bluuebunny/crossref_metadata_2025_split huggingface dataset:
Rare Genetic Variants Underlie Outlying levels of DNA Methylation and Gene-Expression
Authors: Chundru V. Kartik , Marioni Riccardo E. , Pendergast James G. D. , Lin Tian , Beveridge Allan J. , Martin Nicholas G. , Montgomery Grant W. , Hume David A. , Deary Ian J. , Visscher Peter M. , Wray Naomi R. , McRae Allan F. 
Published: February 2020

AbstractTesting the effect of rare variants on phenotypic variation is difficult due to the need for extremely large cohorts to identify associated variants given expected effect sizes. An alternative approach is to investigate the effect of rare genetic variants on low-level genomic traits, such as gene expression or DNA methylation (DNAm), as effect sizes are expected to be larger for low-level compared to higher-order complex traits. Here, we investigate DNAm in healthy ageing populations - the Lothian Birth cohorts of 1921 and 1936 and identify both transient and stable outlying DNAm levels across the genome. We find an enrichment of rare genetic variants within 1kb of DNAm sites in individuals with stable outlying DNAm, implying genetic control of this extreme variation. Using a family-based cohort, the Brisbane Systems Genetics Study, we observed increased sharing of DNAm outliers among more closely related individuals, consistent with these outliers being driven by rare genetic variation. We demonstrated that outlying DNAm levels have a functional consequence on gene expression levels, with extreme levels of DNAm being associated with gene expression levels towards the tails of the population distribution. Overall, this study demonstrates the role of rare variants in the phenotypic variation of low-level genomic traits, and the effect of extreme levels of DNAm on gene expression.
Activation and self-inactivation mechanisms of the cyclic oligoadenylate-dependent CRISPR ribonuclease Csm6
Authors: Garcia-Doval Carmela , Schwede Frank , Berk Christian , Rostøl Jakob T. , Niewoehner Ole , Tejero Oliver , Hall Jonathan , Marraffini Luciano A. , Jinek Martin 
Published: February 2020

AbstractUpon target RNA recognition, type III CRISPR-Cas systems produce cyclic oligoadenylate second messengers to activate downstream effectors including Csm6-family ribonucleases via their CARF domains. Here we show thatEnteroccocus italicusCsm6 (EiCsm6) degrades its cognate cyclic hexa-AMP (cA6) activator and report the crystal structure of EiCsm6 bound to a cA6 mimic. The structure, combined with biochemical and in vivo functional assays, reveal how cA6 recognition by the CARF domain activates the Csm6 HEPN domains for collateral RNA degradation, and how CARF domain-mediated cA6 cleavage provides an intrinsic off-switch to limit Csm6 activity in the absence of ring nucleases. These mechanisms facilitate rapid invader clearance and ensure termination of CRISPR interference to limit self-toxicity.
CoolMPS™: Advanced massively parallel sequencing using antibodies specific to each natural nucleobase
Authors: Drmanac Snezana , Callow Matthew , Chen Linsu , Zhou Ping , Eckhardt Leon , Xu Chongjun , Gong Meihua , Gablenz Scott , Rajagopal Jyothi , Yang Qing , Villarosa Christian , Au Anthony , Davis Kyle , Jorjorian Alexander , Wang Jingjing , Chen Ao , Zhang Xian , Borcherding Adam , Wei Xiaofang , Zhang Mingxuan , Xie Yonghui , Barua Nina , Shafto Jay , Dong Yuliang , Zheng Yue , Wang Lin , Zhai Lili , Li Jiguang , Liao Sha , Zhang Wenwei , Liu Jian , Jiang Hui , Wang Jian , Li Handong , Xu Xun , Drmanac Radoje 
Published: February 2020

AbstractMassively parallel sequencing (MPS) on DNA nanoarrays provides billions of reads at relatively low cost and enables a multitude of genomic applications. Further improvement in read length, sequence quality and cost reduction will enable more affordable and accurate comprehensive health monitoring tests. Currently the most efficient MPS uses dye-labeled reversibly terminated nucleotides (RTs) that are expensive to make and challenging to incorporate. Furthermore, a part of the dye-linker (scar) remains on the nucleobase after cleavage and interferes with subsequent sequencing cycles. We describe here the development of a novel MPS chemistry (CoolMPS™) utilizing unlabeled RTs and four natural nucleobase-specific fluorescently labeled antibodies with fast (30 sec) binding. We implemented CoolMPS™ on MGI’s PCR-free DNBSEQ MPS platform using arrays of 200nm DNA nanoballs (DNBs) generated by rolling circle replication and demonstrate 3-fold improvement in signal intensity and elimination of scar interference. Single-end 100-400 base and pair-end 2×150 base reads with high quality were readily generated with low out-of-phase incorporation. Furthermore, DNBs with less than 50 template copies were successfully sequenced by strong-signal CoolMPS™ with 3-times higher accuracy than in standard MPS. CoolMPS™ chemistry based on natural nucleobases has potential to provide longer, more accurate and less expensive MPS reads, including highly accurate “4-color sequencing” on the most efficient dye-crosstalk-free 2-color imagers with an estimated sequencing error rate of 0.00058% (one error in 170,000 base calls) in a proof-of-concept demonstration.
The brain ofCataglyphisants: neuronal organization and visual projections
Authors: Habenstein Jens , Amini Emad , Grübel Kornelia , el Jundi Basil , Rössler Wolfgang 
Published: February 2020

AbstractCataglyphisants are known for their outstanding navigational abilities. They return to their inconspicuous nest after far-reaching foraging trips using path integration, and whenever available, learn and memorize visual features of panoramic sceneries. To achieve this, the ants combine directional visual information from celestial cues and panoramic scenes with distance information from an intrinsic odometer. The largely vision-based navigation inCataglyphisrequires sophisticated neuronal networks to process the broad repertoire of visual stimuli. AlthoughCataglyphisants have been subject to many neuroethological studies, little is known about the general neuronal organization of their central brain and the visual pathways beyond major circuits. Here, we provide a comprehensive, three-dimensional neuronal map of synapse-rich neuropils in the brain ofCataglyphis nodusincluding major connecting fiber systems. In addition, we examined neuronal tracts underlying the processing of visual information in more detail. This study revealed a total of 33 brain neuropils and 30 neuronal fiber tracts including six distinct tracts between the optic lobes and the cerebrum. We also discuss the importance of comparative studies on insect brain architecture for a profound understanding of neuronal networks and their function.
A quantitative biophysical principle to explain the 3D cellular connectivity in curved epithelia
Authors: Gómez-Gálvez Pedro , Vicente-Munuera Pablo , Anbari Samira , Tagua Antonio , Gordillo-Vázquez Carmen , Andrés-San Román Jesús A. , Franco-Barranco Daniel , Palacios Ana M. , Velasco Antonio , Capitán-Agudo Carlos , Grima Clara , Annese Valentina , Arganda-Carreras Ignacio , Robles Rafael , Márquez Alberto , Buceta Javier , Escudero Luis M. 
Published: February 2020

SUMMARYEpithelial cell organization and the mechanical stability of tissues are closely related. In this context, it has been recently shown that packing optimization in bended/folded epithelia is achieved by a surface tension energy minimization mechanism that leads to a novel cellular shape: thescutoid. However, further cellular and tissue level implications of this new developmental paradigm remain unknown. Here we focus on the relationship between this complex cellular shape and the connectivity between cells. We address this problem using a combination of computational, experimental, and biophysical approaches in tubular epithelia. In particular, we examine how energy drivers affect the three-dimensional packing of these tissues. We challenge our biophysical model by reducing the cell adhesion in epithelial cells. As a result, we observed an increment on the cell apico-basal intercalation propensity that correlated with a decrease of the energy barrier necessary to connect with new cells. We conclude that tubular epithelia satisfy a quantitative biophysical principle, that links tissue geometry and energetics with the average cellular connectivity.
Pupil dilation is sensitive to semantic ambiguity and acoustic degradation
Authors: Kadem Mason , Herrmann Björn , Rodd Jennifer M. , Johnsrude Ingrid S. 
Published: February 2020

AbstractSpeech comprehension is often challenged by background noise or other acoustic interference. It can also be challenged by linguistic factors, such as complex syntax, or the presence of words with more than one meaning. Pupillometry is increasingly recognized as a technique that provides a window onto acoustic challenges, but this work has not been well integrated with an older literature linking pupil dilation to “mental effort”, which would include linguistic challenges. Here, we measured pupil dilation while listeners heard spoken sentences with clear sentence-level meaning that contained words with more than one meaning (“The shell was fired towards the tank”) or matched sentences without ambiguous words (“Her secrets were written in her diary”). This semantic-ambiguity manipulation was crossed with an acoustic manipulation: two levels of a 30-talker babble masker in Experiment 1; and presence or absence of a pink noise masker in Experiment 2. Speech comprehension, indexed by a semantic relatedness task, was high (above 82% correct) in all conditions. Pupils dilated when sentences included semantically ambiguous words compared to matched sentences and when maskers were present compared to absent (Experiment 2) or were more compared to less intense (Experiment 1). The current results reinforce the idea that many different challenges to speech comprehension, that afford different cognitive processes and are met by the brain in different ways, manifest as an increase in pupil dilation.
BiteOscope: an open platform to study mosquito blood-feeding behavior
Authors: Hol Felix JH , Lambrechts Louis , Prakash Manu 
Published: February 2020

AbstractFemale mosquitoes need a blood meal to reproduce, and in obtaining this essential nutrient they transmit deadly pathogens. Although crucial for the spread of mosquito-borne diseases, our understanding of skin exploration, probing, and engorgement, is limited due to a lack of quantitative tools. Indeed, studies often expose human subjects to assess biting behavior. Here, we present the biteOscope, a device that attracts mosquitoes to a host mimic which they bite to obtain an artificial blood meal. The host mimic is transparent, allowing high-resolution imaging of the feeding mosquito. Using machine learning we extract detailed behavioral statistics describing the locomotion, pose, biting, and feeding dynamics ofAedes aegypti, Aedes albopictus, Anopheles stephensi, andAnopheles coluzzii. In addition to characterizing behavioral patterns, we discover that the common insect repellent DEET repelsAnopheles coluzziiupon contact with their legs. The biteOscope provides a new perspective on mosquito blood feeding, enabling high-throughput quantitative characterization of the effects physiological and environmental factors have on this lethal behavior.
Increasing muscle speed drives changes in the neuromuscular transform of motor commands during postnatal development in songbirds
Authors: Adam Iris , Elemans Coen P.H. 
Published: February 2020

AbstractProgressive changes in vocal behavior over the course of vocal imitation leaning are often attributed exclusively to developing neural circuits, but the effects of postnatal body changes remain unknown. In songbirds, the syrinx transforms song system motor commands into sound, and exhibits changes during song learning. Here we test the hypothesis that the transformation from motor commands to force trajectories by syringeal muscles functionally changes over vocal development in zebra finches. Our data collected in both sexes show that only in males, muscle speed significantly increases and that supralinear summation occurs and increases with muscle contraction speed. Furthermore, we show that previously reported sub-millisecond spike timing in the avian cortex can be resolved by superfast syringeal muscles and that the sensitivity to spike timing increases with speed. Because motor neuron and muscle properties are tightly linked, we make predictions on the boundaries of the yet unknown motor code that correspond well with cortical activity. Taken together, we show that syringeal muscles undergo essential transformations during song learning that drastically change how neural commands are translated into force profiles and thereby acoustic features. We propose that the song system motor code must compensate for these changes to achieve its acoustic targets. Our data thus supports the hypothesis that the neuromuscular transformation changes over vocal development and emphasizes the need for an embodied view of song motor learning.Significance statementFine motor skill learning typically occurs in a postnatal period when the brain is learning to control a body that is changing dramatically due to growth and development. How the developing body influences motor code formation and vice versa remains largely unknown. Here we show that vocal muscles in songbirds undergo critical transformations during song learning that drastically change how neural commands are translated into force profiles and thereby acoustic features. We propose that the motor code must compensate for these changes to achieve its acoustic targets. Our data thus support the hypothesis that the neuromuscular transformation changes over vocal development and emphasizes the need for an embodied view of song motor learning.
Enhanced production of heterologous proteins by a synthetic microbial community: Conditions and trade-offs
Authors: Mauri Marco , Gouzé Jean-Luc , de Jong Hidde , Cinquemani Eugenio 
Published: February 2020

AbstractSynthetic microbial consortia have been increasingly utilized in biotechnology and experimental evidence shows that suitably engineered consortia can outperform individual species in the synthesis of valuable products. Despite significant achievements, though, a quantitative understanding of the conditions that make this possible, and of the trade-offs due to the concurrent growth of multiple species, is still limited. In this work, we contribute to filling this gap by the investigation of a known prototypical synthetic consortium. A firstE. colistrain, producing a heterologous protein, is sided by a secondE. colistrain engineered to scavenge toxic byproducts, thus favoring the growth of the producer at the expense of diverting part of the resources to the growth of the cleaner. The simplicity of the consortium is ideal to perform an in depth-analysis and draw conclusions of more general interest. We develop a coarse-grained mathematical model that quantitatively accounts for literature data from different key growth phenotypes. Based on this, assuming growth in chemostat, we first investigate the conditions enabling stable coexistence of both strains and the effect of the metabolic load due to heterologous protein production. In these conditions, we establish when and to what extent the consortium outperforms the producer alone in terms of productivity. Finally, we show in chemostat as well as in a fed-batch scenario that gain in productivity comes at the price of a reduced yield, reflecting at the level of the consortium resource allocation trade-offs that are well-known for individual species.
Endosomes facilitate mitochondrial clearance by enhancing Parkin recruitment to mitochondria
Authors: Ravindran Rishith , Velikkakath Anoop Kumar G. , Narendradev Nikhil Dev , Chandrasekharan Aneesh , Santhoshkumar T. R. , Srinivasula Srinivasa M. 
Published: February 2020

AbstractMutations in ubiquitin ligase Parkin are associated with Parkinson’s disease and defective mitophagy. Conceptually, Parkin-dependent mitophagy is classified into two phases; 1. Parkin recruits to and ubiquitinates mitochondrial proteins, 2. Formation of autophagosome membrane, sequestering mitochondria for degradation. Recently, endosomal machineries were reported to contribute to the later stage for membrane assembly. We report a role for endosomes in the events upstream of phase 1. We demonstrate that an endosomal ubiquitin ligase CARP2 associates with damaged mitochondria, and this association precedes that of Parkin. CARP2 interacts with Parkin, and stable recruitment of Parkin to damaged mitochondria was substantially reduced in CARP2 KO cells. Our study unravels a novel role of endosomes in modulating upstream pathways of Parkin-dependent mitophagy initiation.
Analysis of structure of the population, kinship coefficients and inbreeding trend depending on sex, type of breeding of Tatra Sheepherd dogs
Authors: Edyta Sweklej , Elżbieta Horoszewicz , Roman Niedziółka 
Published: February 2020

AbstractThe aim of the study was to analyse the structure of the population, kinship coefficients and inbreeding trend taking into account the sex, breeding system: champions (CH) and non-champions (nCH), breeding country: Poland (PL) and foreign country (Z) and the inbreeding degree of Tatra Shepherd dogs. Out of the currently registered 587 Tatra Shepherd dogs, 41.9% have been qualified for breeding. In the past decade, 1961 puppies were born, which corresponds to an average litter of 5.8 puppies. The breed’s inbreeding rate amounted to 6.34%, and for a 4-generation population was 6.68%. The highest inbreeding rate was found in nCH and PL groups consisting of both male and female dogs. The inbreeding rate was significantly higher in 2005-2014 compared to the years 1994-2004. The limit value FXwas exceeded for 25.65% of Shepherd dogs, and the critical value was exceeded for 11.52%. An increasing ancestor loss coefficient (AVK) was found, which may result in an increased number of inbred animals. In particular, it referred to female dogs in the nCH, PL, and F group, whereas a significant increase of AVK was observed in the group of male dogs from foreign kennels. The resulting COR values, respectively 55.58% for males and 55.44% for females, testify to insignificant inbreeding and suggest that breeders look for male inbreds. Studies have shown that there is no risk of inbred depression yet; however, the gene pool of the Tatra Shepherd dog breed has become noticeably restricted. In addition, leaving the stud book for the breed open must be considered due to an increase in the popularity of the breed, and thus an increase in mating.
Temporal and spatial dynamics in the apple flower microbiome in the presence of the phytopathogenErwinia amylovora
Authors: Cui Zhouqi , Huntley Regan B. , Zeng Quan , Steven Blaire 
Published: February 2020

AbstractPlant microbiomes have important roles in plant health and productivity. However, despite flowers being directly linked to reproductive outcomes, little is known about the microbiomes of flowers and their potential interaction with pathogen infection. Here, we investigated the temporal dynamics and spatial traits of the apple stigma microbiome when challenged with a phytopathogenErwinia amylovora, the causal agent of fire blight disease. We profiled the microbiome from the stigmas of a single flower, greatly increasing the resolution at which we can characterize shifts in the composition of the microbiome. Individual flowers harbored unique microbiomes at the OTU level. However, taxonomic analysis of community succession showed a population gradually dominated by bacteria within the familiesEnterobacteriaceaeandPseudomonadaceae. Flowers inoculatedE. amylovoraestablished large populations of the phytopathogen, with pathogen specific gene counts of >3.0 × 107in 90% of the flowers. Yet, only 42% of inoculated flowers later developed fire blight symptoms. This reveals pathogen amount on the stigma is not sufficient to predict disease outcome. Our data demonstrate that apple flowers represent an excellent model in which to characterize how plant microbiomes establish, develop, and interact with biological processes such as disease progression in an experimentally tractable plant organ.
The Sigma-2 Receptor/TMEM97, PGRMC1, and LDL Receptor complex are responsible for the cellular uptake of Aβ42 and its protein aggregates
Authors: Riad Aladdin , Lengyel-Zhand Zsofia , Zeng Chenbo , Weng Chi-Chang , Lee Virginia M.-Y. , Trojanowski John Q. , Mach Robert H. 
Published: February 2020

ABSTRACTBackgroundOur lab has recently shown that the Sigma-2 Receptor/Transmembrane Protein 97 (TMEM97) and Progesterone Receptor Membrane Component 1 (PGRMC1) form a complex with the Low Density Lipoprotein Receptor (LDLR), and this intact complex is required for efficient uptake of lipoproteins such as LDL and apolipoprotein E (apoE). These receptors are expressed in the nervous system where they have implications in neurodegenerative diseases such as Alzheimer’s Disease (AD), where apoE is involved in neuronal uptake and accumulation of Aβ42, eventually cascading into neurodegeneration, synaptic dysfunction, and ultimately, dementia.HypothesisWe hypothesize that the intact Sigma-2 receptor complex –TMEM97, PGRMC1, and LDLR— is necessary for internalization of apoE and Aβ42 monomers (mAβ42) and oligomers (oAβ42), and the disruption of the receptor complex inhibits uptake.ResultsThe results of this study suggest that the intact Sigma-2 receptor complex is a binding site for mAβ42 and oAβ42, in the presence or absence of apoE2, apoE3, and apoE4. The loss or pharmacological inhibition of one or both of these proteins results in the disruption of the complex leading to decreased uptake of mAβ42 and oAβ42 and apoE in primary neurons.ConclusionThe TMEM97, PGRMC1, and LDLR complex is a pathway for the cellular uptake of Aβ42 via apoE dependent and independent mechanisms. This study suggests that the complex may potentially be a novel pharmacological target to decrease neuronal Aβ42 internalization and accumulation, which may represent a new strategy for inhibiting the rate of neurotoxicity, neurodegeneration, and progression of AD.
Redundant function of Ets1 and Ets2 in regulating M-phase progression in post-natal angiogenesis
Authors: Ghosh Sankha , MarElia-Bennett Catherine B. , Hildreth Blake E. , Lefler Julia E. , Sharma Sudarshana M. , Ostrowski Michael C. 
Published: February 2020

ABSTRACTAngiogenesis is a highly orchestrated process involving complex crosstalk between several endothelial cell processes including cell cycle, cell survival and migration. Transcription factors ETS1 and ETS2 are required for EC functions necessary for embryonic angiogenesis. Here, by utilizing endothelial cell-specific deletion ofEts1andEts2on post-natal angiogenesis we demonstrate that ETS1 and ETS2 have a redundant regulatory role in controlling the expression of key G2/M regulators and anti-apoptotic gene modules by recruiting the transcriptional activator CBP/p300 to the enhancers of these genes. Further, cultured aortic ECs lacking both ETS1 and ETS2 demonstrated G2/M phase arrest and increased apoptosis.In vivo, EC infiltration and invasion was attenuated when matrigel admixed with mouse mammary tumor cells was injected into adult mice with EC-specific ablation ofEts1andEts2. These results demonstrate that deletion ofEts1andEts2in endothelial cells inhibits angiogenesis by altering cell cycle progression and decreasing cell survival.