not involved in recruitment using opaque sealed envelopes. The main outcome measures were descriptions of study feasibility (recruitment/retention rates, MI delivery by clinical staff, use of AC) and acceptability (through qualitative interviews and completion of study measures), and fidelity to MI and AC (through review of session audio-recordings). Information was also collected on participants’ mood, quality of life, adjustment, and resource-use. Results Over 12 months, 461 patients were screened, 124 were screened eligible, and 49 were randomised: 23 to MI, 26 to AC. At 3 months, 13 MI and 18 AC participants completed the follow-up assessment (63% retention). This was less than expected based on our original trial. An AC was successfully implemented. Alternative approaches would be required to ensure the feasibility of clinical staff delivering MI. The study measures, MI, and AC interventions were considered acceptable, and there was good fidelity to the interventions. There were no adverse events related to study participation. Conclusions It was possible to recruit and retain participants, train clinical staff to deliver MI, and implement an appropriate AC. Changes would be necessary to conduct a future multi-centre trial, including: assuming a recruitment rate lower than that in the current study; implementing more strategies to increase participant retention; and considering alternative clinical staff groups to undertake the delivery of MI and AC

Homologous and heterologous desensitization of guanylyl cyclase-B signaling in GH3 somatolactotropes

The guanylyl cyclases, GC-A and GC-B, are selective receptors for atrial and C-type natriuretic peptides (ANP and CNP, respectively). In the anterior pituitary, CNP and GC-B are major regulators of cGMP production in gonadotropes and yet mouse models of disrupted CNP and GC-B indicate a potential role in growth hormone secretion. In the current study, we investigate the molecular and pharmacological properties of the CNP/GC-B system in somatotrope lineage cells. Primary rat pituitary and GH3 somatolactotropes expressed functional GC-A and GC-B receptors that had similar EC50 properties in terms of cGMP production. Interestingly, GC-B signaling underwent rapid homologous desensitization in a protein phosphatase 2A (PP2A)-dependent manner. Chronic exposure to either CNP or ANP caused a significant down-regulation of both GC-A- and GC-B-dependent cGMP accumulation in a ligand-specific manner. However, this down-regulation was not accompanied by alterations in the sub-cellular localization of these receptors. Heterologous desensitization of GC-B signaling occurred in GH3 cells following exposure to either sphingosine-1-phosphate or thyrotrophin-releasing hormone (TRH). This heterologous desensitization was protein kinase C (PKC)-dependent, as pre-treatment with GF109203X prevented the effect of TRH on CNP/GC-B signaling. Collectively, these data indicate common and distinct properties of particulate guanylyl cyclase receptors in somatotropes and reveal that independent mechanisms of homologous and heterologous desensitization occur involving either PP2A or PKC. Guanylyl cyclase receptors thus represent potential novel therapeutic targets for treating growth-hormone-associated disorders

Behavior and Impact of Zirconium in the Soil–Plant System: Plant Uptake and Phytotoxicity

Because of the large number of sites they pollute, toxic metals that contaminate terrestrial ecosystems are increasingly of environmental and sanitary concern (Uzu et al. 2010, 2011; Shahid et al. 2011a, b, 2012a). Among such metals is zirconium (Zr), which has the atomic number 40 and is a transition metal that resembles titanium in physical and chemical properties (Zaccone et al. 2008). Zr is widely used in many chemical industry processes and in nuclear reactors (Sandoval et al. 2011; Kamal et al. 2011), owing to its useful properties like hardness, corrosion-resistance and permeable to neutrons (Mushtaq 2012). Hence, the recent increased use of Zr by industry, and the occurrence of the Chernobyl and Fukashima catastrophe have enhanced environmental levels in soil and waters (Yirchenko and Agapkina 1993; Mosulishvili et al. 1994 ; Kruglov et al. 1996)

Uncoupling proteins, dietary fat and the metabolic syndrome

There has been intense interest in defining the functions of UCP2 and UCP3 during the nine years since the cloning of these UCP1 homologues. Current data suggest that both UCP2 and UCP3 proteins share some features with UCP1, such as the ability to reduce mitochondrial membrane potential, but they also have distinctly different physiological roles. Human genetic studies consistently demonstrate the effect of UCP2 alleles on type-2 diabetes. Less clear is whether UCP2 alleles influence body weight or body mass index (BMI) with many studies showing a positive effect while others do not. There is strong evidence that both UCP2 and UCP3 protect against mitochondrial oxidative damage by reducing the production of reactive oxygen species. The evidence that UCP2 protein is a negative regulator of insulin secretion by pancreatic β-cells is also strong: increased UCP2 decreases glucose stimulated insulin secretion ultimately leading to β-cell dysfunction. UCP2 is also neuroprotective, reducing oxidative stress in neurons. UCP3 may also transport fatty acids out of mitochondria thereby protecting the mitochondria from fatty acid anions or peroxides. Current data suggest that UCP2 plays a role in the metabolic syndrome through down-regulation of insulin secretion and development of type-2 diabetes. However, UCP2 may protect against atherosclerosis through reduction of oxidative stress and both UCP2 and UCP3 may protect against obesity. Thus, these UCP1 homologues may both contribute to and protect from the markers of the metabolic syndrome

Whodunnit? Electrophysiological correlates of agency judgements.

Sense of agency refers to the feeling that "I" am responsible for those external events that are directly produced by one's own voluntary actions. Recent theories distinguish between a non-conceptual "feeling" of agency linked to changes in the processing of self-generated sensory events, and a higher-order judgement of agency, which attributes sensory events to the self. In the current study we explore the neural correlates of the judgement of agency by means of electrophysiology. We measured event-related potentials to tones that were either perceived or not perceived as triggered by participants' voluntary actions and related these potentials to later judgements of agency over the tones. Replicating earlier findings on predictive sensory attenuation, we found that the N1 component was attenuated for congruent tones that corresponded to the learned action-effect mapping as opposed to incongruent tones that did not correspond to the previously acquired associations between actions and tones. The P3a component, but not the N1, directly reflected the judgement of agency: deflections in this component were greater for tones judged as self-generated than for tones judged as externally produced. The fact that the outcome of the later agency judgement was predictable based on the P3a component demonstrates that agency judgements incorporate early information processing components and are not purely reconstructive, post-hoc evaluations generated at time of judgement