bluuebunny/crossref_metadata_2025 huggingface dataset:
AUTS2 Governs Cerebellar Development, Purkinje Cell Maturation, Motor Function and Social Communication
Authors: Yamashiro Kunihiko , Hori Kei , Lai Esther S.K. , Aoki Ryo , Shimaoka Kazumi , Egusa Saki F. , Sakamoto Asami , Abe Manabu , Sakimura Kenji , Watanabe Takaki , Uesaka Naofumi , Kano Masanobu , Hoshino Mikio
Published: January 2020

Autism susceptibility candidate 2(AUTS2), a risk gene for autism spectrum disorders (ASDs), is implicated in telencephalon development. Because AUTS2 is also expressed in the cerebellum where defects have been linked to ASDs, we investigated AUTS2 functions in the cerebellum. AUTS2 is specifically localized in Purkinje cells (PCs) and Golgi cells during postnatal development.Auts2conditional knockout (cKO) mice exhibited smaller and deformed cerebella containing immature-shaped PCs with reduced expression ofCacna1a.Auts2cKO and knock-down experiments implicated AUTS2 participation in elimination and translocation of climbing fiber synapses, and restriction of parallel fiber synapse numbers.Auts2cKO mice exhibited behavioral impairments in motor learning and vocal communications. BecauseCacna1ais known to regulate synapse development in PCs, it suggests that AUTS2 is required for PC maturation to elicit normal development of PC synapses and thus the impairment ofAUTS2may cause cerebellar dysfunction related to psychiatric illnesses such as ASDs.
Model-based detection of whole-genome duplications in a phylogeny
Authors: Zwaenepoel Arthur , Van de Peer Yves
Published: January 2020

Ancient whole-genome duplications (WGDs) leave signatures in comparative genomic data sets that can be harnessed to detect these events of presumed evolutionary importance. Current statistical approaches for the detection of ancient WGDs in a phylogenetic context have two main drawbacks. The first is that unwarranted restrictive assumptions on the ‘background’ gene duplication and loss rates make inferences unreliable in the face of model violations. The second is that most methods can only be used to examine a limited set ofa prioriselected WGD hypotheses; and cannot be used to discover WGDs in a phylogeny. In this study we develop an approach for WGD inference using gene count data that seeks to overcome both issues. We employ a phylogenetic birth-death model that includes WGD in a flexible hierarchical Bayesian approach, and use reversible-jump MCMC to perform Bayesian inference of branch-specific duplication, loss and WGD retention rates accross the space of WGD configurations. We evaluate the proposed method using simulations, apply it to data sets from flowering plants and discuss the statistical intricacies of model-based WGD inference.
Polyamine metabolism regulates the T cell epigenome through hypusination
Authors: Puleston Daniel J. , Baixauli Francesc , Sanin David E. , Villa Matteo , Kabat Agnieszka , Kamiński Marcin M. , Weiss Hauke , Grzes Katarzyna , Flachsmann Lea , Field Cameron S. , Stanckzak Michal , Schimmelpfennig Lena , Hassler Fabian , Wang Chao , Yosef Nir , Kuchroo Vijay K. , Musa Yaarub , Mittler Gerhard , Buescher Joerg M. , Balabanov Stefan , Pearce Edward J. , Green Douglas R. , Pearce Erika L.
Published: January 2020

We report here a central role for polyamines in T cell differentiation and function. Deficiency in ornithine decarboxylase (ODC), a critical enzyme for polyamine synthesis, resulted in a profound failure of CD4+T cells to adopt correct subset specification, underscored by ectopic expression of multiple cytokines and lineage-defining transcription factors across TH1, TH2, TH17, and Tregpolarizing conditions, and enhanced colitogenic potential. T cells deficient in deoxyhypusine synthase (DHPS) or deoxyhypusine hydroxylase (DOHH), which sequentially utilize polyamines to generate hypusine, phenocopiedOdc-deficient T cells, and mice in which T cells lackedDhpsorDohhdeveloped colitis. Polyamine-hypusine pathway enzyme deficiency caused widespread chromatin and transcriptional dysregulation accompanied by alterations in histone methylation, histone acetylation, and TCA cycle metabolites. Epigenetic modulation by 2-hydroxyglutarate, or histone acetyltransferase inhibition, restored CD4+T cell subset specification. Thus, polyamine synthesis via hypusine is critical for maintaining the epigenome to focus THcell subset fidelity.
Asymmetric transcallosal conduction delay leads to finer bimanual coordination
Authors: Bortoletto Marta , Bonzano Laura , Zazio Agnese , Ferrari Clarissa , Pedullà Ludovico , Gasparotti Roberto , Miniussi Carlo , Bove Marco
Published: January 2020

It has been theorized that hemispheric dominance and a more segregated information processing have evolved to overcome long conduction delay through the corpus callosum (TCD) but that this may still impact behavioral performance mostly in tasks requiring high timing accuracy. Nevertheless, a thorough understanding of the temporal features of interhemispheric communication is missing due to methodological shortcomings. Here, we show in the motor system that TCD can be measured from transcranial magnetic stimulation (TMS) -evoked potentials (TEPs): by integrating TEPs with diffusion tensor imaging (DTI) and peripheral measures of interhemispheric inhibition (i.e., the ipsilateral silent period-iSP), we show that P15 TEP component reflects TCD between motor areas. Importantly, we report that better bimanual coordination is achieved when TCD between motor areas is asymmetric. These results suggest that interhemispheric communication can be optimized through asymmetric connectivity, in which information transfer is faster from the dominant hemisphere to the non-dominant hemisphere.
Differentiating between integration and non-integration strategies in perceptual decision making
Authors: Stine Gabriel M , Zylberberg Ariel , Ditterich Jochen , Shadlen Michael N
Published: January 2020

Many tasks used to study decision-making encourage subjects to integrate evidence over time. Such tasks are useful to understand how the brain operates on multiple samples of information over prolonged timescales, but only if subjects actually integrate evidence to form their decisions. We explored the behavioral observations that corroborate evidence-integration in a number of task-designs. Several commonly accepted signs of integration were also predicted by non-integration strategies. Furthermore, an integration model could fit data generated by non-integration models. We identified the features of non-integration models that allowed them to mimic integration and used these insights to design a motion discrimination task that disentangled the models. In human subjects performing the task, we falsified a non-integration strategy in each and confirmed prolonged integration in all but one subject. The findings illustrate the difficulty of identifying a decision-maker’s strategy and support solutions to achieve this goal.
Community sequencing on a natural experiment reveals little influence of host species and timing but a strong influence of compartment on the composition of root endophytes in three annual Brassicaceae
Authors: Maciá-Vicente Jose G. , Nam Bora , Thines Marco
Published: January 2020

The plant family Brassicaceae includes some of the most studied hosts of plant microbiomes, targeting microbial diversity, community assembly rules, and effects on host performance. Compared to bacteria, eukaryotes in the brassicaceous microbiome remain understudied, especially under natural settings. Here, we assessed the impact of host identity and age on the assembly of fungal and oomycete root communities, using DNA metabarcoding of roots and associated soil of three annual co-habiting Brassicaceae collected at two time points. Our results showed that fungal communities are more diverse and structured than those of oomycetes. In both cases, plant identity and sampling time had little influence on community variation, whereas root/soil compartment had a strong effect by exerting control on the entry of soil microorganisms into the roots. The enrichment in roots of specific fungi suggests a specialization towards the asymptomatic colonization of plant tissues, which could be relevant to host’s fitness and health.
Systematic and functional analysis of horizontal gene transfer events in diatoms
Authors: Vancaester Emmelien , Depuydt Thomas , Osuna-Cruz Cristina Maria , Vandepoele Klaas
Published: January 2020

1.

Diatoms are a diverse group of mainly photosynthetic algae, responsible for 20% of worldwide oxygen production, which can rapidly respond to favourable conditions and often outcompete other phytoplankton. We investigated the contribution of horizontal gene transfer (HGT) to its ecological success. A systematic phylogeny-based bacterial HGT detection procedure across nine sequenced diatoms showed that 3-5% of their proteome has a horizontal origin and a large influx occurred at the ancestor of diatoms. More than 90% of HGT genes are expressed, and species-specific HGT genes inPhaeodactylum tricornutumundergo strong purifying selection. They are implicated in several processes including environmental sensing, and expand the metabolic toolbox. Cobalamin (vitamin B12) is an essential cofactor for roughly half of the diatoms and is only produced by bacteria. Genes involved in its final synthesis were detected as HGT, including five consecutive enzymes inFragilariopsis cylindrus. This might give diatoms originating from the Southern Ocean, a region typically depleted in cobalamin, a competitive advantage. Overall, we show that HGT is a prevalent mechanism that is actively used in diatoms to expand its adaptive capabilities.
Evaluation of Genetic Diversity in Cultivated and Exotic Germplasm Sources of Faba Bean Using Important Morphological Traits
Authors: Kumar Praveen , Kaushik Prashant
Published: January 2020

Background and Objective

Faba bean is an important crop for achieving nutritional food security, but there is very limited diversity in the cultivated varieties of faba bean. Moreover, genetic diversity is vital for its use in faba bean genetic imporvement.

Material and Methods

Here we determined the diversity in the sixty-four genotypes of faba bean of different agro-ecological origins. Plants were grown in randomized block design in three replications. Further, the genotypes were characterized based on the ten morphological traits.

Results

Highly significant differences were determined for all of the studied traits. Whereas, the number of cluster per plant was positively correlated with the pods per plants. Moreover, the trait number of cluster per plant determined the most substantial positive effect on seed yield.

Conclusions

Overall, our results indicate a wide range of variability for further selection and improvement of faba bean ideotype.
Comparison of visualisation tools for single-cell RNAseq data
Authors: Çakır Batuhan , Prete Martin , Huang Ni , van Dongen Stijn , Pir Pınar , Kiselev Vladimir Yu.
Published: January 2020

In the last decade, single cell RNAseq (scRNAseq) datasets have grown from a single cell to millions of cells. Due to its high dimensionality, the scRNAseq data contains a lot of valuable information, however, it is not always feasible to visualise and share it in a scientific report or an article publication format. Recently, a lot of interactive analysis and visualisation tools have been developed to address this issue and facilitate knowledge transfer in the scientific community. In this study, we review and compare several of the currently available analysis and visualisation tools and benchmark those that allow to visualize the scRNAseq data on the web and share it with others. To address the problem of format compatibility for most visualisation tools, we have also developed a user-friendly R package,sceasy, which allows users to convert their own scRNAseq datasets into a specific data format for visualisation.
SBOL Visual 2 Ontology
Authors: Misirli Göksel , Beal Jacob , Gorochowski Thomas E. , Stan Guy-Bart , Wipat Anil , Myers Chris
Published: January 2020

Standardising the visual representation of genetic parts and circuits is vital for unambiguously creating and interpreting genetic designs. To this end, an increasing number of tools are adopting well-defined glyphs from the Synthetic Biology Open Language (SBOL) Visual standard to represent various genetic parts and their relationships. However, the implementation and maintenance of the relationships between biological elements or concepts and their associated glyphs has to now been left up to tool developers. We address this need with the SBOL Visual 2 Ontology, a machine-accessible resource that provides rules for mapping from genetic parts, molecules, and interactions between them, to agreed SBOL Visual glyphs. This resource, together with a web service, can be used as a library to simplify the development of visualization tools, as a stand-alone resource to computationally search for suitable glyphs, and to help facilitate integration with existing biological ontologies and standards in synthetic biology.

Graphical TOC Entry
A paleogenetic perspective of the Sabana de Bogotá (Northern South America) population history over the Holocene (9000 – 550 cal BP)
Authors: Delgado Miguel , Rodríguez Freddy , Kassadjikova Kalina , Fehren-Schmitz Lars
Published: January 2020

ABSTRACT

On the basis of distinct lines of evidence, detailed reconstructions of the Holocene population history of the Sabana de Bogotá (SB) region, Northern South America, have been performed. Currently, there exist two competing models that support temporal continuity or, alternatively, divergence. Despite recent research that lends support to the population discontinuity model, several discrepancies remain, calling for other kinds of evidences to be explored for a more detailed picture of Holocene biocultural evolution. In this study, we analyze the mitochondrial genetic diversity of 30 individuals (including 15 newly reported complete mitochondrial genomes) recovered from several archaeological sites spanning from the late Pleistocene (12,164 cal BP) until the final late Holocene (2,751 cal BP) along with published data from the region dating ∼9,000-550 cal BP in order to investigate diachronic genetic change. Genetic diversity and distance indices were calculated, and demographic models tested in an approximate Bayesian computation (ABC) framework to evaluate whether patterns of genetic affinities of the SB prehispanic populations support genetic continuity or discontinuity. The results show that mitochondrial genomes of the complete dataset fall within the Native American haplogroups A2, B2, C1b, D1 and D4h3a. Haplotype and nucleotide diversity declined over time with further evidence of genetic drift and remarkable reduction of genetic diversity during the final late Holocene. Inter-population distances and the exact test of population differentiation, as well as demographic simulations show no population differentiation and population continuity over time. Consequently, based on the analyzed data, we cannot reject the genetic continuity in the SB region as a plausible population history scenario. However, the restriction of the analyses to the Hyper Variable Region 1 of the mitochondrial genome, and the very low sample size both constitute significant limitations to infer evolutionary history.
Extending rnaSPAdes functionality for hybrid transcriptome assembly
Authors: Prjibelski Andrey D. , Puglia Giuseppe D. , Antipov Dmitry , Bushmanova Elena , Giordano Daniela , Mikheenko Alla , Vitale Domenico , Lapidus Alla
Published: January 2020

Background

De novoRNA-Seq assembly is a powerful method for analysing transcriptomes when the reference genome is not available or poorly annotated. However, due to the short length of Illumina reads it is usually impossible to reconstruct complete sequences of complex genes and alternative isoforms. Recently emerged possibility to generate long RNA reads, such as PacBio and Oxford Nanopores, may dramatically improve the assembly quality, and thus the consecutive analysis. While reference-based tools for analysing long RNA reads were recently developed, there is no established pipeline forde novoassembly of such data.

Results

In this work we present a novel method that allows to perform high-qualityde novotranscriptome assemblies by combining accuracy and reliability of short reads with exon structure information carried out from long error-prone reads. The algorithm is designed by incorporating existing hybridSPAdes approach into rnaSPAdes pipeline and adapting it for transcriptomic data.

Conclusion

To evaluate the benefit of using long RNA reads we selected several datasets containing both Illumina and Iso-seq or Oxford Nanopore Technologies (ONT) reads. Using an existing quality assessment software, we show that hybrid assemblies performed with rnaSPAdes contain more full-length genes and alternative isoforms comparing to the case when only short-read data is used.

Availability and implementation

rnaSPAdes is implemented in C++ and Python and is freely available for Linux and MacOS under GPLv2 license at cab.spbu.ru/software/rnaspades/ and github.com/ablab/spades.
The two zinc fingers in the nucleocapsid domain of the HIV-1 Gag precursor are equivalent for the interaction with the genomic RNA in the cytoplasm, but not for the recruitment of the complexes at the plasma membrane
Authors: Boutant E. , Bonzi J. , Anton H. , Nasim M. B. , Cathagne R. , Réal E. , Dujardin D. , Carl P. , Didier P. , Paillart J-C. , Marquet R. , Mély Y. , de Rocquigny H. , Bernacchi S.
Published: January 2020

The HIV-1 Gag precursor specifically selects the unspliced viral genomic RNA (gRNA) from the bulk of cellular and spliced viral RNAsviaits nucleocapsid (NC) domain and drives gRNA encapsidation at the plasma membrane (PM). To further identify the determinants governing the intracellular trafficking of Gag-gRNA complexes and their accumulation at the PM, we compared, in living and fixed cells, the interactions between gRNA and wild-type (WT) Gag or Gag mutants carrying deletions in NC zinc fingers (ZFs), or a non-myristoylated version of Gag. Our data showed that the deletion of both ZFs simultaneously or the complete NC domain completely abolished intracytoplasmic Gag-gRNA interactions. Deletion of either ZF delayed the delivery of gRNA to the PM but did not prevent Gag-gRNA interactions in the cytoplasm, indicating that the two ZFs display redundant roles in this respect. However, ZF2 played a more prominent role than ZF1 in the accumulation of the ribonucleoprotein complexes at the PM. Finally, the myristate group which is mandatory for anchoring the complexes at the MP, was found to be dispensable for the association of Gag with the gRNA in the cytosol.

STATEMENT of SIGNIFICANCE

Formation of HIV-1 retroviral particles relies on specific interactions between the retroviral Gag precursor and the unspliced genomic RNA (gRNA). During the late phase of replication, Gag orchestrates the assembly of newly formed viruses at the plasma membrane (PM). It has been shown that the intracellular HIV-1 gRNA recognition is governed by the two-zinc finger (ZF) motifs of the nucleocapsid (NC) domain in Gag. Here we provided a clear picture of the role of ZFs in the cellular trafficking of Gag-gRNA complexes to the PM by showing that either ZF was sufficient to efficiently promote these interactions in the cytoplasm, while interestingly, ZF2 played a more prominent role in the relocation of these ribonucleoprotein complexes at the PM assembly sites.
A comprehensive atlas of white matter tracts in the chimpanzee
Authors: Bryant Katherine L. , Li Longchuan , Eichert Nicole , Mars Rogier B.
Published: January 2020

Chimpanzees (Pan troglodytes) are, along with bonobos, humans’ closest living relatives. The advent of diffusion MRI tractography in recent years has allowed a resurgence of comparative neuroanatomical studies in humans and other primate species. Here we offer, in comparative perspective, the first chimpanzee white matter atlas, constructed fromin vivochimpanzee diffusion-weighted scans. Comparative white matter atlases provide a useful tool for identifying neuroanatomical differences and similarities between humans and other primate species. Until now, comprehensive fascicular atlases have been created for humans (Homo sapiens), rhesus macaques (Macaca mulatta), and several other nonhuman primate species, but never in a nonhuman ape. Information on chimpanzee neuroanatomy is essential for understanding the anatomical specializations of white matter organization that are unique to the human lineage.
The Effects of Copper Addition on The Structure and Antibacterial Properties of Biomedical Glasses
Authors: Mojtabavi Leyla , Razavi Amir
Published: January 2020

In this work, we studied the effects of copper incorporation in the composition of bioactive glass. Three different glass compositions were synthesized with 0, 3, and 6 mol% of copper addition. X-Ray Diffraction (XRD) patterns confirmed that an amorphous microstructure was obtained for all three glass compositions. Results from Differential Thermal Analysis (DTA) showed that the copper addition in the glass lowers the glass transition temperature, from 646°C to 590°C when added at 6 mol%. X-ray Photoelectron (XPS) survey and high-resolution scans were performed to study the structural effects of copper addition in the glass. Results indicated that the incorporation of copper changes the ratio of bridging to non-birding oxygens in the structure. Glasses were further analyzed for their structure with Nuclear Magnetic Resonance (NMR) spectroscopy, which indicated that copper acts as a network modifier in the glass composition and copper-containing glasses show a less connected microstructure. Antibacterial efficacy of the glasses was analyzed against E. coli and S. epidermis. Copper-containing glasses showed a significantly higher inhibition zone compared to control glass. The glass with 6 mol% copper, exhibited inhibition zones of 9 and 16mm against E. coli and S. epidermis bacteria, respectively.
Competition sensing alters antibiotic production inStreptomyces
Authors: Westhoff Sanne , Kloosterman Alexander , van Hoesel Stephan F. A. , van Wezel Gilles P. , Rozen Daniel E.
Published: January 2020

One of the most important ways that bacteria compete for resources and space is by producing antibiotics that inhibit competitors. Because antibiotic production is costly, the biosynthetic gene clusters coordinating their synthesis are under strict regulatory control and often require “elicitors” to induce expression, including cues from competing strains. Although these cues are common, they are not produced by all competitors and so the phenotypes causing induction remain unknown. By studying interactions between 24 antibiotic-producing streptomycetes we show that inhibition between competitors is common and occurs more frequently if strains are closely related. Next, we show that antibiotic production is more likely to be induced by cues from strains that are closely related or that share secondary metabolite biosynthetic gene clusters (BGCs). Unexpectedly, antibiotic production is less likely to be induced by competitors that inhibit the growth of a focal strain, indicating that cell damage is not a general cue for induction. In addition to induction, antibiotic production often decreased in the presence of a competitor, although this response was not associated with genetic relatedness or overlap in BGCs. Finally, we show that resource limitation increases the chance that antibiotic production declines during competion. Our results reveal the importance of social cues and resource availability in the dynamics of interference competition in streptomycetes.

SIGNIFICANCE STATEMENT

Bacteria secrete antibiotics to inhibit their competitors, but the presence of competitors can determine whether these toxins are produced. Here, we study the role of the competitive and resource environment on antibiotic production inStreptomyces, bacteria renowned for their production of antibiotics. We show thatStreptomycesare more likely to produce antibiotics when grown with closely related competitors or that share biosynthetic pathways for secondary metabolites, but not when they are threatened by competitor’s toxins, in contrast to predictions of the competition sensing hypothesis.Streptomycesalso often reduce their output of antibiotics when grown with competitors, especially under nutrient limitation. Our findings highlight that interactions between the social and resource environments strongly regulate antibiotic production in these medicinally important bacteria.
Improvement of glymphatic-lymphatic drainage of beta-amyloid by focused ultrasound in Alzheimer’s disease model
Authors: Lee Youngsun , Choi Yoori , Park Eun-Joo , Kwon Seokjun , Kim Hyun , Lee Jae Young , Lee Dong Soo
Published: January 2020

Drainage of parenchymal waste through the lymphatic system maintains brain homeostasis. Age-related changes of glymphatic-lymphatic clearance lead to the accumulation beta-amyloid (Aβ) in dementia models. In this study, focused ultrasound treatment in combination with microbubbles (FUS-MB) improved Aβ drainage in early dementia model mice, 5XFAD. FUS-MB enhanced solute Aβ clearance from brain, but not plaques, to cerebrospinal fluid (CSF) space and then deep cervical lymph node (dCLN). dCLN ligation exaggerated memory impairment and progress of plaque formation and also the beneficial effects of FUS-MB upon Aβ removal through CSF-lymphatic routes. In this ligation model, FUS-MB improved memory despite accumulation of Aβ in CSF. In conclusion, FUS-MB enhances glymphatic-lymphatic clearance of Aβ mainly by increasing brain-to-CSF Aβ drainage. We suggest that FUS-MB can delay dementia progress in early period and benefits of FUS-MB depend on the effect of Aβ disposal through CSF-lymphatics.
Changing and stable chromatin accessibility supports transcriptional overhaul during neural stem cell activation
Authors: Maybury-Lewis Sun Y. , Brown Abigail K. , Yeary Mitchell , Sloutskin Anna , Dhakal Shleshma , McCarthy-Sinclair Brendan , Juven-Gershon Tamar , Webb Ashley E.
Published: January 2020

Adult neural stem cells are largely quiescent, and require transcriptional reprogramming to reenter the cell cycle and undergo neurogenesis. However, the precise mechanisms that underlie the rapid transcriptional overhaul during NSC activation remain undefined. Here, we identify the genome-wide chromatin accessibility differences between primary neural stem and progenitor cells in quiescent and activated states. We show that these distinct cellular states exhibit both shared and unique chromatin profiles, which are both associated with gene regulation. Interestingly, we find that accessible chromatin states specific to quiescent or activated cells are active enhancers bound by pro-neurogenic and quiescence factors, ASCL1 and NFI. In contrast, shared sites are gene promoters harboring constitutively accessible chromatin enriched for particular core promoter elements that are functionally associated with translation and metabolic functions. Together, our findings reveal how accessible chromatin states regulate a transcriptional overhaul and drive the switch between quiescence and proliferation in NSC activation.
Bayesian copy number detection and association in large-scale studies
Authors: Cristiano Stephen , McKean David , Carey Jacob , Bracci Paige , Brennan Paul , Chou Michael , Du Mengmeng , Gallinger Steven , Goggins Michael G. , Hassan Manal , Hung Rayjean , Kurtz Robert , Li Donghui , Lu Lingeng , Neale Rachel , Olson Sara , Petersen Gloria , Rabe Kari , Fu Jack , Risch Harvey , Rosner Gary , Ruczinski Ingo , Klein Alison P. , Scharpf Robert B.
Published: January 2020

Germline copy number variants (CNVs) increase risk for many diseases, yet detection of CNVs and quantifying their contribution to disease risk in large-scale studies is challenging. We developed an approach called CNPBayes to identify latent batch effects, to provide probabilistic estimates of integer copy number across the estimated batches, and to fully integrate the copy number uncertainty in the association model for disease. We demonstrate this approach in a Pancreatic Cancer Case Control study of 7,598 participants where the major sources of technical variation were not captured by study site and varied across the genome. Candidate associations aided by this approach include deletions of 8q24 near regulatory elements of the tumor oncogeneMYCand of Tumor Supressor Candidate 3 (TUSC3). This study provides a robust Bayesian inferential framework for estimating copy number and evaluating the role of copy number in heritable diseases.
Acetylation-mediated phase control of the nucleolus regulates cellular acetyl-CoA responses
Authors: Houston Ryan , Sekine Shiori , Calderon Michael J. , Seifuddin Fayaz , Wang Guanghui , Kawagishi Hiroyuki , Malide Daniela A. , Li Yuesheng , Gucek Marjan , Pirooznia Mehdi , Nelson Alissa J. , Stokes Matthew P. , Stewart-Ornstein Jacob , Wendell Stacy G. , Watkins Simon C. , Finkel Toren , Sekine Yusuke
Published: January 2020

The metabolite acetyl-CoA serves as an essential element for a wide range of cellular functions including ATP production, lipid synthesis and protein acetylation. Intracellular acetyl-CoA concentrations are associated with nutrient availability, but the mechanisms by which a cell responds to fluctuations in acetyl-CoA levels remain elusive. Here, we generate a cell system to selectively manipulate the nucleo-cytoplasmic levels of acetyl-CoA using CRISPR-mediated gene editing and acetate supplementation of the culture media. Using this system and quantitative omics analyses, we demonstrate that acetyl-CoA depletion alters the integrity of the nucleolus, impairing ribosomal RNA synthesis and evoking the ribosomal protein-dependent activation of p53. This nucleolar remodeling appears to be mediated through the class IIa HDAC deacetylases regulating the phase state of the nucleolus. Our findings highlight acetylation-mediated control of the nucleolus as an important hub linking acetyl-CoA fluctuations to cellular stress responses.
Calsyntenin-3 directly interacts with neurexins to orchestrate excitatory synapse development in the hippocampus
Authors: Kim Hyeonho , Kim Dongwook , Kim Jinhu , Lee Hee-Yoon , Park Dongseok , Kang Hyeyeon , Matsuda Keiko , Sterky Fredrik H. , Yuzaki Michisuke , Kim Jin Young , Choi Se-Young , Ko Jaewon , Um Ji Won
Published: January 2020

Calsyntenin-3 (Clstn3) is a postsynaptic adhesion molecule that induces presynaptic differentiation via presynaptic neurexins (Nrxns), but whether Nrxns directly bind to Clstn3 has been a matter of debate. Here, we show that β-Nrxns directly interact via their LNS domain with Clstn3 and Clstn3 cadherin domains. Expression of splice site 4 (SS4) insert-positive β-Nrxn variants, but not insert-negative variants, reversed the impaired Clstn3 synaptogenic activity observed in Nrxn-deficient neurons. Consistently, Clstn3 selectively formed complexes with SS4-positive Nrxnsin vivo. Neuron-specific Clstn3 deletion caused significant reductions in number of excitatory synaptic inputs, and moderate impairment of light-induced anxiety-like behaviors in mice. Moreover, expression of Clstn3 cadherin domains in CA1 neurons of Clstn3 conditional knockout mice rescued structural deficits in excitatory synapses, especially within the stratum radiatum layer. Collectively, our results suggest that Clstn3 links to SS4-positive Nrxns to induce presynaptic differentiation and orchestrate excitatory synapse development in specific hippocampal neural circuits.
Flexible contextual modulation of naturalistic texture perception in peripheral vision
Authors: Herrera-Esposito Daniel , Coen-Cagli Ruben , Gomez-Sena Leonel
Published: January 2020

Peripheral vision comprises most of our visual field, and is essential in guiding visual behavior. Its characteristic capabilities and limitations, which distinguish it from foveal vision, have been explained by the most influential theory of peripheral vision as the product of representing the visual input using summary-statistics. Despite its success, this account may provide a limited understanding of peripheral vision, because it neglects processes of perceptual grouping and segmentation. To test this hypothesis, we studied how contextual modulation, namely the modulation of the perception of a stimulus by its surrounds, interacts with segmentation in human peripheral vision. We used naturalistic textures, which are directly related to summary-statistics representations. We show that segmentation cues affect contextual modulation, and that this is not captured by our implementation of the summary-statistics model. We then characterize the effects of different texture statistics on contextual modulation, providing guidance for extending the model, as well as for probing neural mechanisms of peripheral vision.
Sir2 mitigates an intrinsic imbalance in origin licensing efficiency between early and late replicating euchromatin
Authors: Hoggard Timothy , Müller Carolin A. , Nieduszynski Conrad A. , Weinreich Michael , Fox Catherine A.
Published: January 2020

A eukaryotic chromosome relies on the function of multiple spatially distributed DNA replication origins for its stable inheritance. The location of an origin is determined by the chromosomal position of an MCM complex, the inactive form of the DNA replicative helicase that is assembled on chromosomal DNA in G1-phase (a.k.a. origin licensing). While the biochemistry of origin licensing is understood, the mechanisms that promote an adequate spatial distribution of MCM complexes across chromosomes are not. We have elucidated a role for the Sir2 histone deacetylase in establishing the normal distribution of MCM complexes acrossSaccharomyces cerevisiaechromosomes. In the absence of Sir2, MCM complexes accumulated within both early-replicating euchromatin and telomeric heterochromatin, and replication activity within these regions was enhanced. Concomitantly, the duplication of several regions of late-replicating euchromatin were delayed. Thus, Sir2-mediated attenuation of origin licensing established the normal spatial distribution of origins across yeast chromosomes required for normal genome duplication.

Significance statement

In eukaryotes, multiple DNA replication origins, the sites where new DNA synthesis begins during the process of cell division, must be adequately distributed across chromosomes to maintain normal cell proliferation and genome stability. This study describes a repressive chromatin-mediated mechanism that acts at the level of individual origins to attenuate the efficiency of origin formation. This attenuation is essential for achieving the normal spatial distribution of origins across the chromosomes of the eukaryotic microbeSaccharomyces cerevisiae. While the importance of chromosomal origin distribution to cellular fitness is now widely acknowledged, this study is the first to define a specific chromatin modification that establishes the normal spatial distribution of origins across a eukaryotic genome.
Proteomic changes in bacteria caused by exposure to environmental conditions can be detected by Matrix-Assisted Laser Desorption/Ionization – Time of Flight (MALDI-ToF) Mass Spectrometry
Authors: Chac Denise , Kordahi Melissa , Brettner Leandra , Verma Arushi , McCleary Paul , Crebs Kelly , Yee Cara , DePaolo R. William
Published: January 2020

In the past decade, matrix-assisted laser desorption/ionization time-of-flight (MALDI-ToF) mass spectrometry (MS) has become a timely and cost-effective alternative to bacterial identification. The MALDI-ToF MS technique analyzes the total protein of culturable microorganisms at the species level and produces a mass spectra based on peptides which is compared to a database of identified profiles. Consequently, unique signatures of each microorganism are produced allowing identification at the species and, more importantly, strain level. Our present study proposes that the MALDI-ToF MS can be further used to screen functional and metabolic differences. While other studies applied the MALDI-ToF technique to identify subgroups within species, we investigated how various environmental factors could alter the unique bacterial signatures. We found that genetic and phenotypic differences between microorganisms belonging to the same species can be reflected in peptide-mass fingerprints generated by MALDI-ToF MS. These results suggest that MALDI-ToF MS can screen intra-species phenotypic differences of several microorganisms.
Captive-reared migratory monarch butterflies show natural orientation when released in the wild
Authors: Wilcox Alana A. E. , Newman Amy E. M. , Raine Nigel E. , Norris D. Ryan
Published: January 2020

Eastern North American migratory monarch butterflies (Danaus plexippus) have faced sharp declines over the last two decades. Although captive rearing has been used as an important tool for engaging the public and supplementing conservation efforts, a recent study that tested monarchs in a flight simulator suggested that captive-reared monarchs lose their capacity to orient southward during fall migration to their Mexican overwintering sites. We raised offspring of wild-caught monarchs on swamp milkweed (Asclepias incarnata) and, after eclosion, individuals were either tested in a flight simulator or radio-tracked in the wild using array of over 100 automated telemetry towers. While only 33% (7/39) of monarchs tested in the flight simulator showed strong southeast to southwest orientation, 97% (28/29) of the radio-tracked individuals were detected by automated towers south or southeast of the release site, up to 200 km away. Our results suggest that, though captive rearing of monarch butterflies may cause temporary disorientation, proper orientation is likely re-established after exposure to natural skylight cues.
Differential processing and habituation in distinct spatial frequency channels in V1 of a mouse model of fragile X syndrome
Authors: Pak Alexandr , Kissinger Samuel T. , Chubykin Alexander A.
Published: January 2020

Extraction of both common and unique features across different visual inputs is crucial for animal survival. Regularities in the visual input lead to learning of the general principles governing an environment, whereas unique features are important for novelty detection. Low and high spatial frequencies (SF) represent two different channels of visual perception, which may be playing different roles in the processing of global pattern and local details. Alterations in the processing of these different SF channels may lead to impaired visual perception. Excessive detail-oriented processing and reduced habituation to sensory stimuli are some of the hallmarks of altered sensory perception in autism. However, the underlying neural mechanisms of these impairments are not understood. To gain insight into the pathophysiology of these impairments, we investigated the low and high SF channels in V1 of Fmr1 KO mice, the mouse model of Fragile X syndrome (FX). We first provide behavioral evidence for reduced habituation of both pupillary baseline and surprise responses in FX mice. Using silicon probe recordings, we demonstrate excessive processing of high SF stimuli in the late stages of visual responses in V1 of FX mice. We then show a reduced adaptation during a visual oddball paradigm in neurons preferring low but not high SF. Overall, our findings suggest that altered processing in distinct SF channels might contribute to altered visual perception and learning in FX and autism.
Neurons in Visual Cortex are Driven by Feedback Projections when their Feedforward Sensory Input is Missing
Authors: Keller Andreas J , Roth Morgane M , Scanziani Massimo
Published: January 2020

We sense our environment through pathways linking sensory organs to the brain. In the visual system, these feedforward pathways define the classical feedforward receptive field (ffRF), the area in space where visual stimuli excite a neuron1. The visual system also uses visual context, the visual scene surrounding a stimulus, to predict the content of the stimulus2, and accordingly, neurons have been found that are excited by stimuli outside their ffRF3–8. The mechanisms generating excitation to stimuli outside the ffRF are, however, unclear. Here we show that feedback projections onto excitatory neurons in mouse primary visual cortex (V1) generate a second receptive field driven by stimuli outside the ffRF. Stimulating this feedback receptive field (fbRF) elicits slow and delayed responses compared to ffRF stimulation. These responses are preferentially reduced by anesthesia and, importantly, by silencing higher visual areas (HVAs). Feedback inputs from HVAs have scattered receptive fields relative to their putative V1 targets enabling the generation of the fbRF. Neurons with fbRFs are located in cortical layers receiving strong feedback projections and are absent in the main input layer, consistent with a laminar processing hierarchy. The fbRF and the ffRF are mutually antagonistic since large, uniform stimuli, covering both, suppress responses. While somatostatin-expressing inhibitory neurons are driven by these large stimuli, parvalbumin and vasoactive-intestinal-peptide-expressing inhibitory neurons have antagonistic fbRF and ffRF, similar to excitatory neurons. Therefore, feedback projections may enable neurons to use context to predict information missing from the ffRF and to report differences in stimulus features across visual space, regardless if excitation occurs inside or outside the ffRF. We have identified a fbRF which, by complementing the ffRF, may contribute to predictive processing.
2019-20 Wuhan coronavirus outbreak: Intense surveillance is vital for preventing sustained transmission in new locations
Authors: Thompson R.N.
Published: January 2020

The outbreak of pneumonia originating in Wuhan, China, has generated 830 confirmed cases, including 26 deaths, as of 24 January 2020. The virus (2019-nCoV) has spread elsewhere in China and to other countries, including South Korea, Thailand, Japan and USA. Fortunately, there has not yet been evidence of sustained human-to-human transmission outside of China. Here we assess the risk of sustained transmission whenever the coronavirus arrives in other countries. Data describing the times from symptom onset to hospitalisation for 47 patients infected in the current outbreak are used to generate an estimate for the probability that an imported case is followed by sustained human-to-human transmission. Under the assumptions that the imported case is representative of the patients in China, and that the 2019-nCoV is similarly transmissible to the SARS coronavirus, the probability that an imported case is followed by sustained human-to-human transmission is 0.37. However, if the mean time from symptom onset to hospitalisation can be halved by intense surveillance, then the probability that an imported case leads to sustained transmission is only 0.005. This emphasises the importance of current surveillance efforts in countries around the world, to ensure that the ongoing outbreak will not become a large global epidemic.
Single generation exposure to a captive diet: a primer for domestication selection in a salmonid fish?
Authors: Islam Shahinur S. , Yates Matthew C. , Fraser Dylan J.
Published: January 2020

Millions of wild animals in captivity are reared on diets that differ in their uptake and composition from natural conditions. Few studies have investigated whether such novel diets elicit unintentional domestication selection in captive rearing and supplementation programs. In highly fecund salmonid fishes, natural and captive mortality is highest in the first few months of exogenous feeding. This high early mortality might be a potent driver of unintentional selection because wild fish normally forage on live prey whereas they are fed almost exclusively pellet feed in captivity: fish that do not adapt pellet feed well under captive conditions experience reduced growth and/or die. We tested this hypothesis by generating a large number of families from F1captive and wild fish originating from the same three populations and then rearing them each on pellet and natural, live, drifting feed for three months at the beginning of exogenous feeding. We found that captive fish of every population grew faster than wild fish in all diet treatments. Populations exhibited an idiosyncratic response to diet treatment, with two populations exhibiting faster growth on a pellet diet versus the natural diet but another population exhibiting similar growth in both diet treatments. Fish exposed to a natural diet also exhibited higher survival relative to those given a pellet diet. Captive and wild fish did not differ in survival, regardless of population of origin. Overall, we found evidence that rapid domestication selection associated with a single generation exposure to a novel captive diet generates genetically-based changes to individual fitness (e.g., growth and survival) in a wild fish.
Complete genome characterisation of a novel coronavirus associated with severe human respiratory disease in Wuhan, China
Authors: Wu Fan , Zhao Su , Yu Bin , Chen Yan-Mei , Wang Wen , Hu Yi , Song Zhi-Gang , Tao Zhao-Wu , Tian Jun-Hua , Pei Yuan-Yuan , Yuan Ming-Li , Zhang Yu-Ling , Dai Fa-Hui , Liu Yi , Wang Qi-Min , Zheng Jiao-Jiao , Xu Lin , Holmes Edward C. , Zhang Yong-Zhen
Published: January 2020

Emerging and re-emerging infectious diseases, such as SARS, MERS, Zika and highly pathogenic influenza present a major threat to public health1–3. Despite intense research effort, how, when and where novel diseases appear are still the source of considerable uncertainly. A severe respiratory disease was recently reported in the city of Wuhan, Hubei province, China. At the time of writing, at least 62 suspected cases have been reported since the first patient was hospitalized on December 12nd2019. Epidemiological investigation by the local Center for Disease Control and Prevention (CDC) suggested that the outbreak was associated with a sea food market in Wuhan. We studied seven patients who were workers at the market, and collected bronchoalveolar lavage fluid (BALF) from one patient who exhibited a severe respiratory syndrome including fever, dizziness and cough, and who was admitted to Wuhan Central Hospital on December 26th2019. Next generation metagenomic RNA sequencing4identified a novel RNA virus from the familyCoronaviridaedesigned WH-Human-1 coronavirus (WHCV).

Phylogenetic analysis of the complete viral genome (29,903 nucleotides) revealed that WHCV was most closely related (89.1% nucleotide similarity similarity) to a group of Severe Acute Respiratory Syndrome (SARS)-like coronaviruses (genusBetacoronavirus, subgenusSarbecovirus) previously sampled from bats in China and that have a history of genomic recombination. This outbreak highlights the ongoing capacity of viral spill-over from animals to cause severe disease in humans.
MHC*IMP – Imputation of Alleles for Genes in the Major Histocompatibility Complex
Authors: Squire David McG. , Motyer Allan , Ahn Richard , Nititham Joanne , Huang Zhi-Ming , Oksenberg Jorge R. , Foerster John , Liao Wilson , Leslie Stephen
Published: January 2020

We report the development of MHC*IMP, a method for imputing non-classical HLA and other genes in the human Major Histocompatibility Complex (MHC). We created a reference panel for 25 genes in the MHC using allele calls from Whole Genome Sequencing data, combined with SNP data for the same individuals. We used this to construct an allele imputation model, MHC*IMP, for each gene. Cross-validation showed that MHC*IMP performs very well, with allele prediction accuracy 93% or greater for all but two of the genes, and greater than 95% for all but four.