bluuebunny/crossref_metadata_2025 huggingface dataset:
Use of liposome encapsulation in a combined single-liquid reagent for homogeneous enzyme immunoassay.
Authors: Ullman E F , Tarnowski T , Felgner P , Gibbons I
Published: February 2020

A technique has been developed to permit mutually reactive macromolecular reagents used in immunoassays to be combined without premature reaction. A conjugate of glucose-6-phosphate dehydrogenase (EC 1.1.1.49) and theophylline has been encapsulated in 0.2-micron-diameter bi-lamellar liposomes. Suspensions of these liposomes had excellent stability. Whereas the enzyme activity of the free conjugate is rapidly inhibited by anti-theophylline antibody, a suspension of the encapsulated conjugate in a solution of the antibody and NAD+ (6.0 mmol/L) retained greater than 92% of the initial enzyme activity after standing for one year at 4 degrees C. At higher NAD+ concentrations the liposomes aggregated, and enzyme activity was inhibited by leakage of the NAD+ hydrolysis product, adenosine diphosphoryl 5-ribose (ADP-ribose), into the liposomes. Inhibition by ADP-ribose could be blocked and partly reversed by adding semicarbazide. The liposomes were efficiently lysed by Triton X-100, deoxycholate, or octyl glucoside, the kinetics and extent of lysis being affected by liposome size and correlating with the acid strength of various cholate derivatives. Addition of a serum sample and a solution of buffer, substrate, and detergent to a single reagent containing the liposomes and anti-theophylline antibody provided assay results equivalent to those obtained by conventional two-reagent EMIT homogeneous enzyme immunoassay for theophylline.
Capillary blood, dried on filter paper, as sample for monitoring cyclosporin A concentrations.
Authors: Lampe D , Scholz D , Prümke H J , Blank W , Hüller H
Published: February 2020

For monitoring the immunosuppressive drug cyclosporin A by radioimmunoassay (Sandoz Ltd.) we propose a simple method of sampling in which 20 microL of capillary blood is dried on filter paper. Patients can collect their own samples and mail or bring them to the laboratory. Results for such samples, and their variability, correspond to those for conventional methods of sampling (collection of venous or capillary blood into buffer). Capillary blood can be stored on paper at room temperature for more than four weeks with no effect on assay results.
Measurement of glycated protein by a rapid and specific method for absolute quantification of lysine-bound glucose.
Authors: Drexel H , Klocker H , Patsch J R , Breier C , Braunsteiner H
Published: February 2020

We modified the liquid-chromatographic assay of Schleicher and Wieland (J Clin Chem Clin Biochem 1981; 19:81-7) for measuring lysine-bound glucose in serum proteins, increasing its performance and practicality. After precipitating serum proteins from 10- to 50-microL samples with ethanol (700 mL/L) and hydrolyzing these in 6 mol/L HCl, we inject 20 microL of the diluted hydrolysate directly into the chromatograph, which consists of an acid-resistant C18 precolumn combined with a high-resolution C18 main column. The eluent is 3.5 mmol/L H3PO4 solution containing 30 mL of acetonitrile per liter. These modifications increase sensitivity, provide excellent resolution and longevity of stationary phases, shorten assay times to 15 to 20 min, and are suited for automation. The assay is highly sensitive and highly specific, quantifying nanomoles of lysine-bound glucose per milligram of protein. A precision (CV) of 5.1% is achievable at physiological and supra-physiological glucose concentrations, and analytical recovery is 99%. This inexpensive method has been applied to serum albumin, bulk serum proteins, and preparations of low-density lipoproteins and immunoglobulins.
Decreased drug absorption in a patient with Behçet's syndrome.
Authors: Chaleby K , el-Yazigi A , Atiyeh M
Published: February 2020

Observing a lack of response to orally administered drugs in a patient with Behçet's disease, we studied the absorption of amitriptyline, diazepam, carbamazepine, phenytoin, and acetaminophen in this patient after single and (or) multiple dose administrations. The relative oral/intramuscular bioavailability of amitriptyline was only 13%, and the steady-state concentrations of this drug on four consecutive days were acutely subtherapeutic (i.e., 3.6, 3.7, 3.9, and 3.7 micrograms/L). The concentrations of diazepam, phenytoin, and acetaminophen in plasma were nonmeasurable. Examination of the gastrointestinal tract by endoscopy and by light and electronic microscopy of a biopsy section revealed inflammatory and vascular changes in the duodenum. In the absence of clinical evidence for malabsorption syndrome, we believe that the decreased drug absorption observed in this patient was caused by inflammatory changes associated with Behçet's syndrome.
Sir, Yes, Sir! Hierarchy, Coups and the Political Preferences of Army Officers
Authors: Fajardo Gustavo
Published: February 2020

I show that coups that break the chain of command polarise the military along hierarchical lines. I study an instance of Venezuelan history in which the political preferences of individual members of the army towards former coup leader Hugo Chávez became observable. Outranking Chávez at the time of the insubordination increases the probability of later opposing his presidency. Causal estimates rely on a fuzzy regression discontinuity design, where minimum time requirements for promotion in the army provide exogenous variation in the ranking of officers at the time of the coup. I discuss implications for the literature on civil–military relations.
‘Cologne Changed Everything’—The Effect of Threatening Events on the Frequency and Distribution of Intergroup Conflict in Germany
Authors: Frey Arun
Published: February 2020

In this article, I study the role that threatening events play in shaping both the occurrence and the distribution of intergroup conflict. Using the case of anti-refugee attacks in Germany, the study finds that the 2015 New Year’s Eve (NYE) sexual assaults led to a dramatic surge in the daily rate of violence, far surpassing the more short-lived effect of domestic and European terrorist attacks. Importantly, this effect was more pronounced among districts with low prior levels of anti-refugee hostility and far-right support. The NYE event both increased the frequency and changed the distribution of subsequent attacks—mobilizing new, previously peaceful communities to behave aggressively towards local refugee populations. Together, these findings reveal that threatening events not only affect the amount of intergroup conflict, but may also alter the structural conditions under which such conflict emerges in the first place.
‘If he sees it with his own eyes, he will understand’: how gender informed the content and delivery of a maternal nutrition intervention in Burkina Faso
Authors: Isler Jasmin , Sawadogo N Hélène , Harling Guy , Bärnighausen Till , Adam Maya , Sié Ali , McMahon Shannon A
Published: February 2020

A growing body of literature urges policymakers, practitioners and scientists to consider gender in the design and evaluation of health interventions. We report findings from formative research to develop and refine an mHealth maternal nutrition intervention in Nouna, Burkina Faso, one of the world’s most resource-poor settings. Gender was not an initial research focus, but emerged as highly salient during data collection, and thus guided lines of inquiry as the study progressed. We collected data in two stages, first using focus group discussions (FGD; n = 8) and later using FGDs (n = 2), interviews (n = 30) and observations of intervention delivery (n = 30). Respondents included pregnant women, breastfeeding mothers and Close-to-Community (CTC) providers, who execute preventative and curative tasks at the community level. We applied Morgan et al.’s gender framework to examine intervention content (what a gender-sensitive nutrition programme should entail) and delivery (how a gender-sensitive programme should be administered). Mothers emphasized that although they are often the focus of nutrition interventions, they are not empowered to make nutrition-based decisions that incur costs. They do, however, wield some control over nutrition-related tasks such as farming and cooking. Mothers described how difficult it is to consider only one’s own children during meal preparation (which is communal), and all respondents described how nutrition-related requests can spark marital strife. Many respondents agreed that involving men in nutrition interventions is vital, despite men’s perceived disinterest. CTC providers and others described how social norms and gender roles underpin perceptions of CTC providers and dictate with whom they can speak within homes. Mothers often prefer female CTC providers, but these health workers require spousal permission to work and need to balance professional and domestic demands. We recommend involving male partners in maternal nutrition interventions and engaging and supporting a broader cadre of female CTC providers in Burkina Faso.
Symptomatic primary cardiac haemangioendothelioma during late pregnancy
Authors: Bislimovski Darko , Nikolic Aleksandar , Mustafa Elvis , Milojevic Milan
Published: February 2020

Primary cardiac haemangioendothelioma is an uncommon vascular neoplasm with an infiltrative growth pattern and malignant potential. The treatment of this tumour alone is challenging, but the symptomatic presentation during late pregnancy creates a complex clinical situation for both the mother and physician. To the best of our knowledge, <40 cases of primary cardiac haemangioendothelioma have been reported worldwide, but none of these were associated with pregnancy. We report a case of symptomatic primary haemangioendothelioma in the right atrium of a pregnant woman in the 36th week of gestation. A primary caesarean section, followed by complete resection of the cardiac tumour, was carried out without any complications. The mother and child were discharged home 5 days after the surgical procedure and birth, respectively. At the 2-month follow-up, positron emission tomography showed signs of hypermetabolic activity in the right atrium, without signs of tumour recurrence on the subsequent computed tomography and magnetic resonance imaging, thus a close clinical follow-up was recommended.
Structural diversity of disc galaxies originating in the cold gas inflow from cosmic webs
Authors: Noguchi Masafumi
Published: February 2020

Disc galaxies show a large morphological diversity with varying contribution of three major structural components: thin discs, thick discs, and central bulges. Dominance of bulges increases with the galaxy mass (Hubble sequence), whereas thick discs are more prominent in lower mass galaxies. Because galaxies grow with the accretion of matter, this observed variety should reflect diversity in accretion history. On the basis of the prediction by the cold-flow theory for galactic gas accretion and inspired by the results of previous studies, we put a hypothesis that associates different accretion modes with different components. Namely, thin discs form as the shock-heated hot gas in high-mass haloes gradually accretes to the central part, thick discs grow by the direct accretion of cold gas from cosmic webs when the halo mass is low, and finally bulges form by the inflow of cold gas through the shock-heated gas in high-redshift massive haloes. We show that this simple hypothesis reproduces the mean observed variation of galaxy morphology with the galaxy mass. This scenario also predicts that thick discs are older and poorer in metals than thin discs, in agreement with the currently available observations.
Ownership, agency, and trusteeship: an assessment
Authors: Mayer Colin
Published: February 2020

This article argues that the two dominant concepts of theory of the firm and the bases of modern management education, business practice, and public policy towards the firm, namely shareholder primacy and agency theory, are at best incomplete and at worst erroneous. They omit what was a substantial basis of discourse on the company in the first half of the nineteenth century, namely the notion of trusteeship. The article argues that reintroducing trusteeship addresses many of the current debates around capitalism, explains the bewildering patterns of ownership observed around the world, accounts for the recent failures of capitalism, and is a potential source of enhancing firm performance in the future.
‘Killing Mie Softly’: Analytic Integrals for Complex Resonant States
Authors: Mcphedran R C , Stout B
Published: February 2020

We consider integrals of products of Bessel functions and of spherical Bessel functions, combined with a Gaussian factor guaranteeing convergence at infinity. These integrals arise in wave and quantum mechanical scattering problems of open systems containing cylindrical or spherical scatterers, particularly when those problems are considered in the framework of complex resonant modes. Explicit representations are obtained for the integrals, building on those in the 1992 paper by McPhedran, Dawes and Scott. Attention is paid to those sums with a distributive part arising as the Gaussian tends towards the unit function. In this limit, orthogonality and normalisability of complex modes are investigated.
Simulated Comparison of a Bayesian Clinical Decision Support System Versus Standard of Care For Achieving Gentamicin Pharmacokinetic Targets in Neonates
Authors: Yu Collin Z. , Myers Scott R. , Faldasz Jonathan D.
Published: February 2020

Background:

Gentamicin therapy in neonates is optimized through achieving specific peak and trough concentrations. The objective of this study was to compare the ability a Bayesian clinical decision support system (CDSS) with standard of care (SOC) in determining personalized gentamicin therapies for neonates, at regimen initiation and in response to measured drug concentrations.

Methods:

This retrospective review and simulation compared target attainment among 4 arms: historical dosing according to SOC, via nomogram for initial dosing (SOC-initial) and via clinician judgment in response to measured concentrations (SOC-adjusted), and simulated dosing using the CDSS, incorporating a neonatal pharmacokinetic model for initial dosing (CDSS-initial) and incorporating maximum a posteriori-Bayesian analysis in response to measured concentrations (CDSS-adjusted). “True” patient pharmacokinetic parameters and peak and trough concentration predictions were calculated via the CDSS using the entirety of the patient dosing and concentration history. The primary outcome was pharmacokinetic target attainment of desired gentamicin peak and trough concentrations.

Results:

The study included 564 gentamicin concentrations among 339 patients. Mean demographics were 35 weeks gestational age (52% premature births) and 2.44 kg dosing weight. Mean PK parameters were 0.0533 L/h/kg clearance, 0.458 L/kg volume of distribution, and 8.66 hours half-life. Peak concentrations in the desired range were achieved in 96% of significantly more often in the CDSS-initial regimens and 94% of CDSS-adjusted regimens versus 86% of SOC-initial regimens and 66% of SOC-adjusted regimens. No difference was found in trough target attainment among study groups.

Conclusions:

In simulation, a Bayesian CDSS showed superiority to SOC in achieving gentamicin pharmacokinetic exposure targets in neonates. Use of a CDSS may improve the safety and efficacy of gentamicin therapy for neonates.
Nicotine Replacement Therapy and Healthy Lifestyle Psychoeducation for Smoking Reduction in Acute Psychiatric Inpatients
Authors: Chan Hung-Yu , Chen Jiahn-Jyh , Pan Yi-Ju , Hsu Chun-Chi
Published: February 2020

Background

Effectiveness of nicotine replacement therapies in acute psychiatric inpatient settings remains under-researched. The aim of this study was to compare effectiveness and acceptability of 3 different forms of nicotine replacement therapy in achieving smoking reduction among acute psychiatric inpatients.

Methods

This cluster-randomized, parallel study compared effectiveness and acceptability of nicotine inhalers, nicotine gum, and nicotine patches for smoking reduction in the acute psychiatric inpatient setting. The primary outcome was the exhaled breath carbon monoxide (CO) level change from baseline at weeks 4 and 8. Secondary outcomes included changes in nicotine withdrawal symptoms and psychiatric symptom severity.

Results

Three hundred ten inpatients on the acute care wards were randomly assigned to nicotine inhalers (n = 184), gum (n = 71), and patches (n = 55). Only the nicotine inhaler group showed statistically significant reduction in CO level from baseline at both weeks 4 and 8 (P < 0.001 and P = 0.032, respectively). The nicotine inhaler and the patch group showed significant decrease in nicotine withdrawal symptoms from baseline at both weeks 4 and 8. Meanwhile, the nicotine inhaler and the gum group showed significant decrease in psychiatric symptom severity from baseline at both weeks 4 and 8. Post hoc comparisons revealed that the inhaler group had a greater decrease in psychiatric symptom severity compared with the patch group.

Conclusions

Nicotine inhalers may be an effective choice for smoking reduction in acute psychiatric inpatient settings given its significant effects on CO level, withdrawal symptoms, and psychiatric symptom severity, particularly during the first 4 weeks of treatment.
Semantic and Prosodic Threat Processing in Trait Anxiety
Authors: Busch-Moreno Simon , Tuomainen Jyrki , Vinson David
Published: February 2020

The present study attempts to identify how trait anxiety, measured as worry-level, affects the processing of threatening speech. Two experiments using dichotic listening tasks were implemented; where participants had to identify sentences that convey threat through three different information channels: prosody-only, semantic-only and both semantic and prosody (congruent threat). We expected different ear advantages (left or right) depending on task demands, information type, and worry level. We used a full Bayesian approach for statistical modelling and analysis. Results indicate that when participants made delayed responses (Experiment 1), reaction times barely increased as a function of worry level, but under time pressure (Experiment 2) worry level induced clear decreases in reaction times. We explain these results in terms of multistep models of anxiety and language, concluding that present results mainly indicate effects threat aversion-related over-attention to threat, and that we do not provide enough evidence for supporting the integration of anxiety and language multiphasic models.
An overcomplete approach to fitting drift-diffusion decision models to trial-by-trial data
Authors: Feltgen Q. , Daunizeau J.
Published: February 2020

Drift-diffusion models or DDMs are becoming a standard in the field of computational neuroscience. They extend models from signal detection theory by proposing a simple mechanistic explanation for the observed relationship between decision outcomes and reaction times (RT). In brief, they assume that decisions are triggered once the accumulated evidence in favor of a particular alternative option has reached a predefined threshold. Fitting a DDM to empirical data then allows one to interpret observed group or condition differences in terms of a change in the underlying model parameters. However, current approaches only yield reliable parameter estimates in specific situations (c.f. fixed drift rates vs drift rates varying over trials). In addition, they become computationally unfeasible when more general DDM variants are considered (e.g., with collapsing bounds). In this note, we propose a fast and efficient approach to parameter estimation that relies on fitting a “self-consistency” equation that RT fulfill under the DDM. This effectively bypasses the computational bottleneck of standard DDM parameter estimation approaches, at the cost of estimating the trial-specific neural noise variables that perturb the underlying evidence accumulation process. For the purpose of behavioral data analysis, these act as nuisance variables and render the model “overcomplete”, which is finessed using a variational Bayesian system identification scheme. But for the purpose of neural data analysis, estimates of neural noise perturbation terms are a desirable (and unique) feature of the approach. Using numerical simulations, we show that this “overcomplete” approach matches the performance of current parameter estimation approaches for simple DDM variants, and outperforms them for more complex DDM variants. Finally, we demonstrate the added-value of the approach, when applied to a recent value-based decision making experiment.
Effect of 10 UV filters on the brine shrimpArtemia salinaand the marine microalgaeTetraselmissp
Authors: Thorel Evane , Clergeaud Fanny , Jaugeon Lucie , Rodrigues Alice M. S. , Lucas Julie , Stien Didier , Lebaron Philippe
Published: February 2020

The presence of pharmaceutical and personal care products’ (PPCPs) residues in the aquatic environment is an emerging issue due to their uncontrolled release, through grey water, and accumulation in the environment that may affect living organisms, ecosystems and public health. The aim of this study is to assess the toxicity of benzophenone-3 (BP-3), bis-ethylhexyloxyphenol methoxyphenyl triazine (BEMT), butyl methoxydibenzoylmethane (BM), methylene bis-benzotriazolyl tetramethylbutylphenol (MBBT), 2-Ethylhexyl salicylate (ES), diethylaminohydroxybenzoyl hexyl benzoate (DHHB), diethylhexyl butamido triazone (DBT), ethylhexyl triazone (ET), homosalate (HS), and octocrylene (OC) to marine organisms from two major trophic levels including autotrophs (Tetraselmis sp.) and heterotrophs (Artemia salina). In general, EC50results show that both HS and OC are the most toxic for our tested species, followed by a significant effect of BM onArtemia salinabut only at high concentrations (1 mg/L) and then an effect of ES, BP3 and DHHB on the metabolic activity of the microalgae at 100 μg/L. BEMT, DBT, ET, MBBT had no effect on the tested organisms, even at high concentrations (2mg/L). OC toxicity represent a risk for those species since it is observed at concentrations only 15 to 90 times higher than the highest concentrations reported in the natural environment and HS toxicity is for the first time reported on microalgae and was very important onTetraselmis sp.at concentrations close to the natural environment concentrations.
A plant pathogen utilizes effector proteins for microbiome manipulation
Authors: Snelders Nick C. , Rovenich Hanna , Petti Gabriella C. , Rocafort Mercedes , Vorholt Julia A. , Mesters Jeroen R. , Seidl Michael F. , Nijland Reindert , Thomma Bart P.H.J.
Published: February 2020

During colonization of their hosts, pathogens secrete effector proteins to promote disease development through various mechanisms. Increasing evidence shows that the host microbiome plays a crucial role in health, and that hosts actively shape their microbiomes to suppress disease. We hypothesized that pathogens evolved to manipulate host microbiomes to their advantage in turn. Here, we show that the fungal plant pathogenVerticillium dahliaeutilizes effector proteins for niche colonization through selective manipulation of host microbiomes by suppressing microbes with antagonistic activities. Moreover, we show that effector proteins are similarly exploited for microbiome manipulation in the soil environment, where the fungus resides in absence of a host. In conclusion, we demonstrate that pathogens utilize effector proteins to modulate microbiome compositions and propose that their effector catalogs represent an untapped resource for novel antibiotics.
A unified model of species abundance, genetic diversity, and functional diversity reveals the mechanisms structuring ecological communities
Authors: Overcast Isaac , Ruffley Megan , Rosindell James , Harmon Luke , Borges Paulo A. V. , Emerson Brent C. , Etienne Rampal S. , Gillespie Rosemary , Krehenwinkel Henrik , Mahler D. Luke , Massol Francois , Parent Christine E. , Patiño Jairo , Peter Ben , Week Bob , Wagner Catherine , Hickerson Michael J. , Rominger Andrew
Published: February 2020

Biodiversity accumulates hierarchically by means of ecological and evolutionary processes and feedbacks. Reconciling the relative importance of these processes is hindered by current theory, which tends to focus on a single spatial, temporal or taxonomic scale. We introduce a mechanistic model of community assembly, rooted in classic island biogeography theory, which makes temporally explicit joint predictions across three biodiversity data axes: i) species richness and abundances; ii) population genetic diversities; and iii) trait variation in a phylogenetic context. We demonstrate that each data axis captures information at different timescales, and that integrating these axes enables discriminating among previously unidentifiable community assembly models. We combine our massive eco-evolutionary synthesis simulations (MESS) with supervised machine learning to fit the parameters of the model to real data and infer processes underlying how biodiversity accumulates, using communities of tropical trees, arthropods, and gastropods as case studies that span a range of spatial scales.
Further Perceptions of Probability: In Defence of Associative Models – A Commentary on Gallistel et al. 2014
Authors: Forsgren Mattias , Juslin Peter , van den Berg Ronald
Published: February 2020

Extensive research in the behavioural sciences has addressed people’s ability to learn stationary probabilities, which stay constant over time, but only recently have there been attempts to model the cognitive processes whereby people learn – and track –non-stationaryprobabilities. In this context, the old debate on whether learning occurs by gradual formation of associations or by occasional shifts between hypotheses representing beliefs about distal states of the world has resurfaced. Gallistel et al. (2014) pitched the two theories against each other in a non-stationary probability learning task. They concluded that various qualitative patterns in their data were incompatible with trial-by-trial associative learning and could only be explained by a hypothesis-testing model. Here, we contest that claim and demonstrate that it was premature. First, we argue that their experimental paradigm consisted of two distinct tasks: probability tracking (an estimation task) and change detection (a decision-making task). Next, we present a model that uses the (associative) delta learning rule for the probability tracking task and bounded evidence accumulation for the change-detection task. We find that this combination of two highly established theories accounts well for all qualitative phenomena and outperforms the alternative model proposed by Gallistel et al. in a quantitative model comparison. In the spirit of cumulative science, we conclude that current experimental data on human learning of non-stationary probabilities can be explained as acombinationof associative learning and bounded evidence accumulation and does not require a new model.
Nucleotide Analogues as Inhibitors of Viral Polymerases
Authors: Ju Jingyue , Kumar Shiv , Li Xiaoxu , Jockusch Steffen , Russo James J.
Published: February 2020

Coronaviruses such as the newly discovered virus from Wuhan, China, 2019-nCoV, and the viruses that cause SARS and MERS, have resulted in regional and global public health emergencies. Based on our molecular insight that the hepatitis C virus and the coronavirus use a similar viral genome replication mechanism, we reasoned that the FDA-approved drug EPCLUSA (Sofosbuvir/Velpatasvir) for the treatment of hepatitis C will also inhibit the above coronaviruses, including 2019-nCoV. To develop broad spectrum anti-viral agents, we further describe a novel strategy to design and synthesize viral polymerase inhibitors, by combining the ProTide Prodrug approach used in the development of Sofosbuvir with the use of 3’-blocking groups that we have previously built into nucleotide analogues that function as polymerase terminators.
Mechanistic Modeling of Biochemical Systems Without A Priori Parameter Values Using the Design Space Toolbox v.3.0
Authors: Valderrama-Gómez Miguel Á. , Lomnitz Jason G. , Fasani Rick A. , Savageau Michael A.
Published: February 2020

Mechanistic models of biochemical systems provide a rigorous kinetics-based description of various biological phenomena. They are indispensable to elucidate biological design principles and to devise and engineer systems with novel functionalities. To date, mathematical analysis and characterization of these models remain a challenging endeavor, the main difficulty being the lack of information for most system parameters. Here, we introduce the Design Space Toolbox v.3.0 (DST3), a software implementation of the Design Space formalism that enables mechanistic modeling of complex biological processes without requiring previous knowledge of the parameter values involved. This is achieved by making use of a phenotype-centric modeling approach, in which the system is first decomposed into a series of biochemical phenotypes. Parameter values realizing phenotypes of interest are predicted in a second step. DST3 represents the most generally applicable implementation of the Design Space formalism to date and offers unique advantages over earlier versions. By expanding the capabilities of the Design Space formalism and streamlining its distribution, DST3 represents a valuable tool for elucidating biological design principles and guiding the design and optimization of novel synthetic circuits.
Retinotopic remapping of the visual system in deaf adults
Authors: Levine Alexandra T. , Yuen Kate , Gouws André , Wade Alex R. , Morland Antony B. , Codina Charlotte , Buckley David , Baseler Heidi A.
Published: February 2020

Deaf individuals rely on visual rather than auditory cues to detect events in the periphery, putting a greater demand on neural resources for vision. Comparing visual maps in the brains of early deaf and hearing adults, we found a redistribution of neural resources in the lateral geniculate nucleus and primary visual cortex, with larger representations of the periphery, at a cost of smaller representations of the central visual field.
Cryo-EM structures of calcium homeostasis modulator channels in diverse oligomeric assemblies
Authors: Demura Kanae , Kusakizako Tsukasa , Shihoya Wataru , Hiraizumi Masahiro , Nomura Kengo , Shimada Hiroto , Yamashita Keitaro , Nishizawa Tomohiro , Taruno Akiyuki , Nureki Osamu
Published: February 2020

Calcium homeostasis modulator (CALHM) family proteins are Ca2+-regulated ATP-release channels involved in neural functions including neurotransmission in gustation. Here we present the cryo-EM structures of killifish CALHM1, human CALHM2, andC. elegansCLHM-1 at resolutions of 2.66, 3.51, and 3.60 Å, respectively. The CALHM1 octamer structure reveals that the N-terminal helix forms the constriction site at the channel pore in the open state, and modulates the ATP conductance. The CALHM2 undecamer and CLHM-1 nonomer structures show the different oligomeric stoichiometries among CALHM homologs. We further report the cryo-EM structures of the chimeric construct, revealing that the inter-subunit interactions at the transmembrane domain define the oligomeric stoichiometry. These findings advance our understanding of the ATP conduction and oligomerization mechanisms of CALHM channels.

One Sentence Summary

Cryo-EM structures reveal the ATP conduction and oligomeric assembly mechanisms of CALHM channels.
Hierarchical modeling of haplotype effects based on a phylogeny
Authors: Selle Maria Lie , Steinsland Ingelin , Lindgren Finn , Brajkovic Vladimir , Cubric-Curik Vlatka , Gorjanc Gregor
Published: February 2020

This paper introduces a hierarchical model to estimate haplotype effects based on phylogenetic relationships between haplotypes and their association with observed phenotypes. In a population there are usually many, but not all possible, distinct haplotypes and few observations per haplotype. Further, haplotype frequencies tend to vary substantially - few haplotypes have high frequency and many haplotypes have low frequency. Such data structure challenge estimation of haplotype effects. However, haplotypes often differ only due to few mutations and leveraging these similarities can improve the estimation of haplotype effects. There is extensive literature on this topic. Here we build on these observations and develop an autoregressive model of order one that hierarchically models haplotype effects by leveraging phylogenetic relationships between the haplotypes described with a directed acyclic graph. The phylogenetic relationships can be either in a form of a tree or a network and we therefore refer to the model as the haplotype network model. The haplotype network model can be included as a component in a phenotype model to estimate associations between haplotypes and phenotypes. The key contribution of this work is that by leveraging the haplotype network structure we obtain a sparse model and by using hierarchical autoregression the flow of information between similar haplotypes is estimated from the data. We show with a simulation study that the hierarchical model can improve estimates of haplotype effects compared to an independent haplotype model, especially when there are few observations for a specific haplotype. We also compared it to a mutation model and observed comparable performance, though the haplotype model has the potential to capture background specific effects. We demonstrate the model with a case study of modeling the effect of mitochondrial haplotypes on milk yield in cattle.
Glutamate and γ-aminobutyric acid differentially modulate glymphatic clearance of amyloid β through pulsation- and aquaporin-4 dependent mechanisms
Authors: Wu Cheng , Feng Yi-wei , Zhang Qun , Liang Feng-yin , Lan Yue , Pei Zhong , Xu Guang-qing
Published: February 2020

The glymphatic system contributes to a large proportion of brain waste clearance, including removal of amyloid β (Aβ). We have demonstrated that glutamate and γ-aminobutyric acid (GABA) influence glymphatic clearance through distinct mechanisms whereby GABA exerts modulatory effects in an aquaporin-4 (AQP4)-dependent manner while the actions of glutamate are pulsation-dependent. The efficacy of GABA and glutamate in alleviating Aβ in APP-PS1 and Angiotensin-II (Ang-II) induced hypertension mouse models was further evaluated. Notably, increasing GABA or inhibiting glutamate levels led to reduced binding of Aβ to pre-labeled plaques to similar extents in APP-PS1 mice while GABA appeared more efficient in Aβ clearance in hypertensive animals than the glutamate inhibitor. Our findings support the modulation of neurotransmitters that influence the glymphatic pathway via distinct mechanisms as a potentially effective therapeutic strategy for clearance of Aβ deposits from the brain.
Field and mesocosm methods to test biodegradable plastic film under marine conditions
Authors: Lott Christian , Eich Andreas , Unger Boris , Makarow Dorothée , Battagliarin Glauco , Schlegel Katharina , Lasut Markus T. , Weber Miriam
Published: February 2020

The pollution of the natural environment, especially the world’s oceans, with conventional plastic is of major concern. Biodegradable plastics are an emerging market bringing along potential chances and risks. The fate of these materials in the environment and their possible effects on organisms and ecosystems has rarely been studied systematically and is not well understood. For the marine environment, reliable field test methods and standards for assessing and certifying biodegradation to bridge laboratory respirometric data are lacking. In this work we present newly developed field tests to assess the performance of (biodegradable) plastics under natural marine conditions. These methods were successfully applied and validated in three coastal habitats (eulittoral, benthic and pelagic) and two climate zones (Mediterranean Sea and tropical Southeast Asia). Additionally, a stand-alone mesocosm test system which integrated all three habitats in one technical system at 400-L scale independent from running seawater is presented as a methodological bridge. Films of polyhydroxyalkanoate copolymer (PHA) and low density polyethylene (LD-PE) were used to validate the tests. While LD-PE remained intact, PHA disintegrated to a varying degree depending on the habitat and the climate zone. Together with the existing laboratory standard test methods, the field and mesocosm test systems presented in this work provide a 3-tier testing scheme for the reliable assessment of the biodegradation of (biodegradable) plastic in the marine environment. This toolset of tests can be adapted to other aquatic ecosystems.
Epigenetic clocks predict prevalence and incidence of leading causes of death and disease burden
Authors: Hillary Robert F. , Stevenson Anna J. , McCartney Daniel L. , Campbell Archie , Walker Rosie M. , Howard David M. , Ritchie Craig W. , Horvath Steve , Hayward Caroline , McIntosh Andrew M. , Porteous David J. , Deary Ian J. , Evans Kathryn L. , Marioni Riccardo E.
Published: February 2020

Individuals of the same chronological age display different rates of biological ageing. A number of measures of biological age have been proposed which harness age-related changes in DNA methylation profiles. These include methylation-based predictors of chronological age (HorvathAge, HannumAge), all-cause mortality (DNAm PhenoAge, DNAm GrimAge) and telomere length (DNAm Telomere Length). In this study, we test the association between these epigenetic markers of ageing and the prevalence and incidence of the leading causes of disease burden and mortality in high-income countries. Furthermore, we test the clocks’ relationships with phenotypic measures associated with these conditions, including spirometric and biochemical traits. We carry out these analyses in 9,537 individuals from the Generation Scotland: Scottish Family Health Study. We find that DNAm GrimAge outperforms other epigenetic clocks in its associations with self-report disease prevalence and related clinical traits. DNAm GrimAge associates with chronic obstructive pulmonary disease (COPD) prevalence (Odds Ratio = 3.29, P = 3.0 × 10-4) and pulmonary spirometry tests (β = [-0.10 to −0.15], P = [1.4 × 10-4to 1.4 × 10-6]) at study baseline after adjusting for possibly confounding risk factors including alcohol, body mass index, deprivation, education and smoking. After adjusting for these confounding risk factors, DNAm GrimAge, DNAm PhenoAge and DNAm Telomere Length, measured at study baseline, predict incidence of ICD-10-coded disease states including COPD, type 2 diabetes and cardiovascular disease after thirteen years of follow-up (Hazard Ratios = [0.80 (telomere length) to 2.19 (GrimAge)], P = [9.9 × 10-4, 1.9 × 10-14]). Our data show that despite accounting for several possible confounding variables, epigenetic markers of ageing predict incidence of common disease. This may have significant implications for their potential utility in clinical settings to complement gold-standard methods of clinical assessment and management.
Contrasting species functional trait structuring of subarctic versus subtropical copepod communities
Authors: García-Comas Carmen , Hsieh Chih-hao , Chiba Sanae , Sugisaki Hiroya , Hashioka Taketo , Smith S. Lan
Published: February 2020

Classic niche theory assumes that species-level functional traits affect species relative fitness and thus community structuring, but empirical tests of this assumption are scarce. Moreover, recent evidence shows increasing functional over-redundancy towards the tropics, suggesting that the extent to which functional traits confer species’ fitness and thus impact community structuring differs across latitudes. Here, we develop a new method: comparing the frequencies of trait categories in the species-rank abundance distributions of local communities versus their frequencies in the regional average species pool. We contrasted subarctic versus subtropical copepod communities for six important traits. In subarctic communities, medium-sized and cold-water species are selected to dominate, thus traits affect relative fitness as predicted by classic niche theory. In subtropical communities, most species are small and warm-water, but these categories are not selected to dominate, suggesting that greater diversity towards the tropics results from lesser trait-based fitness differences allowing more species to coexist.
A tentacle for every occasion: comparing the hunting tentacles and sweeper tentacles, used for territorial competition, in the coralGalaxea fascicularis
Authors: Yosef Oshra , Popovits Yotam , Malik Assaf , Ofek-Lalzer Maya , Mass Tali , Sher Daniel
Published: February 2020

Coral reefs are among the most diverse, complex and densely populated marine ecosystems. To survive, morphologically simple and sessile cnidarians have developed mechanisms to catch prey, deter predators and compete with adjacent corals for space, yet the mechanisms underlying these functions are largely unknown. Here, we characterize the histology, toxic activity and gene expression patterns in two different types of tentacles from the scleractinian coralGalaxea fascilcularis– catch tentacles (CTs), used to catch prey and deter predators, and sweeper tentacles (STs), specialized tentacles used for territorial aggression. STs exhibit more mucocytes and higher expression of mucin genes than CTs, and lack the ectodermal cilia used to deliver food to the mouth and remove debris. STs and CTs also express different sensory g-protein coupled receptors, suggesting they may employ different sensory pathways. Each tentacle type has a different complement of stinging cells (nematocytes), and the expression in the two tentacles of genes encoding structural nematocyte proteins suggests the stinging cells develop within the tentacles. CTs have higher neurotoxic and hemolytic activities, consistent with a role in prey capture, whereas the STs have higher phospholipase A2 activity, which we speculate may have a role in inducing tissue damage during territorial aggression. The toxin genes expressed in each tentacle are also different. These results show that the same organism utilizes two distinct tentacle types, each equipped with a different venom apparatus and toxin composition, for prey capture and defense and for territorial aggression.
The McGill-Mouse-Marmoset Platform: A Standardized Approach for High-throughput Imaging of Neuronal Dynamics During Behavior
Authors: Mosser Coralie-Anne , Haqqee Zeeshan , Nieto-Posadas Andres , Murai Keith , Stifani Stefano , Williams Sylvain , Brandon Mark P.
Published: February 2020

Understanding the rules that govern neuronal dynamics throughout the brain to subserve behavior and cognition remain one of the biggest challenges in neuroscience research. Recent technical advances enable the recording of increasingly larger neuronal populations to produce increasingly more sophisticated datasets. Despite bold and important open-science and data-sharing policies, these datasets tend to include unique data acquisition methods, behavior, and file structures. Discrepancies between experimental protocols present several key challenges including the analysis of the data itself, comparison of data collected between laboratories, and for the comparison of dynamics between brain regions and species. Here, we discuss our recent efforts to create a standardized and high-throughput research platform to address these issues. The McGill-Mouse-Marmoset (M3) platform combines miniscope calcium imaging recording in both mice and marmosets with standardized touchscreen-based behavioral testing. The goal is to curate an open-source and standardized framework for acquiring, analyzing, and accessing high-quality data of the neuronal dynamics that underly cognition throughout the brain in mice, marmosets, and models of disease. We end with a discussion of future developments and a call for users to adopt this standardized approach.
Anacardic acid protects against phenylephrine-induced mouse cardiac hypertrophy through JNK signaling-dependent regulation of histone acetylation
Authors: Peng Bohui , Peng Chang , Luo Xiaomei , Huang Lixin , Mao Qian , Zhang Huanting , Han Xiao
Published: February 2020

Cardiac hypertrophy is a complex process induced by the activation of multiple signaling pathways. We previously reported that anacardic acid (AA), a histone acetylase (HAT) inhibitor, attenuates phenylephrine (PE)-induced cardiac hypertrophy by downregulating histone H3 acetylation at lysine 9 (H3K9ac). Unfortunately, the upstream signaling events remained unknown. The mitogen-activated protein kinase (MAPK) pathway is an important regulator of cardiac hypertrophy. In this study, we explored the role of JNK/MAPK signaling in cardiac hypertrophy. A mouse model of cardiomyocyte hypertrophy was successfully establishedin vitrousing PE. This study showed that p-JNK directly interacts with HATs (P300 and P300/CBP-associated factor, PCAF) and alters H3K9ac. In addition, both the JNK inhibitor SP600125 and the HAT inhibitor AA attenuated p-JNK overexpression and H3K9 hyperacetylation by inhibiting P300 and PCAF during PE-induced cardiomyocyte hypertrophy. Moreover, we demonstrated that both SP600125 and AA attenuate the overexpression of cardiac hypertrophy-related genes (MEF2A, ANP, BNP, andβ-MHC), preventing cardiomyocyte hypertrophy and dysfunction. These results revealed a novel mechanism through which AA might protect mice from PE-induced cardiac hypertrophy. In particular, AA inhibits the effects of JNK signaling on HAT-mediated histone acetylation, and could therefore be used to prevent and treat hypertrophic cardiomyopathy.
A Pre-computed Probabilistic Molecular Search Engine for Tandem Mass Spectrometry Proteomics
Authors: Jones Jeff
Published: February 2020

Mass spectrometry methods of peptide identification involve comparing observed tandem spectra within-silicoderived spectrum models. Presented here is a proteomics search engine that offers a new variation of the standard approach, with improved results. The proposed method employs information theory and probabilistic information retrieval on a pre-computed and indexed fragmentation database generating a peptide-to-spectrum match (PSM) score modeled on fragment ion frequency. As a result, the direct application of modern document mining, allows for treating the collection of peptides as a corpus and corresponding fragment ions as indexable words, leveraging ready-built search engines and common predefined ranking algorithms. Fast and accurate PSM matches are achieved yielding a 5-10% higher rate of peptide identities than current database mining methods. Immediate applications of this search engine are aimed at identifying peptides from large sequence databases consisting of homologous proteins with minor sequence variations, such as genetic variation expected in the human population.