A “Golden Age” for the discovery of new antileishmanial agents: Current status of leishmanicidal gold complexes and prospective targets beyond the trypanothione system

Leishmaniasis is one of the most neglected diseases worldwide and is considered a serious public health issue. The current therapeutic options have several disadvantages that make the search for new therapeutics urgent. Gold compounds are emerging as promising candidates based on encouraging in vitro and limited in vivo results for several Au^I and Au^III complexes. The antiparasitic mechanisms of these molecules remain only partially understood. However, a few studies have proposed the trypanothione redox system as a target, similar to the mammalian thioredoxin system, pointed out as the main target for several gold compounds with significant antitumor activity. In this review, we present the current status of the investigation and design of gold compounds directed at treating leishmaniasis. In addition, we explore potential targets in Leishmania parasites beyond the trypanothione system, taking into account previous studies and structure modulation performed for gold-based compounds.     

Towards identifying the roll motion parameters of a motorcycle simulator

This study aimed at identifying the roll motion parameters of a motorcycle simulator prototype. Experienced motorcyclists tuned the angular physical movement of the mock-up and that of the visual scene to achieve an optimal riding experience during curves. The participants exceeded the rolling angles that would be required in real-world riding, while avoiding leaning the mock-up beyond 10°. In addition, they were more influenced by the speed of the virtual motorcycle than by road curvature, especially in a wide field of view. Heterogeneity was found in the roll applied to the visual scene. The overall patterns suggest that at least when washout is not applied to remove the side forces that in real-world riding are compensated by a centrifugal force, greater roll of the visual at the expense of the mock-up is mandatory to avoid performance biases that might be enhanced due to fear of falling off the simulator. Future roll motion models must take into consideration factors such as riding postures, which might not only influence the forces operating on the rider-motorcycle system, but also how motorcyclists perceive the visual world.     

Molecular aspects of the transport and toxicity of ochratoxin a

Ochratoxins are a class of naturally occurring compounds produced by several fungi. The most toxic is ochratoxin A (OTA), and occurrence of some human nephropathies and tumors correlate with enhanced OTA exposure. In this Account, the following areas are examined: molecular details of the binding of OTA to human serum albumin (HSA), the influences of binding to HSA on the trans-port of OTA across epithelial cell membranes by organic anion transport proteins, the oxidative activation of OTA, and the formation of OTA adducts with biological molecules. These studies are beginning to provide a detailed chemical model for the trans-port, accumulation, and genotoxic and carcinogenic effects of OTA.     

Naturalistic study of the risky situations faced by novice riders

This article sets out to identify the typical risky situations experienced by novice motorcyclists in the real world just after licensing. The procedure consists of a follow-up of six novices during their first two months of riding with their own motorbike instrumented with cameras. The novices completed logbooks on a daily basis in order to identify the risky situations they encountered, and were given face-to-face interviews to identify the context and their shortcomings during the reported events. Data show a large number of road configurations considered as risky by the riders (248 occurrences), especially during the first two weeks. The results revealed that a lack of hazard perception skills contributed to the majority of these incidents. These situations were grouped together to form clusters of typical incident scenarios on the basis of their similarities. The most frequent scenario corresponds to a lane change in dense traffic (15% of all incidents). The discussion shows how this has enhanced our understanding of novice riders’ behaviour and how the findings can improve training and licensing. Lastly, the main methodological limitations of the study and some guidelines for improving future naturalistic riding studies are presented.

Practitioner Summary:

This article aims to identify the risky situations of novice motorcyclists in real roads. Two hundred forty-eight events were recorded and 13 incident scenarios identified. Results revealed that a lack of hazard perception contributed to the majority of these events. The most frequent scenario corresponds to a lane change in dense traffic.     

The contribution of visual and proprioceptive information to the perception of leaning in a dynamic motorcycle simulator

Compared with driving or flight simulation, little is known about self-motion perception in riding simulation. The goal of this study was to examine whether or not continuous roll motion supports the sensation of leaning into bends in dynamic motorcycle simulation. To this end, riders were able to freely tune the visual scene and/or motorcycle simulator roll angle to find a pattern that matched their prior knowledge. Our results revealed idiosyncrasy in the combination of visual and proprioceptive information. Some subjects relied more on the visual dimension, but reported increased sickness symptoms with the visual roll angle. Others relied more on proprioceptive information, tuning the direction of the visual scenery to match three possible patterns. Our findings also showed that these two subgroups tuned the motorcycle simulator roll angle in a similar way. This suggests that sustained inertially specified roll motion have contributed to the sensation of leaning in spite of the occurrence of unexpected gravito-inertial stimulation during the tilt. Several hypotheses are discussed.

Practitioner Summary: Self-motion perception in motorcycle simulation is a relatively new research area. We examined how participants combined visual and proprioceptive information. Findings revealed individual differences in the visual dimension. However, participants tuned the simulator roll angle similarly, supporting the hypothesis that sustained inertially specified roll motion contributes to a leaning sensation.     

Betula alba Bark Extract and Empetrum nigrum Fruit Juice,a Natural Alternative to Niacinamide for Skin Barrier Benefits

The Scandinavian region is home to a unique biome with endemic plant species. The aim of this study was to explore this natural diversity and identify plant extracts providing positive skin barrier effects. Six plant extracts were identified as starting material. Following biochemical screening, two candidates outperformed the rest: Betula alba (BA) and Empetrum nigrum (EN). Quantitative PCR analysis showed that BA and EN upregulated barrier genes, when used individually and in combination. Betula alba increased AQP3 and OCLN protein expression, something niacinamide was incapable of. Additionally, the skin barrier was strengthened, evidenced by inhibition of KLK5 and hyaluronidase and showed strong antioxidant and anti-inflammatory activity through DPPH and COX2 inhibition, respectively. A first split-face clinical study was conducted using the combination of extracts versus placebo. There was a significantly better skin restructuring effect and corneocyte cohesion on the side treated with combined extracts. A second split-face clinical study assessed the combined extracts versus 3% niacinamide. Significant variations in skin hydration and TEWL were observed in favor of the extract treated side. In conclusion, we identified a natural alternative to niacinamide for improving skin barrier health, in Scandinavian plant extracts, which yield strong performance, but at a lower concentration.     

Spatial–Spectral Analysis of Hyperspectral Images Reveals Early Detection of Downy Mildew on Grapevine Leaves

Downy mildew is a highly destructive disease of grapevine. Currently, monitoring for its symptoms is time-consuming and requires specialist staff. Therefore, an automated non-destructive method to detect the pathogen before the visible symptoms appear would be beneficial for early targeted treatments. The aim of this study was to detect the disease early in a controlled environment, and to monitor the disease severity evolution in time and space. We used a hyperspectral image database following the development from 0 to 9 days post inoculation (dpi) of three strains of Plasmopara viticola inoculated on grapevine leaves and developed an automatic detection tool based on a Support Vector Machine (SVM) classifier. The SVM obtained promising validation average accuracy scores of 0.96, a test accuracy score of 0.99, and it did not output false positives on the control leaves and detected downy mildew at 2 dpi, 2 days before the clear onset of visual symptoms at 4 dpi. Moreover, the disease area detected over time was higher than that when visually assessed, providing a better evaluation of disease severity. To our knowledge, this is the first study using hyperspectral imaging to automatically detect and show the spatial distribution of downy mildew on grapevine leaves early over time.     

BK Polyomavirus bkv-miR-B1-5p: A Stable Micro-RNA to Monitor Active Viral Replication after Kidney Transplantation

Background: Bkv-miR-B1-5p is a viral micro-RNA (miRNA) specifically produced during BK polyomavirus (BKPyV) replication. Recent studies have suggested using bkv-miR-B1-5p as a biomarker to monitor viral infection and predict complications in kidney transplant patients. To identify the technical limitations of this miRNA quantification in biological samples, knowledge of its stability and distribution in the extracellular compartment is necessary. Moreover, a proof of concept for using bkv-miR-B1-5p as a biomarker of active replication in chronic infection is still missing in the published literature. Methods: The stability of bkv-miR-B1-5p was evaluated in samples derived from cell cultures and in urine from BKPyV-infected kidney transplant recipients. The miRNA was quantified in different fractions of the extracellular compartment, including exosomes, and protein binding was evaluated. Finally, we developed an in vitro model for chronic culture of BKPyV clinical isolates to observe changes in the bkv-miR-B1-5p level during persistent infections. Results: Bkv-miR-B1-5p is a stable biomarker in samples from humans and in vitro experiments. Marginally associated with the exosomes, most of the circulating bkv-miR-B1-5p is bound to proteins, especially Ago2, so the miRNA quantification does not require specific exosome isolation. The bkv-miR-B1-5p level is predictable of viral infectivity, which makes it a potential specific biomarker of active BKPyV replication after kidney transplantation.     

Porous protein-based scaffolds prepared through freezing as potential scaffolds for tissue engineering

Successful tissue engineering with the aid of a polymer scaffold offers the possibility to produce a larger construct and to mould the shape after the defect. We investigated the use of cryogelation to form protein-based scaffolds through different types of formation mechanisms; enzymatic crosslinking, chemical crosslinking, and non-covalent interactions. Casein was found to best suited for enzymatic crosslinking, gelatin for chemical crosslinking, and ovalbumin for non-covalent interactions. Fibroblasts and myoblasts were used to evaluate the cryogels for tissue engineering purposes. The stability of the cryogels over time in culture differed depending on formation mechanism. Casein cryogels showed best potential to be used in skeletal tissue engineering, whereas gelatin cryogels would be more suitable for compliable soft tissues even though it also seemed to support a myogenic phenotype. Ovalbumin cryogels would be better suited for elastic tissues with faster regeneration properties due to its faster degradation time. Overall, the cryogelation technique offers a fast, cheap and reproducible way of creating porous scaffolds from proteins without the use of toxic compounds.