bluuebunny/crossref_metadata_2025_split huggingface dataset:
FlywheelTools: Data Curation and Manipulation on the Flywheel Platform
Authors: Tapera Tinashe M. , Cieslak Matthew , Bertolero Max , Adebimpe Azeez , Aguirre Geoffrey K. , Butler Ellyn R. , Cook Philip A. , Davila Diego , Elliott Mark A. , Linguiti Sophia , Murtha Kristin , Tackett William , Detre John A. , Satterthwaite Theodore D. 
Published: March 2021

ABSTRACTThe recent and growing focus on reproducibility in neuroimaging studies has led many major academic centers to use cloud-based imaging databases for storing, analyzing, and sharing complex imaging data. Flywheel is one such database platform that offers easily accessible, large-scale data management, along with a framework for reproducible analyses through containerized pipelines. The Brain Imaging Data Structure (BIDS) is a data storage specification for neuroimaging data, but curating neuroimaging data into BIDS can be a challenging and time-consuming task. In particular, standard solutions for BIDS curation are not designed for use on cloud-based systems such as Flywheel. To address these challenges, we developed “FlywheelTools”, a software toolbox for reproducible data curation and manipulation on Flywheel. FlywheelTools includes two elements:fw-heudiconv, for heuristic-driven curation of data into BIDS, andflaudit, which audits and inventories projects on Flywheel. Together, these tools accelerate reproducible neuroscience research on the widely used Flywheel platform.
Molecular Response to PARP1 Inhibition in Ovarian Cancer Cells as Determined by Mass Spectrometry Based Proteomics
Authors: Franz Alexandra , Coscia Fabian , Shen Ciyue , Charaoui Lea , Mann Matthias , Sander Chris 
Published: March 2021

AbstractPoly (ADP)-ribose polymerase (PARP) inhibitors have entered routine clinical practice for the treatment of high-grade serous ovarian cancer (HGSOC), yet the molecular mechanisms underlying treatment response to PARP1 inhibition (PARP1i) are not fully understood. Here, we used unbiased mass spectrometry based proteomics with data-driven protein network analysis to systematically characterize how HGSOC cells respond to PARP1i treatment. We found that PARP1i leads to pronounced proteomic changes in a diverse set of cellular processes in HGSOC cancer cells, consistent with transcript changes in an independent perturbation dataset. We interpret decreases in the levels of the pro-proliferative transcription factors SP1 and β-catenin and in growth factor signaling as reflecting the anti-proliferative effect of PARP1i; and the strong activation of pro-survival processes NF-ϰB signaling and lipid metabolism as PARPi-induced adaptive resistance mechanisms. Based on these observations, we nominate several protein targets for therapeutic inhibition in combination with PARP1i. When tested experimentally, the combination of PARPi with an inhibitor of fatty acid synthase (TVB-2640) has a 3-fold synergistic effect and is therefore of particular pre-clinical interest. Our study improves the current understanding of PARP1 function, highlights the potential that the anti-tumor efficacy of PARP1i may not only rely on DNA damage repair mechanisms and informs on the rational design of PARP1i combination therapies in ovarian cancer.
Cdk8 directly regulates glycolysis via phosphorylation of Gcr2
Authors: Aristizabal Maria J. , O’Duibhir Eoghan , de Jonge Wim , Dever Kristy , Hawe Nicole , Koerkamp Marian Groot , Brok Mariel , van Leenen Dik , Lijnzaad Philip , Kobor Michael S. , Holstege Frank C.P. , Sadowski Ivan 
Published: March 2021

AbstractCDK8encodes an evolutionarily conserved Mediator complex kinase subunit that functions in general and context-specific transcription regulation by phosphorylating core components of the transcription machinery and gene-specific transcription factors. To better understand the role Cdk8 in transcription regulation, we performed high-resolution gene expression time course analysis following nuclear depletion of Cdk8. Focusing on the earliest gene expression alterations revealed dysregulation of genes encoding glycolysis enzymes, suggesting a functional link to Gcr1 and Gcr2, key transcriptional activators of these genes. Consistently, we found that nuclear depletion of Cdk8 altered the mRNA levels of glycolysis genes as well as the promoter occupancy of Gcr2, but not Gcr1. Examination of the Gcr2 protein sequence revealed a putative Cdk8 phosphorylation site at serine 365, which we confirmed usingin vitroandin vivoassays. Importantly, phospho-mutantGCR2recapitulated the growth and gene expression defects of theGCR2deletion mutant, effects not observed with a phospho mimetic mutant. As such, our work highlights Gcr2 as a new Cdk8 substrate, revealing that its phosphorylation is critical for the activation of genes encoding glycolysis enzymes.
Mental health explains individual deviations from normative range in cognition-associated brain states
Authors: Zhang Wei , Vidaurre Diego , Bijsterbosch Janine Diane 
Published: March 2021

AbstractLinks between cognitive deficits and psychiatric disorders have been studied predominantly at the group level, leaving unique individual characteristics largely elusive. Here, we applied normative modeling to UK Biobank data (N=18,634) and estimated the individual-level interplay of large-scale brain networks over time (i.e., dynamic brain state) as a function of general cognitive ability. Abnormality in such brain states was linked to individual variation in mental health. Specifically, brain state measures including fractional occupancy that indicates the brain state probability over time were estimated using a Hidden Markov Model, followed by a Gaussian process regression to estimate the normative range of these brain state measures from general cognitive ability. Abnormality scores per participant were quantified to represent the degree of deviations relative to the estimated population norm. We found significant associations between the abnormality scores of several brain states and individuals’ overall mental health. Our findings suggest potential impact of mental health on dynamic brain states that subserve cognitive functions and shed light on the relevant brain mechanisms underlying cognitive deficits in mental illness.
Neuronal mechanisms of novelty seeking
Authors: Ogasawara Takaya , Sogukpinar Fatih , Zhang Kaining , Feng Yang-Yang , Pai Julia , Jezzini Ahmad , Monosov Ilya E. 
Published: March 2021

AbstractHumans and other primates interact with the world by observing and exploring visual objects. In particular, they often seek out the opportunities to view novel objects that they have never seen before, even when they have no extrinsic primary reward value. However, despite the importance of novel visual objects in our daily life, we currently lack an understanding of how primate brain circuits control the motivation to seek out novelty. We found that novelty-seeking is regulated by a small understudied subcortical region, the zona incerta (ZI). In a task in which monkeys made eye movements to familiar objects to obtain the opportunity to view novel objects, many ZI neurons were preferentially activated by predictions of future novel objects and displayed burst excitations before gaze shifts to gain access to novel objects. Low intensity electrical stimulation of ZI facilitated gaze shifts, while inactivations of ZI reduced novelty-seeking. Surprisingly, additional experiments showed that this ZI-dependent novelty seeking behavior is not regulated by canonical neural circuitry for reward seeking. The habenula-dopamine pathway, known to reflect reward predictions that control reward seeking, was relatively inactive during novelty-seeking behavior in which novelty had no extrinsic reward value. Instead, high channel-count electrophysiological experiments and anatomical tracing identified a prominent source of control signals for novelty seeking in the anterior ventral medial temporal cortex (AVMTC), a brain region known to be crucially involved in visual processing and object memory. In addition to their well-known function in signaling the novelty or familiarity of objects in the current environment, AVMTC neurons reflected the predictions of future novel objects, akin to the way neurons in reward-circuitry predict future rewards in order to control reward-seeking. Our data uncover a network of primate brain areas that regulate novelty-seeking. The behavioral and neural distinctions between novelty-seeking and reward-processing highlight how the brain can accomplish behavioral flexibility, providing a mechanism to explore novel objects.
Learning accurate path integration in a ring attractor model of the head direction system
Authors: Vafidis Pantelis , Owald David , D’Albis Tiziano , Kempter Richard 
Published: March 2021

SummaryRing attractor models for angular path integration have recently received strong experimental support. To function as integrators, head-direction (HD) circuits require precisely tuned connectivity, but it is currently unknown how such tuning could be achieved. Here, we propose a network model in which a local, biologically plausible learning rule adjusts synaptic efficacies during development, guided by supervisory allothetic cues. Applied to theDrosophilaHD system, the model learns to path-integrate accurately and develops a connectivity strikingly similar to the one reported in experiments. The mature network is a quasi-continuous attractor and reproduces key experiments in which optogenetic stimulation controls the internal representation of heading, and where the network remaps to integrate with different gains. Our model predicts that path integration requires supervised learning during a developmental phase. The model setting is general and also applies to architectures that lack the physical topography of a ring, like the mammalian HD system.
Face processing of social cognition in patients with first episode psychosis: Its deficits and association with the right subcallosal anterior cingulate cortex
Authors: Narita Zui , Kuga Hironori , Piancharoen Peeraya , Faria Andreia , Mihaljevic Marina , Longo Luisa , Etyemez Semra , Namkung Ho , Coughlin Jennifer , Nestadt Gerald , Nucifora Frederik , Sedlak Thomas , Schaub Rebecca , Crawford Jeff , Schretlen David , Ishizuka Koko , Miyata Jun , Yang Kun , Sawa Akira 
Published: March 2021

ABSTRACTThe clinical importance of social cognition is well acknowledged in patients with psychosis, in particular those with first episode psychosis (FEP). Nevertheless, its brain substrates and circuitries remain elusive, lacking precise analysis between multimodal brain characteristics and behavioral sub-dimensions within social cognition. In the present study, we examined face processing of social cognition in 79 FEP patients and 80 healthy controls (HCs). We looked for a possible correlation between face processing and multimodal MRI characteristics such as resting-state functional connectivity (rsFC) and brain volume. We observed worse recognition accuracy, longer recognition response time, and longer memory response time in FEP patients when compared with HCs. Of these, memory response time was selectively correlated with specific rsFCs, which included the right subcallosal sub-region of BA24 in the ACC (scACC), only in FEP patients. The volume of this region was also correlated with memory response time in FEP patients. The scACC is functionally and structurally important in FEP-associated abnormalities of face processing measures in social cognition.
Altered cortico-subcortical network after adolescent alcohol exposure mediates behavioral deficits in flexible decision-making
Authors: Gómez-A Alexander , Dannenhoffer Carol A. , Elton Amanda , Lee SungHo , Ban Woomi , Shih Yen-Yu Ian , Boettiger Charlotte A. , Robinson Donita L. 
Published: March 2021

AbstractBehavioral flexibility, the ability to modify behavior according to changing conditions, is essential to optimize decision-making. Deficits in behavioral flexibility that persist into adulthood are one consequence of adolescent alcohol exposure, and another is decreased functional connectivity in brain structures involved in decision-making; however, a link between these two outcomes has not been established. We assessed effects of adolescent alcohol and sex on both Pavlovian and instrumental behaviors and functional connectivity in adult animals to determine associations between behavioral flexibility and resting-state functional connectivity. Alcohol exposure impaired attentional set reversals and decreased functional connectivity among cortical and subcortical regions-of-interest that underlie flexible behavior. Moreover, mediation analyses indicated that adolescent alcohol-induced reductions in functional connectivity within a subnetwork of affected brain regions mediated errors committed during reversal learning. These results provide a novel link between persistent reductions in brain functional connectivity and deficits in behavioral flexibility resulting from adolescent alcohol exposure.
KS-WNK1 amplifies kidney tubule responsiveness to potassium via WNK body condensates
Authors: Boyd-Shiwarski Cary R. , Beacham Rebecca T. , Lashway Jared A. , Querry Katherine E. , Griffiths Shawn E. , Shiwarski Daniel J. , Knoell Sophia A. , Nguyen Nga H. , Nkashama Lubika J. , Valladares Melissa N. , Bandaru Anagha , Marciszyn Allison L. , Rodan Aylin R. , Huang Chou-Long , Stocker Sean D. , Kashlan Ossama B. , Subramanya Arohan R. 
Published: March 2021

AbstractTo maintain potassium homeostasis, the kidney’s distal convoluted tubule (DCT) converts small changes in blood [K+] into robust effects on salt reabsorption. This process requires NaCl cotransporter (NCC) activation by WNK kinases. During hypokalemia, the Kidney-Specific WNK1 isoform (KS-WNK1) scaffolds the DCT-expressed WNK signaling pathway within biomolecular condensates of unknown function termed WNK bodies. Here, we show that KS-WNK1 amplifies the dynamic range of NCC activity in response to potassium imbalance, in part via WNK bodies. Targeted condensate disruption traps the WNK pathway, causing renal salt-wasting that is more pronounced in females. In humans, WNK bodies accumulate as plasma potassium falls below 4.0mmol/L, suggesting avid condensate-mediated salt reabsorption even when [K+] is low-normal. These data identify WNK bodies as signal amplifiers that mediate tubular potassium responsiveness, nephron sexual dimorphism, and blood pressure salt-sensitivity. Our results illustrate how condensate specialization can optimize a mammalian physiologic stress response that impacts human health.
Management programs as a key factor for genetic conservation of small populations : The case of French local chicken breeds
Authors: Restoux Gwendal , Rognon Xavier , Vieaud Agathe , Guemene Daniel , Petitjean Florence , Rouger Romuald , Brard-Fudulea Sophie , Lubac-Paye Sophie , Chiron Geoffrey , Tixier-Boichard Michèle 
Published: March 2021

AbstractOn-going climate change will drastically modify agriculture in the future, with a need for more sustainable systems, for animal production in particular. In this context, genetic diversity is a key factor for adaptation to new conditions: local breeds are likely to harbor unique adaptive features and represent a key component of diversity to reach resilience. Nevertheless, they are often suffering from small population size putting these valuable resources at risk of extinction. In chickens, management programs have been initiated a few decades ago in France, relying on a particular niche market aiming at promoting and protecting local breeds. We conducted a unique comprehensive study of 23 French local populations, along with 4 commercial lines, to evaluate their genetic conservation status and the efficiency of management programs. Using a 57K SNP chip we demonstrated that both between and within breeds genetic diversity were high in French populations. Diversity was mainly structured according to selection and breeds’ history. Nevertheless, we observed a prominent sub-structuring of breeds according to farmer’s practices in terms of exchange, leading to more or less isolated flocks. Analysing demographic parameters as well as molecular information, we showed the efficiency of consistent management programs to conserve genetic diversity, since the earlier the breeds integrated programs the lower was the inbreeding. Finally we stressed that management programs can benefit from molecular markers and runs of homozygosity, ROH, in particular, as a valuable and affordable tool to monitor genetic diversity of local breeds which often lack pedigree information.
Evolution of class-structured populations in periodic environments
Authors: Lion Sébastien , Gandon Sylvain 
Published: March 2021

AbstractWhat is the influence of periodic environmental fluctuations on life-history evolution? We present a general theoretical framework to understand and predict the long-term evolution of lifehistory traits under a broad range of ecological scenarios. Specifically, we investigate how periodic fluctuations affect selection when the population is also structured in distinct classes. This analysis yields time-varying selection gradients that clarify the influence of the fluctuations of the environment on the competitive ability of a specific life-history mutation. We use this framework to analyse the evolution of key life-history traits of pathogens. We examine three different epidemiological scenarios and we show how periodic fluctuations of the environment can affect the evolution of virulence and transmission as well as the preference for different hosts. These examples yield new and testable predictions on pathogen evolution, and illustrate how our approach can provide a better understanding of the evolutionary consequences of time-varying environmental fluctuations in a broad range of scenarios.
A Fragment-based approach to assess the ligandability of ArgB, ArgC, ArgD and ArgF in the L-arginine biosynthetic pathway ofMycobacterium tuberculosis
Authors: Gupta Pooja , Thomas Sherine E. , Cory-Wright James , Sebastián-Pérez Víctor , Burgess Ailidh , Cattermole Emma , Meghir Clio , Abell Chris , Coyne Anthony G. , Jacobs William R. , Blundell Tom L. , Tiwari Sangeeta , Mendes Vítor 
Published: March 2021

AbstractThe L-arginine biosynthesis pathway consists of eight enzymes that catalyse the conversion of L-glutamate to L-arginine, appears to be attractive target for anti-Tuberculosis (TB) drug discovery. Starvation ofM.tuberculosis deleted for eitherargBorargFgenes led to rapid sterilization of these strains in mice while Chemical inhibition of ArgJ with Pranlukast was also found to clear chronicM. tuberculosisinfection in animal models. In this work, the ligandability of four enzymes of the pathway ArgB, ArgC, ArgD and ArgF is explored using a fragment-based approach. We reveal several hits for these enzymes validated with biochemical and biophysical assays, and X-ray crystallographic data, which in the case of ArgB were further confirmed to have on-target activity againstM. tuberculosis. These results demonstrate the potential of more enzymes in this pathway to be targeted with dedicated drug discovery programmes.
Introspection confidence predicts EEG decoding of self-generated thoughts and meta-awareness
Authors: Polychroni Naya , Ruiz Maria Herrojo , Terhune Devin B. 
Published: March 2021

AbstractThe neurophysiological bases of mind wandering (MW) – an experiential state wherein attention is disengaged from the external environment in favour of internal thoughts, and state meta-awareness are poorly understood. In parallel, the relationship between introspection confidence in experiential state judgements and neural representations remains unclear. Here, we recorded EEG whilst participants completed a listening task within which they made experiential state judgments and rated their confidence. Alpha power was reliably greater during MW episodes, with unaware MW further associated with greater delta and theta power. Multivariate pattern classification analysis revealed that MW, and meta-awareness can be decoded from the distribution of power in these three frequency bands. Critically, we show that individual decoding accuracies positively correlate with introspection confidence. Our results reaffirm the role of alpha oscillations in MW, implicate lower frequencies in meta-awareness, and are consistent with the proposal that introspection confidence indexes neurophysiological discriminability of representational states.
Measuring context-dependent memory in rodents: a systematic review and meta-analysis of important variables in the object-in-context task
Authors: Sep Milou S.C. , Vellinga Marijn , Sarabdjitsingh R. Angela. , Joëls Marian 
Published: March 2021

AbstractEnvironmental information plays an important role in remembering events. Information about stable aspects of the environment (here referred to as ‘context’) and the event are combined by the hippocampal system and stored as context-dependent memory. In rodents (such as rats and mice), context-dependent memory is often investigated with the object-in-context task. However, the implementation and interpretation of this task varies considerably across studies. This variation hampers the comparison between studies and - for those who design a new experiment or carry out pilot experiments – the estimation of whether observed behavior is within the expected range. Also, it is currently unclear which of the variables critically influence the outcome of the task. To address these issues, we carried out a preregistered systematic review (PROSPERO CRD42020191340) and provide an up-to-date overview of the animal-, task-, and protocol-related variations in the object-in-context task for rodents. Using a data-driven explorative meta-analysis we next identified critical factors influencing the outcome of this task, such as sex, testbox size and the delay between the learning trials. Based on these observations we provide recommendations to create more consensus in the set-up, procedure and interpretation of the object-in-context task for rodents. This could contribute to a more robust and evidence-based design in future animal experiments.
Crosstalk in oxygen homeostasis networks: SKN-1/NRF inhibits the HIF-1 hypoxia-inducible factor inCaenorhabditis elegans
Authors: Feng Dingxia , Zhai Zhiwei , Shao Zhiyong , Zhang Yi , Powell-Coffman Jo Anne 
Published: March 2021

AbstractDuring development, homeostasis, and disease, organisms must balance responses that allow adaptation to low oxygen (hypoxia) with those that protect cells from oxidative stress. The evolutionarily conserved hypoxia-inducible factors are central to these processes, as they orchestrate transcriptional responses to oxygen deprivation. Here, we employ genetic strategies inC. elegansto identify stress-responsive genes and pathways that modulate the HIF-1 hypoxia-inducible factor and facilitate oxygen homeostasis. Through a genome-wide RNAi screen, we show that RNAi-mediated mitochondrial or proteasomal dysfunction increases the expression of hypoxia-responsive reporterPnhr-57:GFPinC. elegans.Interestingly, only a subset of these effects requireshif-1.Of particular importance, we found thatskn-1RNAi increases the expression of hypoxia-responsive reporterPnhr-57:GFPand elevates HIF-1 protein levels. The SKN-1/NRF transcription factor has been shown to promote oxidative stress resistance. We present evidence that the crosstalk between HIF-1 and SKN-1 is mediated by EGL-9, the prolyl hydroxylase that targets HIF-1 for oxygen-dependent degradation. Treatment that induces SKN-1, such as heat, increases expression of aPegl-9:GFPreporter, and this effect requiresskn-1function and a putative SKN-1 binding site inegl-9regulatory sequences. Collectively, these data support a model in which SKN-1 promotesegl-9transcription, thereby inhibiting HIF-1. We propose that this interaction enables animals to adapt quickly to changes in cellular oxygenation and to better survive accompanying oxidative stress.