Rapid and reversible humidity-dependent colour change by water film formation in a scaled springtail.

Colour is often not a static trait but can change over time either through biotic or abiotic factors. Humidity-dependent colour change can occur through either morphological change (e.g. to feather barbules in birds) or by the replacement of air by water causing a shift in refractive index, as seen in arthropod multi-layer cuticles or scales. The scaled springtail Lepidocyrtus cyaneus has scales that produce colour largely via thin film interference from their lamina. We observed a marked colour change from golden to violet/purple coloration in humid conditions. Light microscopy, micro-spectrophotometry, contact angle goniometry and optical modelling indicate that the formation of a thin film of water on top of the hydrophilic scales increases their laminar thin film thickness, causing a shift towards violet/purple colour. Evaporation of the water film causes the metallic golden colour to return. This constitutes a remarkably rapid colour change (in the order of seconds), only limited by the speed of water film condensation and evaporation, that may serve as inspiration for new dynamically coloured materials and sensors.

An updated checklist of Collembola in Taiwan, with DNA barcoding of Papirioidesjacobsoni Folsom, 1924 (Symphypleona, Dicyrtomidae).

From urban green space to pristine forest, Collembola is one of the most numerous and species-rich members of the soil fauna around the world. However, due to lack of taxonomic expertise and research, its diversity is poorly understood, especially in tropical and subtropical regions. Collembola biodiversity studies in Taiwan have not seen much progress since 1981, when Hsin Chi reviewed 26 species belonging to 20 genera and eight families. Additionally, reports of new records in Taiwan in the last 40 years are scattered amongst several publications and not easily accessible to most end-users. Thus, a concise summary of related research is urgently needed. In this study, we updated the checklist of Collembola in Taiwan, based on published papers as well as images recorded in 2020-2022. We concluded that 58 species of Collembola belonging to 31 genera and 12 families have been reported in Taiwan, including 13 newly-recorded species. This species richness marks a 123% increase from the 1981 review. The results have been made publicly available in the Catalog of Life in Taiwan database and the images recorded have been used to update species information in collembola.org. We also characterised morphological and genetic variations in the globular springtail species Papirioidesjacobsoni Folsom, 1924 using DNA barcodes and highlighted potential research directions.

Springtail coloration at a finer scale: mechanisms behind vibrant collembolan metallic colours.

The mechanisms and evolution of metallic structural colours are of both fundamental and applied interest, yet most work in arthropods has focused on derived butterflies and beetles with distinct hues. In particular, basal hexapods-groups with many scaled, metallic representatives-are currently poorly studied and controversial, with some recent studies suggesting either that thin-film (lamina thickness) or diffraction grating (longitudinal ridges, cross-ribs) elements produce these colours in early Lepidoptera and one springtail (Collembola) species. Especially the collembolan basal scale design, consisting of a single lamina and longitudinal ridges with smooth valleys lacking cross-ribs, makes them an interesting group to explore the mechanisms of metallic coloration. Using microspectroscopy, Raman spectroscopy, electron microscopy and finite-difference time-domain optical modelling, we investigated scale colour in seven springtail species that show clear metallic coloration. Reflectance spectra are largely uniform and exhibit a broadband metallic/golden coloration with peaks in the violet/blue region. Our simulations confirm the role of the longitudinal ridges, working in conjunction with thin-film effects to produce a broadband metallic coloration. Broadband coloration occurs through spatial colour mixing, which probably results from nanoscale variation in scale thickness and ridge height and distance. These results provide crucial insights into the colour production mechanisms in a basal scale design and highlight the need for further investigation of scaled, basal arthropods.

Selection of a respiratory syncytial virus fusion inhibitor clinical candidate. 2. Discovery of a morpholinopropylaminobenzimidazole derivative (TMC353121).

A preceding paper (Bonfanti et al. J. Med Chem. 2007, 50, 4572-4584) reported the optimization of the pharmacokinetic profile of substituted benzimidazoles by reducing their tissue retention. However, the modifications that were necessary to achieve this goal also led to a significant drop in anti-RSV activity. This paper describes a molecular modeling study followed by a lead optimization program that led to the recovery of the initial potent antiviral activity and the selection of TMC353121 as a clinical candidate.

Selection of a respiratory syncytial virus fusion inhibitor clinical candidate, part 1: improving the pharmacokinetic profile using the structure-property relationship.

We previously reported the discovery of substituted benzimidazole fusion inhibitors with nanomolar activity against respiratory syncytial virus (Andries, K.; et al. Antiviral Res. 2003, 60, 209-219). A lead compound of the series was selected for preclinical evaluation. This drug candidate, JNJ-2408068 (formerly R170591, 1), showed long tissue retention times in several species (rat, dog, and monkey), creating cause for concern. We herein describe the optimization program to develop compounds with improved properties in terms of tissue retention. We have identified the aminoethyl-piperidine moiety as being responsible for the long tissue retention time of 1. We have investigated the replacement or the modification of this group, and we suggest that the pKa of this part of the molecules influences both the antiviral activity and the pharmacokinetic profile. We were able to identify new respiratory syncytial virus inhibitors with shorter half-lives in lung tissue.

Toward a model of school inspections in a polycentric system.

Many education systems are developing towards more lateral structures where schools collaborate in networks to improve and provide (inclusive) education. These structures call for bottom-up models of network evaluation and accountability instead of the current hierarchical arrangements where single schools are evaluated by a central agency. This paper builds on available research about network effectiveness to present evolving models of network evaluation. Network effectiveness can be defined as the achievement of positive network level outcomes that cannot be attained by individual organizational participants acting alone. Models of network evaluation need to take into account the relations between network members, the structure of the network, its processes and its internal mechanism to enforce norms in order to understand the achievement and outcomes of the network and how these may evolve over time. A range of suitable evaluation models are presented in this paper, as well as a tentative school inspection framework which is inspired by these models. The final section will present examples from Inspectorates of Education in Northern Ireland and Scotland who have developed newer inspection models to evaluate the effectiveness of a range of different networks.

Norpiperidine imidazoazepines as a new class of potent, selective, and nonsedative H1 antihistamines.

Clinical doses of available H(1) antihistamines are limited mainly by sedative side effects. However, higher doses are often required to obtain optimal therapeutic activity, especially in dermatology. We report the synthesis of three norpiperidine imidazoazepines representative of a new class of selective and nonsedating H(1) antihistamines. The compounds were at least as potent as cetirizine and loratadine as measured by H(1) receptor binding affinity, by protection against compound 48/80- and histamine-induced lethality in rats and guinea pigs, respectively, and by skin reaction tests in rats, guinea pigs, and dogs. The compounds, in particular 3a, were less prone than the reference compounds to penetrate the brain and to occupy central H(1) receptors, suggesting absence of sedative side effects. In vitro and in vivo cardiovascular safety tests showed that 3a had no intrinsic potential to prolong ventricular repolarization or induce cardiac arrhythmias. Compound 3a has been selected for further clinical development, mainly for application in dermatology.

Dual Alleviation of Acute and Neuropathic Pain by Fused Opioid Agonist-Neurokinin 1 Antagonist Peptidomimetics.

Herein, the synthesis and biological evaluation of dual opioid agonists-neurokinin 1 receptor (NK1R) antagonists is described. In these multitarget ligands, the two pharmacophores do not overlap, and this allowed maintaining high NK1R affinity and antagonist potency in compounds 12 and 13. Although the fusion of the two ligands resulted in slightly diminished opioid agonism at the µ- and δ-opioid receptors (MOR and DOR, respectively), as compared to the opioid parent peptide, balanced MOR/DOR activities were obtained. Compared to morphine, compounds 12 and 13 produced more potent antinociceptive effects in both acute (tail-flick) and neuropathic pain models (von Frey and cold plate). Similarly to morphine, analgesic tolerance developed after repetitive administration of these compounds. To our delight, compound 12 did not produce cross-tolerance with morphine and high antihyperalgesic and antiallodynic effects could be reinstated after chronic administration of each of the two compounds.

Substituted benzimidazoles with nanomolar activity against respiratory syncytial virus.

A cell-based assay was used to discover compounds inhibiting respiratory syncytial virus (RSV)-induced fusion in HeLa/M cells. A lead compound was identified and subsequent synthesis of >300 analogues led to the identification of JNJ 2408068 (R170591), a low molecular weight (MW 395) benzimidazole derivative with an EC(50) (0.16 nM) against some lab strains almost 100,000 times better than that of ribavirin (15 microM). Antiviral activity was confirmed for subgroup A and B clinical isolates of human RSV and for a bovine RSV isolate. The compound did not inhibit the growth of representative viruses from other Paramyxovirus genera, i.e. HPIV2 and Mumps Virus (genus Rubulavirus), HPIV3 (genus Respirovirus), Measles virus (genus Morbillivirus) and hMPV. Efficacy in cytopathic effect inhibition assays correlated well with efficacy in virus yield reduction assays. A concentration of 10nM reduced RSV production 1000-fold in multi-cycle experiments, irrespective of the multiplicity of infection. Time of addition studies pointed to a dual mode of action: inhibition of virus-cell fusion early in the infection cycle and inhibition of cell-cell fusion at the end of the replication cycle. Two resistant mutants were raised and shown to have single point mutations in the F-gene (S398L and D486N). JNJ 2408068 was also shown to inhibit the release of proinflammatory cytokines IL-6, IL-8 and Rantes from RSV-infected A549 cells.

Experimental studies to improve the reliability and validity of regulatory judgments on health care in the Netherlands: a randomized controlled trial and before and after case study.

RATIONALE, AIMS AND OBJECTIVES: We examined the effect of two interventions on both the reliability and validity of regulatory judgments: adjusting the regulatory instrument and attending a consensus meeting. METHOD: We adjusted the regulatory instrument. With a randomized controlled trial (RCT) we examined the effect of the adjustments we made to the instrument. In the consensus meeting inspectors discussed cases and had to reach consensus about the order of the cases. We used a before and after case study to assess the effect of the consensus meeting. We compared the judgments assigned in the RCT with the unadjusted instrument with the judgments assigned with the unadjusted instrument after the consensus meeting. Moreover we explored the effect of increasing the number of inspectors per regulatory visit based on the estimates of the two interventions. RESULTS: The consensus meeting improved the agreement between inspectors; the variance between inspectors was smallest (0.03) and the reliability coefficient was highest (0.59). Validity is assessed by examining the relation between the assigned judgments and the corporate standard and expressed by a correlation coefficient. This coefficient was highest after the consensus meeting (0.48). Adjustment of the instrument did not increase reliability and validity coefficients. CONCLUSIONS: Participating in a consensus meeting improved reliability and validity. Increasing the number of inspectors resulted in both higher reliability and validity values. Organizing consensus meetings and increasing the number of inspectors per regulatory visit seem to be valuable interventions for improving regulatory judgments.

Reducing interrater variability and improving health care: a meta-analytical review.

OBJECTIVES: In the scientific literature about reliability, the main approach to increasing reliability seems to involve increasing the number of observers and improving the instrument used. Other aspects for improving reliability - like the training of raters - seem to receive less notice. It is worth asking whether this technical approach could be complemented by training the user of the instrument. A systematic meta-analytical review of the research literature was performed to answer this question and examine the effectiveness of planned interventions for improving interrater reliability of health care professionals. METHOD: The databases of PubMed (MEDLINE), Embase, Omega and PsycINFO were searched. The inclusion criteria were met by 57 studies. Details extracted from the studies included the study design, the number of observers and the number of observed cases, the intervention, the type of instrument (whether or not it was highly technical), and statistical information about the agreement before and after the intervention. Interventions were categorized into three groups: training of professionals, improving the diagnostic instrument and a combination of training and improving the instrument. A meta-analysis was performed by means of linear regression. RESULTS: The interventions were arranged according to their effectiveness in improving the diagnostic instrument (mean change: ß = 0.13), training combined with improving the instrument (mean change: ß = 0.10) and training (mean change: ß = 0.09). CONCLUSION: On average, although all types of interventions are effective, improving the diagnostic instrument seems to be the most effective. Especially when highly technical instruments were concerned, improvement proved to be very effective (ß = 0.52). Because instrumental variables constitute a major source of error, improving the instrument is an important approach. However, this review offers solid arguments that can complement the literature and practice, with a focus on training the user of the instrument.

Evaluating instruments for regulation of health care in the Netherlands.

OBJECTIVES: Reliable and valid judgments are necessary for regulatory authorities to merit confidence from care institutions and society and preserve authority. Moreover, limited reliability and validity of regulatory judgments increase the risk of limited improvement of the quality of health care. The goal of the study is to obtain insight in (dis) advantages of different regulatory instruments for regulation of health care. METHOD: In this study, the reliability and validity of judgments generated by a lightly structured and highly structured regulatory instrument used by the Dutch Health Care Inspectorate are compared. RESULTS: Results indicate that the lightly structured instrument causes a large variety in discussed topics in regulatory visits: indicators pointing out potential risks in care are not always part of these discussions, by which incentives to improve care remain unjustly undone. Both types of instruments show variations in the meaning of judgments, indicating validity problems. CONCLUSION: The results of our study suggest that regulation of health care requires thorough appraisal of instruments. Several requirements are identified: first, an instrument that justifies the complexity of care with an accompanying explicit set of standards is necessary. Second, commitment of inspectors to the instrument is essential. And third, training of inspectors is indispensable.

Quantification of the neurokinin 1 receptor ligand [¹¹C]R116301.

PURPOSE: Neurokinin 1 (NK1) receptors have been implicated in depression, anxiety, and pain perception. Recently, it was shown that, in the human brain, a specific NK1 receptor-related signal was obtained with the novel radioligand, [¹¹C]R116301, using positron emission tomography. The purpose of this study was to evaluate various methods for quantifying specific [¹¹C]R116301 binding. METHODS: Two dynamic 90-min [¹¹C]R116301 scans, separated by 5 h, were performed in 11 healthy volunteers. In three patients, the second scan was performed after an oral blocking dose of 125 mg of aprepitant, whereas in the other eight, no intervention was performed (test-retest). Whole striatum was used as the tissue of interest, as it has the highest density of NK1 receptors. Cerebellum was used as the reference tissue. RESULTS: Reference tissue models were stable with the simplified reference tissue model (SRTM) performing best. Average (± standard deviation) SRTM-derived mean nondisplaceable binding potential (BP(ND)) of all (first) baseline scans was 0.64±0.31 (n=11), which reduced to -0.01±0.03 (n=3) after aprepitant administration. Test-retest results showed low variability (14.0±10.7%) and excellent reliability, as indicated by the intraclass correlation coefficient (0.93). The ratio of standardized uptake values of striatum and cerebellum minus 1, an approximation of BP(ND), showed very low variability (6.2±3.1%) with excellent reliability (intraclass correlation coefficient=0.98), and correlated well with SRTM-derived BP(ND) (R²=0.96). CONCLUSION: SRTM is the model of choice for quantifying [¹¹C]R116301 binding. Semiquantitative tissue ratios hold promise for routine clinical applications.

4-Phenyl-4-[1H-imidazol-2-yl]-piperidine derivatives as non-peptidic selective delta-opioid agonists with potential anxiolytic/antidepressant properties. Part 2.

Novel 4-phenyl-4-[1H-imidazol-2-yl]-piperidine derivatives have been prepared and their synthesis described herein. In vitro affinities for delta-, micro-, and kappa-opioid receptors are reported. Evaluation of some representative compounds from this series in the mouse neonatal ultrasonic vocalization test and the mouse tail suspension test revealed anxiolytic- and antidepressant-like effects, respectively, upon subcutaneous administration.

4-Phenyl-4-[1H-imidazol-2-yl]-piperidine derivatives, a novel class of selective delta-opioid agonists.

A novel series of 4-phenyl-4-[1H-imidazol-2-yl]-piperidine derivatives has been prepared and their synthesis described herein. In vitro affinities for delta-, mu-, and kappa-opioid receptors, as well as the functional activity in the [(35)S]GTPgammaS assay are reported. The most potent and selective delta-opioid agonist 18a exhibited a K(i) of 18 nM, and was >258-fold and 28-fold selective over mu- and kappa-receptors, respectively; the compound is a full agonist with an EC(50) value of 14 nM.