bluuebunny/crossref_metadata_2025 huggingface dataset:
βIII spectrin controls the planarity of Purkinje cell dendrites by modulating perpendicular axon-dendrite interaction
Authors: Fujishima Kazuto , Kurisu Junko , Yamada Midori , Kengaku Mineko
Published: February 2020

The mechanism underlying the geometrical patterning of axon and dendrite wiring remains elusive, despite its critical importance in the formation of functional neural circuits. Cerebellar Purkinje cell (PC) arborizes a typical planar dendrite, which forms an orthogonal network with granule cell (GC) axons. By using electrospun nanofiber substrates, we reproduce the perpendicular contacts between PC dendrites and GC axons in culture. In the model system, PC dendrites show preference to grow perpendicular to aligned GC axons, which presumably contribute to the planar dendrite arborizationin vivo. We show that βIII spectrin, a causal gene for spinocerebellar ataxia type 5 (SCA5), is required for the biased growth of dendrites. βIII spectrin deficiency causes actin mislocalization and excessive microtubule invasion in dendritic protrusions, resulting in abnormally oriented branch formation. Furthermore, disease-associated mutations affect the ability of βIII spectrin to control dendrite orientation. These data indicate that βIII spectrin organizes the dendritic cytoskeleton and thereby regulates the oriented growth of dendrites with respect to the afferent axons.

Summary statement

βIII spectrin suppress the microtubule dynamics at the neuronal dendrite to inhibit the abnormal lateral branching, which causes misoriented branch formation.
Resolving a QTL complex for height, heading, and grain yield on chromosome 3A in bread wheat
Authors: Martinez Alba Farre , Lister Clare , Freeman Sue , Ma Jun , Berry Simon , Wingen Luzie , Griffiths Simon
Published: February 2020

Crop height (Ht), heading date (Hd), and grain yield (GY) are interrelated traits in wheat. Independent manipulation of each is important for adaptation and performance. Validated QTL for all three collocate on chromosome 3A in the Avalon x Cadenza population. We asked if these are linked or pleiotropic effects. The region was dissected using recombinants derived from Near Isogenic Lines. It was shown that Ht and Hd are controlled by independent genes. The newly defined Ht QTL interval contained a gene cluster involved in cell wall growth and displaying high levels of differential transcript expression. The Hd locus is much larger and rearranged compared to the reference genome butFT2is a candidate of particular interest. The Hd effect was shown to act independently of photoperiod and vernalization but did exhibit genotype x environment interaction suggesting a role in ambient temperature sensitivity. It was the Hd locus that was most associated with increased GY of Cadenza alleles, supporting physiological studies proposing that ‘late’ alleles at this locus increase spike fertility and grain number. The work has uncoupled height from heading and yield and shown that one of very few validated GY QTL in wheat is probably mediated by phenological variation.

Highlight

There only are three validated wheat yield QTL. Here, one of them was genetically dissected.

This showed that the physiological basis of the yield effect is likely to be phenological.
Accelerated Simulations of Chemical Reaction Systems using the Stochastic Simulation Algorithm on GPUs
Authors: Pino James C. , Prugger Martina , Lubbock Alexander L. R. , Harris Leonard A. , Lopez Carlos F.
Published: February 2020

1

Stochasticity due to fluctuations in chemical reactions can play important roles in cellular network-driven processes. Although the Stochastic Simulation Algorithm (SSA, aka Gillespie Algorithm) has long been accepted as a suitable method to solve the time-dependent chemical master equation, its computational cost is prohibitive for large scale complex networks such as those found in cellular processes. Here we present GPU-SSA, an implementation of the SSA formalism utilizing Graphics Processing Units for use in Python using the PySB modeling framework. We show that the GPU implementation of SSA can achieve significant speedup compared to parallel CPU or single-core CPU implementations. We further include supplementary didactic material to demonstrate how to incorporate GPU-SSA workflows for interested readers.
Simultaneous human intracerebral stimulation and HD-EEG: ground-truth for source localization methods
Authors: Mikulan Ezequiel , Russo Simone , Parmigiani Sara , Sarasso Simone , Zauli Flavia Maria , Rubino Annalisa , Avanzini Pietro , Cattani Anna , Sorrentino Alberto , Gibbs Steve , Cardinale Francesco , Sartori Ivana , Nobili Lino , Massimini Marcello , Pigorini Andrea
Published: February 2020

Precisely localizing the sources of brain activity as recorded by EEG is a fundamental procedure and a major challenge for both research and clinical practice. Even though many methods and algorithms have been proposed, their relative advantages and limitations are still not well established. Moreover, these methods involve tuning multiple parameters, for which no principled way of selection exists yet. These uncertainties are emphasized due to the lack of ground-truth for their validation and testing. Here we provide the first open dataset that comprises EEG recorded electrical activity originating from precisely known locations inside the brain of living humans. High-density EEG was recorded as single-pulse biphasic currents were delivered at intensities ranging from 0.1 to 5 mA through stereotactically implanted electrodes in diverse brain regions during pre-surgical evaluation of patients with drug-resistant epilepsy. The uses of this dataset range from the estimation of in vivo tissue conductivity to the development, validation and testing of forward and inverse solution methods.
Steroid hormone agonists reduce female fitness in insecticide-resistantAnophelespopulations
Authors: Brown Faye , Paton Douglas G , Catteruccia Flaminia , Ranson Hilary , Ingham Victoria A
Published: February 2020

Insecticide based vector control tools such as insecticide treated bednets and indoor residual spraying represent the cornerstones of malaria control programs. Resistance to chemistries used in these programs is now widespread and represents a significant threat to the gains seen in reducing malaria-related morbidity and mortality. Recently, disruption of the 20-hydroxyecdysone steroid hormone pathway was shown to reducePlasmodiumdevelopment time and significantly reduce both longevity and egg production in a laboratory susceptibleAnopheles gambiaepopulation. Here, we demonstrate that disruption of this pathway by application of methoxyfenozide (MET) to insecticide resistantAn. coluzzii, An. gambiae slandAn. funestuspopulations significantly reduces egg production in both topical and tarsal application. Moreover, MET reduces adult longevity when applied topically, and tarsally after blood feeding. As the cytochrome p450s elevated in pyrethroid resistantAnophelesonly bind MET very weakly, this compound is unlikely to be subject to cross-resistance in a field-based setting. Manipulation of this hormonal signalling pathway therefore represents a potential complementary approach to current malaria control strategies, particularly in areas where high levels of insecticide resistance are compromising existing tools.
Conservation Genomic Analyses of African and Asiatic Cheetahs (Acinonyx jubatus) Across Their Current and Historical Species Range
Authors: Prost Stefan , Machado Ana Paula , Zumbroich Julia , Preier Lisa , Mahtani-Williams Sarita , Meissner Rene , Guschanski Katerina , Brealey Jaelle C. , Fernandes Carlos , Vercammen Paul , Hunter Luke T. B. , Abramov Alexei V. , Godsall-Bottriell Lena , Bottriell Paul , Dalton Desire Lee , Kotze Antoinette , Burger Pamela Anna
Published: February 2020

Cheetahs (Acinonyxjubatus)are majestic carnivores and the fastest land animals; yet, they are quickly heading towards an uncertain future. Threatened by habitat loss, human-interactions and illegal trafficking, there are only approximately 7,100 individuals remaining in the wild. Cheetahs used to roam large parts of Africa, and Western and Southern Asia. Today they are confined to about 9% of their original distribution. To investigate their genetic diversity and conservation status, we generated genome-wide data from historical and modern samples of all four currently recognized subspecies, along with mitochondrial DNA (mtDNA) and major histo-compatibility complex (MHC) data. We found clear genetic differentiation between the sub-species, thus refuting earlier assumptions that cheetahs show only little population differentiation. Our genome-wide nuclear data indicate that cheetahs from East Africa may be more closely related toA. j. soemmeringiithan they are toA. j. jubatus. This supports the need for further research on the classification of cheetah subspecies, as East African cheetahs are currently included in the Southern Africa subspecies,A. j. jubatus. We detected stronger inbreeding in individuals of the Critically EndangeredA. j. venaticus(Iran) andA. j. hecki(Northwest Africa), and show that overall genome-wide heterozygosity in cheetah is lower than that reported for other threatened and endangered felids, such as tigers and lions. Furthermore, we show that MHC class II diversity in cheetahs is generally higher than previously reported, but still lower than in other felids. Our results provide new and important information for efficient genetic monitoring, subspecies assignments and evidence-based conservation policy decisions.
Precise automatic classification of 46 different pollen types with convolutional neural networks
Authors: Sevillano Víctor , Holt Katherine , Aznarte José L.
Published: February 2020

In palynology, the visual classification of pollen grains from different species is a hard task which is usually tackled by human operators using microscopes. Many industries, including medical and farmaceutical, rely on the accuracy of this manual classification process, which is reported to be around 67%. In this paper, we propose a new method to automatically classify pollen grains using deep learning techniques that improve the correct classification rates in images not previously seen by the models. Our proposal manages to properly classify up to 98% of the examples from a dataset with 46 different classes of pollen grains, produced by the Classifynder classification system. This is an unprecedented result which surpasses all previous attempts both in accuracy and number and difficulty of taxa under consideration, which include types previously considered as indistinguishable.
Sentinel Interaction Mapping (SIM) – A generic approach for the functional analysis of human disease gene variants using yeast
Authors: Young Barry P , Post Kathryn L , Chao Jesse T , Meili Fabian , Haas Kurt , Loewen Christopher JR
Published: February 2020

Advances in sequencing technology have led to an explosion in the number of known genetic variants of human genes. A major challenge is to now determine which of these variants contribute to diseases as a result of their effect on gene function. Here we describe a generic approach using the yeastSaccharomyces cerevisiaeto quickly develop gene-specificin vivoassays that can be used to quantify the level of function of a genetic variant. Using Synthetic Dosage Lethality screening, “sentinel” yeast strains are identified that are sensitive to overexpression of a human disease gene. Variants of the gene can then be functionalized in high-throughput fashion through simple growth assays using either solid or liquid media. Sentinel Interaction Mapping (SIM) has the potential to create functional assays for the large majority of human disease genes that do not have a yeast orthologue. Using the tumour suppressor genePTENas an example, we show that SIM assays can provide a fast and economical means to screen a large number of genetic variants.
A fast linkage disequilibrium-based statistical test for Genome-Wide Epistatic Selection Scans in structured populations
Authors: Boyrie Léa , Moreau Corentin , Frugier Florian , Jacquet Christophe , Bonhomme Maxime
Published: February 2020

The quest for genome-wide signatures of selection in populations using SNP data has proven efficient to uncover genes involved in conserved or adaptive molecular functions, but none of the statistical methods were designed to identify interacting genes as targets of selective processes. Here, we propose a straightforward statistical test aimed at detecting epistatic selection, based on a linkage disequilibrium (LD) measure accounting for population structure and heterogeneous relatedness between individuals. SNP-based (Trv) and window-based (TcorPC1v) statistics fit a Student distribution, allowing to easily and quickly test the significance of correlation coefficients in the frame of Genome-Wide Epistatic Selection Scans (GWESS) using candidate genes as baits. As a proof of concept, use of SNP data from theMedicago truncatulasymbiotic legume plant uncovered a previously unknown gene coadaptation between theMtSUNN(Super Numeric Nodule) receptor and theMtCLE02(CLAVATA3-Like) signalling peptide, and experimental evidence accordingly supported aMtSUNN-dependent negative role ofMtCLE02in symbiotic root nodulation. Using human HGDP-CEPH SNP data, our new statistical test uncovered strong LD betweenSLC24A5andEDARworldwide, which persists after correction for population structure and relatedness in Central South Asian populations. This result suggests adaptive genetic interaction or coselection between skin pigmentation and the ectodysplasin pathway involved in the development of ectodermal organs (hairs, teeth, sweat glands), in some human populations. Applying this approach to genome-wide SNP data will foster the identification of evolutionary coadapted gene networks.

Author summary

Population genomic methods have allowed to identify many genes associated with adaptive processes in populations with complex histories. However, they are not designed to identify gene coadaptation between genes through epistatic selection, in structured populations. To tackle this problem, we developed a straightforward LD-based statistical test accounting for population structure and heterogeneous relatedness between individuals, using SNP-based (Trv) or windows-based (TcorPC1v) statistics. This allows easily and quickly testing for significance of correlation coefficients between polymorphic loci in the frame of Genome Wide Epistatic Selection Scans (GWESS). Following detection of gene coadaptation using SNP data from human and the model plantMedicago truncatula, we report experimental evidence of genetic interaction between two receptors involved in the regulation of root nodule symbiosis inMedicago truncatula. This test opens new avenues for exploring the evolution of genes as interacting units and thus paves the way to infer new networks based on evolutionary coadaptation between genes.
Bicaudal Cis required for the function of the follicular epithelium during oogenesis inRhodnius prolixus
Authors: Pascual Agustina , Vilardo Emiliano S. , Taibo Catalina , García Julia Sabio y , Pomar Rolando Rivera
Published: February 2020

The morphology and physiology of the oogenesis have been well studied in the vector of Chagas diseaseRhodnius prolixus. However, the molecular interactions that regulate the process of egg formation, key for the reproductive cycle of the vector, is still largely unknown. In order to understand the molecular and cellular basis of the oogenesis we examined the function of the geneBicaudal C(BicC) during oogenesis and early development ofR. prolixus. We show thatR. prolixus BicC(Rp-BicC) gene is expressed in the germarium, with cytoplasmic distribution, as well as in the follicular epithelium of the developing oocytes. RNAi silencing ofRp-BicCresulted in sterile females that lay few, small, non-viable eggs. The ovaries are reduced in size and show a disarray of the follicular epithelium. This indicates thatRp-BicChas a central role in the regulation of oogenesis. Although the follicular cells are able to form the chorion, the uptake of vitelline by the oocytes is compromised. We show evidence that the polarity of the follicular epithelium and the endocytic pathway, which is crucial for the proper yolk deposition, are affected. This study provides insights into the molecular mechanisms underlying oocyte development and show thatRp-BicCis important for de developenta of the egg and, therefore, a key player in the reproduction of this Chagas disease vector.

Author summary

The oogenesis is the process of egg formation. It is essential to guarantee transgenerational inheritance. It implies the differentiation of the gamete (oocyte) from a niche of stem cells in the germ line, the accumulation of yolk, and the formation of the chorion. These events are entangled in a regulated manner by the concerted communication between the different cell types that form the ovary. It is regulated by endogenous gene networks and linked to the physiological state of the insect by hormonal clues. This timely orchestrated process represents the interaction of gene networks. The genetic regulation behind the oogenesis is largely unknown inRhodnius prolixus. Here we identified a gene required for egg formation that interferes the uptake of the yolk by affecting the functional integrity of the follicular epithelium. Our results are of interest for a better understanding of a complex process essential for the survival of vector populations and provide knowledge to envisage and design new strategies for vector control.
Dynamic regulation of JAK-STAT signaling through the prolactin receptor predicted by computational modeling
Authors: Mortlock Ryland D. , Georgia Senta K. , Finley Stacey D.
Published: February 2020

Introduction

Hormones signal through various receptors and cascades of biochemical reactions to expand beta cell mass during pregnancy. Harnessing this phenomenon to treat beta cell dysfunction requires quantitative understanding of the signaling at the molecular level. This study explores how different regulatory elements impact JAK-STAT signaling through the prolactin receptor in pancreatic beta cells.

Methods

A mechanistic computational model was constructed to describe the key reactions and molecular species involved in JAK-STAT signaling in response to the hormone prolactin. The effect of including and excluding different regulatory modules in the model structure was explored through ensemble modeling. A Bayesian approach for likelihood estimation was used to parametrize the model to experimental data from the literature.

Results

Receptor upregulation, combined with either inhibition by SOCS proteins, receptor internalization, or both, was required to obtain STAT5 dynamics matching experimental results for INS-1 cells treated with prolactin. Multiple model structures could fit the experimental data, and key findings were conserved across model structures, including faster dimerization and nuclear import rates of STAT5B compared to STAT5A. The model was validated using experimental data from rat primary beta cells not used in parameter estimation. Probing the fitted, validated model revealed possible strategies to modulate STAT5 signaling.

Conclusions

JAK-STAT signaling must be tightly controlled to obtain the biphasic response in STAT5 activation seen experimentally. Receptor up-regulation, combined with SOCS inhibition, receptor internalization, or both is required to match experimental data. Modulating reactions upstream in the signaling can enhance STAT5 activation to increase beta cell mass.
Coordination betweenE. coliCell Size and Cell Cycle Mediated by DnaA
Authors: Zhang Qing , Zhang Zhichao , Shi Hualin
Published: February 2020

Sixty years ago, bacterial cell size was found as an exponential function of growth rate. Fifty years ago, a more general relationship was proposed, in which the cell mass was equal to the initiation mass multiplied by the ratio of the total time of the C and D periods to the doubling time. This relationship has recently been experimentally confirmed by perturbing doubling time, C period, D period or the initiation mass. However, the underlying molecular mechanism remains unclear. Here, we developed a mechanistic and kinetic model to describe how the initiator protein DnaA mediates the initiation of DNA replication inE. coli.In the model, we introduced an initiation probability function involving competitive binding of DnaA-ATP (active) and DnaA-ADP (inactive) at replication origin to determine the initiation of replication. In addition, we considered RNAP availability, ppGpp inhibition, DnaA autorepression, DnaA titration by chromosomal sites, hydrolysis of DnaA-ATP along with DNA replication, reactivation of DnaA-ADP and established a kinetic description of these DnaA regulatory processes. We simulated DnaA kinetics and obtained a self-consistent cell size and a regular DnaA oscillation coordinated with the cell cycle at steady state. The relationship between the cell size obtained by the simulation and the growth rate, C period, D period or initiation mass reproduces the results of the experiment. This model also predicts how the number of DnaA and the initiation mass vary with the perturbation parameters (including those reflecting the mutation or interference of DnaA regulatory processes), which is comparable to experimental data. The results suggest that the regulatory mechanisms of DnaA level and activity are associated with the invariance of initiation mass and the cell size general relationship for matching frequencies of replication initiation and cell division. This study may provide clues for concerted control of cell size and cell cycle in synthetic biology.
Autophagy is induced during plant grafting for wound healing
Authors: Kurotani Ken-ichi , Tabata Ryo , Kawakatsu Yaichi , Sugita Ryohei , Okayasu Koji , Tanoi Keitaro , Notaguchi Michitaka
Published: February 2020

Grafting is an important technique in agriculture to obtain several good traits such as high disease tolerance and high yield by exchanging root system. However, the underlined cellular processes to compensate the wound damage and repair tissues were largely unknown.

We analyzed two graft combinations: Nicotiana benthamiana (Nb) homograft as a compatible, wound repairing model and Nb heterograft with Arabidopsis thaliana (At) as an incompatible and more stressful model, which we recently identified as an exceptional maintainable interfamily grafting.

In both graft combinations, nutrient loss was observed in gene expression after grafting, where the level of nutrient loss was more sever in heterografts. Transmission electron micrographs of Nb/At heterografts suggested that microautophagy was induced in cells near the graft boundary. In At seedling micrografting, the fluorescence of autophagy protein marker GFP-ATG8 was highly observed at graft junction especially in cambial region. In At atg2 mutant homografts, growth after grafting decreased compared with wild-type homografts. Moreover, when NbATG5 knocked-down Nb scion was grafted to At stock, the successful rate of grafting was significantly decreased.

Altogether, these results suggest that component of autophagy is induced during grafting and has a role in wound healing.
Cytosine methylation dynamics during post-testicular sperm maturation in mammals
Authors: Galan Carolina , Serra Ryan W. , Sun Fengyun , Rinaldi Vera D. , Conine Colin C. , Rando Oliver J.
Published: February 2020

Beyond the haploid genome, mammalian sperm contribute a payload of epigenetic information which can modulate offspring phenotypes. Recent studies have shown that the small RNA payload of sperm undergoes extensive remodeling during post-testicular maturation in the epididymis. Intriguingly, epididymal maturation has also been linked to changes in the sperm methylome, suggesting that the epididymis might play a broader role in remodeling the sperm epigenome. Here, we build on prior studies of the maturing sperm methylation landscape, further characterizing the genome-wide methylation landscape in seven germ cell populations collected from throughout the male reproductive tract. Overall, we find very few changes in the cytosine methylation landscape between testicular germ cell populations and cauda epididymal sperm, demonstrating that the sperm methylome is largely stable throughout post-testicular maturation. Intriguingly, although our sequencing data suggested that caput epididymal sperm exhibit a highly unusual methylome, follow-up studies revealed that this resulted from contamination of caput sperm by extracellular DNA. Extracellular DNA formed web-like structures that ensnared sperm, was present only in the caput epididymis of virgin males, where it was associated with citrullinated histone H3 and presumably resulted from a PAD-driven genome decondensation process. Taken together, our data emphasize the stability of the cytosine methylation landscape in mammalian sperm, and identify a surprising but transient period during which immature sperm are associated with extracellular DNA.
Generating synthetic aging trajectories with a weighted network model using cross-sectional data
Authors: Farrell Spencer , Mitnitski Arnold , Rockwood Kenneth , Rutenberg Andrew
Published: February 2020

We develop a computational model of human aging that generates individual health trajectories with a set of observed health attributes. Our model consists of a network of interacting health attributes that stochastically damage with age to form health deficits, leading to eventual mortality. We train and test the model for two different cross-sectional observational aging studies that include simple binarized clinical indicators of health. In both studies, we find that cohorts of simulated individuals generated from the model resemble the observed cross-sectional data in both health characteristics and mortality. We can generate large numbers of synthetic individual aging trajectories with our weighted network model. Predicted average health trajectories and survival probabilities agree well with the observed data.
Antibiotics affect migratory restlessness orientation
Authors: Werber Yuval , Natan Eviatar , Lavner Yizhar , Vortman Yoni
Published: February 2020

Magnetoreception is a sense that allows the organism to perceive and act according to different parameters of the magnetic field. This magnetic sense plays a part in many fundamental processes in various living organisms. Much effort was expended in finding the ‘magnetic sensor’ in animals. While some experiments show a role of the ophthalmic nerve in magnetic sensing, others show that effects of light on processes in the retina are involved. According to these inconclusive and puzzling findings, the scientific community has yet to reach an agreement concerning the underlying mechanism behind animal magnetic sensing. Recently, the symbiotic magnetotaxis hypothesis has been forwarded as a mechanistic explanation for the phenomenon of animal magnetoreception. It suggests a symbiotic relationship between magnetotactic bacteria (MTB) and the navigating host. Here we show that in contrast to the control group, antibiotic treatment caused a lack of clear directionality in an Emlen funnel experiment. Accordingly, the antibiotics treatment group showed a significant increase in directional variance. This effect of antibiotics on behaviors associated with animal magnetic sensing is, to the best of our knowledge, the first experimental support of the symbiotic magnetotactic hypothesis.
Network efficiency predicts resilience to cognitive decline in elderly at risk for Alzheimer’s
Authors: Fischer Florian U. , Wolf Dominik , Fellgiebel Andreas ,   for the Alzheimer’s Disease Neuroimaging Initiative
Published: February 2020

To determine whether white matter network efficiency (WMNE) may be a surrogate marker of the physiological basis of resilience to cognitive decline in elderly persons without dementia and age and AD-related cerebral pathology, we quantified WMNE from baseline MRI scans and investigated its association with longitudinal neuropsychological assessments independent of baseline amyloid, tau and white matter hyperintensity volume. 85 cognitively normal elderly subjects and patients with mild cognitive impairment (MCI) with baseline diffusion imaging, CSF specimens, AV45-PET and longitudinal cognitive assessments were included. WMNE was calculated from reconstructed cerebral white matter networks for each individual. Mixed linear effects models were estimated to investigate the association of higher resilience to cognitive decline with higher WMNE and the modulation of this association by increased cerebral amyloid, CSF tau or WMHV. For the majority of cognitive outcome measures, higher WMNE was associated with higher resilience to cognitive decline independently of pathology measures (beta: .074 – .098; p: .011 – .039). Additionally, WMNE was consistently associated with higher resilience to cognitive decline in subjects with higher cerebral amyloid burden (beta: .024 – .276; p: .000 – .036) and with lower CSF tau (beta: −.030 – −.074; p: .015 – .002) across all cognitive outcome measures. The results of this study indicate that WMNE in particular and possibly white matter organization in general may be worthy targets of investigation to provide measures quantifying a patient’s resilience to cognitive decline and thus provide an individual prognosis.
Coordinated Interaction: A model and test for globally signed epistasis in complex traits
Authors: Sheppard Brooke , Rappoport Nadav , Loh Po-Ru , Sanders Stephan J. , Dahl Andy , Zaitlen Noah
Published: February 2020

Interactions between genetic variants – epistasis – is pervasive in model systems and can profoundly impact evolutionary adaption, population disease dynamics, genetic mapping, and precision medicine efforts. In this work we develop a model for structured polygenic epistasis, calledCoordinated Interaction(CI), and prove that several recent theories of genetic architecture fall under the formal umbrella of CI. Unlike standard polygenic epistasis models that assume interaction and main effects are independent, in the CI model, sets of SNPs broadly interact positively or negatively, on balance skewing the penetrance of main genetic effects. To test for the existence of CI we propose theeven-odd(EO) test and prove it is calibrated in a range of realistic biological models. Applying the EO test in the UK Biobank, we find evidence of CI in 14 of 26 traits spanning disease, anthropometric, and blood categories. Finally, we extend the EO test to tissue-specific enrichment and identify several plausible tissue-trait pairs. Overall, CI is a new dimension of genetic architecture that can capture structured, systemic interactions in complex human traits.
Activation of WNT signaling restores the facial deficits in a zebrafish with defects in cholesterol metabolism
Authors: Castro Victoria L. , Reyes-Nava Nayeli G. , Sanchez Brianna B. , Gonzalez Cesar G. , Quintana Anita M.
Published: February 2020

Background

Inborn errors of cholesterol metabolism occur as a result of mutations in the cholesterol synthesis pathway (CSP). Although mutations in the CSP cause a multiple congenital anomaly syndrome, craniofacial abnormalities are a hallmark phenotype associated with these disorders. Previous studies have established that mutation of the zebrafishhmgcs1gene (Vu57 allele), which encodes the first enzyme in the CSP, causes defects in craniofacial development and abnormal neural crest cell (NCC) differentiation. However, the molecular mechanisms by which the products of the CSP disrupt NCC differentiation are not completely known. Cholesterol is known to regulate the activity of WNT signaling, an established regulator of NCC differentiation. We hypothesized that defects in cholesterol synthesis reduce WNT signaling, consequently resulting in abnormal craniofacial development.

Methods

To test our hypothesis we performed a combination of pharmaceutical inhibition, gene expression assays, and targeted rescue experiments to understand the function of CSP and WNT signaling during craniofacial development.

Results

We demonstrate reduced expression ofaxin2, a WNT downstream target gene in homozygous carriers of the Vu57 allele and in larvae treated with Ro-48-8071, which inhibits the synthesis of cholesterol. Moreover, activation of WNT signaling via treatment with a WNT agonist completely restored the craniofacial defects present in the Vu57 allele.

Conclusions

Collectively, these data suggest interplay between the CSP and WNT signaling during craniofacial development.
The work of early childhood coaches in one US state
Authors: Hnasko Amy
Published: February 2020

Purpose

This paper discusses the findings of a mixed-methods study of early childhood instructional coaches employed in state-funded preschool (aged three and four years) programs in the state of New Jersey (NJ) in the United States (US), highlighting a case study of one coach that provides an example of individual and organizational factors influencing the work.

Design/methodology/approach

An online survey was distributed to all coaches (master teachers) in 35 districts' early childhood programs. Two master teachers were then studied for a period of five months. During that time, three structured interviews were conducted, focused observations occurred each month, and coach logs were collected.

Findings

The findings of the data analyses illuminated both individual (i.e., a coach's own professional development) and organizational (i.e., varying interpretations of role) factors that influenced the work of the early childhood coaches.

Research limitations/implications

The data in this paper is limited to one US state's approach to early childhood coaching. The case study data examined is limited to the contexts of the specific participating districts and master teachers involved. It is suggested that future research be conducted on a nationwide pool of instructional coaches.

Practical implications

The findings of this study highlight the role of the state in providing more guidance surrounding the primary responsibilities of the master teacher. It is suggested that further attention be placed on creating and sustaining a professional development network for the master teachers serving NJ's early childhood programs.

Originality/value

As one of the few statewide studies of instructional coaching in early childhood, this study provides insights into how policy is translated into practice.
Habitat‐specific effects of bark on wood decomposition: Influences of fragmentation, nitrogen concentration and microbial community composition
Authors: Jones Jennifer M. , Heath Katy D. , Ferrer Astrid , Dalling James W.
Published: February 2020

Identifying the drivers of decomposition is critical for understanding carbon cycling dynamics in forest ecosystems. Woody biomass is an important pool of carbon, composed of bark and underlying wood which vary in structure, nutrient concentrations and exposure to the environment. We hypothesized that higher nutrient concentrations in bark would speed the decomposition of underlying wood, and that this effect would be greater in streams, where nutrients are less available to decomposers than on land.

Replicate branches of three tree species, with and without bark, were placed in streams and on land in a lowland tropical forest in Panama. After 3 and 11 months of decomposition, we measured mass loss and nitrogen (N) concentrations and sequenced the fungal and bacterial communities of both wood and bark tissues.

While bark decomposed faster than the underlying wood and had higher N concentrations, bark presence slowed wood mass loss. Nitrogen concentration could account for interspecific variation in wood mass loss, but not bark mass loss. In contrast, bark mass loss, but not wood mass loss, was faster in streams than on land, suggesting fragmentation is more important for bark mass loss in streams. Differences in fungal and bacterial community composition between bark and wood substrates were significant but small.

Our results indicate that bark can slow wood decomposition instead of promoting it, and that at least for branch wood, the primary drivers of decomposition differ between bark and wood. Differences in the factors driving decomposition rate between bark and wood suggest that the contribution of bark to the decomposition of woody biomass may depend on habitat.

A free Plain Language Summary can be found within the Supporting Information of this article.
Transcriptional response of Emiliania huxleyi under changing nutrient environments in the North Pacific Subtropical Gyre
Authors: Alexander Harriet , Rouco Mónica , Haley Sheean T. , Dyhrman Sonya T.
Published: February 2020

The widespread coccolithophore Emiliania huxleyi is an abundant oceanic phytoplankton, impacting the global cycling of carbon through both photosynthesis and calcification. Here, we examined the transcriptional responses of populations of E. huxleyi in the North Pacific Subtropical Gyre to shifts in the nutrient environment. Using a metatranscriptomic approach, nutrient‐amended microcosm studies were used to track the global metabolism of E. huxleyi. The addition of nitrate led to significant changes in transcript abundance for gene pathways involved in nitrogen and phosphorus metabolism, with a decrease in the abundance of genes involved in the acquisition of nitrogen (e.g. N‐transporters) and an increase in the abundance of genes associated with phosphate acquisition (e.g. phosphatases). Simultaneously, after the addition of nitrate, genes associated with calcification and genes unique to the diploid life stages of E. huxleyi significantly increased. These results suggest that nitrogen is a major driver of the physiological ecology of E. huxleyi in this system and further suggest that the addition of nitrate drives shifts in the dominant life‐stage of the population. Together, these results underscore the importance of phenotypic plasticity to the success of E. huxleyi, a characteristic that likely underpins its ability to thrive across a variety of marine environments.
Helping decision making for reliable and cost‐effective 2b‐RAD sequencing and genotyping analyses in non‐model species
Authors: Barbanti Anna , Torrado Hector , Macpherson Enrique , Bargelloni Luca , Franch Rafaella , Carreras Carlos , Pascual Marta
Published: February 2020

High‐throughput sequencing has revolutionized population and conservation genetics. RAD sequencing methods, such as 2b‐RAD, can be used on species lacking a reference genome. However, transferring protocols across taxa can potentially lead to poor results. We tested two different IIB enzymes (AlfI and CspCI) on two species with different genome sizes (the loggerhead turtle Caretta caretta and the sharpsnout seabream Diplodus puntazzo) to build a set of guidelines to improve 2b‐RAD protocols on non‐model organisms while optimising costs. Good results were obtained even with degraded samples, showing the value of 2b‐RAD in studies with poor DNA quality. However, library quality was found to be a critical parameter on the number of reads and loci obtained for genotyping. Resampling analyses with different number of reads per individual showed a trade‐off between number of loci and number of reads per sample. The resulting accumulation curves can be used as a tool to calculate the number of sequences per individual needed to reach a mean depth ≥20 reads to acquire good genotyping results. Finally, we demonstrated that selective‐base ligation does not affect genomic differentiation between individuals, indicating that this technique can be used in species with large genome sizes to adjust the number of loci to the study scope, to reduce sequencing costs and to maintain suitable sequencing depth for a reliable genotyping without compromising the results. Here, we provide a set of guidelines to improve 2b‐RAD protocols on non‐model organisms with different genome sizes, helping decision‐making for a reliable and cost‐effective genotyping.
TRPV1 activation alleviates cognitive and synaptic plasticity impairments through inhibiting AMPAR endocytosis in APP23/PS45 mouse model of Alzheimer’s disease
Authors: Du Yehong , Fu Min , Huang Zhilin , Tian Xin , Li Junjie , Pang Yayan , Song Weihong , Tian Wang Yu , Dong Zhifang
Published: February 2020

Alzheimer's disease (AD) is one of the most common causes of neurodegenerative diseases in the elderly. The accumulation of amyloid‐β (Aβ) peptides is one of the pathological hallmarks of AD and leads to the impairments of synaptic plasticity and cognitive function. The transient receptor potential vanilloid 1 (TRPV1), a nonselective cation channel, is involved in synaptic plasticity and memory. However, the role of TRPV1 in AD pathogenesis remains largely elusive. Here, we reported that the expression of TRPV1 was decreased in the brain of APP23/PS45 double transgenic AD model mice. Genetic upregulation of TRPV1 by adeno‐associated virus (AAV) inhibited the APP processing and Aβ deposition in AD model mice. Meanwhile, upregulation of TRPV1 ameliorated the deficits of hippocampal CA1 long‐term potentiation (LTP) and spatial learning and memory through inhibiting GluA2‐containing α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid receptor (AMPAR) endocytosis. Furthermore, pharmacological activation of TRPV1 by capsaicin (1 mg/kg, i.p.), an agonist of TRPV1, dramatically reversed the impairments of hippocampal CA1 LTP and spatial learning and memory in AD model mice. Taken together, these results indicate that TRPV1 activation effectively ameliorates cognitive and synaptic functions through inhibiting AMPAR endocytosis in AD model mice and could be a novel molecule for AD treatment.
Associations between neighborhood‐level factors and opioid‐related mortality: A multi‐level analysis using death certificate data
Authors: Flores Michael William , Lê Cook Benjamin , Mullin Brian , Halperin‐Goldstein Gabriel , Nathan Aparna , Tenso Kertu , Schuman‐Olivier Zev
Published: February 2020

Aim

To identify associations between opioid‐related mortality and neighborhood‐level risk factors.

Design

Cross‐sectional study.

Setting

Massachusetts, USA.

Participants

Using 2011–14 Massachusetts death certificate data, we identified opioid‐related (n = 3089) and non‐opioid‐related premature deaths (n = 8729).

Measurements

The independent variables consisted of four sets of neighborhood‐level factors: (1) psychosocial, (2) economic, (3) built environment and (4) health‐related. At the individual level we included the following compositional factors: age at death, sex, race/ethnicity, marital status, education, veteran status and nativity. The primary outcome of interest was opioid‐related mortality.

Findings

Multi‐level models identified number of social associations per 10 000 [odds ratio (OR) = 0.84, P = 0.002, 95% confidence interval (CI) = 0.75–0.94] and number of hospital beds per 10 000 (OR = 0.78, P < 0.001, 95% CI = 0.68–0.88) to be inversely associated with opioid‐related mortality, whereas the percentage living in poverty (OR = 1.01, P = 0.008, 95% CI = 1.00–1.01), food insecurity rate (OR = 1.21, P = 0.002, 95% CI = 1.07–1.37), number of federally qualified health centers (OR = 1.02, P = 0.028, 95% CI = 1.02–1.08) and per‐capita morphine milligram equivalents of hydromorphone (OR = 1.05, P = 0.003, 95% CI = 1.01–1.08) were positively associated with opioid‐related mortality.

Conclusions

Opioid‐related deaths between 2011 and 2014 in the state of Massachusetts appear to be positively associated with the percentage living in poverty, food insecurity rate, number of federally qualified health centers and per‐capita morphine milligram equivalents of hydromorphone, but inversely associated with number of social associations per 10 000 and number of hospital beds per 10 000.
Association between alcohol consumption and subclinical femoral atherosclerosis in smoking and non‐smoking men: the AWHS study
Authors: Moreno‐Franco Belén , Pérez‐Esteban Alejandro , Civeira Fernando , Guallar‐Castillón Pilar , Casasnovas José Antonio , Mateo‐Gállego Rocío , Jarauta Estíbaliz , Malo Sara , Laclaustra Martín
Published: February 2020

Background and Aims

Many addictive substances, such as tobacco and alcohol, influence atherosclerosis development. Whether or not tobacco's pro‐atherosclerotic effect is influenced by alcohol consumption is unknown. We aimed to estimate the impact of alcohol intake on the presence of subclinical atherosclerosis in femoral arteries in smoking and non‐smoking middle‐aged men.

Design, Setting and Participants

Cross‐sectional analysis of a subset of the Aragon Workers Health Study (AWHS), comprising 2099 men with mean age 50.9 years without previous cardiovascular disease.

Measurements

The presence of plaques in femoral arteries was assessed by high‐resolution sonography. Self‐reported alcohol consumption over the previous year was measured with a food frequency questionnaire. The sample was divided into four groups according to their daily grams of alcohol consumption ≤ 1 (abstainers), ≥ 2 to < 30, ≥ 30 to < 60 and ≥ 60 g/day. Participants were divided on ever‐smoking (current and former) versus never‐smoking strata in the main analysis.

Findings

We did not find a significant association between the different levels of alcohol intake and the likelihood of developing femoral artery atherosclerosis in never‐smokers. Ever‐smoking was positively associated with femoral atherosclerosis overall [odds ratio (OR) = 3.00; 95% confidence interval (CI) = 2.40, 3.74; P < 0.001] and within each level of alcohol consumption. Atherosclerosis was lower in ever‐smokers who consumed 2 g/day or more but less than 30 g/day with respect to those ever‐smokers who were abstainers (OR = 0.70; 95% CI = 0.49, 0.99; P < 0.05). However, among these ever‐smokers, atherosclerosis prevalence was still higher than among never‐smokers who consumed alcohol in the same amount (2 g/day or more but less than 30 g/day) (OR = 2.73; 95% CI = 2.07, 3.61; P < 0.001).

Conclusions

Among middle‐aged men, moderate alcohol consumption appears to be associated with lower prevalence of femoral artery subclinical atherosclerosis compared with alcohol abstinence only in ever‐smokers.
New genomic features of the polled intersex syndrome variant in goats unraveled by long‐read whole‐genome sequencing
Authors: Simon R. , Lischer H. E. L. , Pieńkowska‐Schelling A. , Keller I. , Häfliger I. M. , Letko A. , Schelling C. , Lühken G. , Drögemüller C.
Published: February 2020

In domestic goats, the polled intersex syndrome (PIS) refers to XX female‐to‐male sex reversal associated with the absence of horn growth (polled). The causal variant was previously reported as a 11.7 kb deletion at approximately 129 Mb on chromosome 1 that affects the transcription of both FOXL2 and several long non‐coding RNAs. In the meantime the presence of different versions of the PIS deletion was postulated and trials to establish genetic testing with the existing molecular genetic information failed. Therefore, we revisited this variant by long‐read whole‐genome sequencing of two genetically female (XX) goats, a PIS‐affected and a horned control. This revealed the presence of a more complex structural variant consisting of a deletion with a total length of 10 159 bp and an inversely inserted approximately 480 kb‐sized duplicated segment of a region located approximately 21 Mb further downstream on chromosome 1 containing two genes, KCNJ15 and ERG. Publicly available short‐read whole‐genome sequencing data, Sanger sequencing of the breakpoints and FISH using BAC clones corresponding to both involved genome regions confirmed this structural variant. A diagnostic PCR was developed for simultaneous genotyping of carriers for this variant and determination of their genetic sex. We showed that the variant allele was present in all 334 genotyped polled goats of diverse breeds and that all analyzed 15 PIS‐affected XX goats were homozygous. Our findings enable for the first time a precise genetic diagnosis for polledness and PIS in goats and add a further genomic feature to the complexity of the PIS phenomenon.