bluuebunny/crossref_metadata_2025_split huggingface dataset:
PKM2 ablation enhanced retinal function and survival in a preclinical model of retinitis pigmentosa
Authors: Zhang Ethan , Ryu Joseph , Levi Sarah R. , Oh Jin Kyun , Hsu Chun Wei , Lima de Carvalho Jose Ronaldo , Cui Xuan , Yang Tingting , Tsang Stephen H. 
Published: November 2019

ABSTRACTRetinitis pigmentosa (RP) is a neurodegenerative disorder that causes irreversible vision loss in over 1.5 million individuals world-wide. In this study, we demonstrate that a metabolic reprogramming can treat degeneration in a Pde6β preclinical model of RP. Pyruvate kinase M2 (PKM2) is a glycolytic enzyme that transfers phosphate from phosphoenolpyruvate (PEP) to adenosine diphosphate (ADP), promoting glucose catabolism. Ablation of PKM2 resulted in enhanced photoreceptor survival and function in Pde6β-mutated mice compared with those without ablation. Electroretinogram (ERG) analyses revealed that the maximum b-wave is on average greater in Pkm2 knockout mice than in mice with Pkm2 intact. These rescue phenotypes from Pkm2 ablation in a preclinical model of RP indicate that a metabolome reprogramming may be useful in treating RP.
Plumage manipulation alters the integration of social behavior, physiology, internal microbiome, and fitness
Authors: Taff Conor C. , Zimmer Cedric , Scheck David , Ryan Thomas A. , Houtz Jennifer L. , Smee Melanie R. , Hendry Tory A. , Vitousek Maren N. 
Published: November 2019

ABSTRACTSignals often covary with physiological and behavioral traits to form an axis of integrated phenotypic variation associated with reproductive performance. This pattern of phenotypic integration could result from intrinsic between-individual differences that are causally related to signal production, physiology, and behavior. Alternatively, signal expression itself might generate dynamic feedback between physiology, behavior, and the experienced social environment, resulting in an integrated phenotype. Here, we manipulated the plumage of female tree swallows (Tachycineta bicolor) to decouple the expression of a social signal from any pre-existing behavioral or physiological differences. We collected a time series of physiological samples, monitored social interactions with a sensor network, and tracked reproductive performance. Relative to sham controls, dulled females experienced an altered social environment; overall, these females were visited more by conspecific females and less by males. Dulled females subsequently changed their own behavior by initiating fewer interactions and increasing nestling provisioning. These differences resulted in an altered internal microbiome and glucose levels and, ultimately, dulled females produced more offspring. Moreover, dulled females produced larger clutches than control females in the year after the manipulation. Thus, signal variation alone—independent from any pre-existing differences—had a sustained causal affect on a suite of integrated traits. This finding suggests that dynamic feedback may play an important role in coordinating an integrated signaling phenotype. Our results have implications for understanding how variation in signal expression arises and is maintained and the extent to which the information encoded in signals is contingent upon their use in a social environment.
On the Boundary Conditions of Avoidance Memory Reconsolidation: An Attractor Network Perspective
Authors: Santiago Rodrigo MM , Tort Adriano BL 
Published: November 2019

AbstractThe reconsolidation and extinction of aversive memories and their boundary conditions have been extensively studied. Knowing their network mechanisms may lead to the development of better strategies for the treatment of fear and anxiety-related disorders. In 2011, Osan et al. developed a computational model for exploring such phenomena based on attractor dynamics, Hebbian plasticity and synaptic degradation induced by prediction error. This model was able to explain, in a single formalism, experimental findings regarding the freezing behavior of rodents submitted to contextual fear conditioning. In 2017, through the study of inhibitory avoidance in rats, Radiske et al. showed that the previous knowledge of a context as non-aversive is a boundary condition for the reconsolidation of the shock memory subsequently experienced in that context. In the present work, by adapting the model of Osan et al. (2011) to simulate the experimental protocols of Radiske et al. (2017), we show that such boundary condition is compatible with the dynamics of an attractor network that supports synaptic labilization common to reconsolidation and extinction. Additionally, by varying parameters such as the levels of protein synthesis and degradation, we predict behavioral outcomes, and thus boundary conditions that can be tested experimentally.
Collective MAPK Signaling Dynamics Coordinates Epithelial Homeostasis
Authors: Aikin Timothy J. , Peterson Amy F. , Pokrass Michael J. , Clark Helen R. , Regot Sergi 
Published: November 2019

ABSTRACTEpithelial tissues are constantly challenged by individual cell fate decisions while maintaining barrier function. During oncogenesis, mutant and normal cells also differ in their signaling states and cellular behaviors creating competitive interactions that are poorly understood. Here we show that the temporal patterns of MAPK activity are decoded by the ADAM17-EGFR paracrine signaling axis to coordinate migration of neighboring cells and promote extrusion of aberrantly-signaling cells. Concurrently, neighboring cells increase proliferation to maintain cell density while oncogene expressing cells undergo cell cycle arrest. Moreover, the stress MAPK p38 elicits the same paracrine signaling and extrusion response, suggesting that the ADAM17-EGFR pathway constitutes a quality control mechanism to eliminate and replace unfit cells from epithelial tissues. Overall, we show that the temporal patterns of MAPK activity coordinates both single and collective cell behaviors to maintain tissue homeostasis.
A Compendium of Kinetic Cell Death Modulatory Profiles Identifies Ferroptosis Regulators
Authors: Conlon Megan , Poltorack Carson , Forcina Giovanni C. , Wells Alex , Mallais Melodie , Kahanu Alexis , Magtanong Leslie , Pratt Derek A. , Dixon Scott J. 
Published: November 2019

AbstractCell death can be executed by regulated apoptotic and non-apoptotic pathways, including the iron-dependent process of ferroptosis. Small molecules are essential tools for studying the regulation of cell death. Using live-cell, time-lapse imaging, and a library of 1,833 small molecules including FDA-approved drugs and investigational agents, we assemble a large compendium of kinetic cell death ‘modulatory profiles’ for inducers of apoptosis and ferroptosis. From this dataset we identified dozens of small molecule inhibitors of ferroptosis, including numerous investigational and FDA-approved drugs with unexpected off-target antioxidant or iron chelating activities. ATP-competitive mechanistic target of rapamycin (mTOR) inhibitors, by contrast, were on-target ferroptosis inhibitors. Further investigation revealed both mTOR-dependent and mTOR-independent mechanisms linking amino acid levels to the regulation of ferroptosis sensitivity in cancer cells. These results highlight widespread bioactive compound pleiotropy and link amino acid sensing to the regulation of ferroptosis.
Iterative Subtractive Binning of Freshwater Chronoseries Metagenomes Identifies of over Four Hundred Novel Species and their Ecologic Preferences
Authors: Rodriguez-R LM , Tsementzi D , Luo C , Konstantinidis KT 
Published: November 2019

AbstractRecent advances in sequencing technology and accompanying bioinformatic pipelines have allowed unprecedented access to the genomes of yet-uncultivated microorganisms from a wide array of natural and engineered environments. However, the catalogue of available genomes from uncultivated freshwater microbial populations remains limited, and most genome recovery attempts in freshwater ecosystems have only targeted few specific taxa. Here, we present a novel genome recovery pipeline, which incorporates iterative subtractive binning and apply it to a time series of metagenomic datasets from seven connected locations along the Chattahoochee River (Southeastern USA). Our set of Metagenome-Assembled Genomes (MAGs) represents over four hundred genomospecies yet to be named, which substantially increase the number of high-quality MAGs from freshwater lakes and represent about half of the total microbial community sampled. We propose names for two novel species that were represented by high-quality MAGs: “CandidatusElulimicrobium humile” (“Ca. Elulimicrobiota” in the “Patescibacteria” group) and “CandidatusAquidulcis frankliniae” (“Chloroflexi”). To evaluate the prevalence of these species in the chronoseries, we introduce novel approaches to estimate relative abundance and a habitat-preference score that control for uneven quality of the genomes and sample representation. Using these metrics, we demonstrate a high degree of habitat-specialization and endemicity for most genomospecies observed in the Chattahoochee lacustrine ecosystem, as well as wider species ecological ranges associated with smaller genomes and higher coding densities, indicating an overall advantage of smaller, more compact genomes for cosmopolitan distributions.
Individualized multi-omic pathway deviation scores using multiple factor analysis
Authors: Rau Andrea , Manansala Regina , Flister Michael J. , Rui Hallgeir , Jaffrézic Florence , Laloë Denis , Auer Paul L. 
Published: November 2019

SummaryMalignant progression of normal tissue is typically driven by complex networks of somatic changes, including genetic mutations, copy number aberrations, epigenetic changes, and transcriptional reprogramming. To delineate aberrant multi-omic tumor features that correlate with clinical outcomes, we present a novel pathway-centric tool based on the multiple factor analysis framework called padma. Using a multi-omic consensus representation, padma quantifies and characterizes individualized pathway-specific multi-omic deviations and their underlying drivers, with respect to the sampled population. We demonstrate the utility of padma to correlate patient outcomes with complex genetic, epigenetic, and transcriptomic perturbations in clinically actionable pathways in breast and lung cancer.
A probabilistic framework for decoding behavior from in vivo calcium imaging data
Authors: Etter Guillaume , Manseau Frederic , Williams Sylvain 
Published: November 2019

AbstractUnderstanding the role of neuronal activity in cognition and behavior is a key question in neuroscience. Previously,in vivostudies have typically inferred behavior from electrophysiological data using probabilistic approaches including Bayesian decoding. While providing useful information on the role of neuronal subcircuits, electrophysiological approaches are often limited in the maximum number of recorded neurons as well as their ability to reliably identify neurons over time. This can be particularly problematic when trying to decode behaviors that rely on large neuronal assemblies or rely on temporal mechanisms, such as a learning task over the course of several days. Calcium imaging of genetically encoded calcium indicators has overcome these two issues. Unfortunately, because calcium transients only indirectly reflect spiking activity and calcium imaging is often performed at lower sampling frequencies, this approach suffers from uncertainty in exact spike timing and thus activity frequency, making rate-based decoding approaches used in electrophysiological recordings difficult to apply to calcium imaging data. Here we describe a probabilistic framework that can be used to robustly infer behavior from calcium imaging recordings and relies on a simplified implementation of a naive Baysian classifier. Our method discriminates between periods of activity and periods of inactivity to compute probability density functions (likelihood and posterior), significance and confidence interval, as well as mutual information. We next devise a simple method to decode behavior using these probability density functions and propose metrics to quantify decoding accuracy. Finally, we show that neuronal activity can be predicted from behavior, and that the accuracy of such reconstructions can guide the understanding of relationships that may exist between behavioral states and neuronal activity.
Cerebellar patients have intact feedback control that can be leveraged to improve reaching
Authors: Zimmet Amanda M. , Bastian Amy J. , Cowan Noah J. 
Published: November 2019

ABSTRACTIt is thought that the brain does not simply react to sensory feedback, but rather uses an internal model of the body to predict the consequences of motor commands before sensory feedback arrives. Time-delayed sensory feedback can then be used to correct for the unexpected—perturbations, motor noise, or a moving target. The cerebellum has been implicated in this predictive control process. Here we show that the feedback gain in patients with cerebellar ataxia matches that of healthy subjects, but that patients exhibit substantially more phase lag. This difference is captured by a computational model incorporating a Smith predictor in healthy subjects that is missing in patients, supporting the predictive role of the cerebellum in feedback control. Lastly, we improve cerebellar patients’ movement control by altering (phase advancing) the visual feedback they receive from their own self movement in a simplified virtual reality setup.
Including Crystallographic Symmetry in Quantum-based Refinement: Q|R#2
Authors: Zheng Min , Biczysko Malgorzata , Xu Yanting , Moriarty Nigel W. , Kruse Holger , Urzhumtsev Alexandre , Waller Mark P. , Afonine Pavel V. 
Published: November 2019

AbstractThree-dimensional structure models refined using low-resolution data from crystallographic or electron cryo-microscopy experiments can benefit from high quality restraints derived from quantum chemical methods. However, non-periodic atom-centered quantum chemistry codes do not inherently account for nearest neighbor interactions of crystallographic symmetry related copies in a satisfactory way. Herein, we have included these nearest neighbor effects in our model by expanding to a super-cell, and then truncating the super-cell to only include residues from neighboring cells that are interacting with the asymmetric unit. In this way our fragmentation approach can adequately and efficiently include the nearest neighbor effects. We have shown previously that a moderately sized X-ray structure can be treated with quantum methods if a fragmentation approach was applied. In this study, we partition a target protein (4gif) into a number of large fragments. The use of large fragments (typically hundreds of atoms) is tractable when a GPU based package such as TeraChem is employed or cheaper (semi-empirical) methods are used. We run the QM calculations at the HF-D3/6-31G level. We compare and contrast the models refined using a recently developed semi-empirical method (GFN2-xTB). To validate the refinement procedure for a non-P1 structure, we use a standard set of crystallographic metrics. We show the robustness of our implementation by refining 13 additional protein models across multiple space-groups and present the summary of the refinement metrics.SynopsisC-terminal coiled-coil domain of transient receptor potential channel TRPP3 in the P321 space group (PDB code: 4gif) is re-refined with restraints from quantum chemistry using Hartree-Fock theory.
The basal ganglia can control learned motor sequences independently of motor cortex
Authors: Dhawale Ashesh K. , Wolff Steffen B. E. , Ko Raymond , Ölveczky Bence P. 
Published: November 2019

SummaryHow the basal ganglia contribute to the execution of learned motor skills has been thoroughly investigated. The two dominant models that have emerged posit roles for the basal ganglia in action selection and in the modulation of movement vigor. Here we test these models in rats trained to execute highly stereotyped and idiosyncratic task-specific motor sequences. Recordings and manipulations of neural activity in the striatum were not well explained by either model, and suggested that the basal ganglia, in particular its sensorimotor arm, are crucial for controlling the detailed kinematic structure of the learned behaviors. Importantly, the neural representations in the striatum, and the control functions they subserve, did not depend on the motor cortex. Taken together, these results extend our understanding of basal ganglia function, by suggesting that they can control and modulate lower-level subcortical motor circuits on a moment-by-moment basis to generate stereotyped learned motor sequences.
MCMBP maintains genome integrity by protecting the MCM subunits from degradation
Authors: Santosa Venny , Kanemaki Masato T. 
Published: November 2019

AbstractThe hetero-hexameric MCM2–7 helicase plays a central role in eukaryotic DNA replication. The expression of MCM2–7 is maintained at a high level for creating dormant origins, which are important for maintaining genome integrity. However, other than transcriptional activation for the de novo synthesis, little is known about how cells maintain a high level of MCM2–7. We show that human MCMBP is a short-lived nuclear protein associating mainly with MCM5, 6, and 7. Loss of MCMBP down-regulates MCM2–7, leading to replication stress and DNA-damage accumulation. Our work demonstrates MCMBP protects the MCM subunits from degradation and suggests its chaperone-like role to achieve a high level of functional MCM2–7 using the nascent and recycled subunits.
DNB-Based On-Chip Motif Finding (DocMF): a High-Throughput Method to Profile Different Types of Protein-DNA Interactions
Authors: Li Zhuokun , Wang Xiaojue , Xu Dongyang , Zhang Dengwei , Wang Dan , Dai Xuechen , Wang Qi , Li Zhou , Gu Ying , Ouyang Wenjie , Zhao Shuchang , Huang Baoqian , Gong Jian , Zhao Jing , Chen Ao , Shen Yue , Dong Yuliang , Zhang Wenwei , Xu Xun , Xu Chongjun , Jiang Yuan 
Published: November 2019

ABSTRACTHere we report a highly sensitive DNB-based on-chip Motif Finding (DocMF) system that utilizes high throughput next-generation-sequencing (NGS) chips to profile protein binding or cleaving activity. Using DocMF, we successfully identified a variety of endonuclease recognition sites and the protospacer-adjacent-motif (PAM) sequences of different CRISPR systems. Our DocMF platform can simultaneously screen both 5’ and 3’ PAM regions with high coverage using the same NGS library/chip. For the well-studied SpCas9, our DocMF platform identified a small proportion of noncanonical 5’-NAG-3’ (∼5%) and 5’-NGA-3’ (∼1.6%), in addition to its common PAMs, 5’-NGG-3’ (∼89.9%). We also used the DocMF to assay two uncharacterized Cas endonucleases, VeCas9 and BvCpf1. VeCas9 PAMs were not detected by the conventional PAM depletion method. However, DocMF discovered that both VeCas9 and BvCpf1 required broader and more complicated PAM sequences for target recognition. VeCas9 preferred the R-rich motifs, whereas BvCpf1 used the T-rich PAMs. Moreover, after slightly changing the experimental protocol, we observed that dCas9, a DNA-binding protein lacking endonuclease activity, preferably binded to the previously reported PAMs 5’-NGG-3’. In summary, our studies demonstrate that DocMF is the first tool with the capacity to exhaustively assay both the binding and the cutting properties of different DNA-binding proteins.
Heritable genetic variants in key cancer genes link cancer risk with anthropometric traits
Authors: Di Giovannantonio Matteo , Harris Benjamin H.L , Zhang Ping , Kitchen-Smith Isaac , Xiong Lingyun , Sahgal Natasha , Stracquadanio Giovanni , Wallace Marsha , Blagden Sarah , Lord Simon , Harris David A. , Harris Adrian L. , Buffa Francesca M. , Bond Gareth 
Published: November 2019

AbstractInherited genetic variants in tumour suppressors and oncogenes can increase the cancer risk, but little is known about their influence on anthropometric traits. Through the integration of inherited and somatic cancer genetic data, we define functional single nucleotide polymorphisms (SNPs) associated with cancer risk and explore potential pleiotropic associations with anthropometic traits in a cohort of 500,000 individuals. We identify three regulatory SNPs for three important cancer genes that associate with both anthropometric traits and cancer risk. We describe a novel association of a SNP in TP53 (rs78378222) with height, lean body mass measures and basal metabolic rate, as well as validating its known associations with brain and non-melanomatous skin cancer susceptibility. Our results clearly demonstrate that heritable variants in key cancer genes can associate with both differential cancer risk and anthropometric traits in the general population, thereby lending support for a role of genetics in linking these human phenotypes.
Phasic and tonic serotonin modulate alarm reactions and post-exposure behavior in zebrafish
Authors: Lima-Maximino Monica , Pyterson Maryana Pereira , do Carmo Silva Rhayra Xavier , Vidal Gomes Gabriela Cristini , Rocha Sueslene Prado , Herculano Anderson Manoel , Rosemberg Denis Broock , Maximino Caio 
Published: November 2019

AbstractCurrent theories on the role of serotonin (5-HT) in vertebrate defensive behavior suggest that this monoamine increases anxiety but decreases fear, by acting at different levels of the neuroaxis. This paradoxical, dual role of 5-HT suggests that a serotonergic tone inhibits fear responses, while an acute increase in 5-HT would produce anxiety-like behavior. However, so far no evidence for a serotonergic tone has been found. Using zebrafish alarm responses, we investigate the participation of phasic and tonic 5-HT levels in fear-like behavior, as well as in behavior after stimulation. Conspecific alarm substance (CAS) increased bottom-dwelling and erratic swimming, and animals transferred to a novel environment after CAS exposure (post-exposure behavior) showed increased bottom-dwelling and freezing. Clonazepam blocked CAS effects during and after exposure. Acute fluoxetine dose-dependently decreased fear-like behavior, but increased post-exposure freezing. Metergoline had no effect on fear-like behavior, but blocked the effects of CAS on post-exposure behavior; similar effects were observed with pCPA. Finally, CAS was shown to decrease the activity of monoamine oxidase in the zebrafish brain after exposure. These results suggest that phasic and tonic serotonin encode an aversive expectation value, switching behavior towards cautious exploration/risk assessment/anxiety when the aversive stimulus is no longer present.
Phosphatidylinositol 4-kinase III beta regulates cell shape, migration and Focal Adhesion number
Authors: Bilodeau Patricia , Jacobsen Daniel , Law-Vinh Denise , Lee Jonathan M 
Published: November 2019

AbstractCell shape is regulated by cell adhesion and cytoskeletal and membrane dynamics. Cell shape, adhesion and motility have a complex relationship and understanding them is important in understanding developmental patterning and embryogenesis. Here we show that the lipid kinase phosphatidylinositol 4-kinase III beta (PI4KIIIβ) regulates cell shape, migration and Focal Adhesion (FA) number. PI4KIIIβ generates phosphatidylinositol 4-phosphate from phosphatidylinositol and is highly expressed in a subset of human breast cancers. PI4KIIIβ and the PI4P it generates regulate a variety of cellular functions, ranging from control of Golgi structure, fly fertility and Akt signaling. Here, we show that loss of PI4KIIIβ expression decreases cell migration and alters cell shape in NIH3T3 fibroblasts. The changes are accompanied by an increase in the number of FA in cells lacking PI4KIIIβ. Furthermore, we find that PI4P-containing vesicles move to the migratory leading-edge during migration and that some of these vesicles tether to and fuse with FA. Fusion is associated with FA disassembly. This suggests a novel regulatory role for PI4KIIIβ and PI4P in cell adhesion and cell shape maintenance.