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IntroductionGlaucoma is a complex, multifactorial neurodegenerative disease, which can lead to blindness if left untreated. It seems that, among others, immune processes, elevated intraocular pressure (IOP), or a combination of these factors are responsible for glaucomatous damage. Here, we combined two glaucoma models to examine if a combination of risk factors (IOP and immune response) results in a more severe damage of retinal ganglion cells (RGCs) and the optic nerves as well as an additional glia activation.MethodsSix-week-old wildtype (WT+ONA) and βB1-Connective Tissue Growth Factor (CTGF) mice (CTGF+ONA) were immunized with 1 mg ONA (optic nerve antigen). A WT and a CTGF control group (CTGF) received sodium chloride instead. IOP was measured before and every two weeks after immunization. After six weeks, electroretinogram (ERG) measurements were performed. Then, retinae and optic nerves were processed for (immuno-) histology. Further, mRNA levels of corresponding genes in optic nerve and retina were analyzed via RT-qPCR.ResultsSix weeks after immunization, the IOP in CTGF and CTGF+ONA mice was increased. The optic nerve of CTGF+ONA animals displayed the most severe cell inflammation, demyelination, and macroglia activation. Fewer numbers of oligodendrocytes were only observed in WT+ONA optic nerves, while more apoptotic cells triggered by the extrinsic pathway could be revealed in all three glaucoma groups. The number of microglia/macrophages was not altered within the optic nerves of all groups. The loss of neuronal cells, especially RGCs was most pronounced in CTGF+ONA retinae in the central part and this was accompanied by an enhanced activation of microglia/macrophages. Also, Müller cell activation could be noted in CTGF and CTGF+ONA retinae.DiscussionIn this new model, an additive degeneration could be noted in optic nerves as well as in the number of RGCs. These results suggest a potential additive role of high IOP and immune factors in glaucoma development, which will aid for understanding this multifactorial disease more precisely in the future.

Background Binge drinking can increase an individual's risk of developing alcohol use disorder (AUD). Ethanol targets multiple neurotransmitter systems; however, not much is known about its effects on the cholinergic system. Nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels, the heteromeric α4β2 nAChR being a commonly expressed subtype. Desformylflustrabromine (dFBr), a positive allosteric modulator (PAM), increases the efficacy of α4β2 nAChR in vitro and has previously been shown to have translational potential. In this study, we investigated whether dFBr modulates the hypnotic response to ethanol. Methods : Ethanol-induced loss of righting reflex (LORR) duration was measured in the presence and absence of dFBr. The β2 nAChR selective antagonist dihydro-β-erythroidine (DHβE) was used to study the involvement of the β2 subunit. Additionally, we used a crosslinking-based western blot assay to estimate changes in total versus intracellular α4 nAChR protein in thalamic tissue of rats treated with vehicle, dFBr, ethanol, or ethanol and dFBr. Lastly, using Xenopus oocyte two-electrode voltage clamp (TEVC) studies, we determined the effects of ethanol and dFBr on α4β2 nAChR. Results Pretreatment with 6 mg/kg dFBr reduced ethanol-induced LORR duration as compared to rats treated with ethanol alone. LORR studies with DHβE suggest that dFBr reduced ethanol-induced LORR duration via the β2 nAChR subunit. Crosslinking-based western analyses revealed that ethanol caused early increases in total and presumably surface thalamic α4 nAChR subunit protein levels. This ethanol-induced α4 nAChR upregulation was significantly reduced in rats pretreated with 6 mg/kg dFBr. In TEVC studies, ethanol potentiated ACh-induced currents in α4β2 nAChR, while it slightly reduced dFBr potentiation of maximal ACh currents. Conclusions Our results suggest that thalamic nAChRs containing the α4 subunit are rapidly upregulated by a single intoxicating dose of ethanol. Furthermore, dFBr, an α4β2 nAChR-selective PAM, significantly attenuates the hypnotic response to ethanol via actions on β2 nAChR. Overall, these results indicate that dFBr represents an option to reverse ethanol intoxication.

Objectives: Despite calls for better supportive care, patients and families still commonly bear significant responsibility for managing the physical and mental health and social challenges of being diagnosed with and treated for cancer. As such, there is increased advocacy for integrated supportive care to ease the burden of this responsibility. The purpose of this study was to understand patient and caregiver experiences with supportive care to advance its delivery at a large provincial cancer care organization in Canada. Method: We used a qualitative descriptive approach to analyze focus groups with patients and caregivers from seven sites across the large provincial cancer care organization. Results: Focus group participants (n = 69) included cancer patients (n = 57) and caregivers (n = 12). Participants highlighted positive and negative aspects of their experience and strategies for improvement. These are depicted in three themes: (1) improving patient and provider awareness of services, (2) increasing access, (3) enhancing coordination and integration. Participants’ specific suggestions included centralizing relevant information about services, implementing a coach or navigator to help advocate for access, and delivering care virtually. Conclusions: Participants highlighted barriers to access and made suggestions for improving supportive care that they believed would reduce the burden associated with trying to manage their cancer journey.

We previously reported that N-(3-chlorophenyl)guanidine (1) represents a novel α7 nicotinic ACh (nACh) receptor antagonist chemotype. In the present study, a small series of compounds was synthesized with the intent to investigate the structure-activity relationship (SAR). Preliminary data suggested that the N-methyl analog of 1, 2, was several times more potent. Therefore, the chloro group at the aryl 3-position of 1 and its N1-methyl counterpart 2 were replaced with a number of substituents considering the electronic, lipophilic, and steric nature of the substituents. The potencies of the compounds to inhibit acetylcholine (ACh)-induced responses were obtained in Xenopus laevis oocytes expressing human α7 nicotinic ACh receptors (nAChRs) using a two-electrode voltage-clamp assay. We found that the nature of the 3-position substituents had relatively little (i.e.

At Goethe-University, a novel concept of heating metallic cathodes is currently under investigation. In the scope of the ARIES collaboration WP16, an RF-modulated electron gun was developed and manufactured for application in electron lenses for space charge compensation. The goal of this project is to increase the intensity of primary beams, especially in low energy booster synchrotrons like the SIS18 and SIS100 at GSI/FAIR or the SPS at CERN. The gun was designed to produce electron currents of 10 A at extraction voltages of 30 kV. The tungsten electron emitter (TE2) and the grid electrode were designed and manufactured to be integrated in the extractor of the original volume type ion source. Significant effort was put into a robust and flexible design with highly reliable key components. The cathode is heated by a plasma stream generated in the plasma chamber of the source. Different heating options of the cathode are currently being studied. This contribution presents the working principles of the electron gun and first measurements results of cathode heating.

Galantamine (1), one of only five agents currently approved for the treatment of Alzheimer’s disease, is thought to act primarily as an inhibitor of acetylcholinesterase (AChE) and possibly as a positive allosteric modulator (PAM) of neuronal α7 nicotinic acetylcholine (nACh) receptors. Here, the structure of 1 was deconstructed to ten “abbreviated” analogs and examined electrophysiologically at α7 nACh receptors and as inhibitors of AChE. Neither 1, nor its reduced analog lycoramine (3), displayed PAM action, but at high concentrations both inhibited the agonist action of 100 μM ACh. The other deconstructed analogs lacked a PAM effect and also the inhibitory action of 1/3 indicating that the cyclohexa(e)nyl ring and/or hydroxyl group of 1/3 are important for the latter. All of the deconstructed analogs examined behaved as inhibitors of AChE but were >400-fold less potent than 1, again indicating that the cyclohexanol portion of 1 is a major determinant for optimal activity.

ZusammenfassungIntoxikationen stellen einen häufigen Grund der Notfallbehandlung im Rettungs- und Notarztdienst und in der zentralen Notaufnahme dar. An erster Stelle stehen hierbei Alkohol- gefolgt von Medikamentenintoxikationen (z. B. mit Benzodiazepinen). Der Gebrauch von Lachgas und daraus resultierende Intoxikationen sind in den letzten Jahren vermehrt berichtet worden. Auch Mischintoxikationen in Kombination mit Lachgas sind beschrieben. Der vorliegende Fallbericht stellt eine Mischintoxikation mit zunächst unklarer Vigilanzminderung vor und beleuchtet die systematische Abarbeitung wesentlicher Differenzialdiagnosen.

Erst seit wenigen Jahren werden Immun-Checkpoint-Inhibitoren (ICI) im Rahmen onkologischer Therapien eingesetzt. Sie dienen der Reaktivierung der endogenen Tumorantwort. Neben einer effektiven Tumorkontrolle sind diverse immunologisch vermittelte Nebenwirkungen an unbeteiligten Organen, so auch der Niere, beschrieben. Da diese Nebenwirkungen potenziell schwerwiegend sind, ist das fruhzeitige Erkennen wichtig. Da die Datenlage im Rahmen der Therapie mit ICI aufgrund nur weniger verfugbarer klinischer Studien zu renalen Toxizitaten sparlich ist, erfolgte eine Literaturrecherche in PubMed, Fallberichte und -serien eingeschlossen. Verwendet wurden die Schlagworter „Immun-Checkpoint-Inhibitor“, „PD-1-Inhibitor“, „PD-L1-Inhibitor“, „CTLA-4-Antagonist“, „renale Toxizitat“, „Nierenversagen“, „irAE“, „ATIN“, „Proteinurie“ und „Nephritis“. Zur Evidenzaufarbeitung wurden insbesondere Fallberichte und -serien priorisiert, in denen eine detaillierte klinische Beschreibung mit Nierenbiopsie und entsprechender histologischer Aufarbeitung erfolgte. Renale Toxizitaten unter ICI-Therapie treten zwar im Durchschnitt lediglich in etwa 2 % der Falle auf, sind jedoch potenziell schwerwiegende Nebenwirkungen. Am haufigsten tritt eine akute (tubulo-)interstitielle Nephritis auf. Beim Auftreten einer renalen Toxizitat sollten nephrotoxische Medikamente pausiert werden, weiterhin sollte die Durchfuhrung einer Nierenbiospie zum Ausschluss wichtiger Differenzialdiagnosen fruhzeitig erwogen werden. Bei hohergradiger Toxizitat sind das Pausieren und ggf. das Beenden der ICI-Therapie indiziert. I. d. R. lasst sich die Toxizitat gut durch Glukokortikoide kontrollieren. Essenziell erscheint dabei die enge interdisziplinare Zusammenarbeit zwischen Onkologen und Nephrologen.

Das Alter der Bevolkerung in Deutschland nimmt dem weltweiten Trend folgend stetig zu. Betrachtet man die hinzugewonnenen „krankheitsfreien“ Lebensjahre, so steigen diese jedoch in Deutschland im internationalen Vergleich signifikant geringer. Als Konsequenz daraus erhoht sich die Anzahl der behandlungspflichtigen und operationspflichtigen alteren, aber vor allem gebrechlicheren Patienten relevant. Mit dem Ziel, das perioperative Risiko dieser Patientengruppen besser zu erfassen, wurden bereits zahlreiche Scoring-Systeme veroffentlicht. Klinisch etabliert haben sich diese Systeme zur Risikoabschatzung in der Chirurgie bis zum aktuellen Zeitpunkt nicht. Die Gruppe der gebrechlichen Patienten in der Chirurgie ist somit insgesamt unterdiagnostiziert. Jedoch gerade diese Patienten bedurfen oft einer individualisierten Behandlung oder einer Anpassung der routinemasigen perioperativen Betreuung. Es konnte bereits sicher gezeigt werden, dass gebrechliche Patienten eine deutlich hohere Inzidenz fur bestimmte Risikofaktoren (postoperatives Delir, Hypovolamie, pharmakologische Nebenwirkungen und Medikamenteninteraktionen) aufweisen. Bei bis zu 70 % der Personen dieser Patientengruppe kann bereits bei der stationaren Aufnahme eine Mangelernahrung nachgewiesen werden. Unbemerkt und unbehandelt fuhren diese Risikofaktoren zu hoheren Komplikationsraten, einer eingeschrankten Rehabilitationsfahigkeit, einer verlangerten Liegedauer bis hin zu einer erhohten Mortalitat. Spezielle praoperative Risikoscores, welche sowohl physische und psychische als auch soziale Aspekte beleuchten, sollten flachendeckend in den chirurgischen Kliniken implementiert werden. Eine standardisierte Risikoabschatzung und darauf aufbauende evidenzbasierte Prarehabilitationsprogramme, implementiert an gerontochirurgischen Zentren, konnen so in Zukunft helfen, das Outcome dieser fragilen Patientengruppe zu verbessern.

We previously reported that

This paper comparatively examines how the League of Women Voters and Lake Erie sportsmen emerged to awaken the public to the pollution crisis affecting the Lake Erie watershed in the mid-twentieth century. Recognizing the degradation of the smallest of the Great Lakes due to the explosion of wartime industrial development and population growth, the League and the sportsmen commenced a decades-long struggle to clean up the lake and its tributaries through direct action in urban areas throughout the Lake Erie watershed. Disgusted by a fall in the number of fish, caused by cyanide poisoning, and the effect of oil on waterfowl, the sportsmen pressed for pollution control. The League members’ approach to water resources, on the other hand, was based on a broad and academic perspective regarding water quality and quantity in response to a series of regionally severe droughts that plagued the United States in the late 1940s and mid-1950s, and led to a national debate on water shortages and supplies. Ultimately, this paper examines two distinctly different approaches to an environmental emergency in the immediate postwar era.

Arylguanidines, depending upon their aromatic substitution pattern, display varying actions at 5-HT3 receptors (e.g., partial agonist, agonist, superagonist). Here, we demonstrate that conformational constraint of these agents as dihydroquinazolines (such as A6CDQ; 1) results in their conversion to 5-HT3 receptor antagonists. We examined the structure-activity relationships of 1. Replacement/removal of any of the guanidinium nitrogen atoms of 1 resulted in decreased affinity. All three nitrogen atoms of 1 are necessary for optimal binding affinity at 5-HT3 receptors. Introduction of substituents as small as an N2-methyl group abolishes affinity. The results are consistent with homology modeling/docking studies and binding data from site-directed mutagenesis studies. Introducing a "methylene bridge" to the arylguanidine structure, regardless of its functional activity, results in a 5-HT3 receptor antagonist.

Journal of Instrumentation 16(03), P03044 (2021). doi:10.1088/1748-0221/16/03/P03044, Published by Inst. of Physics, London

Binge drinking can increase an individual's risk of developing alcohol use disorder (AUD). Ethanol targets multiple neurotransmitter systems; however, not much is known about its effects on the cholinergic system. Nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels, the heteromeric αEthanol-induced loss of righting reflex (LORR) duration was measured in the presence and absence of dFBr. The βPretreatment with 6 mg/kg dFBr reduced ethanol-induced LORR duration as compared to rats treated with ethanol alone. LORR studies with DHβE suggest that dFBr reduced ethanol-induced LORR duration via the βOur results suggest that thalamic nAChRs containing the α

The use of scanning gradients can significantly reduce method-development time in reversed-phase liquid chromatography. However, there is no consensus on how they can best be used. In the present work we set out to systematically investigate various factors and to formulate guidelines. Scanning gradients are used to establish retention models for individual analytes. Different retention models were compared by computing the Akaike information criterion and the prediction accuracy. The measurement uncertainty was found to influence the optimum choice of model. The use of a third parameter to account for non-linear relationships was consistently found not to be statistically significant. The duration (slope) of the scanning gradients was not found to influence the accuracy of prediction. The prediction error may be reduced by repeating scanning experiments or – preferably – by reducing the measurement uncertainty. It is commonly assumed that the gradient-slope factor, i.e. the ratio between slopes of the fastest and the slowest scanning gradients, should be at least three. However, in the present work we found this factor less important than the proximity of the slope of the predicted gradient to that of the scanning gradients. Also, interpolation to a slope between that of the fastest and the slowest scanning gradient is preferable to extrapolation. For comprehensive two-dimensional liquid chromatography (LC × LC) our results suggest that data obtained from fast second-dimension gradients cannot be used to predict retention in much slower first-dimension gradients.

Inflammation is a key physiological phenomenon that can be pervasive when dysregulated. Persistent chronic inflammation precedes several pathophysiological conditions forming one of the critical cellular homeostatic checkpoints. With a steady global surge in inflammatory diseases, it is imperative to delineate underlying mechanisms and design suitable drug molecules targeting the cellular partners that mediate and regulate inflammation. Nicotinic acetylcholine receptors have a confirmed role in influencing inflammatory pathways and have been a subject of scientific scrutiny underlying drug development in recent years. Drugs designed to target allosteric sites on the nicotinic acetylcholine receptors present a unique opportunity to unravel the role of the cholinergic system in regulating and restoring inflammatory homeostasis. Such a therapeutic approach holds promise in treating several inflammatory conditions and diseases with inflammation as an underlying pathology. Here, we briefly describe the potential of cholinergic allosterism and some allosteric modulators as a promising therapeutic option for the treatment of neuroinflammation.

The German population is aging in accordance with the worldwide trend; however, in comparison to most other industrial countries the number of disease-free years of life gained by patients is significantly lower in Germany. Subsequently, the number of hospitalizations and necessary surgical treatment for older and especially frail patients is significantly increasing. Several frailty scoring systems have been published with the aim of improving the assessment of the perioperative risk for these patients; however, these systems for risk assessment have not yet become clinical routine in surgery and therefore this group of frail patients remains underdiagnosed in the field of surgery. Frail patients in particular often need individualized treatment or the adaptation of standard of perioperative care. It has already been clearly shown that frail patients have a markedly higher incidence for certain risk factors (e.g. postoperative delirium, hypovolemia, pharmacological side effects and drug interactions). Additionally, malnutrition is common at the time of hospital admission in up to 70% of this patient group. If not recognized and treated accordingly all these risk factors lead to a compromised rehabilitation, higher complication rates, a prolonged length of hospital stay and a higher mortality. Special preoperative risk assessment scores, which highlight physical, psychological and social evaluation should be widely implemented in surgical departments. A standardized risk assessment embedded in evidence-based prerehabilitation programs and implemented in geriatric surgery centers can help to improve the outcome in this group of fragile patients.

Particle accelerators utilize high voltage, high magnetic fields, and radio frequencies range amplifiers in order to guide and accelerate the particle beam. Particle beam modulation is a new challenge in accelerator design and research in high energy physics. Article deal with challenges into particle accelerators beam modulators from a power electronics point of view.

Developing species distribution models (SDMs) to detect invasive species cover and evaluate habitat suitability are high priorities for land managers. We tested SDMs fit with different variable combinations to provide guidelines for future invasive species model development based on transferability between landscapes. Generalized linear model, boosted regression trees, multivariate adaptive regression splines, and Random Forests were fit with location data for high cheatgrass (Bromus tectorum) cover in situ for two post-burn sites independently using topographic indices, spectral indices derived from multiple dates of Landsat 8 satellite imagery, or both. Models developed for one site were applied to the other, using independent cheatgrass cover data from the respective ex situ site to test model transferability. Fitted models were statistically robust and comparable when fit with at least 200 cover plots in situ and transferred to the ex situ site. Only the Random Forests models were robust when fit with a small number of cover plots in situ. Our study indicated spectral indices can be used in SDMs to estimate species cover across landscapes (e.g., both within the same Landsat scene and in an adjacent Landsat scene). Important considerations for transferability include the model employed, quantity of cover data used to train/test the models, and phenology of the species coupled with the timing of imagery. The results also suggest that when cover data are limited, SDMs fit with topographic indices are sufficient for evaluating cheatgrass habitat suitability in new post-disturbance landscapes; however, spectral indices can provide a more robust estimate for detection based on local phenology.

Rabies virus induces drastic behaviour modifications in infected hosts. The mechanisms used to achieve these changes in the host are not known. The main finding of this study is that a region in the rabies virus glycoprotein, with homologies to snake toxins, has the ability to alter behaviour in animals through inhibition of nicotinic acetylcholine receptors present in the central nervous system. This finding provides a novel aspect to virus receptor interaction and host manipulation by pathogens in general. The neurotoxin-like region of the rabies virus glycoprotein inhibited acetylcholine responses of α4β2 nicotinic receptors in vitro, as did full length ectodomain of the rabies virus glycoprotein. The same peptides significantly altered a nicotinic receptor induced behaviour in C. elegans and increased locomotor activity levels when injected into the central nervous system of mice. These results provide a mechanistic explanation for the behavioural changes in hosts infected by rabies virus.

BackgroundNeuronal nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels. The 42 subtype of nAChRs plays an important role in the mediation of pain and several nicotine-evoked responses. Agonists and partial agonists of 42 nAChRs show efficacy in animal pain models. In addition, the antinociceptive properties of nicotine, a non-selective nAChR agonist with a high affinity for 42 nAChRs, is well-known. There is a growing body of evidence pointing to allosteric modulation of nAChRs as an alternative treatment strategy in experimental pain. Desformylflustrabromine (dFBr) is a positive allosteric modulator (PAM) at 42 nAChRs that enhances agonist responses without activating receptors. We hypothesized that dFBr may enhance nicotine-induced antinociception. MethodsThe present study investigated whether dFBr could attenuate mouse chronic constriction injury (CCI)-induced neuropathic pain by increasing endogenous cholinergic tone or potentiating the nicotine-evoked antiallodynic response. ResultsWe found that subcutaneous administration of dFBr failed to reduce pain behaviour on its own. However, the combination of dFBr with nicotine significantly reversed neuropathic pain behaviour dose- and time-dependently without motor impairment. Our data revealed that this effect was mediated by the 42 nAChRs by using competitive 42 antagonist dihydro--erythroidine. In addition, dFBr failed to potentiate the antiallodynic effect of morphine, which shows the effect of dFBr is unique to 42 nAChRs. ConclusionsThe present results suggest that allosteric modulation of 42 nAChR may provide new strategies in chronic neuropathic pain. Significance42 nAChRs are involved in pain modulation. dFBr, a PAM at 42 nAChRs, potentiates the nicotine response dose-dependently in neuropathic pain. Thus, the present results suggest that allosteric modulation of 42* nAChR may provide new strategies in chronic neuropathic pain. United States Department of Health & Human Services National Institutes of Health (NIH) - USA (R01-CA206028) United States Department of Health & Human Services National Institutes of Health (NIH) - USA NIH National Cancer Institute (NCI) (R01CA206028)

Following fertilization in mammals, it is generally accepted that totipotent cells are exclusive to the zygote and to each of the two blastomeres originating from the first mitotic division. This model of totipotency was inferred from a minority of cases in which blastomeres produced monozygotic twins in mice. Was this due to experimental limitation or biological constraint? Here we removed experimental obstacles and achieved reliable quantification of the prevalence of dual totipotency among mouse two-cell stage blastomeres. We separated the blastomeres of 1,252 two-cell embryos, preserving 1,210 of the pairs. Two classes of monozygotic twins became apparent at the blastocyst stage: 27% formed a functional epiblast in both members (concordant), and 73% did so in only one member of the pair (discordant) – a partition that proved insensitive to oocyte quality, sperm-entry point, culture environment and pattern of cleavage. In intact two-cell embryos, the ability of sister blastomeres to generate epiblast was also skewed. Class discovery clustering of the individual blastomeres’ and blastocysts’ transcriptomes points to an innate origin of concordance and discordance rather than developmental acquisition. Our data place constraints on the commonly accepted idea that totipotency is allocated equally between the two-cell stage blastomeres in mice.