bluuebunny/crossref_metadata_2025 huggingface dataset:
Chipper: Open-source software for semi-automated segmentation and analysis of birdsong and other natural sounds
Authors: Searfoss Abigail M. , Pino James C. , Creanza Nicole
Published: October 2019

Audio recording devices have changed significantly over the last 50 years, making large datasets of recordings of natural sounds, such as birdsong, easier to obtain. This increase in digital recordings necessitates an increase in high-throughput methods of analysis for researchers. Specifically, there is a need in the community for open-source methods that are tailored to recordings of varying qualities and from multiple species collected in nature.

We developed Chipper, a Python-based software to semi-automate both the segmentation of acoustic signals and the subsequent analysis of their frequencies and durations. For avian recordings, we provide widgets to best determine appropriate thresholds for noise and syllable similarity, which aid in calculating note measurements and determining syntax. In addition, we generated a set of synthetic songs with various levels of background noise to test Chipper’s accuracy, repeatability, and reproducibility.

Chipper provides an effective way to quickly generate reproducible estimates of birdsong features. The cross-platform graphical user interface allows the user to adjust parameters and visualize the resulting spectrogram and signal segmentation, providing a simplified method for analyzing field recordings.

Chipper streamlines the processing of audio recordings with multiple user-friendly tools and is optimized for multiple species and varying recording qualities. Ultimately, Chipper supports the use of citizen-science data and increases the feasibility of large-scale multi-species birdsong studies.
Spatial preferences account for inter-animal variability during the continual learning of a dynamic cognitive task
Authors: Kastner David B. , Miller Eric A. , Yang Zhounan , Roumis Demetris K. , Liu Daniel F. , Frank Loren M. , Dayan Peter
Published: October 2019

Individual animals perform tasks in different ways, yet the nature and origin of that variability is poorly understood. In the context of spatial memory tasks, variability is often interpreted as resulting from differences in memory ability, but the validity of this interpretation is seldom tested since we lack a systematic approach for identifying and understanding factors that make one animal’s behavior different than another. Here we identify such factors in the context of spatial alternation in rats, a task often described as relying solely on memory of past choices. We combine hypothesis-driven behavioral design and reinforcement learning modeling to identify spatial preferences that, when combined with memory, support learning of a spatial alternation task. Identifying these preferences allows us to capture differences among animals, including differences in overall learning ability. Our results show that to understand the complexity of behavior requires quantitative accounts of the preferences of each animal.
Overexpression of CD47 is associated with brain overgrowth in 16p11.2 deletion syndrome
Authors: Li Jingling , Brickler Thomas , Banuelos Allison , Marjon Kristopher , Bian Jing , Narayanan Cyndhavi , Weissman Irving L. , Chetty Sundari
Published: October 2019

One of the most common genetic linkages associated with neuropsychiatric disorders, such as autism spectrum disorder and schizophrenia, occurs at the 16p11.2 locus. Copy number variants (CNVs) of the 16p gene can manifest in opposing head sizes. 16p11.2 deletion carriers tend to have macrocephaly (or brain enlargement), while those with 16p11.2 duplication frequently have microcephaly. Increases in both gray and white matter volume have been observed in brain imaging studies in 16p11.2 deletion carriers with macrocephaly. Here, we use human induced pluripotent stem cells (hiPSCs) derived from controls and subjects with 16p11.2 deletion and 16p11.2 duplication to understand the underlying mechanisms regulating brain overgrowth. To model both gray and white matter, we differentiated patient-derived iPSCs into neural progenitor cells (NPCs) and oligodendrocyte progenitor cells (OPCs). In both NPCs and OPCs, we show that CD47 (a ‘don’t eat me’ signal) is overexpressed in the 16p11.2 deletion carriers contributing to reduced phagocytosis bothin vitroandin vivo. Treatment of 16p11.2 deletion NPCs and OPCs with an anti-CD47 antibody to block CD47 restores phagocytosis to control levels. Furthermore, 16p11.2 deletion NPCs and OPCs upregulate cell surface expression of calreticulin (a pro-phagocytic ‘eat me’ signal) and its binding sites, indicating that these cells should be phagocytosed but fail to be eliminated due to elevations in CD47. While the CD47 pathway is commonly implicated in cancer progression, we document a novel role for CD47 in regulating brain overgrowth in psychiatric disorders and identify new targets for therapeutic intervention.
Does a passerine hibernate?
Authors: McNab Brian K. , Weston Kerry
Published: October 2019

The thermal physiology of the highly endangered Rock Wren (Xenicus gilviventris) from New Zealand is examined. It is a member of the Acanthisittidae, a family unique to New Zealand. This family, derived from Gondwana, is thought to be the sister taxon to all other passerines. Rock Wrens permanently reside above the climatic timberline at altitudes from 1,000 to 2,900 meters in the mountains of South Island. They feed on invertebrates and in winter face ambient temperatures well below freezing and deep deposits of snow. Their body temperature and rate of metabolism are highly variable. Rock Wrens regulate body temperature at ca. 36C, which in one individual decreased to 33.1C at an ambient temperature of 9.4C, which returned to 36C at 30.1C; its rate of metabolism decreased by 30%. The rate of metabolism in a second individual twice decreased by 35%, nearly to the basal rate expected from mass. The Rock Wren food habits, entrance into torpor, and continuous residence in a thermally demanding environment suggest that it may hibernate. For that conclusion to be accepted, evidence of its use of torpor for extended periods is required. Those data are not presently available. Acanthisittids are distinguished from other passerines by the combination of their temperate distribution, thermal flexibility, and a propensity to evolve a flightless condition. These characteristics may reflect their phylogenetic status, but they are so different from those found in other passerines that it is more likely that they reflect the geographical isolation of acanthisittids in a temperate environment for 85 million years in the absence of mammalian predators.
A phenotypic screening platform utilising human spermatozoa identifies new compounds with contraceptive activity
Authors: Gruber Franz , Barratt Christopher L.R. , Andrews Paul D.
Published: October 2019

There is an urgent need to develop new methods for male contraception, however a major barrier to drug discovery has been the lack of validated targets and the absence of an effective high-throughput phenotypic screening system. To address this deficit, we developed a fully-automated robotic screening platform that provided quantitative evaluation of compound activity against two key attributes of human sperm function: motility and acrosome reaction. In order to accelerate contraceptive development, we screened the comprehensive collection of 12,000 molecules that make up the ReFRAME repurposing library, comprising nearly all the small molecules that have been approved or have undergone clinical development, or have significant preclinical profiling. We identified several compounds that potently inhibit motility representing either novel drug candidates or routes to target identification. This platform will now allow for major drug discovery programmes that address the critical gap in the contraceptive portfolio as well as uncover novel human sperm biology.
Fibronectin-dependent tissue mechanics regulate the translation of segmentation clock oscillations into periodic somite formation
Authors: Gomes de Almeida Patrícia , Rifes Pedro , Martins-Jesus Ana Patrícia , Pinheiro Gonçalo G. , Andrade Raquel P. , Thorsteinsdóttir Sólveig
Published: October 2019

Somitogenesis starts with cyclic waves of expression of segmentation clock genes in the presomitic mesoderm (PSM) and culminates with periodic budding of somites in its anterior-most region. How cyclic clock gene expression is translated into timely morphological somite formation has remained unclear. A posterior to anterior gradient of increasing PSM tissue cohesion correlates with increasing fibronectin matrix complexity around the PSM, suggesting that fibronectin-dependent tissue mechanics may be involved in this transition. Here we address whether the mechanical properties of the PSM tissue play a role in regulating the pathway leading to cleft formation in the anterior PSM. We first interfered with cytoskeletal contractility in the chick PSM by disrupting actomyosin-mediated contractility directly or via Rho-associated protein kinase function. Then we perturbed fibronectin matrix accumulation around the PSM tissue by blocking integrin-fibronectin binding or fibronectin matrix assembly. All four treatments perturbedhairy1andmeso1expression dynamics and resulted in defective somitic clefts. A model is presented where a gradient of fibronectin-dependent tissue mechanics participates in the PSM wavefront of maturation by ensuring the correct spatio-temporal conversion of cyclic segmentation clock gene expression into periodic somite formation.
Modeling behaviorally relevant neural dynamics enabled by preferential subspace identification (PSID)
Authors: Sani Omid G. , Pesaran Bijan , Shanechi Maryam M.
Published: October 2019

Neural activity exhibits dynamics that in addition to a behavior of interest also relate to other brain functions or internal states. Understanding how neural dynamics explain behavior requires dissociating behaviorally relevant and irrelevant dynamics, which is not achieved with current neural dynamic models as they are learned without considering behavior. We develop a novel preferential subspace identification (PSID) algorithm that models neural activity while dissociating and prioritizing its behaviorally relevant dynamics. Applying PSID to large-scale neural activity in two monkeys performing naturalistic 3D reach-and-grasps uncovered new features for neural dynamics. First, PSID revealed the behaviorally relevant dynamics to be markedly lower-dimensional than otherwise implied. Second, PSID discovered distinct rotational dynamics that were more predictive of behavior. Finally, PSID more accurately learned the behaviorally relevant dynamics for each joint and recording channel. PSID provides a general new tool to reveal behaviorally relevant neural dynamics that can otherwise go unnoticed.
Direct observation of the setular web that fuses thoracopodal setae of a calanoid copepod into a collapsible fan
Authors: von Dassow George , Emlet Richard B.
Published: October 2019

Copepods are numerically dominant planktonic grazers throughout the waters of Earth, preyed upon in turn by a wide diversity of pelagic animals (1,2). Their feeding and swimming performance thus has global importance to aquatic food webs and oceanic carbon flux. These crustaceans swim and feed using cuticle-covered, segmented, muscular appendages whose reach is extended greatly by setae, extracellular chitinous extensions with diverse structure and function (3). Plumose setae, with subsidiary setules arranged like barbs on a feather, have well-documented roles in generating feeding and swimming currents (4,5). Recent work showed that plumose setae of barnacle cyprid thoracopods are permanently linked by setules into a single fan that opens and closes as one sheet during high-speed swimming (6). Intersetular linkage across cyprid thoracopods may greatly decrease leakage between extended setae, ensure even spread of setae within the fan, and promote ordered collapse of the fan to avoid entanglement of adjacent appendages. Here we demonstrate similar setular webbing amongst thoracopod setae in the calanoid copepod Acartia sp. High-speed video directly documents the existence of such links, and reveals that individuals experience apparently-irreparable degradation of the setal array due to de-linkage, with likely consequences for swimming performance.
Pinhole Optical Tweezers: Extending the Photobleaching Lifetime in the Presence of an Optical Trap by Wavefront Engineering
Authors: Zhang Zheng , Milstein Joshua N.
Published: October 2019

We present a new method for combining optical tweezers with single-molecule fluorescence in an engineered geometry we have coined a ‘pinhole’ optical trap. By utilizing an appropriately constructed Laguerre-Gaussian (LG) or ‘donut’ beam, and applying force along the axis of the trapping laser, one can maintain a low-intensity region of near-infrared (IR) light directly below the optical trap in which a biomolecule may be probed by both force spectroscopy and fluorescence. We show that within this region of low IR light intensity, the photobleaching lifetime of Alexa-647, an organic dye that is particularly sensitive to the high intensity trap light, can be significantly extended. This approach enables us to spatially separate the trap light from the fluorescence illumination without the need to physically separate, by many micrometers, the optical trap from the biological sample.
Structural variation in Drosophila melanogaster spermathecal ducts and its association with sperm competition dynamics
Authors: Hopkins Ben R. , Sepil Irem , Wigby Stuart
Published: October 2019

The ability of female insects to retain and use sperm for days, months, or even years after mating requires specialised storage organs in the reproductive tract. In most orders these organs include a pair of sclerotised capsules known as spermathecae. Here, we report that some Drosophila melanogaster females exhibit previously uncharacterised structures within the distal portion of the muscular duct that links a spermatheca to the uterus. We find that these ‘spermathecal duct presences’ (SDPs) may form in either or both ducts and can extend from the duct into the sperm-storing capsule itself. We further find that the incidence of SDPs varies significantly between genotypes, but does not change significantly with the age or mating status of females, the latter indicating that SDPs are not composed of or stimulated by sperm or male seminal proteins. We show that SDPs affect neither the number of first male sperm held in a spermatheca nor the number of offspring produced after a single mating. However, we find evidence that SDPs are associated with a lack of second male sperm in the spermathecae after females remate. This raises the possibility that SDPs provide a mechanism for variation in sperm competition outcome among females.
Data-Driven Analysis of a Mechanistic Model of CAR T Cell Signaling Predicts Effects of Cell-to-cell Heterogeneity
Authors: Cess Colin G. , Finley Stacey D.
Published: October 2019

Due to the variability of protein expression, cells of the same population can exhibit different responses to stimuli. It is important to understand this heterogeneity at the individual level, as population averages mask these underlying differences. Using computational modeling, we can interrogate a system much more precisely than by using experiments alone, in order to learn how the expression of each protein affects a biological system. Here, we examine a mechanistic model of CAR T cell signaling, which connects receptor-antigen binding to MAPK activation, to determine intracellular modulations that can increase cellular response. CAR T cell cancer therapy involves removing a patient’s T cells, modifying them to express engineered receptors that can bind to tumor-associated antigens to promote cell killing, and then injecting the cells back into the patient. This population of cells, like all cell populations, would have heterogeneous protein expression, which could affect the efficacy of treatment. Thus, it is important to examine the effects of cell-to-cell heterogeneity. We first generated a dataset of simulated cell responses via Monte Carlo simulations of the mechanistic model, where the initial protein concentrations were randomly sampled. We analyzed the dataset using partial least-squares modeling to determine the relationships between protein expression and ERK phosphorylation, the output of the mechanistic model. Using this data-driven analysis, we found that only the expressions of proteins relating directly to the receptor and the MAPK cascade, the beginning and end of the network, respectively, are relevant to the cells’ response. We also found, surprisingly, that increasing the amount of receptor present can actually inhibit the cell’s ability to respond due to increasing the strength of negative feedback from phosphatases. Overall, we have combined data-driven and mechanistic modeling to generate detailed insight into CAR T cell signaling.
An Adaptable Prosthetic Wrist Reduces Subjective Workload
Authors: Olsen Nathaniel R. , George Jacob A. , Brinton Mark R. , Paskett Michael D. , Kluger David T. , Tully Troy N. , Duncan Christopher C. , Clark Gregory A.
Published: October 2019

Many presently available prostheses lack a functional wrist. To fill this niche and to better understand the impact a wrist has in prosthetic functionality, we designed a low-cost, adaptable, 3D-printable prosthetic wrist that can be adapted to various prosthetic hands and sockets. The wrist utilizes inexpensive but powerful servo motors to provide simultaneous and proportional control of two degrees of freedom: pronation/supination and flexion/extension or radial/ulnar deviation. Participants used both our wrist and a commercially available wrist (DEKA “LUKE” Arm) to complete a modified version of the clothespin relocation task with and without the wrists enabled. Through use of the NASA Task Load Index we found that both wrists significantly reduced the subjective workload associated with clothespin relocation task (p < 0.05). However, we found no significant difference in task completion speed, presumably due to compensation strategies. This inexpensive and adaptable prosthetic wrist can be used by amputees to reduce task workload, or by researchers to further explore the importance of wrist function.
Polygenic risk modeling with latent trait-related genetic components
Authors: Aguirre Matthew , Tanigawa Yosuke , Venkataraman Guhan Ram , Tibshirani Rob , Hastie Trevor , Rivas Manuel A.
Published: October 2019

Polygenic risk models have led to significant advances in understanding complex diseases and their clinical presentation. While models like polygenic risk scores (PRS) can effectively predict outcomes, they do not generally account for disease subtypes or pathways which underlie within-trait diversity. Here, we introduce a latent factor model of genetic risk based on components from Decomposition of Genetic Associations (DeGAs), which we call the DeGAs polygenic risk score (dPRS). We compute DeGAs using genetic associations for 977 traits in the UK Biobank and find that dPRS performs comparably to standard PRS while offering greater interpretability. We show how to decompose an individual’s genetic risk for a trait across DeGAs components, highlighting specific results for body mass index (BMI), myocardial infarction (heart attack), and gout in 337,151 white British individuals, with replication in a further set of 25,486 non-British white individuals from the Biobank. We find that BMI polygenic risk factorizes into components relating to fat-free mass, fat mass, and overall health indicators like physical activity measures. Most individuals with high dPRS for BMI have strong contributions from both a fat mass component and a fat-free mass component, whereas a few ‘outlier’ individuals have strong contributions from only one of the two components. Overall, our method enables fine-scale interpretation of the drivers of genetic risk for complex traits.
Insights into the aetiology of snoring from observational and genetic investigations in the UK Biobank (n=408,317)
Authors: Campos Adrián I. , García-Marín Luis M. , Byrne Enda M. , Martin Nicholas G. , Cuéllar-Partida Gabriel , Rentería Miguel E.
Published: October 2019

We conducted the largest study of snoring using data from the UK Biobank (n∼ 408,000; snorers ∼152,000). A genome-wide association study (GWAS) identified 42 genome-wide significant loci, with a SNP-based heritability estimate of ∼10% on the liability scale. Genetic correlations with body mass index, alcohol intake, smoking, schizophrenia, anorexia nervosa and neuroticism were observed. Gene-based associations identified 173 genes, includingDLEU7, MSRB3andPOC5highlighting genes expressed in brain, cerebellum, lungs, blood, and oesophagus tissues. We used polygenic scores (PGS) to predict recent snoring and probable obstructive sleep apnoea (OSA) in an independent Australian sample (n∼8,000). Mendelian randomisation analyses provided evidence that larger whole body fat mass causes snoring. Altogether, our results uncover new insights into the aetiology of snoring as a complex sleep-related trait and its role in health and disease beyond being a cardinal symptom of OSA.
Great tits in noisy territories and avoiding overlapping respond stronger to territorial intruders
Authors: Akçay Çağlar , Porsuk Y. Kağan , Avşar Alican , Çabuk Dilan , Bilgin C. Can
Published: October 2019

Animals often communicate with each other in noisy environments where interference from the ambient noise and other signallers may reduce the effectiveness of signals. Signalling behaviours may also evolve to interfere with signals of their opponents, e.g. by temporally overlapping them with their own, such as the song overlapping behaviour that is seen in some songbirds during aggressive interactions. Song overlapping has been proposed to be a signal of aggressive intent, but few studies directly examined the association between song overlapping and aggressive behaviours of the overlapping bird (the predictive criterion). In the present paper we examined the question of whether song overlapping is correlated with aggressive behaviours displayed during a simulated territorial intrusion in a population of great tits (Parus major) living in an urban-rural gradient. We also examined whether aggressive behaviours are correlated with the ambient noise levels. We found that overlapping was associated negatively with aggressive behaviours males displayed against a simulated intruder. These results fail to support the predictive criterion for song overlapping, raising the question whether overlapping is in fact a signal of aggressive intent. Ambient noise levels were associated positively with aggressive behaviours but did not correlate with song rate, song duration or song overlapping. Great tits in noisy urban habitats may display higher levels of aggressive behaviours due to either interference of noise in aggressive communication or another indirect effect of noise.
A stable leading strand polymerase/clamp loader complex is required for normal and perturbed eukaryotic DNA replication
Authors: Stokes Katy , Winczura Alicja , Song Boyuan , De Piccoli Giacomo , Grabarczyk Daniel B.
Published: October 2019

The eukaryotic replisome must faithfully replicate DNA and cope with replication fork blocks and stalling, while simultaneously promoting sister chromatid cohesion. Ctf18-RFC is an alternative PCNA loader that links all these processes together by an unknown mechanism. Here, we use integrative structural biology combined with yeast genetics and biochemistry to highlight the specific functions that Ctf18-RFC plays within the leading strand machineryviaan interaction with the catalytic domain of DNA Pol ε. We show that a large and unusually flexible interface enables this interaction to occur constitutively throughout the cell cycle and regardless of whether forks are replicating or stalled. We reveal that, by being anchored to the leading strand polymerase, Ctf18-RFC can rapidly signal fork stalling to activate the S phase checkpoint. Moreover, we demonstrate that, independently of checkpoint signaling or chromosome cohesion, Ctf18-RFC functions in parallel to Chl1 and Mrc1 to protect replication forks and cell viability.
Punishment insensitivity emerges from impaired contingency detection, not aversion insensitivity or reward dominance
Authors: Jean-Richard-dit-Bressel Philip , Ma Cassandra , Bradfield Laura A. , Killcross Simon , McNally Gavan P.
Published: October 2019

Our behaviour is shaped by its consequences – we seek rewards and avoid harm. It has been reported that individuals vary markedly in their avoidance of detrimental consequences, i.e. in their sensitivity to punishment. The underpinnings of this variability are poorly understood; they may be driven by differences in aversion sensitivity, motivation for reward, and/or instrumental control. We examined these hypotheses by applying several analysis strategies to the behaviour of rats (n = 48; 18 female) trained in a task permitting concurrent assessment of punishment, reward-seeking, and Pavlovian fear. We show that punishment insensitivity is a unique phenotype, unrelated to differences in reward-seeking and Pavlovian fear, and due to a failure of instrumental control. Subjects insensitive to punishment are afraid of aversive events, they are simply unable to change their behaviour to avoid them.
GenIE-Sys: Genome Integrative Explorer System
Authors: Mannapperuma Chanaka , Waterworth John , Street Nathaniel
Published: October 2019

There are an ever-increasing number of genomes being sequenced, many of which have associated RNA sequencing and other genomics data. The availability of user-friendly web-accessible mining tools ensures that these data repositories provide maximum benefit to the community. However, there are relatively few options available for setting up such standalone frameworks. We developed the Genome Integrative Explorer System (GenIE-Sys) to set up web resources to enable search, visualization and exploration of genomics data typically generated by a genome project.

GenIE-Sys is implemented in PHP, JavaScript and Python and is freely available under the GNU GPL 3 public license. All source code is freely available at the GenIE-Sys website (https://geniesys.org) or GitHub (http://github.com/plantgenie/geniesys.git). Documentation is available at http://geniesys.readthedocs.io.
Pseudo-repeats in doublecortin make distinct mechanistic contributions to microtubule regulation
Authors: Manka Szymon W. , Moores Carolyn A.
Published: October 2019

Doublecortin (DCX) is a neuronal microtubule-associated protein (MAP) indispensable for brain development. Its flexibly linked DC domains – NDC and CDC – mediate microtubule (MT) nucleation and stabilisation, but it is unclear how. Using high-resolution time-resolved cryo-EM, we mapped NDC and CDC interactions with tubulin at different MT polymerisation stages and studied their functional effects on MT dynamics using TIRF microscopy. Although coupled, each DC repeat appears to have a distinct role in MT nucleation and stabilisation by DCX: CDC is a conformationally plastic tubulin binding module that appears to facilitate MT nucleation by binding tubulin oligomers and stabilising tubulin-tubulin contacts in the nascent MT lattice, while NDC appears to be favoured along the mature lattice, providing enhanced and durable MT stabilisation. Our near-atomic resolution structures of MT-bound DC domains also explain in unprecedented detail the DCX mutation-related brain defects observed in the clinic. This modular composition of DCX reflects a common design principle among MAPs where pseudo-repeats of tubulin/MT binding elements chaperone or stabilise distinct conformational transitions to regulate distinct stages of MT dynamic instability.
Potential Outbreak in Brazil by Equine Herpesvirus Type 2 (EHV-2): Detection, Clinical and Genetic Analysis of Equine Gammaherpesvirus 2
Authors: Cicolo Sofia , de Almeida Campos Angélica Cristine , de Oliveira Cairo Monteiro , Poltronieri Thais , Góes Luiz Gustavo Bentim , da Silveira Vanessa Barbosa , Barbosa Carla Meneguin , Baccarin Raquel Yvonne Arantes , Oliveira Danielle Bruna Leal , Belli Carla Bargi , Durigon Edison Luiz
Published: October 2019

Equine herpesvirus (EHV) commonly affects horses causing neurologic and respiratory symptoms beside spontaneous abortions, meaning huge economic losses for equine industry worldwide. In foals the virus can facilitate secondary infections byRhodococcus equi, important in morbidity and mortality in equines. A total of five genotypes of EHV were previously described in Brazil including EHV-1, EHV-2, EHV-3, EHV-4 and EHV-5. EHV-2 genotype had only been previously described in Brazil in asymptomatic animals. We report the dead of 11 foals in Middle-west region of Brazil showing respiratory and neurological symptoms, as well as several abortions in mares from the same farm. Laboratory exams revealed neutrophilia leukocytosis. Necroscopic and histopathologic findings were suppurative bronchopneumonia and ulcerative enteritis. Molecular assays point to the absence of the bacteriaRhodococcus equiand other EHV. The presence of EHV-2 DNA was confirmed by sequencing in serum sample from one foal. This is the first confirmed outbreak of EHV-2 causing disease in Brazilian horses with confirmed presence of the virus. EHV-2 has been neglected and could be highlight the important role of EHV-2 in equine respiratory disease and spontaneous abortions in equid in Brazil.

Author Summary

Equid herpesvirus type 2 (EHV-2), a gammaherpesvirus, has been neglected and can cause respiratory infection, abortion and in extreme cases neurologic symptoms and dead.

Outbreaks of EHV-2 never was described in Brazil and can be critical to losses in equid industry. Our report provides evidence for a direct link between the EHV-2 strain and the outbreak in foals. We proved the clinical, histopathological and phylogenetic analysis of segment of EHV-2 polymerase.

In summary, our study confirm that Gammaherpesvirus 2 is circulating in Brazil and the EHV-2 is a cause of the first outbreak in foals showing the important role of EHV-2 in equid respiratory disease.
Interdependent Allosteric FFA2R Modulators Synergistically Induce Functional Selective Activation and Desensitization in Neutrophils
Authors: Lind Simon , Holdfeldt André , Mårtensson Jonas , Sundqvist Martina , Kenakin Terry P. , Björkman Lena , Forsman Huamei , Dahlgren Claes
Published: October 2019

The non-activating allosteric modulator AZ1729, specific for free fatty acid receptor 2 (FFA2R), transfers the orthosteric FFA2R agonists propionate and the P2Y2R specific agonist ATP into activating ligands that trigger an assembly of the neutrophil superoxide generating NADPH-oxidase. The homologous priming effect on the propionate response and the heterologous receptor cross-talk sensitized ATP response mediated by AZ1729 are functional characteristics shared with Cmp58, another non-activating allosteric FFA2R modulator. In addition, AZ1729 also turned Cmp58 into a potent activator of the superoxide generating neutrophil NADPH-oxidase, and in agreement with the allosteric modulation concept, the effect was reciprocal in that Cmp58 turned AZ1729 into a potent activating allosteric agonist. The activation signals down-stream of FFA2R when stimulated by the two interdependent allosteric modulators were biased in that, unlike for orthosteric agonists, the two complementary modulators together triggered an activation of the NADPH-oxidase, but not any transient rise in the cytosolic concentration of free Ca2+. In addition, following AZ1729/Cmp58 activation, signaling by the desensitized FFA2Rs was functionally selective in that the orthosteric agonist propionate could still induce a transient rise in intracellular Ca2+. The novel neutrophil activation and receptor down-stream signaling pattern mediated by the two cross-sensitizing allosteric FFA2R modulators represents a new regulatory mechanism that controls receptor signaling.

Significance Statement

A novel activation mechanism of a G-protein coupled free fatty acid receptor (FFA2R), is synergistically triggered by two otherwise non-activating allosteric modulators in the absence of orthosteric agonists. The receptor down-stream signaling proved to be functionally selective (biased); a superoxide generating enzyme is assembled and activated without involvement of the Ca2+signaling pathway. The novel activation mechanism and the receptor down-stream signaling pattern mediated by the two cross-sensitizing allosteric FFA2R modulators, represents a new regulatory mechanism for control of GPCR-signaling.
The Swedish example of food animal production without extensive use of antibiotics – or “healthy animals do not need antibiotics”
Authors: Björkman Ingeborg , Röing Marta , Eriksen Jaran , Lundborg Cecilia Stålsby
Published: October 2019

Objective

To describe how stakeholders at different levels in food animal production in Sweden work to contain antibiotic resistance, with a special focus on poultry production. The stakeholders’ perceptions of antibiotic resistance and awareness of the One Health concept were also studied.

Methods

This is an interview study with thirteen informants. They represent policymakers, trade organisations, and veterinarians and farmers in the poultry industry. Interview transcripts were analysed using content analysis. The analysis continued until a latent theme emerged, and then the content was rearranged in four domains.

Findings

A latent theme “Working in unison” emerged, based on the consistency expressed by the informants when they discussed antibiotic resistance, use of antibiotics and food animal production methods. The theme was built on four domains, representing the content of the interviews: Knowledge and engagement; Cooperation; Animal health concept; and Development in balance with economic prerequisites. The work for healthy animals started in Sweden already in the 1920-ies and continued step by step in cooperation and with support from the government. In 1986 Sweden became the first country to ban antibiotics for growth promotion. Veterinarians were considered important drivers of processes by spreading knowledge and working close to the farmers. Farmers felt involved in the development of production methods. The One Health concept was well known among stakeholders working at national level but not among veterinarians in production or farmers.

Conclusions

Sweden has come far in work to contain antibiotic resistance in the animal sector by practicing restrictive use of antibiotics in food animal production. This practise is based on a long tradition of cooperation among stakeholders, from policymakers to farmers, and with a primary focus on animal health and welfare.
Quantifying the individual impact of artificial barriers in freshwaters: A standardized and absolute genetic index of fragmentation
Authors: Prunier Jérôme G. , Poesy Camille , Dubut Vincent , Veyssière Charlotte , Loot Géraldine , Poulet Nicolas , Blanchet Simon
Published: October 2019

Fragmentation by artificial barriers is an important threat to freshwater biodiversity. Mitigating the negative aftermaths of fragmentation is of crucial importance, and it is now essential for environmental managers to benefit from a precise estimate of the individual impact of weirs and dams on river connectivity. Although the indirect monitoring of fragmentation using molecular data constitutes a promising approach, it is plagued with several constraints preventing a standardized and individual quantification of barrier effects. Indeed, observed levels of genetic differentiation depend on both the age of the obstacle and the effective size of the populations it separates, making difficult comparisons of the actual barrier effect of different obstacles. Here, we developed a standardized genetic index of fragmentation (FINDEX), allowing an absolute and independent assessment of the individual effects of obstacles on connectivity. TheFINDEXis the standardized ratio (expressed as a percentage) between the observed genetic differentiation between pairs of populations located on either side of an obstacle and the genetic differentiation expected if this obstacle completely prevented gene flow. The expected genetic differentiation is calculated from simulations taking into account two nuisance parameters: the number of generations since barrier creation (the age of the obstacle) and the expected heterozygosity of the targeted populations, a proxy for effective population sizes. Using both simulated and published empirical datasets, we explored and discussed the validity and the limits of theFINDEX. We demonstrated that it allows quantifying genetic effects of fragmentation only from a few generations after barrier creation and provides valid comparisons among populations (or species) of different effective populations sizes and obstacles of different ages. The computation of theFINDEXrequires a minimum amount of fieldwork and genotypic data, and solves some of the difficulties inherent to the study of artificial fragmentation in rivers and potentially in other ecosystems. This makes theFINDEXa promising and objective tool for managers aiming at at planning restoration programs and at evaluating the efficiency of these programs.
Alzheimer’s Disease risk modifier genes do not impact tau aggregate uptake, seeding or maintenance in cell models
Authors: Kolay Sourav , Diamond Marc I.
Published: October 2019

Alzheimer’s disease (AD) afflicts millions of people worldwide, and is caused by accumulated amyloid beta and tau pathology. Progression of tau pathology in AD may utilize prion mechanisms of propagation in which pathological tau aggregates released from one cell are taken up by neighboring or connected cells and act as templates for their own replication, a process termed “seeding.” In cultured cells we have modeled various aspects of pathological tau propagation, including uptake of aggregates, induced (naked) seeding by exogenous aggregates, seeding caused by Lipofectamine-mediated delivery to the cell interior, and chronic maintenance of aggregates in cells through mother-to-daughter transmission. The factors that regulate these processes are not well understood, and we hypothesized that AD risk modifier genes might play a role. We identified 22 genes strongly linked to AD via meta-analysis of genome-wide association studies (GWAS). We used CRISPR/Cas-9 to individually knock out each in gene in HEK293T cells, and verified disruption using genomic sequencing. We then tested the effect of gene knockout in tau aggregate uptake, naked and Lipofectamine-mediated seeding, and aggregate maintenance in cultured cell lines. GWAS gene knockouts had no effect on these models of tau pathology. With obvious caveats due to the model systems used, these results imply that these 22 AD risk modifier genes do not directly modulate tau uptake, seeding, or aggregate maintenance.
In vivodeuterated water labeling allows tumor visualization via deuterium magnetic resonance spectroscopic imaging of cholesterol
Authors: Assmann Julian C. , Brender Jeffrey R. , Farthing Don E. , Saito Keita , Kishimoto Shun , Warrick Kathrynne A. , Maglakelidze Natella , Crooks Daniel R. , Merkle Hellmut , Gress Ronald E. , Krishna Murali C. , Buxbaum Nataliya P.
Published: October 2019

Water is an essential component of many biochemical reactions. Deuterated water (D2O) has been used to study cell kinetics, protein synthesis, and metabolism. We hypothesized that rapidly proliferating cancer cells would become preferentially labeled with deuterium due to high metabolic activity, thus allowing imaging of biosynthetically labeled metabolites within tumorsin vivo. We initiated systemic D2O labeling in two established tumor xenograft models, HT-29 and MiaPaCa-2 and imaged mice by deuterium magnetic resonance spectroscopic imaging (dMRSI). After 14 days of tumor growth and 7 days ofin vivolabeling, a clear contrast was demonstrated between the xenograft and the contralateral control limb in both models. The origin of the contrast was traced to an aliphatic peak at 1.8 ppm, which was identified byex vivoNMR analysis to originate from cholesterol and cholesterol esters. Cholesterol is important for tumor cell proliferation, signaling, and malignant transformation, while current methods to monitor cholesterol synthesis and accumulation are limited. This deuterated water labeling-imaging approach could complement current cancer imaging techniques, allowing not only imaging of uptake but also synthesis of cholesterol to elucidate effects on tumor cholesterol metabolismin vivo.
Nectins rather than E-cadherin anchor the actin belts at cell-cell junctions of epithelia
Authors: Mangeol Pierre , Massey-Harroche Dominique , Bivic André Le , Lenne Pierre-François
Published: October 2019

Cell-cell junctions support the mechanical integrity of epithelia by enabling adhesion and tension transmission between neighboring cells. The prevailing mechanistic dogma is that E-cadherin supports and transmits mechanical tension between cells through actin belts in a region named thezonula adherens. Using super-resolution microscopy on human intestinal biopsies and Caco-2 cells, we show that thezonula adherensconsists of E-cadherin and nectin belts that are separated by about 150 nm along the apico-basal direction, the nectin belt being in the immediate vicinity of the actin belt. The segregation of nectins and E-cadherin increases as the tissue matures. Our data redefine the structure of thezonula adherensand show that nectins, rather than E-cadherin, are the major connectors of actin belts in epithelia.
Conserved nuclear receptors controlling a novel trait target fast-evolving genes expressed in a single cell
Authors: Sieriebriennikov Bogdan , Sun Shuai , Lightfoot James W. , Witte Hanh , Moreno Eduardo , Rödelsperger Christian , Sommer Ralf J.
Published: October 2019

Environment shapes development through a phenomenon called developmental plasticity. Deciphering its genetic basis has implications for understanding evolution and adaptation to novel environments, yet molecular studies are scarce. Here, we expanded the gene regulatory network controlling predatoryvs.non-predatory morphology in the nematodePristionchus pacificus. First, we isolated a mutant in the nuclear hormone receptornhr-1with a previously unseen phenotypic effect. It disrupts mouth-form determination and results in animals combining features of both wild-type morphs. Further, we identified common targets of NHR-1 and the previously identified nuclear hormone receptor NHR-40 through transcriptomics. Unlike their highly conserved regulators, the target genes have no orthologs inCaenorhabditis elegansand likely result from lineage-specific expansions. An array of transcriptional reporters revealed co-expression of all tested targets in the same pharyngeal gland cell. The morphological remodeling of this cell accompanied the evolution of teeth and predation, linking rapid gene turnover with morphological innovations.
A two-way molecular dialogue between embryo and endosperm required for seed development
Authors: Doll N. M. , Royek S. , Fujita S. , Okuda S. , Stintzi A. , Widiez T. , Hothorn M. , Schaller A. , Geldner N. , Ingram G.
Published: October 2019

The plant embryonic cuticle is a hydrophobic barrier depositedde novoby the embryo during seed development. At germination it protects the seedling from water loss and is thus critical for survival. Embryonic cuticle formation is controlled by a signaling pathway involving the protease ALE1 and the receptor-like kinases GSO1 and GSO2. We show that a sulfated peptide, TWISTED SEED1 (TWS1) acts as a GSO1/GSO2 ligand. Cuticle surveillance depends on the action of ALE1 which, unlike TWS1 and GSO1/2, is not produced in the embryo but in the neighboring endosperm. Cleavage of an embryo-derived TWS1 precursor by ALE1 releases the active peptide, triggering GSO1/2-dependent cuticle reinforcement in the embryo. A bidirectional molecular dialogue between embryo and endosperm thus safeguards cuticle integrity prior to germination.

One Sentence Summary

Subtilase-mediated activation of the TWISTED SEED1 peptide provides spatial cues during embryo cuticle integrity monitoring.
Plants with self-sustained luminescence
Authors: Mitiouchkina Tatiana , Mishin Alexander S. , Gonzalez Somermeyer Louisa , Markina Nadezhda M. , Chepurnyh Tatiana V. , Guglya Elena B. , Karataeva Tatiana A. , Palkina Kseniia A. , Shakhova Ekaterina S. , Fakhranurova Liliia I. , Chekova Sofia V. , Tsarkova Aleksandra S. , Golubev Yaroslav V. , Negrebetsky Vadim V. , Dolgushin Sergey A. , Shalaev Pavel V. , Melnik Olesya A. , Shipunova Victoria O. , Deyev Sergey M. , Bubyrev Andrey I. , Pushin Alexander S. , Choob Vladimir V. , Dolgov Sergey V. , Kondrashov Fyodor A. , Yampolsky Ilia V. , Sarkisyan Karen S.
Published: October 2019

In contrast to fluorescent proteins, light emission from luciferase reporters requires exogenous addition of a luciferin substrate. Bacterial bioluminescence has been the single exception, where an operon of five genes is sufficient to produce light autonomously. Although commonly used in prokaryotic hosts, toxicity of the aldehyde substrate has limited its use in eukaryotes1. Here we demonstrate autonomous luminescence in a multicellular eukaryotic organism by incorporating a recently discovered fungal bioluminescent system2into tobacco plants. We monitored these light-emitting plants from germination to flowering, observing temporal and spatial patterns of luminescence across time scales from seconds to months. The dynamic patterns of luminescence reflected progression through developmental stages, circadian oscillations, transport, and response to injuries. As with other fluorescent and luminescent reporters, we anticipate that this system will be further engineered for varied purposes, especially where exogenous addition of substrate is undesirable.
Cascabel: a flexible, scalable and easy-to-use amplicon sequence data analysis pipeline
Authors: Asbun Alejandro Abdala , Besseling Marc A , Balzano Sergio , van Bleijswijk Judith , Witte Harry , Villanueva Laura , Engelmann Julia C
Published: October 2019

Marker gene sequencing of the rRNA operon (16S, 18S, ITS) or cytochrome c oxidase I (CO1) is a popular means to assess microbial communities of the environment, microbiomes associated with plants and animals, as well as communities of multicellular organisms via environmental DNA sequencing. Since this technique is based on sequencing a single gene rather than the entire genome, the number of reads needed per sample is lower than that required for metagenome sequencing, making marker gene sequencing affordable to nearly any laboratory. Despite the relative ease and cost-efficiency of data generation, analyzing the resulting sequence data requires computational skills that may go beyond the standard repertoire of a current molecular biologist/ecologist. We have developed Cascabel, a flexible and easy-to-use amplicon sequence data analysis pipeline, which uses Snakemake and a combination of existing and newly developed solutions for its computational steps. Cascabel takes the raw data as input and delivers a table of operational taxonomic units (OTUs) and a representative sequence tree. Our pipeline allows customizing the analyses by offering several choices for most of the steps, for example different OTU generating methods. The pipeline can make use of multiple computing nodes and scales from personal computers to computing servers. The analyses and results are fully reproducible and documented in an HTML and optional pdf report. Cascabel is freely available at Github: https://github.com/AlejandroAb/CASCABEL and licensed under GNU GPLv3.