bluuebunny/crossref_metadata_2025_split huggingface dataset:
Combinatorial morphogenetic and mechanical cues to mimic bone development for defect repair
Authors: Herberg S. , McDermott A. M. , Dang P. N. , Alt D. S. , Tang R. , Dawahare J. H. , Varghai D. , Shin J-Y. , McMillan A. , Dikina A. D. , He F. , Lee Y. , Cheng Y. , Umemori K. , Wong P.C. , Park H. , Boerckel J. D. , Alsberg E. 
Published: February 2019

AbstractEndochondral ossification during long bone development and natural fracture healing initiates by mesenchymal cell condensation and is directed by local morphogen signals and mechanical cues. Here, we aimed to mimic these developmental conditions for regeneration of large bone defects. We hypothesized that engineered human mesenchymal stem cell (hMSC) condensations with in situ presentation of transforming growth factor-β1 (TGF-β1) and/or bone morphogenetic protein-2 (BMP-2) from encapsulated microparticles would promote endochondral regeneration of critical-sized rat femoral bone defects in a manner dependent on the in vivo mechanical environment. Mesenchymal condensations induced bone formation dependent on morphogen presentation, with dual BMP-2 + TGF-β1 fully restoring mechanical bone function by week 12. In vivo ambulatory mechanical loading, initiated at week 4 by delayed unlocking of compliant fixation plates, significantly enhanced the bone formation rate in the four weeks after load initiation in the dual morphogen group. In vitro, local presentation of either BMP-2 alone or BMP-2 + TGF-β1 initiated endochondral lineage commitment of mesenchymal condensations, inducing both chondrogenic and osteogenic gene expression through SMAD3 and SMAD5 signaling. In vivo, however, endochondral cartilage formation was evident only in the BMP-2 + TGF-β1 group and was enhanced by mechanical loading. The degree of bone formation was comparable to BMP-2 soaked on collagen but without the ectopic bone formation that limits the clinical efficacy of BMP-2/collagen. In contrast, mechanical loading had no effect on autograft-mediated repair. Together, this study demonstrates a biomimetic template for recapitulating developmental morphogenic and mechanical cues in vivo for tissue engineering.One Sentence SummaryMimicking aspects of the cellular, biochemical, and mechanical environment during early limb development, chondrogenically-primed human mesenchymal stem cell condensations promoted functional healing of critical-sized femoral defects via endochondral ossification, and healing rate and extent was a function of the in vivo mechanical environment.
The kinesin-like protein Pavarotti functions non-canonically to regulate actin dynamics
Authors: Nakamura Mitsutoshi , Verboon Jeffrey M. , Prentiss Clara L. , Parkhurst Susan M. 
Published: February 2019

SummaryPavarotti, the Drosophila MKLP1 ortholog, is a kinesin-like protein that with Tumbleweed (MgcRacGAP) works together as the centralspindlin complex. This complex is essential for cytokinesis where it helps to organize the contractile actomyosin ring at the equator of dividing cells by activating the RhoGEF Pebble. Actomyosin rings also function as the driving force during cell wound repair. We previously showed that Tumbleweed and Pebble are required for the cell wound repair process. Here, we show that Pavarotti also functions during wound repair and confirm that while Pavarotti, Tumbleweed, and Pebble are utilized during this cellular repair, it is not as the conserved centralspindlin complex. Surprisingly,in vitroandin vivowork show that the classically microtubule-associated Pavarotti binds directly to actin and has a non-canonical role directly regulating actin dynamics. We show that Pavarotti also works independently from Tumbleweed in several actin-related processes during the normal developmental process of oogenesis.
Crosstalk with the GAR-3 receptor contributes to feeding defects inCaenorhabditis elegans eat-2mutants
Authors: Kozlova Alena A. , Lotfi Michele , Okkema Peter G. 
Published: February 2019

AbstractPrecise signaling at the neuromuscular junction (NMJ) is essential for proper muscle contraction. In theC. eleganspharynx, acetylcholine (ACh) released from the MC and M4 motor neurons stimulates two different types of contractions in adjacent muscle cells, termed pumping and isthmus peristalsis. MC stimulates rapid pumping through the nicotinic ACh receptor EAT-2, which is tightly localized at the MC NMJ, andeat-2mutants exhibit a slow pump rate. Surprisingly, we found thateat-2mutants also hyperstimulated peristaltic contractions, and these are characterized by increased and prolonged Ca2+transients in the isthmus muscles. This hyperstimulation depends on crosstalk with the GAR-3 muscarinic acetylcholine receptor asgar-3mutation specifically suppressed the prolonged contraction and increased Ca2+observed ineat-2mutant peristalses. Similar GAR-3 dependent hyperstimulation was also observed in mutants lacking theace-3acetylcholinesterase, and we suggest that NMJ defects ineat-2andace-3mutants result in ACh stimulation of extrasynaptic GAR-3 receptors in isthmus muscles.gar-3mutation also suppressed slow larval growth and prolonged lifespan phenotypes that result from dietary restriction ineat-2mutants, indicating that crosstalk with the GAR-3 receptor has a long-term impact on feeding behavior andeat-2mutant phenotypes.Article SummaryAcetylcholine stimulates different contractions in adjacent muscle cells in theC. eleganspharynx called pumping and peristalsis. The signaling mechanisms stimulating pumping have been characterized, but how these mechanisms affect peristalsis is unknown. Here we examined muscle contractions and Ca2+transients during peristalsis in wild-type animals and acetylcholine signaling mutants. Surprisingly we found that while mutants affecting theeat-2nicotinic acetylcholine receptor exhibited reduced pumping, they also hyperstimulated peristalses. This hyperstimulation depends on crosstalk with the GAR-3 muscarinic acetylcholine receptor in adjacent cells, and it contributes to the well-characterized dietary restriction and extended adult lifespan observed ineat-2mutants.
Association between development of early cortical activity on amplitude-integrated EEG and 5-years neurodevelopmental outcome in the preterm infant
Authors: Feldmann Maria , Rousson Valentin , Nguyen Thi Dao , Bernet Vera , Hagmann Cornelia , Latal Beatrice , Natalucci Giancarlo 
Published: March 2019

AbstractAimTo analyse the association between early aEEG and cognitive outcome at early school-age in very preterm infants.MethodsProspective cohort study including infants with gestational age (GA) <32.0 weeks, undergoing continuous aEEG recording during first 4 days of life. Semiquantitative and quantitative (maximum/minimum amplitude) measures were averaged over the recording period. Cognitive outcome was assessed with the Kaufman-Assessment Battery for Children at 5 years of age. Uni- and multivariate logistic regressions were calculated between aEEG parameters and normal cognitive outcome (IQ≥85).ResultsAmong 118 monitored preterm children, 89 were assessed at median(IQR) corrected age of 68.6 months (65.5-71.2) [48% female, median(IQR) GA 29.9(28.2,30.9) weeks, mean(SD) birth weight 1235(363) grams]. Mean(SD) IQ was 97.8(12.7). IQ<85 occurred in 21.3 %, cerebral palsy was found in 3.4%. Despite univariate associations of total maturity scores, cycling subscores, background pattern and minimum aEEG amplitude with normal cognitive outcome none of the associations remained significant after adjustment for confounders. Socioeconomic status was identified as independent predictor of neurodevelopmental outcome.ConclusionIn this cohort of very preterm infants, early short-term aEEG was not predictive of later cognitive outcome. Further research is needed to explore how aEEG could help to inform long-term prognosis in this population group.Key notesPreterm born infants are at high risk for neurodevelopmental impairment.Early amplitude integrated electroencephalography characteristics are univariately associated with cognitive outcome at 5 years of age in preterm born children.However, socioeconomic factors and neonatal morbidity were stronger predictors of long-term neurodevelopmental outcome than early aEEG measures.
Optimised FRET pairs and quantification approaches to detect the activation of Aurora kinase A at mitosis
Authors: Bertolin Giulia , Sizaire Florian , Déméautis Claire , Chapuis Catherine , Mérola Fabienne , Erard Marie , Tramier Marc 
Published: February 2019

AbstractGenetically-encoded Förster’s Resonance Energy Transfer (FRET) biosensors are indispensable tools to sense the spatiotemporal dynamics of signal transduction pathways. Investigating the crosstalk between different signalling pathways is becoming increasingly important to follow cell development and fate programs. To this end, FRET biosensors must be optimised to monitor multiple biochemical activities simultaneously and in single cells. In addition, their sensitivity must be increased to follow their activation even when the abundance of the biosensor is low.We describe here the development of a second generation of Aurora kinase A/AURKA biosensors. First, we adapt the original AURKA biosensor –GFP-AURKA-mCherry– to multiplex FRET by using dark acceptors as ShadowG or ShadowY. Then, we use the novel superYFP acceptor protein to measure FRET by 2-colour Fluorescence Cross-Correlation Spectroscopy, in cytosolic regions where the abundance of AURKA is extremely low and undetectable with the original AURKA biosensor.These results pave the way to the use of FRET biosensors to follow AURKA activation in conjunction with substrate-based activity biosensors. In addition, they open up the possibility of tracking the activation of small pools of AURKA and its interaction with novel substrates, which would otherwise remain undetectable with classical biochemical approaches.
Axonemal doublet microtubules can split into two complete singlets in human sperm flagellum tips
Authors: Zabeo Davide , Croft Jacob T , Höög Johanna L 
Published: February 2019

AbstractMotile flagella are crucial for human fertility and embryonic development. The distal tip of the flagellum is where growth and intra-flagellar transport are coordinated. In most, but not all, model organisms the distal tip includes a “singlet region”, where axonemal doublet microtubules terminate and only complete A-tubules extend as singlet microtubules to the tip. How a human flagellar tip is structured is unknown. Here, the flagellar tip structure of human spermatozoa was investigated by cryo-electron tomography, revealing the formation of two complete singlet microtubules from both the A-tubule and B-tubule of doublet microtubules. This different tip arrangement in human spermatozoa shows the need to investigate human flagella directly in order to understand their role in our health and disease.
Prototheca zopfiiGenotype II induces mitochondrial apoptosis in models of bovine mastitis
Authors: Shahid Muhammad , Cobo Eduardo R. , Chen Liben , Cavalcante Paloma A. , Barkema Herman W. , Gao Jian , Xu Siyu , Liu Yang , Knight Cameron G. , Kastelic John P. , Han Bo 
Published: February 2019

AbstractPrototheca zopfiiis an alga increasingly isolated from bovine mastitis. Of the two genotypes ofP. zopfii(genotype I and II (GT-I and II)),P. zopfiiGT-II is the genotype associated with acute mastitis and decreased milk production by unknown mechanisms. The objective was to determine inflammatory and apoptotic roles ofP. zopfiiGT-II in cultured mammary epithelial cells (from cattle and mice) and murine macrophages and using a murine model of mastitis.Prototheca zopfiiGT-II (but not GT-I) invaded bovine and murine mammary epithelial cells (MECs) and induced apoptosis, as determined by the terminal deoxynucleotidyl transferase mediated deoxyuridine triphosphate nick end labeling assay. ThisP. zopfiiGT-II driven apoptosis corresponded to mitochondrial pathways; mitochondrial transmembrane resistance (ΔΨm) was altered and modulation of mitochondrion-mediated apoptosis regulating genes changed (increased transcriptionalBax, cytochrome-c andApaf-1and downregulatedBcl-2), whereas caspase-9 and -3 expression increased. Apoptotic effects byP. zopfiiGT-II were more pronounced in macrophages compared to MECs. In a murine mammary infection model,P. zopfiiGT-II replicated in the mammary gland and caused severe inflammation with infiltration of macrophages and neutrophils and upregulation of pro-inflammatory genes (TNF-α,IL-1βandCxcl-1) and also apoptosis of epithelial cells. Thus, we concludedP. zopfiiGT-II is a mastitis-causing pathogen that triggers severe inflammation and also mitochondrial apoptosis.Author summaryBovine mastitis (inflammation of the udder) reduces milk production and quality, causing huge economic losses in the dairy industry worldwide. Although the algaPrototheca zopfiiis a major cause of mastitis in dairy cows, mechanisms by which it damages mammary tissues are not well known. Here, we used cell cultures and a mouse model of mastitis to determine howProtothecacaused inflammation and cell death in mammary tissues.Protothecainvaded mammary gland cells, from cattle and mice, as well as macrophages (white cells that take up and kill pathogens) and caused cell death by interfering with mitochondria. Furthermore,Protothecacauses severe inflammation and tissue damage when injected into the mammary glands of mice. Although there are two genotypes ofP. zopfii, only genotype II causes tissue damage, whereas gentotype I, common in farm environments, does not damage mammary tissues. SinceP. zopfiiis an alga and not a bacterium, antibiotic treatments, frequently used to treat mastitis in cattle, are not effective against this organism. Understanding howP. zopfiidamages mammary tissue and causes mastitis is important new knowledge to promote future development of evidence-based approaches to prevent and treat mammary gland infections with this organism.
A meta-analysis on the benefits and costs of hosting secondary endosymbionts in sap-sucking insects
Authors: Zytynska Sharon E. , Thighiouart Karim , Frago Enric 
Published: March 2019

AbstractHerbivorous insects host various bacteria that help them to feed, grow, and survive. Sap-sucking insects, in particular, feed on a nutrient-poor resource and have evolved obligate symbioses with nutritional bacteria for survival. Additionally, sap-sucking insects have formed facultative associations with bacterial symbionts that are not essential for growth and survival but assumed to confer some benefits, such as resistance to natural enemies. Several recent reviews have highlighted the importance of these symbionts in understanding their hosts’ biology, but currently there is a lack of a quantitative and systematic analysis of the published evidences exploring whether the different endosymbionts are actually beneficial or not. In this meta-analysis we explored the potential costs and benefits associated with hosting facultative endosymbionts in sap-sucking insects. Our first result is that most of the empirical experimental data information is limited to a few species of aphid and one species of whiteflies. Through the meta-analysis we showed that hosting symbionts generally leads to costs through increased development time, reduced longevity, and reduced fecundity, and benefits via increased resistance to parasitic wasps in sap-sucking insects. However, the impact of these costs and benefits was strongly insect and symbiont species dependent. Many of the insects studied are agricultural pests, and understanding the impact of bacterial symbionts on their hosts across different environments can benefit sustainable management of greenhouses and agricultural land.
Effects of route of administration on oxytocin-induced changes in regional cerebral blood flow in humans
Authors: Martins D. A. , Mazibuko N. , Zelaya F. , Vasilakopoulou S. , Loveridge J. , Oates A. , Maltezos S. , Mehta M. , Wastling S. , Howard M. , McAlonan G. , Murphy D. , Williams S. C. R. , Fotopoulou A. , Schuschnig U. , Paloyelis Y. 
Published: March 2019

ABSTRACTCould nose-to-brain pathways mediate the effects of peptides such as oxytocin (OT) on brain physiology when delivered intranasally? We address this question by contrasting two methods of intranasal administration (a standard nasal spray, and a nebulizer expected to improve OT deposition in nasal areas putatively involved in direct nose-to-brain transport) to intravenous administration in terms of effects on regional cerebral blood flow during two hours post-dosing. We demonstrate that OT-induced decreases in amygdala perfusion, a key hub of the OT central circuitry, are explained entirely by OT increases in systemic circulation following both intranasal and intravenous OT administration. Yet we also provide robust evidence confirming the validity of the intranasal route to target specific brain regions. Our work has important translational implications and demonstrates the need to carefully consider the method of administration in our efforts to engage specific central oxytocinergic targets for the treatment of neuropsychiatric disorders.
Harnessing patient-specific response dynamics to optimize evolutionary therapies for metastatic clear cell renal cell carcinoma – Learning to adapt
Authors: Sorribes I. C. , Basu A. , Brady R. , Enriquez-Navas P. M. , Feng X. , Kather J. N. , Nerlakanti N. , Stephens R. , Strobl M. , Tavassoly I. , Vitos N. , Lemanne D. , Manley B. , O’Farrelly C. , Enderling H. 
Published: March 2019

AbstractRenal cell carcinoma (RCC) is one of the ten most common and lethal cancers in the United States. Tumor heterogeneity and development of resistance to treatment suggest that patient-specific evolutionary therapies may hold the key to better patients prognosis. Mathematical models are a powerful tool to help develop such strategies; however, they depend on reliable biomarker information. In this paper, we present a dynamic model of tumor-immune interactions, as well as the treatment effect on tumor cells and the tumor-immune environment. We hypothesize that the neutrophil-to-lymphocyte ratio (NLR) is a powerful biomarker that can be used to predict an individual patient’s response to treatment. Using randomly sampled virtual patients, we show that the model recapitulates patient outcomes from clinical trials in RCC. Finally, we use in silico patient data to recreate realistic tumor behaviors and simulate various treatment strategies to find optimal treatments for each virtual patient.
The complexity dividend: when sophisticated inference matters
Authors: Tavoni Gaia , Balasubramanian Vijay , Gold Joshua I. 
Published: March 2019

SummaryAnimals continuously infer latent properties of the world from noisy and changing observations. Complex approaches to this challenge such as Bayesian inference are accurate but cognitively demanding, requiring extensive working memory and adaptive learning. Simple strategies such as always using a prior bias or following the last observation are easy to implement but may be less accurate. What is the appropriate balance between complexity and accuracy? We construct a hierarchy of strategies that vary in complexity between these limits and find a power law of diminishing returns: increasing complexity gives progressively smaller gains in accuracy. Moreover, the rate at which the gain decrements depends systematically on the statistical uncertainty in the world, such that complex strategies do not provide substantial benefits over simple ones when uncertainty is too high or too low. In between, when the world is neither too predictable nor too unpredictable, there is a complexity dividend.
Synthetic Promoter Design in Escherichia coli based on Generative Adversarial Network
Authors: Wang Ye , Wang Haochen , Liu Liyang , Wang Xiaowo 
Published: March 2019

ABSTRACTSynthetic promoters are commonly applied elements in circuit design for fine-tuning the protein expression levels. Promoter engineering was mostly focused on the random mutation or combination of regulation elements such as transcription factor binding sites. However, the size of promoter sequence space is still overwhelming and better navigation method is required. On the other hand, the generative adversarial network (GAN) is known for its great ability to reduce the searching space by learning to generate new data on the similar manifold of original data. Here, we applied WGAN-GP model into de novo promoter sequence design to generate entirely new promoter sequences. In total, 83 of model-generated promoter sequences were tested in promoter activity screening by regulating the expression of sfGFP gene in Escherichia coli. As a result, 26 out of 83 newly designed promoters were found functional and successfully expressed with varying activities, with similarity score to natural promoters all less than 0.7. Moreover, 3 of them showed higher promoter strength than the wild type promoters and their highly expression mutants. The much higher successful rate and promoter activity with much lower similarity score in our model-designed novel promoters confirmed the effectiveness of promoter sequence learning. Our work provides insights into an area of navigation of novel functional promoter sequence space automatically, as well as speeding up evolution process of naturally existing promoters, indicating the potential ability for deep generative models to be applied into genetic element designing in the future.
Applying Citizen Science to Gene, Drug, Disease Relationship Extraction from Biomedical Abstracts
Authors: Tsueng Ginger , Nanis Max , Fouquier Jennifer T. , Mayers Michael , Good Benjamin M. , Su Andrew I 
Published: March 2019

AbstractBiomedical literature is growing at a rate that outpaces our ability to harness the knowledge contained therein. In order to mine valuable inferences from the large volume of literature, many researchers have turned to information extraction algorithms to harvest information in biomedical texts. Information extraction is usually accomplished via a combination of manual expert curation and computational methods. Advances in computational methods usually depends on the generation of gold standards by a limited number of expert curators. This process can be time consuming and represents an area of biomedical research that is ripe for exploration with citizen science. Citizen scientists have been previously found to be willing and capable of performing named entity recognition of disease mentions in biomedical abstracts, but it was uncertain whether or not the same could be said of relationship extraction. Relationship extraction requires training on identifying named entities as well as a deeper understanding of how different entity types can relate to one another. Here, we used the web-based application Mark2Cure (https://mark2cure.org) to demonstrate that citizen scientists can perform relationship extraction and confirm the importance of accurate named entity recognition on this task. We also discuss opportunities for future improvement of this system, as well as the potential synergies between citizen science, manual biocuration, and natural language processing.