Search

Gene expression links genomic variation to organismal trait differences. Here, the authors identify regulatory loci underlying gene expression variation in C. elegans and demonstrate how this variation could impact other complex traits.

Summary: Multiple strategies have evolved to compensate for masking noise, leading to changes in call features. One call adjustment is the Lombard effect, an increase in call amplitude in response to noise. Another strategy involves call production in periods where noise is absent. While mechanisms underlying vocal adjustments have been well studied, mechanisms underlying noise avoidance strategies remain largely unclear. We systematically perturbed ongoing phee calls of marmosets to investigate noise avoidance strategies. Marmosets canceled their calls after noise onset and produced longer calls after noise-phases ended. Additionally, the number of uttered syllables decreased during noise perturbation. This behavior persisted beyond the noise-phase. Using machine learning techniques, we found that a fraction of single phees were initially planned as double phees and became interrupted after the first syllable. Our findings indicate that marmosets use different noise avoidance strategies and suggest vocal flexibility at different complexity levels in the marmoset brain.

Filariae are vector-borne nematodes responsible for an enormous burden of disease. Human lymphatic filariasis, caused by Wuchereria bancrofti, Brugia malayi, and Brugia timori, and onchocerciasis (caused by Onchocerca volvulus) are neglected parasitic diseases of major public health significance in tropical regions. To date, therapeutic efforts to eliminate human filariasis have been hampered by the lack of a drug with sufficient macrofilaricidal and/or long-term sterilizing effects that is suitable for use in mass drug administration (MDA) programs, particularly in areas co-endemic with Loa loa, the causative agent of loiasis.Emodepside, a semi-synthetic cyclooctadepsipeptide, has been shown to have broad-spectrum efficacy against gastrointestinal nematodes in a variety of mammalian hosts, and has been approved as an active ingredient in dewormers for cats and dogs. This paper evaluates, compares (where appropriate) and summarizes the in vitro effects of emodepside against a range of filarial nematodes at various developmental stages.Emodepside inhibited the motility of all tested stages of filariae frequently used as surrogate species for preclinical investigations (Acanthocheilonema viteae, Brugia pahangi, Litomosoides sigmodontis, Onchocerca gutturosa, and Onchocerca lienalis), human-pathogenic filariae (B. malayi) and filariae of veterinary importance (Dirofilaria immitis) in a concentration-dependent manner. While motility of all filariae was inhibited, both stage- and species-specific differences were observed. However, whether these differences were detected because of stage- and/or species-specific factors or as a consequence of variations in protocol parameters among the participating laboratories (such as purification of the parasites, read-out units, composition of media, incubation conditions, duration of incubation etc.) remains unclear.This study, however, clearly shows that emodepside demonstrates broad-spectrum in vitro activity against filarial nematode species across different genera and can therefore be validated as a promising candidate for the treatment of human filariases, including onchocerciasis and lymphatic filariasis.

Currently, only a few chemical drug classes are available to control the global burden of nematode infections in humans and animals. Most of these drugs exert their anthelmintic activity by interacting with proteins such as ion channels, and the nematode neuromuscular system remains a promising target for novel intervention strategies. Many commonly-used phenotypic readouts such as motility provide only indirect insight into neuromuscular function and the site(s) of action of chemical compounds. Electrophysiological recordings provide more specific information but are typically technically challenging and lack high throughput for drug discovery. Because drug discovery relies strongly on the evaluation and ranking of drug candidates, including closely related chemical derivatives, precise assays and assay combinations are needed for capturing and distinguishing subtle drug effects.Past studies show that nematode motility and pharyngeal pumping (feeding) are inhibited by most anthelmintic drugs. Here we compare two microfluidic devices (“chips”) that record electrophysiological signals from the nematode pharynx (electropharyngeograms; EPGs) ─ the ScreenChip™ and the 8-channel EPG platform ─ to evaluate their respective utility for anthelmintic research. We additionally compared EPG data with whole-worm motility measurements obtained with the wMicroTracker instrument. As references, we used three macrocyclic lactones (ivermectin, moxidectin, and milbemycin oxime), and levamisole, which act on different ion channels. Drug potencies (IC50 and IC95 values) from concentration-response curves, and the time-course of drug effects, were compared across platforms and across drugs. Drug effects on pump timing and EPG waveforms were also investigated. These experiments confirmed drug-class specific effects of the tested anthelmintics and illustrated the relative strengths and limitations of the different assays for anthelmintic research.

Infections by parasitic nematodes inflict a huge burden on the health of humans and livestock throughout the world. Anthelmintic drugs are the first line of defense against these infections. Unfortunately, resistance to these drugs is rampant and continues to spread. To improve treatment strategies, we must understand the genetics and molecular mechanisms that underlie resistance. Studies of the fungus Aspergillus nidulans and the free-living nematode Caenorhabditis elegans discovered that a beta-tubulin gene is mutated in benzimidazole (BZ) resistant strains. In parasitic nematode populations, three beta-tubulin alleles, F167Y, E198A, and F200Y, have long been correlated with resistance. Additionally, improvements in sequencing technologies have identified new alleles - E198V, E198L, E198K, E198I, and E198Stop - also correlated with BZ resistance. However, none of these alleles have been proven to cause resistance. To empirically demonstrate this point, we independently introduced the F167Y, E198A, and F200Y alleles as well as two of the newly identified alleles, E198V and E198L, into the BZ susceptible C. elegans N2 genetic background using the CRISPR-Cas9 system. These genome-edited strains were exposed to both albendazole and fenbendazole to quantitatively measure animal responses to BZs. We used a range of concentrations for each BZ compound to define response curves and found that all five of the alleles conferred resistance to BZ compounds equal to a loss of the entire beta-tubulin gene. These results prove that the parasite beta-tubulin alleles cause resistance. The E198V allele is found at low frequencies along with the E198L allele in natural parasite populations, suggesting that it could affect fitness. We performed competitive fitness assays and demonstrated that the E198V allele reduces animal health, supporting the hypothesis that this allele might be less fit in field populations. Overall, we present a powerful platform to quantitatively assess anthelmintic resistance and effects of specific resistance alleles on organismal fitness in the presence or absence of the drug.

For more than four decades, the free-living nematode Caenorhabditis elegans has been extensively used in anthelmintic research. Classic genetic screens and heterologous expression in the C. elegans model enormously contributed to the identification and characterization of molecular targets of all major anthelmintic drug classes. Although these findings provided substantial insights into common anthelmintic mechanisms, a breakthrough in the treatment and control of parasitic nematodes is still not in sight. Instead, we are facing increasing evidence that the enormous diversity within the phylum Nematoda cannot be recapitulated by any single free-living or parasitic species and the development of novel broad-spectrum anthelmintics is not be a simple goal. In the present review, we summarize certain milestones and challenges of the C. elegans model with focus on drug target identification, anthelmintic drug discovery and identification of resistance mechanisms. Furthermore, we present new perspectives and strategies on how current progress in C. elegans research will support future anthelmintic research.

William Reindel,1 Gary Mosehauer,1 Marjorie Rah,1 Howard Proskin,2 Robert Steffen1 1Vision Care, Bausch & Lomb Incorporated, Rochester, NY, USA; 2Howard M. Proskin & Associates, Rochester, NY, USACorrespondence: Marjorie RahVision Care, Bausch & Lomb Incorporated, Rochester, NY, USATel +1 585-413-6397Email Marjorie.Rah@bausch.comPurpose: The objective of this study was to evaluate and compare the clinical performance of samfilcon A, a unique, polyvinylpyrrolidone (PVP)-containing, silicone hydrogel contact lens with that of the balafilcon A silicone hydrogel contact lens when worn on a 7-day extended wear basis.Subjects and Methods: A total of 669 subjects completed this 12-month, controlled, parallel group, masked, randomized study; of these, 340 wore samfilcon A lenses and 329 balafilcon A lenses. Subjects wore their respective assigned lenses bilaterally on a 7-day extended wear basis. On the seventh night of each wearing week, lenses were removed, cleaned, and disinfected using Biotrue multi-purpose solution (MPS), then re-inserted the following morning. Lenses were replaced with new lenses monthly. At each follow-up visit, investigators completed a slit lamp evaluation, and subjects rated lenses based upon a predefined set of performance criteria.Results: The samfilcon A lens performed comparably to the balafilcon A lens in terms of most graded and ungraded slit lamp findings, differing significantly only for corneal staining Grade 2 or greater, which favored samfilcon A, and anterior segment abnormalities, which favored balafilcon A. Subjects rated both lenses highly when queried about various lens-wearing characteristics. When comparing the number of subjects with findings on either eye on at least one follow-up visit, the two lenses were comparable in many aspects but favored samfilcon A with respect to cleanliness upon removal, overall comfort, comfort at end of day, dryness, vision, vision in low light, vision at end of day, and overall impression (all p < 0.05).Conclusion: While subjects rated both highly, samfilcon A lenses worn for 7-day extended wear and replaced on a monthly basis performed comparably to or better than balafilcon A lenses when worn for the same 7-day wear time and replacement cycle.Keywords: PVP, contact lens, extended wear

Summary: Communication is a keystone of animal behavior. However, the physiological states underlying natural vocal signaling are still largely unknown. In this study, we investigated the correlation of affective vocal utterances with concomitant cardiorespiratory mechanisms. We telemetrically recorded electrocardiography, blood pressure, and physical activity in six freely moving and interacting cynomolgus monkeys (Macaca fascicularis). Our results demonstrate that vocal onsets are strengthened during states of sympathetic activation, and are phase locked to a slower Mayer wave and a faster heart rate signal at ∼2.5 Hz. Vocalizations are coupled with a distinct peri-vocal physiological signature based on which we were able to predict the onset of vocal output using three machine learning classification models. These findings emphasize the role of cardiorespiratory mechanisms correlated with vocal onsets to optimize arousal levels and minimize energy expenditure during natural vocal production.

Current mass drug administration (MDA) programs for the treatment of human river blindness (onchocerciasis) caused by the filarial worm Onchocerca volvulus rely on ivermectin, an anthelmintic originally developed for animal health. These treatments are primarily directed against migrating microfilariae and also suppress fecundity for several months, but fail to eliminate adult O. volvulus. Therefore, elimination programs need time frames of decades, well exceeding the life span of adult worms. The situation is worsened by decreased ivermectin efficacy after long-term therapy. To improve treatment options against onchocerciasis, a drug development candidate should ideally kill or irreversibly sterilize adult worms. Emodepside is a broad-spectrum anthelmintic used for the treatment of parasitic nematodes in cats and dogs (Profender and Procox). Our current knowledge of the pharmacology of emodepside is the result of more than 2 decades of intensive collaborative research between academia and the pharmaceutical industry. Emodepside has a novel mode of action with a broad spectrum of activity, including against extraintestinal nematode stages such as migrating larvae or macrofilariae. Therefore, emodepside is considered to be among the most promising candidates for evaluation as an adulticide treatment against onchocerciasis. Consequently, in 2014, Bayer and the Drugs for Neglected Diseases initiative (DNDi) started a collaboration to develop emodepside for the treatment of patients suffering from the disease. Macrofilaricidal activity has been demonstrated in various models, including Onchocerca ochengi in cattle, the parasite most closely related to O. volvulus. Emodepside has now successfully passed Phase I clinical trials, and a Phase II study is planned. This Bayer-DNDi partnership is an outstanding example of "One World Health," in which experience gained in veterinary science and drug development is translated to human health and leads to improved tools to combat neglected tropical diseases (NTDs) and shorten development pathways and timelines in an otherwise neglected area.

Onchocerciasis (river blindness), caused by the filarial worm Onchocerca volvulus, is a neglected tropical disease mostly affecting sub-Saharan Africa and is responsible for >1.3 million years lived with disability. Current control relies almost entirely on ivermectin, which suppresses symptoms caused by the first-stage larvae (microfilariae) but does not kill the long-lived adults. Here, we evaluated emodepside, a semi-synthetic cyclooctadepsipeptide registered for deworming applications in companion animals, for activity against adult filariae (i.e., as a macrofilaricide). We demonstrate the equivalence of emodepside activity on SLO-1 potassium channels in Onchocerca volvulus and Onchocerca ochengi, its sister species from cattle. Evaluation of emodepside in cattle as single or 7-day treatments at two doses (0.15 and 0.75 mg/kg) revealed rapid activity against microfilariae, prolonged suppression of female worm fecundity, and macrofilaricidal effects by 18 months post treatment. The drug was well tolerated, causing only transiently increased blood glucose. Female adult worms were mostly paralyzed; however, some retained metabolic activity even in the multiple high-dose group. These data support ongoing clinical development of emodepside to treat river blindness.

Whether marmosets can exhibit complex motor tasks in controlled experimental designs has not yet been demonstrated. Here, the authors show that marmoset monkeys can be trained to call on command in controlled operant conditioning tasks.

Parasitic nematodes cause a massive worldwide burden on human health along with a loss of livestock and agriculture productivity. Anthelmintics have been widely successful in treating parasitic nematodes. However, resistance is increasing, and little is known about the molecular and genetic causes of resistance for most of these drugs. The free-living roundworm Caenorhabditis elegans provides a tractable model to identify genes that underlie resistance. Unlike parasitic nematodes, C. elegans is easy to maintain in the laboratory, has a complete and well annotated genome, and has many genetic tools. Using a combination of wild isolates and a panel of recombinant inbred lines constructed from crosses of two genetically and phenotypically divergent strains, we identified three genomic regions on chromosome V that underlie natural differences in response to the macrocyclic lactone (ML) abamectin. One locus was identified previously and encodes an alpha subunit of a glutamate-gated chloride channel (glc-1). Here, we validate and narrow two novel loci using near-isogenic lines. Additionally, we generate a list of prioritized candidate genes identified in C. elegans and in the parasite Haemonchus contortus by comparison of ML resistance loci. These genes could represent previously unidentified resistance genes shared across nematode species and should be evaluated in the future. Our work highlights the advantages of using C. elegans as a model to better understand ML resistance in parasitic nematodes.

Jeffery Schafer,1 William Reindel,1 Robert Steffen,1 Gary Mosehauer,1 Joseph Chinn2 1Vision Care, Bausch and Lomb Incorporated, Rochester, NY, USA; 2J Chinn LLC, Lafayette, CO, USA Background: Sustained digital display viewing reduces eye blink frequency and tear film stability. To retain water and preserve a smooth optical surface, contact lens manufacturers have integrated the humectant polyvinylpyrrolidone (PVP) into silicone hydrogel contact lenses. In this study, extended blink time (EBT) was used to assess visual stability over a prolonged blink interval of two PVP-containing silicone hydrogel lenses, samfilcon A (SAM) and senofilcon A (SEN).Materials and methods: This randomized, bilateral, masked, crossover study assessed lens performance in ten subjects after 16 hours of wear. EBT, ie, the time elapsed between cessation of blinking and blur-out of a threshold letter on the acuity chart, was measured. At the end of the wear period, subjects reported duration of computer use and rated visual quality (VQ) and comfort while wearing the assigned lens, and the investigator evaluated lens surface wetting characteristics. Each lens was removed and immediately weighed to determine total water content.Results: EBTs were 10.42 seconds for SAM and 8.04 seconds for SEN (p = 0.015). Subjective ratings of VQ after 16 hours of wear were 84.6 for SAM and 74.4 for SEN (p = 0.049). Comfort ratings were 85.9 for SAM and 80.2 for SEN (p > 0.05). Median times of computer use were 6–8 hours for both lens types. Post blink, 70.0% of SAM and 30.0% of SEN lenses were completely wet (p = 0.021). Total water content after wear was 43.7% for SAM and 35.5% for SEN (p < 0.001).Conclusion: EBT measurement indicated more stable vision with the PVP-containing SAM polymer compared with the PVP-containing SEN polymer. The SAM polymer also demonstrated better surface wetting and maintained higher water content after a prolonged period of wear. EBT can be valuable in assessing vision stability of patients after hours of computer use. Keywords: polyvinylpyrrolidone, PVP, digital video display, extended blink time, EBT, visual quality, VQ, lens hydration

Cognitive vocal control is indispensable for human language. Frontal lobe areas are involved in initiating purposeful vocalizations, but their functions remain elusive. We explored the respective roles of frontal lobe areas in initiating volitional vocalizations. Macaques were trained to vocalize in response to visual cues. Recordings from the ventrolateral prefrontal cortex (vlPFC), the anterior cingulate cortex (ACC), and the pre-supplementary motor area (preSMA) revealed single-neuron and population activity differences. Pre-vocal activity appeared first after the go cue in vlPFC, showing onset activity that was tightly linked to vocal reaction times. However, pre-vocal ACC onset activity was not indicative of call timing; instead, ramping activity reaching threshold values betrayed call onset. Neurons in preSMA showed weakest correlation with volitional call initiation and timing. These results suggest that vlPFC encodes the decision to produce volitional calls, whereas downstream ACC represents a motivational preparatory signal, followed by a general motor priming signal in preSMA.

The development of mature vocal patterns is shaped by parental influence in many animals. Here, Gultekin and Hage show that parental feedback not only influences vocal development, but is indeed necessary for juvenile marmosets to acquire normal vocal behaviour.

Songbirds are renowned for their acoustically elaborate songs. However, it is unclear whether songbirds can cognitively control their vocal output. Here, we show that crows, songbirds of the corvid family, can be trained to exert control over their vocalizations. In a detection task, three male carrion crows rapidly learned to emit vocalizations in response to a visual cue with no inherent meaning (go trials) and to withhold vocalizations in response to another cue (catch trials). Two of these crows were then trained on a go/nogo task, with the cue colors reversed, in addition to being rewarded for withholding vocalizations to yet another cue (nogo trials). Vocalizations in response to the detection of the go cue were temporally precise and highly reliable in all three crows. Crows also quickly learned to withhold vocal output in nogo trials, showing that vocalizations were not produced by an anticipation of a food reward in correct trials. The results demonstrate that corvids can volitionally control the release and onset of their vocalizations, suggesting that songbird vocalizations are under cognitive control and can be decoupled from affective states.

Study 1a of Giessner and Schubert (2007) found a causal effect of vertical spatial cues on power judgments. Recent work showed that this was a false positive (Klein et al., 2018). Here, we test whether another paradigm (i.e., original Study 3a) can be replicated, and develop an adjusted paradigm of original Study 1a to clarify what kind of vertical spatial cues influence power judgments. Our current preregistered Study 1 confirms original Study 3a of Giessner and Schubert (2007). It shows that information about the power of a leader is represented spatially by placing the leader’s box higher in an organigram. Our current Study 2 distinguishes vertical ranks from magnitude of vertical spatial difference without changes in rank. The original Study 1a and the failed replication manipulated only magnitude while leaving rank equal. We confirm the null finding here. However, we also find that vertical rank order does indeed affect power judgments, again in a preregistered study, and in line with prior work. In sum, building on earlier work and the failed replication, we clarify that vertical rank order, but not magnitude of elevation, are associated with power judgments.

Natural products have moved into the spotlight as possible sources for new drugs in the treatment of helminth infections including schistosomiasis. Surprisingly, insect-derived compounds have largely been neglected so far in the search for novel anthelminthics, despite the generally recognized high potential of insect biotechnology for drug discovery. This motivated us to assess the antischistosomal capacity of harmonine, an antimicrobial alkaloid from the harlequin ladybird Harmonia axyridis that raised high interest in insect biotechnology in recent years. We observed remarkably pleiotropic effects of harmonine on physiological, cellular, and molecular processes in adult male and female Schistosoma mansoni at concentrations as low as 5 μM in vitro. This included tegumental damage, gut dilatation, dysplasia of gonads, a complete stop of egg production at 10 μM, and increased production of abnormally shaped eggs at 5 μM. Motility was reduced with an EC50 of 8.8 μM and lethal effects occurred at 10-20 μM within 3 days of culture. Enzyme inhibition assays revealed acetylcholinesterase (AChE) as one potential target of harmonine. To assess possible effects on stem cells, which represent attractive anthelminthic targets, we developed a novel in silico 3D reconstruction of gonads based on confocal laser scanning microscopy of worms after EdU incorporation to allow for quantification of proliferating stem cells per organ. Harmonine significantly reduced the number of proliferating stem cells in testes, ovaries, and also the number of proliferating parenchymal neoblasts. This was further supported by a downregulated expression of the stem cell markers nanos-1 and nanos-2 in harmonine-treated worms revealed by quantitative real-time PCR. Our data demonstrate a multifaceted antischistosomal activity of the lady beetle-derived compound harmonine, and suggest AChE and stem cell genes as possible targets. Harmonine is the first animal-derived alkaloid detected to have antischistosomal capacity. This study highlights the potential of exploiting insects as a source for the discovery of anthelminthics.

Lightweight materials contribute to an efficient decrease in fuel consumption in the automotive and aircraft industries. Hybrid components made of metal and carbon fiber-reinforced plastics (CFRP) have a high potential in lightweight applications due to their high strength-to-weight ratio. For cost-effective processing of hybrid materials, advanced manufacturing processes such as the prepreg-press-technology have been developed, in which the bonding between a metallic component and a fiber compound is exclusively realized in the forming process. However, upon processing of these hybrid components at elevated temperature, the difference in thermal expansion coefficients of the two materials leads to the formation of tensile residual stresses upon cooling. It is well known that these tensile residual stresses can be detrimentally effective with respect to the durability of a hybrid component. The objective of this work is to accurately measure and analyze residual stresses in hybrid components made of unidirectional CFRP and steel through the incremental hole drilling method. Within this study, the evaluation formalism for orthotropic materials is employed for measuring non-uniform residual stresses in hybrid materials. In order to improve the measurement accuracy, a customized strain gauge with eight grids is employed and a drilling increment size of only 20 µm is utilized. The influence of the angle between the strain gauge rosette and the fiber direction on the evaluation of the residual stresses is investigated. In order to evaluate the reliability of the results determined, a bending test applying a well-defined load is carried out. By direct comparison of the experimentally determined stresses and stress values calculated by the finite element method, the applicability of the hole drilling method for robust determination of residual stresses in CFRP/metal hybrid components is finally validated.

Benzimidazoles (BZ) are essential components of the limited chemotherapeutic arsenal available to control the global burden of parasitic nematodes. The emerging threat of BZ resistance among multiple nematode species necessitates the development of novel strategies to identify genetic and molecular mechanisms underlying this resistance. All detection of parasitic helminth resistance to BZ is focused on the genotyping of three variant sites in the orthologs of the β-tubulin gene found to confer resistance in the free-living nematode Caenorhabditis elegans. Because of the limitations of laboratory and field experiments in parasitic nematodes, it is difficult to look beyond these three sites to identify additional mechanisms that might contribute to BZ resistance in the field. Here, we took an unbiased genome-wide mapping approach in the free-living nematode species C. elegans to identify the genetic underpinnings of natural resistance to the commonly used BZ, albendazole (ABZ). We found a wide range of natural variation in ABZ resistance in natural C. elegans populations. In agreement with known mechanisms of BZ resistance in parasites, we found that a majority of the variation in ABZ resistance among wild C. elegans strains is caused by variation in the β-tubulin gene ben-1. This result shows empirically that resistance to ABZ naturally exists and segregates within the C. elegans population, suggesting that selection in natural niches could enrich for resistant alleles. We identified 25 distinct ben-1 alleles that are segregating at low frequencies within the C. elegans population, including many novel molecular variants. Population genetic analyses indicate that ben-1 variation arose multiple times during the evolutionary history of C. elegans and provide evidence that these alleles likely occurred recently because of local selective pressures. Additionally, we find purifying selection at all five β-tubulin genes, despite predicted loss-of-function variants in ben-1, indicating that BZ resistance in natural niches is a stronger selective pressure than loss of one β-tubulin gene. Furthermore, we used genome-editing to show that the most common parasitic nematode β-tubulin allele that confers BZ resistance, F200Y, confers resistance in C. elegans. Importantly, we identified a novel genomic region that is correlated with ABZ resistance in the C. elegans population but independent of ben-1 and the other β-tubulin loci, suggesting that there are multiple mechanisms underlying BZ resistance. Taken together, our results establish a population-level resource of nematode natural diversity as an important model for the study of mechanisms that give rise to BZ resistance.

Jeffery Schafer,1 Robert Steffen,1 William Reindel,1 Joseph Chinn2 1Vision Care, Bausch & Lomb Incorporated, Rochester, NY, USA; 2J Chinn LLC, Lafayette, CO, USA Purpose: Contact lens wearers today spend much time using digital display devices. Contact lens manufacturers are challenged to develop products that account for longer periods of time where blink rate is reduced and tear-film evaporation rate is increased, affecting both visual acuity and comfort. Two manufacturers recently introduced novel daily disposable contact lenses with high surface water content. The objective of the present study was to compare surface water characteristics before and after initial wear of recently introduced nesofilcon A and delefilcon A high surface water lenses with those of etafilcon A lenses.Patients and methods: Twenty healthy subjects wore each of the three lens types studied in a randomly determined order for 15 minutes. After each wearing, lenses were removed and the surface refractive index (RI) of each lens was immediately measured.Results: The mean RI of the unworn delefilcon A lens was 1.34, consistent with water content in excess of 80%. After 15 minutes of wear, the surface RI shifted to 1.43, consistent with its reported 33% bulk water content. In contrast, the mean surface RI of the nesofilcon A lens was 1.38, both initially and after 15 minutes of wear, and that of the etafilcon A lens was 1.41 initially and 1.42 after 15 minutes of wear.Conclusion: The surface of the delefilcon A lens behaves like a high water hydrogel upon insertion but quickly dehydrates to behave like its low-water silicone-hydrogel bulk material with respect to surface water content during wear, while both nesofilcon A and etafilcon A lenses maintain their water content during initial wear. The nesofilcon A lens appears unique among high water lenses in maintaining high surface and bulk water content during wear. This is important because changes in surface RI due to dehydration are reported to lead to visual aberration affecting user experience.Keywords: contact lens dehydration, poloxamer, visual acuity, wetting

Jeffery Schafer, Robert Steffen, Marjorie J Rah Bausch & Lomb Incorporated, Rochester, NY, USA Purpose: We aimed to evaluate the product performance of a novel one-step hydrogen ­peroxide cleaning and disinfecting solution, PeroxiClear (“Test” solution), when used by habitual Clear Care users to bilaterally clean and disinfect their soft contact lenses, for approximately 2 weeks.Methods: This was a 2-week, open-label, bilateral eye study designed to include subjects ­ranging in age from 18 to 55 years, inclusive. All subjects were habitual users of the Clear Care peroxide regimen for cleaning, disinfecting, and storage of their soft contact lenses, for at least 6 months prior to enrolling in the study. Subjects were examined at two study visits: a screening/­dispensing visit and a 2-week follow-up visit. The primary end point, patient preference for the Test solution, was evaluated with an online survey administered after 7 days of using the Test cleaning and disinfecting solution. Respondents could answer questions with neutral or nonneutral responses (better or worse). Statistical analyses were conducted to compare differences for nonneutral responses.Results: Of the 299 eligible subjects enrolled, 297 completed the study, conducted at 21 sites by 21 investigators in the United States. A significantly higher proportion of nonneutral respondents reported the Test solution was better overall (85.9%) than their habitual contact lens solution (14.1%) (P

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Die Pflanzenzüchtung kann durch die Entwicklung und Bereitstellung neuer Genotypen in zweierlei Hinsicht dem fortschreitenden Klimawandel begegnen. Zum Einen werden Pflanzensorten zur Verfügung gestellt, die unter geänderten Klima- und Witterungsbedingungen hinreichend stabile Erträge ermöglichen und auf diesem Wege einen wesentlichen Beitrag zur Klimaanpassung der Landwirtschaft leisten. Zum Anderen kann die Entwicklung von Kulturarten und Sorten, die z.B. im Hinblick auf den Düngemitteleinsatz betriebsmitteleffizient sowie in ihrem Flächenertrag auf ihren Einsatz als erneuerbare Energieträger optimiert sind, durch die Einsparung fossiler Energieträger einen aktiven Beitrag zum Klimaschutz darstellen. Eine Strategie zur Verbesserung von Nutzpflanzen als erneuerbare Energieträger ist die agrono­mische Anpassung von bislang wenig verwendeten oder neuen Kulturarten mit hohem Biomassepotenzial an hiesige Produktionsbedingungen. Eine weitere Strategie ist die Anpassung traditioneller Kulturarten an neue Nutzungszwecke und Anbausysteme. In der hier vorgestellten Studie wurden exemplarisch die genetisch-züchterischen Biomassepotenziale der Frucht­arten Sorghumhirse und Winterroggen zur Energieerzeugung untersucht. Dabei zeigten Sorghum bicolor × S. bicolor-Hybriden in einem im Witterungsverlauf begüns­tigten Jahr unter norddeutschen Anbaubedingungen nach Aussaat Ende Juni mit einem Gesamttrockenmasse-Ertrag von maximal 146,3 dt/ha ein sehr hohes Ertragspotenzial, das im Untersuchungsjahr im Leistungs­bereich von Silomais lag. Kühlfeuchte Bedingungen während der Jugendentwicklung führten in einem zweiten Anbaujahr allerdings zu erheblich verminderten Erträgen und zeigten den Bedarf an weiterer züchterischer Anpassung der Sorghumhirse auf. Die Prüfung unterschiedlichen Roggenmaterials zur Biomasseproduktion zeigte zu verschiedenen Schnittzeitpunkten eine hohe züchterisch nutzbare Variabilität und viel versprechende Gesamttrockenmasse-Erträge. Auf Grund der nachgewiesenen Kombination von hoher Eigenleistung mit ansprechendem Heterosiszuwachs erscheint die Entwicklung von Hochleistungsenergie-Hybriden für diese Nutzungsrichtung besonders unter Verwendung von Grünschnittroggen und pflanzengenetischen Ressourcen mittelfristig machbar und viel versprechend. Das Ertragspotenzial des Anbausystems 'Roggen/Sorghum' wird als hoch eingeschätzt und kann nach den vorliegenden Ergebnissen in einem günstigen Anbaujahr auf einen Bereich jenseits von 300 dt/ha Gesamttrocken­masse (GTM) prognostiziert werden. Besonders leistungs­stark erscheint das Anbausystem 'Roggen/Sorghum' dabei im Hinblick auf trockenere Standorte.

Extracorporeal liver support has been a much studied topic throughout the last 50 years. Albumin dialysis as a therapeutic option for patients with acute liver failure or acute decompensation of chronic liver disease was introduced in the mid-nineties. The Molecular Adsorbent Recirculating System (MARS) is based on the concept of albumin dialysis and allows for the removal of protein-bound as well as water-soluble toxins. Besides its role as a sufficient volume expander human serum albumin is an important scavenger for molecules with pathophysiological relevance in liver failure. Albumin dialysis enables the selective regeneration of patient’s albumin resulting in an increase of albumin binding capacity. Clinically, an improvement of central and local hemodynamics as well as liver-, brain-, and kidney-functions were observed. Thus, the treatment can contribute to liver regeneration and stabilization of vital organ functions and thus help to bridge patients to liver transplantation or to recovery of native liver function. Proper patient selection is critical for clinical success. Aggressive treatment of infections and sepsis seems to be a decisive pre-requisite for its safe and efficient use. Cautious anticoagulation with heparin is the common standard. Citrate use is recommended for patients prone to bleeding. Today, albumin dialysis MARS is among the best studied liver support methods. It appears as a valuable therapeutic tool for the treatment of various complications of of liver failure, especially hemodynamic instability and hepatic encephalopathy. Further studies will need to help defining the optimal patient selection and technical process parameters such as session-length and frequency of treatment.

In den vorliegenden Untersuchungen wurde divergentes Roggenmaterial (Populationssorten mit Körner- und Grünschnittnutzung, Hybriden, aktuelles Zuchtmaterial, Tetraploider Roggen, pflanzengenetische Ressourcen (PGR)) in einem zweijährigen Anbau anhand seiner Biomasseleistung auf seine Eignung zur energetischen Nutzung von Roggen überprüft, die erfassten agronomischen Merkmale wurden auf ihre Relevanz für die Biomasse­bildung beurteilt, verschiedene Schnittzeitpunkte zur Biomassenutzung untersucht und über einen NIRS-Ansatz Aussagen über das Gasbildungsvermögen der untersuchten Roggenformen getroffen. Für die Merkmale Gesamttrockenmasseertrag (GTM-Ertrag) und Biogasausbeute zu zwei Grünschnitt-Zeitpunkten – Mitte Ährenschieben und Milchreife – sowie Kornertrag lagen im untersuchten Material signifikante genotypische Varianzen vor. Bei den Grünschnitten 1 und 2 betrugen die mittleren GTM-Erträge 70,1 und 131,9 dt/ha. Grünschnittroggen-Sorten erwiesen sich im 1. Grünschnitt und Hybriden im 2. Grünschnitt als über­legen, wogegen in der Testkreuzungsleistung beim 2. Grünschnitt mehrere Grünschnittroggen und PGRs sowie eine Populationssorte die höchsten GTM-Erträge zeigten. Bei den Grünschnitten 1 und 2 sowie dem Kornertrag ergaben sich beachtliche Heterosiszuwächse von durchschnittlich 9,3%, 11,6% bzw. 32,3%. Bedeutsame Merkmale für die Biomasseproduktion (Wuchshöhe, Termin Ährenschieben, TS-Gehalt) wurden identifiziert und deren Korrelationen berechnet. Die für das Gasbildungsvermögen wesentlichen Inhaltstoffe konnten mittels NIRS-Untersuchungen quantifiziert und die Biogas­ausbeute rechnerisch bestimmt werden. Korrelationen zwischen dem GTM-Ertrag, der Biogasausbeute und dem Ligningehalt wurden ermittelt. Die Ergebnisse unter­streichen das hohe Biomassepotenzial verschiedener Roggen-Materialgruppen für die Bioenergienutzung.

When challenged with a complex leaf-rust inoculum, rye plants carrying the dominant leaf-rust resistance gene Pr1 predominantly react with a mixed infection type, IT 2(5). The present study investigates the nature of this mixed infection type. The results demonstrate, that IT 2(5) is not caused by partial dominance of Pr1 nor by the genetic background. Rather, IT 2(5) reflects the occurrence of Pr1-virulent leaf-rust races among the inoculum in low frequency. A simple approach was followed to estimate the frequency of Pr1-virulent races in a leaf-rust population. This approach included comparative detached-leaf testing of Pr1 carriers and Pr1-deficient genotypes and relating the numbers of pustules observed on both genotypes. For the present case we estimated a frequency of 3.19% of Pr1-virulent leaf-rust races among a local leaf-rust population sampled in the field. This estimate was verified in a validation experiment.

Replication studies in psychological science sometimes fail to reproduce prior findings. If these studies use methods that are unfaithful to the original study or ineffective in eliciting the phenomenon of interest, then a failure to replicate may be a failure of the protocol rather than a challenge to the original finding. Formal pre-data-collection peer review by experts may address shortcomings and increase replicability rates. We selected 10 replication studies from the Reproducibility Project: Psychology (RP:P; Open Science Collaboration, 2015) for which the original authors had expressed concerns about the replication designs before data collection; only one of these studies had yielded a statistically significant effect (p