bluuebunny/crossref_metadata_2025_split huggingface dataset:
Overexpression of CD47 is associated with brain overgrowth in 16p11.2 deletion syndrome
Authors: Li Jingling , Brickler Thomas , Banuelos Allison , Marjon Kristopher , Bian Jing , Narayanan Cyndhavi , Weissman Irving L. , Chetty Sundari 
Published: October 2019

AbstractOne of the most common genetic linkages associated with neuropsychiatric disorders, such as autism spectrum disorder and schizophrenia, occurs at the 16p11.2 locus. Copy number variants (CNVs) of the 16p gene can manifest in opposing head sizes. 16p11.2 deletion carriers tend to have macrocephaly (or brain enlargement), while those with 16p11.2 duplication frequently have microcephaly. Increases in both gray and white matter volume have been observed in brain imaging studies in 16p11.2 deletion carriers with macrocephaly. Here, we use human induced pluripotent stem cells (hiPSCs) derived from controls and subjects with 16p11.2 deletion and 16p11.2 duplication to understand the underlying mechanisms regulating brain overgrowth. To model both gray and white matter, we differentiated patient-derived iPSCs into neural progenitor cells (NPCs) and oligodendrocyte progenitor cells (OPCs). In both NPCs and OPCs, we show that CD47 (a ‘don’t eat me’ signal) is overexpressed in the 16p11.2 deletion carriers contributing to reduced phagocytosis bothin vitroandin vivo. Treatment of 16p11.2 deletion NPCs and OPCs with an anti-CD47 antibody to block CD47 restores phagocytosis to control levels. Furthermore, 16p11.2 deletion NPCs and OPCs upregulate cell surface expression of calreticulin (a pro-phagocytic ‘eat me’ signal) and its binding sites, indicating that these cells should be phagocytosed but fail to be eliminated due to elevations in CD47. While the CD47 pathway is commonly implicated in cancer progression, we document a novel role for CD47 in regulating brain overgrowth in psychiatric disorders and identify new targets for therapeutic intervention.
Does a passerine hibernate?
Authors: McNab Brian K. , Weston Kerry 
Published: October 2019

ABSTRACTThe thermal physiology of the highly endangered Rock Wren (Xenicus gilviventris) from New Zealand is examined. It is a member of the Acanthisittidae, a family unique to New Zealand. This family, derived from Gondwana, is thought to be the sister taxon to all other passerines. Rock Wrens permanently reside above the climatic timberline at altitudes from 1,000 to 2,900 meters in the mountains of South Island. They feed on invertebrates and in winter face ambient temperatures well below freezing and deep deposits of snow. Their body temperature and rate of metabolism are highly variable. Rock Wrens regulate body temperature at ca. 36C, which in one individual decreased to 33.1C at an ambient temperature of 9.4C, which returned to 36C at 30.1C; its rate of metabolism decreased by 30%. The rate of metabolism in a second individual twice decreased by 35%, nearly to the basal rate expected from mass. The Rock Wren food habits, entrance into torpor, and continuous residence in a thermally demanding environment suggest that it may hibernate. For that conclusion to be accepted, evidence of its use of torpor for extended periods is required. Those data are not presently available. Acanthisittids are distinguished from other passerines by the combination of their temperate distribution, thermal flexibility, and a propensity to evolve a flightless condition. These characteristics may reflect their phylogenetic status, but they are so different from those found in other passerines that it is more likely that they reflect the geographical isolation of acanthisittids in a temperate environment for 85 million years in the absence of mammalian predators.
A phenotypic screening platform utilising human spermatozoa identifies new compounds with contraceptive activity
Authors: Gruber Franz , Barratt Christopher L.R. , Andrews Paul D. 
Published: October 2019

AbstractThere is an urgent need to develop new methods for male contraception, however a major barrier to drug discovery has been the lack of validated targets and the absence of an effective high-throughput phenotypic screening system. To address this deficit, we developed a fully-automated robotic screening platform that provided quantitative evaluation of compound activity against two key attributes of human sperm function: motility and acrosome reaction. In order to accelerate contraceptive development, we screened the comprehensive collection of 12,000 molecules that make up the ReFRAME repurposing library, comprising nearly all the small molecules that have been approved or have undergone clinical development, or have significant preclinical profiling. We identified several compounds that potently inhibit motility representing either novel drug candidates or routes to target identification. This platform will now allow for major drug discovery programmes that address the critical gap in the contraceptive portfolio as well as uncover novel human sperm biology.
Fibronectin-dependent tissue mechanics regulate the translation of segmentation clock oscillations into periodic somite formation
Authors: Gomes de Almeida Patrícia , Rifes Pedro , Martins-Jesus Ana Patrícia , Pinheiro Gonçalo G. , Andrade Raquel P. , Thorsteinsdóttir Sólveig 
Published: October 2019

AbstractSomitogenesis starts with cyclic waves of expression of segmentation clock genes in the presomitic mesoderm (PSM) and culminates with periodic budding of somites in its anterior-most region. How cyclic clock gene expression is translated into timely morphological somite formation has remained unclear. A posterior to anterior gradient of increasing PSM tissue cohesion correlates with increasing fibronectin matrix complexity around the PSM, suggesting that fibronectin-dependent tissue mechanics may be involved in this transition. Here we address whether the mechanical properties of the PSM tissue play a role in regulating the pathway leading to cleft formation in the anterior PSM. We first interfered with cytoskeletal contractility in the chick PSM by disrupting actomyosin-mediated contractility directly or via Rho-associated protein kinase function. Then we perturbed fibronectin matrix accumulation around the PSM tissue by blocking integrin-fibronectin binding or fibronectin matrix assembly. All four treatments perturbedhairy1andmeso1expression dynamics and resulted in defective somitic clefts. A model is presented where a gradient of fibronectin-dependent tissue mechanics participates in the PSM wavefront of maturation by ensuring the correct spatio-temporal conversion of cyclic segmentation clock gene expression into periodic somite formation.
Modeling behaviorally relevant neural dynamics enabled by preferential subspace identification (PSID)
Authors: Sani Omid G. , Pesaran Bijan , Shanechi Maryam M. 
Published: October 2019

AbstractNeural activity exhibits dynamics that in addition to a behavior of interest also relate to other brain functions or internal states. Understanding how neural dynamics explain behavior requires dissociating behaviorally relevant and irrelevant dynamics, which is not achieved with current neural dynamic models as they are learned without considering behavior. We develop a novel preferential subspace identification (PSID) algorithm that models neural activity while dissociating and prioritizing its behaviorally relevant dynamics. Applying PSID to large-scale neural activity in two monkeys performing naturalistic 3D reach-and-grasps uncovered new features for neural dynamics. First, PSID revealed the behaviorally relevant dynamics to be markedly lower-dimensional than otherwise implied. Second, PSID discovered distinct rotational dynamics that were more predictive of behavior. Finally, PSID more accurately learned the behaviorally relevant dynamics for each joint and recording channel. PSID provides a general new tool to reveal behaviorally relevant neural dynamics that can otherwise go unnoticed.
Direct observation of the setular web that fuses thoracopodal setae of a calanoid copepod into a collapsible fan
Authors: von Dassow George , Emlet Richard B. 
Published: October 2019

SummaryCopepods are numerically dominant planktonic grazers throughout the waters of Earth, preyed upon in turn by a wide diversity of pelagic animals (1,2). Their feeding and swimming performance thus has global importance to aquatic food webs and oceanic carbon flux. These crustaceans swim and feed using cuticle-covered, segmented, muscular appendages whose reach is extended greatly by setae, extracellular chitinous extensions with diverse structure and function (3). Plumose setae, with subsidiary setules arranged like barbs on a feather, have well-documented roles in generating feeding and swimming currents (4,5). Recent work showed that plumose setae of barnacle cyprid thoracopods are permanently linked by setules into a single fan that opens and closes as one sheet during high-speed swimming (6). Intersetular linkage across cyprid thoracopods may greatly decrease leakage between extended setae, ensure even spread of setae within the fan, and promote ordered collapse of the fan to avoid entanglement of adjacent appendages. Here we demonstrate similar setular webbing amongst thoracopod setae in the calanoid copepod Acartia sp. High-speed video directly documents the existence of such links, and reveals that individuals experience apparently-irreparable degradation of the setal array due to de-linkage, with likely consequences for swimming performance.
Pinhole Optical Tweezers: Extending the Photobleaching Lifetime in the Presence of an Optical Trap by Wavefront Engineering
Authors: Zhang Zheng , Milstein Joshua N. 
Published: October 2019

ABSTRACTWe present a new method for combining optical tweezers with single-molecule fluorescence in an engineered geometry we have coined a ‘pinhole’ optical trap. By utilizing an appropriately constructed Laguerre-Gaussian (LG) or ‘donut’ beam, and applying force along the axis of the trapping laser, one can maintain a low-intensity region of near-infrared (IR) light directly below the optical trap in which a biomolecule may be probed by both force spectroscopy and fluorescence. We show that within this region of low IR light intensity, the photobleaching lifetime of Alexa-647, an organic dye that is particularly sensitive to the high intensity trap light, can be significantly extended. This approach enables us to spatially separate the trap light from the fluorescence illumination without the need to physically separate, by many micrometers, the optical trap from the biological sample.
Structural variation in Drosophila melanogaster spermathecal ducts and its association with sperm competition dynamics
Authors: Hopkins Ben R. , Sepil Irem , Wigby Stuart 
Published: October 2019

AbstractThe ability of female insects to retain and use sperm for days, months, or even years after mating requires specialised storage organs in the reproductive tract. In most orders these organs include a pair of sclerotised capsules known as spermathecae. Here, we report that some Drosophila melanogaster females exhibit previously uncharacterised structures within the distal portion of the muscular duct that links a spermatheca to the uterus. We find that these ‘spermathecal duct presences’ (SDPs) may form in either or both ducts and can extend from the duct into the sperm-storing capsule itself. We further find that the incidence of SDPs varies significantly between genotypes, but does not change significantly with the age or mating status of females, the latter indicating that SDPs are not composed of or stimulated by sperm or male seminal proteins. We show that SDPs affect neither the number of first male sperm held in a spermatheca nor the number of offspring produced after a single mating. However, we find evidence that SDPs are associated with a lack of second male sperm in the spermathecae after females remate. This raises the possibility that SDPs provide a mechanism for variation in sperm competition outcome among females.
Data-Driven Analysis of a Mechanistic Model of CAR T Cell Signaling Predicts Effects of Cell-to-cell Heterogeneity
Authors: Cess Colin G. , Finley Stacey D. 
Published: October 2019

ABSTRACTDue to the variability of protein expression, cells of the same population can exhibit different responses to stimuli. It is important to understand this heterogeneity at the individual level, as population averages mask these underlying differences. Using computational modeling, we can interrogate a system much more precisely than by using experiments alone, in order to learn how the expression of each protein affects a biological system. Here, we examine a mechanistic model of CAR T cell signaling, which connects receptor-antigen binding to MAPK activation, to determine intracellular modulations that can increase cellular response. CAR T cell cancer therapy involves removing a patient’s T cells, modifying them to express engineered receptors that can bind to tumor-associated antigens to promote cell killing, and then injecting the cells back into the patient. This population of cells, like all cell populations, would have heterogeneous protein expression, which could affect the efficacy of treatment. Thus, it is important to examine the effects of cell-to-cell heterogeneity. We first generated a dataset of simulated cell responses via Monte Carlo simulations of the mechanistic model, where the initial protein concentrations were randomly sampled. We analyzed the dataset using partial least-squares modeling to determine the relationships between protein expression and ERK phosphorylation, the output of the mechanistic model. Using this data-driven analysis, we found that only the expressions of proteins relating directly to the receptor and the MAPK cascade, the beginning and end of the network, respectively, are relevant to the cells’ response. We also found, surprisingly, that increasing the amount of receptor present can actually inhibit the cell’s ability to respond due to increasing the strength of negative feedback from phosphatases. Overall, we have combined data-driven and mechanistic modeling to generate detailed insight into CAR T cell signaling.
An Adaptable Prosthetic Wrist Reduces Subjective Workload
Authors: Olsen Nathaniel R. , George Jacob A. , Brinton Mark R. , Paskett Michael D. , Kluger David T. , Tully Troy N. , Duncan Christopher C. , Clark Gregory A. 
Published: October 2019

AbstractMany presently available prostheses lack a functional wrist. To fill this niche and to better understand the impact a wrist has in prosthetic functionality, we designed a low-cost, adaptable, 3D-printable prosthetic wrist that can be adapted to various prosthetic hands and sockets. The wrist utilizes inexpensive but powerful servo motors to provide simultaneous and proportional control of two degrees of freedom: pronation/supination and flexion/extension or radial/ulnar deviation. Participants used both our wrist and a commercially available wrist (DEKA “LUKE” Arm) to complete a modified version of the clothespin relocation task with and without the wrists enabled. Through use of the NASA Task Load Index we found that both wrists significantly reduced the subjective workload associated with clothespin relocation task (p < 0.05). However, we found no significant difference in task completion speed, presumably due to compensation strategies. This inexpensive and adaptable prosthetic wrist can be used by amputees to reduce task workload, or by researchers to further explore the importance of wrist function.
Polygenic risk modeling with latent trait-related genetic components
Authors: Aguirre Matthew , Tanigawa Yosuke , Venkataraman Guhan Ram , Tibshirani Rob , Hastie Trevor , Rivas Manuel A. 
Published: October 2019

AbstractPolygenic risk models have led to significant advances in understanding complex diseases and their clinical presentation. While models like polygenic risk scores (PRS) can effectively predict outcomes, they do not generally account for disease subtypes or pathways which underlie within-trait diversity. Here, we introduce a latent factor model of genetic risk based on components from Decomposition of Genetic Associations (DeGAs), which we call the DeGAs polygenic risk score (dPRS). We compute DeGAs using genetic associations for 977 traits in the UK Biobank and find that dPRS performs comparably to standard PRS while offering greater interpretability. We show how to decompose an individual’s genetic risk for a trait across DeGAs components, highlighting specific results for body mass index (BMI), myocardial infarction (heart attack), and gout in 337,151 white British individuals, with replication in a further set of 25,486 non-British white individuals from the Biobank. We find that BMI polygenic risk factorizes into components relating to fat-free mass, fat mass, and overall health indicators like physical activity measures. Most individuals with high dPRS for BMI have strong contributions from both a fat mass component and a fat-free mass component, whereas a few ‘outlier’ individuals have strong contributions from only one of the two components. Overall, our method enables fine-scale interpretation of the drivers of genetic risk for complex traits.
Insights into the aetiology of snoring from observational and genetic investigations in the UK Biobank (n=408,317)
Authors: Campos Adrián I. , García-Marín Luis M. , Byrne Enda M. , Martin Nicholas G. , Cuéllar-Partida Gabriel , Rentería Miguel E. 
Published: October 2019

ABSTRACTWe conducted the largest study of snoring using data from the UK Biobank (n∼ 408,000; snorers ∼152,000). A genome-wide association study (GWAS) identified 42 genome-wide significant loci, with a SNP-based heritability estimate of ∼10% on the liability scale. Genetic correlations with body mass index, alcohol intake, smoking, schizophrenia, anorexia nervosa and neuroticism were observed. Gene-based associations identified 173 genes, includingDLEU7, MSRB3andPOC5highlighting genes expressed in brain, cerebellum, lungs, blood, and oesophagus tissues. We used polygenic scores (PGS) to predict recent snoring and probable obstructive sleep apnoea (OSA) in an independent Australian sample (n∼8,000). Mendelian randomisation analyses provided evidence that larger whole body fat mass causes snoring. Altogether, our results uncover new insights into the aetiology of snoring as a complex sleep-related trait and its role in health and disease beyond being a cardinal symptom of OSA.
Great tits in noisy territories and avoiding overlapping respond stronger to territorial intruders
Authors: Akçay Çağlar , Porsuk Y. Kağan , Avşar Alican , Çabuk Dilan , Bilgin C. Can 
Published: October 2019

AbstractAnimals often communicate with each other in noisy environments where interference from the ambient noise and other signallers may reduce the effectiveness of signals. Signalling behaviours may also evolve to interfere with signals of their opponents, e.g. by temporally overlapping them with their own, such as the song overlapping behaviour that is seen in some songbirds during aggressive interactions. Song overlapping has been proposed to be a signal of aggressive intent, but few studies directly examined the association between song overlapping and aggressive behaviours of the overlapping bird (the predictive criterion). In the present paper we examined the question of whether song overlapping is correlated with aggressive behaviours displayed during a simulated territorial intrusion in a population of great tits (Parus major) living in an urban-rural gradient. We also examined whether aggressive behaviours are correlated with the ambient noise levels. We found that overlapping was associated negatively with aggressive behaviours males displayed against a simulated intruder. These results fail to support the predictive criterion for song overlapping, raising the question whether overlapping is in fact a signal of aggressive intent. Ambient noise levels were associated positively with aggressive behaviours but did not correlate with song rate, song duration or song overlapping. Great tits in noisy urban habitats may display higher levels of aggressive behaviours due to either interference of noise in aggressive communication or another indirect effect of noise.
A stable leading strand polymerase/clamp loader complex is required for normal and perturbed eukaryotic DNA replication
Authors: Stokes Katy , Winczura Alicja , Song Boyuan , De Piccoli Giacomo , Grabarczyk Daniel B. 
Published: October 2019

AbstractThe eukaryotic replisome must faithfully replicate DNA and cope with replication fork blocks and stalling, while simultaneously promoting sister chromatid cohesion. Ctf18-RFC is an alternative PCNA loader that links all these processes together by an unknown mechanism. Here, we use integrative structural biology combined with yeast genetics and biochemistry to highlight the specific functions that Ctf18-RFC plays within the leading strand machineryviaan interaction with the catalytic domain of DNA Pol ε. We show that a large and unusually flexible interface enables this interaction to occur constitutively throughout the cell cycle and regardless of whether forks are replicating or stalled. We reveal that, by being anchored to the leading strand polymerase, Ctf18-RFC can rapidly signal fork stalling to activate the S phase checkpoint. Moreover, we demonstrate that, independently of checkpoint signaling or chromosome cohesion, Ctf18-RFC functions in parallel to Chl1 and Mrc1 to protect replication forks and cell viability.
Punishment insensitivity emerges from impaired contingency detection, not aversion insensitivity or reward dominance
Authors: Jean-Richard-dit-Bressel Philip , Ma Cassandra , Bradfield Laura A. , Killcross Simon , McNally Gavan P. 
Published: October 2019

AbstractOur behaviour is shaped by its consequences – we seek rewards and avoid harm. It has been reported that individuals vary markedly in their avoidance of detrimental consequences, i.e. in their sensitivity to punishment. The underpinnings of this variability are poorly understood; they may be driven by differences in aversion sensitivity, motivation for reward, and/or instrumental control. We examined these hypotheses by applying several analysis strategies to the behaviour of rats (n = 48; 18 female) trained in a task permitting concurrent assessment of punishment, reward-seeking, and Pavlovian fear. We show that punishment insensitivity is a unique phenotype, unrelated to differences in reward-seeking and Pavlovian fear, and due to a failure of instrumental control. Subjects insensitive to punishment are afraid of aversive events, they are simply unable to change their behaviour to avoid them.
GenIE-Sys: Genome Integrative Explorer System
Authors: Mannapperuma Chanaka , Waterworth John , Street Nathaniel 
Published: October 2019

AbstractThere are an ever-increasing number of genomes being sequenced, many of which have associated RNA sequencing and other genomics data. The availability of user-friendly web-accessible mining tools ensures that these data repositories provide maximum benefit to the community. However, there are relatively few options available for setting up such standalone frameworks. We developed the Genome Integrative Explorer System (GenIE-Sys) to set up web resources to enable search, visualization and exploration of genomics data typically generated by a genome project.GenIE-Sys is implemented in PHP, JavaScript and Python and is freely available under the GNU GPL 3 public license. All source code is freely available at the GenIE-Sys website (https://geniesys.org) or GitHub (http://github.com/plantgenie/geniesys.git). Documentation is available at http://geniesys.readthedocs.io.