bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mixing and matching methylotrophic enzymes to design a novel methanol utilization pathway inE. coli
Authors: De Simone A. , Vicente C.M. , Peiro C. , Gales L. , Bellvert F. , Enjalbert B. , Heux S. 
Published: April 2020

ABSTRACTOne-carbon (C1) compounds, such as methanol, have recently gained attention as alternative low-cost and non-food feedstocks for microbial bioprocesses. Considerable research efforts are thus currently focused on the generation of synthetic methylotrophs by transferring methanol assimilation pathways into established bacterial production hosts. In this study, we used an iterative combination of dry and wet approaches to design, implement and optimize this metabolic trait in the most common chassis,E. coli. Throughin silicomodeling, we designed a new route that “mixed and matched” two methylotrophic enzymes: a bacterial methanol dehydrogenase (Mdh) and a dihydroxyacetone synthase (Das) from yeast. To identify the best combination of enzymes to introduce intoE. coli, we built a library of 266 pathway variants containing different combinations of Mdh and Das homologues and screened it using high-throughput13C-labeling experiments. The highest level of incorporation, 22% of labeled methanol carbon into the multi-carbon compound PEP, was obtained using a variant composed of a Mdh fromA. gerneriand a codon-optimized version ofP. angustaDas. Finally, the activity of this new synthetic pathway was further improved by engineering strategic metabolic targets identified using omics and modelling approaches. The final synthetic strain had 1.5 to 5.9 times higher methanol assimilation in intracellular metabolites and proteinogenic amino acids than the starting strain did. Broadening the repertoire of methanol assimilation pathways is one step further toward synthetic methylotrophy inE. coli.
Spectral graph theory efficiently characterises ventilation heterogeneity in lung airway networks
Authors: Whitfield Carl A. , Latimer Peter , Horsley Alex , Wild Jim M. , Collier Guilhem J. , Jensen Oliver E. 
Published: April 2020

AbstractThis paper introduces a linear operator for the purposes of quantifying the spectral properties of transport within resistive trees, such as airflow in lung airway networks. The operator, which we call the Maury matrix, acts only on the terminal nodes of the tree and is equivalent to the adjacency matrix of a complete graph summarising the relationships between all pairs of terminal nodes. We show that the eigenmodes of the Maury operator have a direct physical interpretation as the relaxation, or resistive, modes of the network. We apply these findings to both idealised and image-based models of ventilation in lung airway trees and show that the spectral properties of the Maury matrix characterise the flow asymmetry in these networks more concisely than the Laplacian modes, and that eigenvector centrality in the Maury spectrum is closely related to the phenomenon of ventilation heterogeneity caused by airway narrowing or obstruction. This method has applications in dimensionality reduction in simulations of lung mechanics, as well as for characterisation of models of the airway tree derived from medical images.
Genome-wide identification, characterization, and expression analysis of the monovalent cation-proton antiporter superfamily in maize, and functional analysis of its role in salt tolerance
Authors: Kong Mengsi , Luo Meijie , Li Jingna , Feng Zhen , Zhang Yunxia , Song Wei , Zhang Ruyang , Wang Ronghuan , Wang Yuandong , Zhao Jiuran , Tao Yongsheng , Zhao Yanxin 
Published: April 2020

ABSTRACTNa+, K+and pH homeostasis are important for plant life and they are controlled by the monovalent cation proton antiporter (CPA) superfamily. The roles ofZmCPAsin salt tolerance are not fully elucidated. In this study, we identified 35ZmCPAscomprising 13 Na+/H+exchangers (ZmNHXs), 16 cation/H+exchanger (ZmCHXs), and 6 K+efflux antiporters (ZmKEAs). All ZmCPAs have transmembrane domains and maize protoplasts transient expression showed that ZmNHX5 and ZmCHX17 localized to cell membrane system.ZmCHXswere specifically highly expressed in anthers, whileZmNHXsandZmKEAsshowed high expression in various tissues.ZmNHX5andZmKEA2were up-regulated in maize seedlings under both NaCl and KCl stresses. Yeast complementation experiments revealed the roles ofZmNHX5, ZmKEA2in NaCl tolerance. Analyses of the maize mutants further validated the salt tolerance functions ofZmNHX5andZmKEA2. Our study highlights comprehensive information ofZmCPAsand provides new gene targets for salt tolerance maize breeding.
Macroevolutionary Stability Predicts Interaction Patterns of Species in Seed Dispersal Networks
Authors: Burin Gustavo , Guimaraes Paulo R. , Quental Tiago B. 
Published: April 2020

AbstractAssessing deep-time mechanisms affecting the assembly of ecological networks is key to understanding biodiversity changes on broader time scales. We combined analyses of diversification rates with interaction network descriptors from 468 bird species belonging to 29 seed-dispersal networks to show that bird species that contribute most to the network structure of plant-frugivorous interactions belong to lineages that show higher macroevolutionary stability. This association is stronger in warmer, wetter, less seasonal environments. We infer that the macroevolutionary sorting mechanism acts through the regional pool of species by sorting species based on the available relative differences in diversification rates, rather than absolute rates. Our results illustrate how the interplay between interaction patterns and diversification dynamics may shape the organization and long-term dynamics of ecological networks.
Selective enhancement of low-gamma activity by tACS improves phonemic processing and reading accuracy in dyslexia
Authors: Marchesotti Silvia , Nicolle Johanna , Merlet Isabelle , Arnal Luc H. , Donoghue John P. , Giraud Anne-Lise 
Published: April 2020

AbstractThe phonological deficit in dyslexia is associated with altered low-gamma oscillatory function in left auditory cortex, but a causal relationship between oscillatory function and phonemic processing has never been established. After confirming a deficit at 30 Hz with electroencephalography (EEG), we applied 20 minutes of transcranial alternating current stimulation (tACS) to transiently restore this activity in adults with dyslexia. The intervention significantly improved phonological processing and reading accuracy as measured immediately after tACS. The effect was selective to 30 Hz stimulation, and proportional to dyslexia severity. Importantly, we observed that the focal intervention on the left auditory cortex also decreased 30 Hz activity in the right superior temporal cortex, resulting in reinstating a left dominance for the oscillatory response, as present in controls. These findings formally establish a causal role of neural oscillations in phonological processing, and offer solid neurophysiological grounds for a potential correction of low-gamma anomalies, and for alleviating of the phonological deficit in dyslexia.
multicrispr: gRNA design for prime editing and parallel targeting of thousands of targets
Authors: Bhagwat Aditya M , Graumann Johannes , Wiegandt Rene , Bentsen Mette , Kuenne Carsten , Preussner Jens , Braun Thomas , Looso Mario 
Published: April 2020

AbstractTargeting the coding genome to introduce single nucleotide deletions/insertions via Crispr/Cas9 technology has become a standard procedure in recent years. It has quickly spawned a multitude of methods such as Prime Editing, Crispr/Cas9 assisted APEX proximity labeling of proteins, or homology directed repair (HDR), for which supporting bioinformatic tools are, however, lagging behind. New applications often require specific guide-RNA (gRNA) design functionality, and a generic gRNA design tool is critically missing. Here we review gRNA designer software and introduce multicrispr, an R based tool intended to design individual gRNAs as well as gRNA libraries targeting many genomic loci in parallel. The package is easy to use, detects, scores and filters gRNAs on both efficiency and specificity, visualizes and aggregates results per target or Crispr/Cas9 sequence, and finally returns both genomic ranges as well as sequences of preferred, off target-free gRNAs. In order to be generic, multicrispr defines and implements agenomic arithmetics frameworkas a basis for facile adaptation to techniques yet to arise. Its performance and new gRNA design concepts such astarget set specific filteringfor gRNA libraries render multicrispr the tool of choice when dealing with screening-like approaches.
Neonicotinoids Disrupt Circadian Rhythms and Sleep in Honey Bees
Authors: Tackenberg Michael C. , Giannoni-Guzmán Manuel A. , Doll Caleb A. , Agosto-Rivera José L. , Broadie Kendal , Moore Darrell , McMahon Douglas G. 
Published: April 2020

AbstractHoney bees are critical pollinators in ecosystems and agriculture, but their numbers have significantly declined. Declines in pollinator populations are thought to be due to multiple factors including habitat loss, climate change, increased vulnerability to disease and parasites, and pesticide use. Neonicotinoid pesticides are agonists of insect nicotinic cholinergic receptors, and sub-lethal exposures are linked to reduced honey bee hive survival. Honey bees are highly dependent on circadian clocks to regulate critical behaviors, such as foraging orientation and navigation, time-memory for food sources, sleep, and learning/ memory processes. Because circadian clock neurons in insects receive light input through cholinergic signaling we tested for effects of neonicotinoids on honey bee circadian rhythms and sleep. Neonicotinoid ingestion by feeding over several days results in neonicotinoid accumulation in the bee brain, disrupts circadian rhythmicity in many individual bees, shifts the timing of behavioral circadian rhythms in bees that remain rhythmic, and impairs sleep. Neonicotinoids and light input act synergistically to disrupt bee circadian behavior, and neonicotinoids directly stimulate wake-promoting clock neurons in the fruit fly brain. Neonicotinoids disrupt honey bee circadian rhythms and sleep, likely by aberrant stimulation of clock neurons, to potentially impair honey bee navigation, time-memory, and social communication.
Single-cell analysis of upper airway cells reveals host-viral dynamics in influenza infected adults
Authors: Cao Yuming , Guo Zhiru , Vangala Pranitha , Donnard Elisa , Liu Ping , McDonel Patrick , Ordovas-Montanes Jose , Shalek Alex K. , Finberg Robert W. , Wang Jennifer P. , Garber Manuel 
Published: April 2020

AbstractInfluenza virus infections are major causes of morbidity and mortality. Research using cultured cells, bulk tissue, and animal models cannot fully capture human disease dynamics. Many aspects of virus-host interactions in a natural setting remain unclear, including the specific cell types that are infected and how they and neighboring bystander cells contribute to the overall antiviral response. To address these questions, we performed single-cell RNA sequencing (scRNA-Seq) on cells from freshly collected nasal washes from healthy human donors and donors diagnosed with acute influenza during the 2017-18 season. We describe a previously uncharacterized goblet cell population, specific to infected individuals, with high expression of MHC class II genes. Furthermore, leveraging scRNA-Seq reads, we obtained deep viral genome coverage and developed a model to rigorously identify infected cells that detected influenza infection in all epithelial cell types and even some immune cells. Our data revealed that each donor was infected by a unique influenza variant and that each variant was separated by at least one unique non-synonymous difference. Our results demonstrate the power of massively-parallel scRNA-Seq to study viral variation, as well as host and viral transcriptional activity during human infection.
The role of gene expression on human sexual dimorphism: too early to call
Authors: Porcu Eleonora , Claringbould Annique , Lepik Kaido ,   BIOS Consortium, Richardson Tom G. , Santoni Federico A. , Franke Lude , Reymond Alexandre , Kutalik Zoltán 
Published: April 2020

AbstractThe genetic underpinning of sexual dimorphism is very poorly understood. The prevalence of many diseases differs between men and women, which could be in part caused by sex-specific genetic effects. Nevertheless, only a few published genome-wide association studies (GWAS) were performed separately in each sex. The reported enrichment of expression quantitative trait loci (eQTLs) among GWAS–associated SNPs suggests a potential role of sex-specific eQTLs in the sex-specific genetic mechanism underlying complex traits.To explore this scenario, we performed a genome-wide analysis of sex-specific whole blood RNA-seq eQTLs from 3,447 individuals. Among 9 million SNP-gene pairs showing sex-combined associations, we found 18 genes with significant sex-specificcis-eQTLs (FDR 5%). Our phenome-wide association study of the 18 top sex-specific eQTLs on >700 traits unraveled that these eQTLs do not systematically translate into detectable sex-specific trait-associations. Power analyses using real eQTL- and causal effect sizes showed that millions of samples would be necessary to observe sex-specific trait associations that are fully driven by sex-specificcis-eQTLs. Compensatory effects may further hamper their detection. In line with this observation, we confirmed that the sex-specific trait-associations detected so far are not driven by sex-specificcis-eQTLs.
Identifying Neural Signatures Mediating Behavioral Symptoms and Psychosis Onset: High-Dimensional Whole Brain Functional Mediation Analysis
Authors: Chén Oliver Y. , Cao Hengyi , Phan Huy , Nagels Guy , Reinen Jenna M. , Gou Jiangtao , Qian Tianchen , Di Junrui , Prince John , Cannon Tyrone D. , de Vos Maarten 
Published: April 2020

ABSTRACTAlong the pathway from behavioral symptoms to the development of psychotic disorders sits the multivariate mediating brain. The functional organization and structural topography of large-scale neural mediators among patients with brain disorders, however, are not well understood. Here, we design a high-dimensional brain-wide functional mediation framework to investigate brain regions that intermediate between baseline behavioral symptoms and future conversion to full psychosis among individuals at clinical high risk (CHR). Using resting-state functional magnetic resonance imaging (fMRI) data from 263 CHR subjects, we extract anαbrain atlas and aβbrain atlas: the former underlines brain areas associated with prodromal symptoms and the latter highlights brain areas associated with disease onset. In parallel, we identify thePmediators and theNmediators that respectively facilitate or protect against developing brain disorders among subjects with more severe behavioral symptoms and quantify the effect of each neural mediator on disease development. Taken together, theα-βatlases and theP-Nmediators paint a brain-wide picture of neural markers that are potentially regulating behavioral symptoms and the development of psychotic disorders and highlight a statistical framework that is useful to uncover large-scale intermediating variables in a regulatory biological organization.
Analysis of SARS-CoV-2 Antibodies in COVID-19 Convalescent Blood using a Coronavirus Antigen Microarray
Authors: de Assis Rafael R. , Jain Aarti , Nakajima Rie , Jasinskas Algis , Felgner Jiin , Obiero Joshua M. , Adenaiye Oluwasanmi , Tai Sheldon , Hong Filbert , Norris Philip J. , Stone Mars , Simmons Graham , Bagri Anil , Schreiber Martin , Buser Andreas , Holbro Andreas , Battegay Manuel , Hosimer Philip , Noesen Charles , Milton Donald K. ,   Prometheus Study Group, Davies D. Huw , Contestable Paul , Corash Laurence M. , Busch Michael P. , Felgner Philip L. , Khan Saahir 
Published: April 2020

AbstractThe current practice for diagnosis of COVID-19, based on SARS-CoV-2 PCR testing of pharyngeal or respiratory specimens in a symptomatic patient at high epidemiologic risk, likely underestimates the true prevalence of infection. Serologic methods can more accurately estimate the disease burden by detecting infections missed by the limited testing performed to date. Here, we describe the validation of a coronavirus antigen microarray containing immunologically significant antigens from SARS-CoV-2, in addition to SARS-CoV, MERS-CoV, common human coronavirus strains, and other common respiratory viruses. A comparison of antibody profiles detected on the array from control sera collected prior to the SARS-CoV-2 pandemic versus convalescent blood specimens from virologically confirmed COVID-19 cases demonstrates near complete discrimination of these two groups, with improved performance from use of antigen combinations that include both spike protein and nucleoprotein. This array can be used as a diagnostic tool, as an epidemiologic tool to more accurately estimate the disease burden of COVID-19, and as a research tool to correlate antibody responses with clinical outcomes.
Vesicular GABA-transporter neurons in the zona incerta are maximally active during non rapid-eye movement (NREM) and rapid-eye movement (REM) sleep
Authors: Blanco-Centurion Carlos , Luo SiWei , Vidal-Ortiz Aurelio , Shiromani Priyattam J. 
Published: April 2020

AbstractSleep and wake are opposing behavioral states controlled by the activity of specific neurons. The neurons responsible for sleep/wake control have not been fully identifed due to the lack ofin-vivohigh throughput technology. We use the deep-brain calcium (Ca2+) imaging method to identify activity of hypothalamic neurons expressing the vesicular GABA transporter (vGAT), a marker of GABAergic neurons. vGAT-cre mice (n=5) were microinjected with rAAV-FLEX-GCaMP6Minto the lateral hypothalamus and 21d later the Ca2+influx in vGAT neurons (n=372) was recorded in freely-behaving mice during waking (W), NREM and REM sleep. Post-mortem analysis revealed the lens tip located in the zona incerta/lateral hypothalamus (ZI-LH) and the change in fluorescence of neurons in the field of view was as follows: 54.9% of the vGAT neurons had peak fluorescence during REM sleep (REM-max), 17.2% were NREM-max, 22.8% were wake-max while 5.1% were both wake+REM max. Thus, three quarters of the recorded vGAT neurons in the ZI-LH were most active during sleep. In the NREM-max group Ca2+fluorescence anticipated the initiation of NREM sleep onset and remained high throughout sleep (NREM and REM sleep). In the REM-max neurons Ca2+fluorescence increased before the onset of REM sleep and stayed elevated during the episode. Activation of the vGAT NREM-max neurons in the zona incerta and dorsal lateral hypothalamus would inhibit the arousal neurons to initiate and maintain sleep.
Volatiles defenses of AmazonAztecaants (repellent ants)
Authors: Jardine Kolby J. , de O. Piva Luani R. , Rodrigues Tayana B. , Spanner Gustavo C. , Rodrigues Jardel R. , Menezes Valdiek S. , Sampaio Israel , Oliveira Daniela C. , Gimenez Brunon O. , Higuchi Niro , Chambers Jeffrey 
Published: April 2020

ABSTRACTAztecaants are widely distributed in the neotropics and have been utilized as natural insect repellent for centuries.Aztecaoils provide natural defense against herbivores in mutualistic interactions between ants and their host trees. While chemical characterization of oil secretions revealed a composition dominated by iridoids and ketones, the volatile emissions fromAztecaants, and therefore the active gas-phase semiochemicals, remain uncharacterized. In this study, we determined the composition of volatile emissions from a sample of anAztecaant nest near the Rio Negro in the central Amazon. We foundAztecaemissions were composed of a blend of methyl cyclopentyl and methyl cyclopentenyl based volatiles previously identified inAztecaoil extracts as potent alarm pheromones. The ketone 6-methyl-5-hepten-2-one, which also waspreviously identified as a major component of theAztecaoil, was found to be the dominant volatile emitted. For the first time, we report emissions of the highly volatile ketones 2,3-butadione and acetoin from theAztecanest. Our study has important implications for the better understanding of the ecology and defense strategies ofAztecaants in herbivore defense and provides a base for future commercial applications involvingAztecaant essential oils as natural insect repellents.
Deletion of the mitochondrial matrix protein cyclophilin-D prevents parvalbumin interneuron dysfunction and cognitive deficits in a mouse model of NMDA hypofunction
Authors: Phensy Aarron , Lindquist Kathy L. , Lindquist Karen A. , Bairuty Dania , Gauba Esha , Guo Lan , Tian Jing , Du Heng , Kroener Sven 
Published: April 2020

AbstractRedox dysregulation and oxidative stress are final common pathways in the pathophysiology of a variety of psychiatric disorders, including schizophrenia. Oxidative stress causes dysfunction of GABAergic parvalbumin-positive interneurons (PVI), which are crucial for the coordination of neuronal synchrony during sensory- and cognitive-processing. Mitochondria are the main source of reactive oxygen species (ROS) in neurons and they control synaptic activity through their roles in energy production and intracellular calcium homeostasis. We have previously shown that in male mice transient blockade of NMDA receptors during development (subcutaneous injections of 30 mg/kg ketamine (KET) on postnatal days 7, 9, and 11) results in long-lasting alterations in synaptic transmission and reduced parvalbumin expression in the adult prefrontal cortex (PFC), contributing to a behavioral phenotype that mimics multiple symptoms associated with schizophrenia. These changes correlate with oxidative stress and impaired mitochondrial function in both PVI and pyramidal cells. Here, we show that genetic deletion (Ppif-/-) of the mitochondrial matrix protein cyclophilin D (CypD) prevents perinatal KET-induced increases in ROS and the resulting deficits in PVI function, and changes in excitatory and inhibitory synaptic transmission in the PFC. Deletion of CypD also prevented KET-induced behavioral deficits in cognitive flexibility, social interaction, and novel object recognition. Taken together, these data highlight how mitochondrial activity may play an integral role in modulating PVI-mediated cognitive processes.Significance StatementMitochondria are important modulators of oxidative stress and cell function, yet how mitochondrial dysfunction affects cell activity and synaptic transmission in psychiatric illnesses is not well understood. NMDA receptor blockade with ketamine during development causes oxidative stress, dysfunction of parvalbumin-positive interneurons (PVI), and long-lasting physiological and behavioral changes. Here we show that mice deficient for the mitochondrial matrix protein cyclophilin D show robust protection from PVI dysfunction following perinatal NMDAR-blockade. Mitochondria serve as an essential node for a number of stress-induced signaling pathways and our experiments suggest that failure of mitochondrial redox regulation can contribute to PVI dysfunction.