bluuebunny/crossref_metadata_2025_split huggingface dataset:
Analyzing the neutral and adaptive background of butterfly voltinism reveals structural variation in a core circadian gene
Authors: Lindestad Olle , Nylin Sören , Wheat Christopher W. , Gotthard Karl 
Published: May 2020

ABSTRACTMany insects exhibit geographic variation in voltinism, the number of generations produced per year. This includes high-latitude species in previously glaciated areas, implying divergent selection on life cycle traits during or shortly after recent colonization. Here, we use a whole-genome approach to genetically characterize a set of populations of the butterflyPararge aegeriathat differ in voltinism. We construct a high-quality de novo genome forP. aegeria, and assess genome-wide genetic diversity and differentiation between populations. We then use the inferred phylogeographic relationships as the basis for a scan for loci showing signs of divergent selection associated with voltinism differences. The genic outliers detected include population-specific mutations of circadian loci, most notably a locally fixed 97-amino acid deletion in the circadian gene timeless. Variation in timeless has previously been implicated as underlying variation in life cycle regulation in wild populations in our study species, as well as in other insects. These results add to a growing body of research framing circadian gene variation as a mechanism for generating local adaptation of life cycles.
Upscaling ofIn VivoHR-pQCT Images Enables Accurate Simulations of Human Microstructural Bone Adaptation
Authors: Ohs Nicholas , Tourolle né Betts Duncan C. , Atkins Penny R. , Sebastian Stephanie , van Rietbergen Bert , Blauth Michael , Christen Patrik , Müller Ralph 
Published: May 2020

AbstractIn silicotrials of treatments in a virtual physiological human (VPH) would revolutionize research in the biomedical field. Hallmarks of bone disease and treatments can already be simulated in pre-clinical models and inex vivodata of humans using microstructural bone adaptation simulations. The increasing availability ofin vivohigh resolution peripheral quantitative computed tomography (HR-pQCT) images provides novel opportunities to validate and ultimately utilize microstructural bone adaptation simulations to improve our understanding of bone diseases and move towardsin silicoVPH decision support systems for clinicians.In the present study, we investigated if microstructural bone adaptation simulations ofin vivohuman HR-pQCT images yielded accurate results. Since high-resolution ground truth images cannot be obtainedin vivo, we applied anex vivoapproach to study resolution dependence and the effect of upscaling on morphometric accuracy. To address simulation initialisation issues, we developed an input regularisation approach to reduce initialisation shocks observed in microstructural bone adaptation simulations and evaluated upscaling as a way to improve the accuracy of model inputs. Finally, we compared ourex vivoresults to simulations run onin vivoimages to investigate whetherin vivoimage artefacts further affect simulation outcomes.
An autoregulatory switch in sex-specificphf7transcription causes loss of sexual identity and tumors in theDrosophilafemale germline
Authors: Smolko Anne E. , Shapiro-Kulnane Laura , Salz Helen K. 
Published: May 2020

ABSTRACTMaintenance of germ cell sexual identity is essential for reproduction. Entry into the spermatogenesis or oogenesis pathway requires that the appropriate gene network is activated and the antagonist network is silenced. For example, inDrosophilafemale germ cells, forced expression of the testis-specific PHD finger protein 7 (PHF7) disrupts oogenesis leading to either an agametic or germ cell tumor phenotype. Here we show that PHF7 expressing ovarian germ cells inappropriately express hundreds of genes, many of which are male germline genes. We find that the majority of genes under PHF7 control in female germ cells are not under PHF7 control in male germ cells, suggesting that PHF7 is acting in a tissue-specific manner. Remarkably, transcriptional reprogramming includes a positive autoregulatory feedback mechanism in which ectopic PHF7 overcomes its own transcriptional repression through promoter switching. Furthermore, we find that tumorigenic capacity is dependent on the dosage ofphf7. This study reveals that high levels of ectopic PHF7 in female germ cells leads to a loss of sexual identity and promotion of a regulatory circuit beneficial for tumor initiation and progression.
ToxoplasmaTgATG9 is critical for autophagy and long-term persistence in tissue cysts
Authors: Smith David , Kannan Geetha , Coppens Isabelle , Wang Fengrong , Nguyen Hoa Mai , Cerutti Aude , Schultz Tracey L. , Rimple Patrick A. , Di Cristina Manlio , Besteiro Sébastien , Carruthers Vern B. 
Published: May 2020

ABSTRACTMany of the world’s warm-blooded species are chronically infected withToxoplasma gondiitissue cysts, including up to an estimated one third of the global human population. The cellular processes that permit long-term parasite persistence within the cyst are largely unknown, not only forT. gondiibut also for related coccidian parasites that impact human and animal health. A previous study revealed an accumulation of autophagic material in the lysosome-like Vacuolar Compartment (VAC) of chronic stage bradyzoites lacking functional cathepsin L protease (TgCPL) activity. Furthermore, it was shown that TgCPL knockout bradyzoites have compromised viability, indicating the turnover of autophagic material could be necessary for bradyzoite survival. However, the extent to which autophagy itself contributes to bradyzoite development and fitness remained unknown. Herein we show that genetic ablation ofTgATG9substantially reduces canonical autophagy and compromises bradyzoite viability. Transmission electron microscopy revealed structural abnormalities occurring in Δatg9bradyzoites, including disorganization of the inner membrane complex and plasma membrane, the occurrence of multiple nuclei within a single bradyzoite cell, as well as various anomalies associated with the VAC. TgATG9-deficient bradyzoites accumulated significantly less undigested material in the VAC upon inhibition of TgCPL activity, suggesting that autophagy contributes material to the VAC for degradation. Intriguingly, abnormal mitochondria networks were observed in TgATG9-deficient bradyzoites. They were thin and elongated and often adopted a horseshoe conformation. Some abnormal mitochondrial structures were found to contain numerous different cytoplasmic components and organelles. Bradyzoite fitness was found to be drastically compromised, bothin vitroand in mice, with very few brain cysts identified in mice 5 weeks post-infection. Taken together, our data suggests that TgATG9, and by extension autophagy, is critical for cellular homeostasis in bradyzoites and is necessary for long-term persistence within the cyst of this coccidian parasite.
Compact and contactless reflectance confocal microscope for neurosurgery
Authors: Cui Jiahe , Turcotte Raphaël , Hampson Karen M. , Wincott Matthew , Schmidt Carla C. , Emptage Nigel J. , Charalampaki Patra , Booth Martin J. 
Published: May 2020

AbstractVisual guidance at the cellular level during neurosurgical procedures is essential for complete tumour resection. We present a compact reflectance confocal microscope with a 20 mm working distance that provided <1.2 µm spatial resolution over a 600 µm × 600 µm field of view in the near-infrared region. A physical footprint of 200 mm × 550 mm was achieved using only standard off-the-shelf components. Theoretical performance of the optical design was first evaluated via commercial Zemax software. Then three specimens from rodents: fixed brain, frozen calvaria and live hippocampal slices, were used to experimentally assess system capability and robustness. Results show great potential for the proposed system to be translated into use as a next generation label-free and contactless neurosurgical microscope.
Establishing a transcriptome-based drug discovery paradigm for neurodevelopmental disorders
Authors: Dhindsa Ryan S. , Zoghbi Anthony W. , Krizay Daniel K. , Vasavda Chirag , Goldstein David B. 
Published: May 2020

AbstractAdvances in genetic discoveries have created substantial opportunities for precision medicine in neurodevelopmental disorders. Many of the genes implicated in these diseases encode proteins that regulate gene expression, such as chromatin associated proteins, transcription factors, and RNA-binding proteins. The identification of targeted therapeutics for individuals carrying mutations in these genes remains a challenge, as the encoded proteins can theoretically regulate thousands of downstream targets in a considerable number of cell types. Here, we propose the application of a drug discovery approach called “transcriptome reversal” for these disorders. This approach, originally developed for cancer, attempts to identify compounds that reverse gene-expression signatures associated with disease states.
Depth relationships and measures of tissue thickness in dorsal midbrain
Authors: Truong Paulina , Kim Jung Hwan , Savjani Ricky , Sitek Kevin R. , Hagberg Gisela E. , Scheffler Klaus , Ress David 
Published: May 2020

ABSTRACTDorsal human midbrain contains two nuclei with clear laminar organization, the superior and inferior colliculi. These nuclei extend in depth between the superficial dorsal surface of midbrain and a deep midbrain nucleus, the periaqueductal gray matter (PAG). The PAG, in turn, surrounds the cerebral aqueduct (CA). This study examined the use of two depth metrics to characterize depth and thickness relationships within dorsal midbrain using the superficial surface of midbrain and CA as references. The first utilized nearest-neighbor Euclidean distance from one reference surface, while the second used a level-set approach that combines signed distance from both reference surfaces. Both depth methods provided similar functional depth profiles generated by saccadic eye movements in a functional MRI task, confirming their efficacy for superficial functional activity. Next, the boundaries of the PAG were estimated using Euclidean distance together with elliptical fitting, indicating that the PAG can be readily characterized by a smooth surface surrounding PAG. Finally, we used the level-set approach to measure tissue depth between the superficial surface and the PAG, thus characterizing the variable thickness of the colliculi. Overall, this study demonstrates depth-mapping schemes for human midbrain that enables accurate segmentation of the PAG and consistent depth and thickness estimates of the superior and inferior colliculi.
A druggable oxidative folding pathway in the endoplasmic reticulum of human malaria parasites
Authors: Cobb David W. , Kudyba Heather M. , Villegas Alejandra , Hoopmann Michael R. , Baptista Rodrigo , Bruton Baylee , Krakowiak Michelle , Moritz Robert L. , Muralidharan Vasant 
Published: May 2020

AbstractMalaria remains a major global health problem, and there exists a constant need to identify druggable weaknesses inP. falciparumbiology. The endoplasmic reticulum (ER) has many essential roles in the asexual lifecycle and may offer new drug targets, but it remains critically understudied. We generated conditional mutants of the putative redox-active, ER chaperonePfJ2, and show that it is essential for parasite survival. Using a redox-active cysteine crosslinker, we identify its substrates to be other mediators of oxidative folding,PfPDI8 andPfPDI11, suggesting a redox-regulatory role forPfJ2. Knockdown of these protein disulfide isomerases inPfJ2 conditional mutants show thatPfPDI11 is not essential, whilePfPDI8 is essential for asexual growth and may work in a complex with PfJ2 and other ER chaperones. Finally, we show that these redox interactions in the parasite ER are sensitive to small molecule inhibition. Together these data build a model for how oxidative folding occurs in theP. falciparumER and demonstrate its suitability for antimalarial drug development.
High-Resolution Linkage Map and QTL Analyses for Machine Harvest Traits in Autotetraploid Blueberry
Authors: Cappai Francesco , Amadeu Rodrigo R. , Benevenuto Juliana , Cullen Ryan , Garcia Alexandria , Grossman Adina , Ferrão Luís Felipe V. , Munoz Patricio 
Published: May 2020

ABSTRACTBlueberry (Vaccinium corymbosumand hybrids) is an autotetraploid crop whose commercial relevance has been growing steadily during the last twenty years. However, the ever-increasing cost of labor for hand-picking blueberry is one main constraint in competitive marketing of the fruit. Machine harvestability is, therefore, a key trait for the blueberry industry. Understanding the genetic architecture of traits through quantitative trait locus (QTL) mapping is the first step towards implementation of molecular breeding for faster genetic gains. Despite recent advances in software development for autotetraploid genetic mapping, a high-resolution map is still not available for blueberry. In this study, we crafted a map for autotetraploid low-chill highbush blueberry containing 11,292 SNP markers and a total size of 1,953.97 cM (average density of 5.78 markers/cM). This map was subsequently used to perform QTL analyses for traits relevant to machine harvesting: firmness, firmness retention, and fruit detachment force. Significant QTL peaks were identified for all the traits. The QTL intervals were further explored for putative candidate genes. Genes related to cell wall remodeling were highlighted in the firmness and firmness retention intervals. For fruit detachment force, transcription factors involved in fruit abscission were detected. Altogether, our findings provide the basis for future fine-mapping and molecular breeding efforts for machine harvesting in blueberry.
Phages - bacteria interactions network of the healthy human gut
Authors: Marbouty Martial , Thierry Agnès , Koszul Romain 
Published: May 2020

AbstractWith an estimated 1031particles on earth, bacteriophages are the most abundant genomic entities across all habitats and important drivers of microbial communities. Growing evidence suggest that they play roles in intestinal human microbiota homeostasis, and recent metagenomics studies on the viral fraction of this ecosystem have provided crucial information about their diversity and specificity. However, the bacterial hosts of this viral fraction, a necessary information to characterize further the balance of these ecosystems, remain poorly characterized. Here we unveil, using an enhanced metagenomic Hi-C approach, a large network of 6,651 host-phage relationships in the healthy human gut allowing to studyin situphage-host ratio. We notably found that half of these contigs appear to be sleeping prophages whereas ¼ exhibit a higher coverage than their associated MAG representing potentially active phages impacting the ecosystem. We also detect different candidate members of the crAss-like phage family as well as their bacterial hosts showing that these elusive phages infect different genus of Bacteroidetes. This work opens the door to single sample analysis and concomitant study of phages and bacteria in complex communities.
Distinct large-scale networks are associated with motor and nonmotor symptoms in Parkinson’s disease
Authors: Tinaz Sule , Kamel Serageldin , Aravala Sai S. , Sezgin Mine , Elfil Mohamed , Sinha Rajita 
Published: May 2020

ABSTRACTParkinson’s disease (PD) is characterized clinically by various motor and nonmotor symptoms. The underlying neuroanatomical correlates of nonmotor symptoms in PD remain poorly understood. We investigated the differences and commonalities in the neuroanatomical correlates 1) between highly prevalent nonmotor features including fatigue, anxiety, depression, and apathy, and 2) between these nonmotor features and motor severity in nondemented subjects with mild PD (Hoehn & Yahr disease stage 2) using structural and functional magnetic resonance imaging. Compared to matched controls, the PD group showed atrophy in the basal ganglia and superior frontal cortex. Motor severity correlated with cortical thinning in frontotemporal regions, as well as with reduced functional connectivity between the frontostriatal and cerebellar networks. The composite nonmotor symptom severity did not show any correlation with the structural brain data, but correlated with reduced functional connectivity in a large-scale network consisting of frontostriatal, parietotemporal, and cerebellar nodes. The individual components of the nonmotor symptoms also mapped onto specific neural networks. Our study shows that motor and nonmotor features in PD are associated with distinct large-scale networks. The basal ganglia and cerebellum are core regions in all of these networks. The abnormal functional connectivity in the nonmotor network seems to be related to cognitive and emotional dysregulation and may have implications for future cognitive decline in PD.
The alveolar gas equation: do lessons from WW2 research into high flying pilots provide insights into the adaptation to high altitude flight in birds?
Authors: Seear Michael 
Published: May 2020

AbstractDalton’s law of partial pressures applies equally to birds and mammals so, as gas moves from the nostrils to the smallest gas-diffusion airways, the sequential addition of water vapour and CO2, steadily reduce the partial pressure of O2 (PO2) within the gas mixture. The PO2, at the point of gas exchange, at sea level, will be about 60 mm Hg less than the original PO2 within atmospheric air. As a result, the inspired PO2 is an inaccurate starting point for any model of oxygen transport. In humans, the interactions of gases at the point of diffusion, is described and quantified by the Alveolar Gas Equation (AGE). Its development during WW2, provided valuable insights into human gas exchange and also into the responses to high altitude flight in pilots but, except for an early study of hypoxia in pigeons, the AGE is not mentioned in the avian literature. Even detailed models of oxygen transport in birds omit the effect of CO2 clearance on pulmonary oxygen transfer. This paper develops two related arguments concerning the application of the AGE to birds. The first is that avian blood gas predictions, based on the theory of multicapillary serial arterialization (MSA), are inaccurate because they do not account for the added partial pressure of diffused CO2. The second is that the primary adaptation to hypobaric hypoxia is the same for both classes and consists of defending PaO2 by reducing PaCO2 through increasing hyperventilation. Support for the first is demonstrated by comparing PaO2 predictions made using the AGE, with published values from avian studies and also against values predicted by the theory of MSA. The second is illustrated by comparing the results of high altitude studies of both birds and humans. The application of the AGE to avian respiratory physiology would improve the predictive accuracy of models of the O2 cascade and would also provide better insights into the primary adaptation to high altitude flight.
Psi promotesDrosophilawing growth through transcriptional repression of key developmental networks
Authors: Zaytseva Olga , Mitchell Naomi C. , Delandre Caroline , Nie Zuqin , Evers Maurits , Werner Janis K. , Lis John T. , Hannan Ross D. , Levens David L. , Marshall Owen J. , Quinn Leonie M. 
Published: May 2020

AbstractPsi, the sole FUSE Binding Protein (FUBP) family single stranded DNA/RNA binding protein inDrosophila, is essential for proper cell and tissue growth, however its mechanism of function remains unclear. Here we use Targeted DamID combined with RNA-sequencing to generate the first genome-wide binding and expression profiles for Psi. Surprisingly, we demonstrate Psi drives growth in theDrosophilawing through transcriptional repression of key developmental pathways (e.g. Wnt, Notch and TGFβ). Thus, Psi patterns tissue growth by directly repressing transcription of developmental growth suppressors. Analysis of direct Psi targets identified novel growth inhibitors, includingTolkin(Zinc metallopeptidase implicated in TGFβ signalling),Ephexin(Rho-GEF) andemp(CD36 scavenger receptor-related protein). Their depletion not only suppressed impaired growth associated with Psi knockdown, but alone was sufficient to drive wing overgrowth. Thus, Psi drives wing growth twofold, through direct activation ofMycand through transcriptional repression of growth inhibitors comprising core developmental pathways.
Patient DNA cross-reactivity of the CDC SARS-CoV-2 extraction control leads to an inherent potential for false negative results
Authors: Rosebrock Adam P. 
Published: May 2020

AbstractTesting for RNA viruses such as SARS-CoV-2 requires careful handling of inherently labile RNA during sample collection, clinical processing, and molecular analysis. Tests must include fail-safe controls that affirmatively report the presence of intact RNA and demonstrate success of all steps of the assay. A result of “no virus signal” is insufficient for clinical interpretation: controls must also say “The reaction worked as intended and would have found virus if present.” Unfortunately, a widely used test specified by the US Centers for Disease Control and Prevention (CDC) incorporates a control that does not perform as intended and claimed. Detecting SARS-CoV-2 with this assay requires both intact RNA and successful reverse transcription. The CDC-specified control does not require either of these, due to its inability to differentiate human genomic DNA from reverse-transcribed RNA. Patient DNA is copurified from nasopharyngeal swabs during clinically-approved RNA extraction and is sufficient to return an “extraction control success” signal using the CDC design. As such, this assay fails-unsafe: truly positive patient samples return a false-negative result of “no virus detected, control succeeded” following any of several readily-encountered mishaps. This problem affects tens-of-millions of patients worth of shipped assays, but many of these flawed reagents have not yet been used. There is an opportunity to improve this important diagnostic tool. As demonstrated here, a re-designed transcript-specific control correctly monitors sample collection, extraction, reverse transcription, and qPCR detection. This approach can be rapidly implemented and will help reduce truly positive patients from being incorrectly given the all-clear.One Sentence SummaryA widely-used COVID-19 diagnostic is mis-designed and generates false-negative results, dangerously confusing “No” with “Don’t know” – but it’s fixable