bluuebunny/crossref_metadata_2025_split huggingface dataset:
Macrophage-specific NF-κB activation dynamics can segregate inflammatory bowel disease patients
Authors: Papoutsopoulou Stamatia , Burkitt Michael D. , Bergey François , England Hazel , Hough Rachael , Schmidt Lorraine , Spiller David G , White Michael HR , Paszek Pawel , Jackson Dean A. , Dos Santos Vitor A.P. Martins , Sellge Gernot , Pritchard D. Mark , Campbell Barry J. , Müller Werner , Probert Chris S. 
Published: January 2019

AbstractThe heterogeneous nature of inflammatory bowel disease (IBD) presents challenges, particularly when choosing therapy. Activation of the NF-κB transcription factor is a highly-regulated, dynamic event in IBD pathogenesis. We expressed the human NF-κB/p65 subunit in blood-derived macrophages, using lentivirus. Confocal imaging of p65 activation revealed that a higher proportion of macrophages from Crohn’s patients responded to lipid-A compared to controls. In contrast, cells from ulcerative colitis (UC) patients exhibited a shorter duration of p65 nuclear localisation compared to healthy controls and Crohn’s donors. Using a similar lentivirus approach, NF-κB-regulated luciferase was expressed in patient macrophages, isolated from frozen peripheral blood mononuclear cell samples. Following activation, samples could be segregated into three clusters based on the NF-κB-regulated luciferase response. The majority of UC samples appeared in hypo-responsive cluster 1, with Crohn’s patients representing the majority of hyper-responsive cluster 3. A positive correlation was seen between NF-κB-induced luciferase activity and cytokine levels released to medium from stimulated macrophages, but not in serum or biopsy. Analysis of macrophage cytokine responses and patient metadata revealed a strong correlation between Crohn’s patients who smoked and hyper-activation of p65. Thesein vitrodynamic assays of NF-κB activation in blood-derived macrophages segregate IBD patients into groups with different phenotypes and therefore may help determine response to therapy.Significance statementThis manuscript describes two dynamic assays of NF-κB activation in blood-derived macrophages that can segregate IBD patients into groups with different phenotypes. For the first time we introduce the use of dynamic measurements of a transcription factor activation as a method to stratify patients and we are confident that our approach will lead in future to early patient stratification and prediction of treatment outcome.
Inability to improve performance with control shows limited access to inner states
Authors: Perquin Marlou Nadine , Yang Jessica , Teufel Christoph , Sumner Petroc , Hedge Craig , Bompas Aline 
Published: January 2019

AbstractAny repeatedly performed action is characterised by endogenous variability, affecting both speed and accuracy – for a large part presumably caused by fluctuations in underlying brain and body states. The current research questions were: 1) whether such states are accessible to us, and 2) whether we can act upon this information to reduce variability. For example, when playing a game of darts, there is an implicit assumption that people can wait to throw until they are in the ‘right’ perceptual-attentional state. If this is true, taking away the ability to self-pace the game should worsen performance. We first tested precisely this assumption asking participants to play darts in a self-paced and a fixed-paced condition. There was no benefit of self-pacing, showing that participants were unable to use such control to improve their performance and reduce their variability. Next, we replicated these findings in two computer-based tasks, in which participants performed a rapid action-selection and a visual detection task in one self-paced and three forced-paced conditions. Over four different empirical tests, we show that the self-paced condition did not lead to improved performance or reduced variability, nor to reduced temporal dependencies in the reaction time series. Overall, it seems that, if people have any access to their fluctuating performance-relevant inner states, this access is limited and not relevant for upcoming performance.
Predator-prey nutrient competition undermines predator coexistence
Authors: Klauschies Toni , Gaedke Ursula 
Published: January 2019

AbstractContemporary theory of predator coexistence through relative non-linearity in their functional responses strongly relies on the Rosenzweig-MacArthur equations (1963) in which the (autotrophic) prey exhibits logistic growth in the absence of the predators. This implies that the prey is limited by a resource which availability is independent of the predators. This assumption does not hold under nutrient limitation where both prey and predators bind resources such as nitrogen or phosphorus in their biomass. Furthermore, the prey’s resource uptake-rate is assumed to be linear and the predator-prey system is considered to be closed. All these assumptions are unrealistic for many natural systems. Here, we show that predator coexistence on a single prey is strongly hampered when the prey and predators indirectly compete for the limiting resource in a flow-through system. In contrast, a non-linear resource uptake rate of the prey slightly promotes predator coexistence. Our study highlights that predator coexistence does not only depend on differences in the curvature of their functional responses but also on the type of resource constraining the growth of their prey. This has far-reaching consequences for the relative importance of fluctuation-dependent and -independent mechanisms of species coexistence in natural systems where autotrophs experience light or nutrient limitation.
PGC-1α overexpression partially rescues impaired oxidative and contractile pathophysiology following volumetric muscle loss injury
Authors: Southern William M. , Nichenko Anna S. , Tehrani Kayvan F. , McGranahan Melissa J. , Krishnan Laxminarayanan , Qualls Anita E. , Jenkins Nathan T. , Mortensen Luke J. , Yin Hang , Yin Amelia , Guldberg Robert E. , Greising Sarah M. , Call Jarrod A. 
Published: January 2019

AbstractVolumetric muscle loss (VML) injury is characterized by a non-recoverable loss of muscle fibers due to ablative surgery or severe orthopaedic trauma, that results in chronic functional impairments of the soft tissue. Currently, the effects of VML on the oxidative capacity and adaptability of the remaining injured muscle are unclear. A better understanding of this pathophysiology could significantly shape how VML-injured patients and clinicians approach regenerative medicine and rehabilitation following injury. Herein, the data indicated that VML-injured muscle has diminished mitochondrial content and function (i.e. oxidative capacity), loss of mitochondrial network organization, and attenuated oxidative adaptations to exercise. However, forced PGC-1α over-expression rescued the deficits in oxidative capacity and muscle strength. This implicates physiological activation of PGC1-α as a limiting factor in VML-injured muscle adaptive capacity and provides a mechanistic target for regenerative rehabilitation approaches to address the skeletal muscle dysfunction.
Reliability and correlates of intra-individual variability in the oculomotor system
Authors: Perquin Marlou Nadine , Bompas Aline 
Published: January 2019

AbstractEven if all external circumstances are kept equal, the oculomotor system shows intra-individual variability over time, affecting measures such as microsaccade rate, blink rate, pupil size, and gaze position. Recently, some of these measures have been associated with ADHD on a between-subject level. However, it remains unclear to what extent these measures constitute stable individual traits. In the current study, we investigate the intra-individual reliability of these oculomotor features. Combining results over three experiments (> 100 healthy participants), we find that most measures show good intra-individual reliability over different time points (repeatability) as well as over different conditions (generalisation). However, we find evidence against any correlation with self-assessed ADHD tendencies, mind wandering, and impulsivity. As such, the oculomotor system shows reliable intra-individual reliability, but its benefit for investigating self-assessed individual differences in healthy subjects remains unclear. With our results, we highlight the importance of reliability and statistical power when studying between-subject differences.
“Low-cost” initial burst of root development in wholeFagus crenataseedlings: The key to survival?
Authors: Kurosawa Yoko , Mori Shigeta , Wang Mofei , Ferrio Juan Pedro , Yamaji Keiko , Yoshimura Kenichi , Qur’ani Citra Gilang 
Published: January 2019

AbstractTerrestrial plants are rooted in one place, and therefore their metabolism must be flexible to adapt to continuously changing environments. This flexibility is probably influenced by the divergent metabolic traits of plant organs. However, direct measurements on organ-specific metabolic rates are particularly scarce and little is known about their roles in determining whole-individual meatabolism. To reveal this on seedlings ofFagus crenata, which is one of the most widespread dominant genus in temperate deciduous broad leaf forests in the circum-polar Northern Hemisphere, we measured respiration, fresh mass and surface area for total leaves, stems and roots of 55 individuals in two years from germination and analyzed their relationships with individual metabolism. Proportion of roots to whole plant in mass increased from approximately 17% to 74%, and that in surface area increased from about 11% to 82% in the two years. Nonetheless, the increment of the proportion of root respiration to whole-plant respiration was from 9.2% to only 40%, revealing that the increment in mass and surface area of roots was much larger than the increment in energetic cost. As a result, only the roots showed a substantial decline in both respiration/surface area and respiration/mass among the three organs; roots had about 90% decline in their respiration/surface area, and 84% decline in their respiration/mass, while those in leaves and stems were relatively constant. The low-cost and rapid root development is specific to the two years after germination and would be effective for avoiding water and nutrient deficit, and possibly helps seedling survival. This drastic shift in structure and function with efficient energy use in developmental change from seeds to seedlings may underpin the establishment ofF. crenataforests. We discuss significance of lowering energetic cost for various individual organisms to effectively acquire resources from a wide perspective of view.
A Genome-engineered Bioartificial Implant for Autoregulated Anti-Cytokine Drug Delivery
Authors: Choi Yun-Rak , Collins Kelsey H. , Springer Luke E. , Pferdehirt Lara , Ross Alison K. , Wu Chia-Lung , Moutos Franklin T. , Harasymowicz Natalia S. , Brunger Jonathan M. , Pham Christine T.N. , Guilak Farshid 
Published: January 2019

AbstractBiologic drug therapies are effective treatments for autoimmune diseases such as rheumatoid arthritis (RA) but may cause significant adverse effects, as they are administered continuously at high doses that can suppress the immune system. Using CRISPR-Cas9 genome editing, we engineered stem cells containing a synthetic gene circuit expressing biologic drugs to antagonize interleukin-1 (IL-1) or tumor necrosis factor (TNF) in an autoregulated, feedback-controlled manner in response to activation of the endogenous chemokine (C-C) motif ligand 2 (Ccl2) promoter. To test this approach in vivo, cells were tissue-engineered into a stable cartilaginous construct and implanted subcutaneously in mice with inflammatory arthritis. Bioengineered anti-cytokine implants mitigated arthritis severity as measured by joint pain, structural damage, and systemic and local inflammation. The coupling of synthetic biology with tissue engineering promises a range of potential applications for treating chronic diseases using custom-designed cells that express therapeutic transgenes in response to dynamically changing biological signals.
Transcranial photobiomodulation with infrared laser increases power of brain oscillations
Authors: Wang Xinlong , Dmochowski Jacek P. , Zeng Li , Kallioniemi Elisa , Husain Mustafa , Gonzalez-Lima F. , Liu Hanli 
Published: January 2019

AbstractNon-invasive transcranial photobiomodulation with a 1064-nm laser (tPBML1064) has been reported to improve human performance on cognitive tasks as well as locally upregulate cerebral oxygen metabolism and hemodynamics. However, it is unknown whether tPBML1064 also modulates electrophysiology, and specifically neural oscillations, in the human brain. The hypothesis guiding this study was that tPBML1064 of the right prefrontal cortex enhances neurophysiological rhythms at specific frequency bands in the human brain under resting conditions. To test this hypothesis, we recorded the 64-channel scalp electroencephalogram (EEG) before, during, and after the application of 11 minutes of 4-cm-diameter tPBML1064 to the right forehead of human subjects (n=20) using a within-subject, sham-controlled design. Time-resolved scalp topographies of EEG power at five frequency bands were computed to examine tPBML1064-induced EEG power changes across the scalp. The results showed time-dependent, significant increases of EEG spectral powers at the alpha (8-13 Hz) and beta (13-30 Hz) bands at broad scalp regions, exhibiting a front-to-back pattern. The findings provide the first sham-controlled topographic mapping that tPBML1064 increases the strength of electrophysiological oscillations (alpha and beta bands), while also shedding light on the mechanisms of tPBM in the human brain.
Analysis of metabolic pathways in mycobacteria to aid drug-target identification
Authors: Bannerman Bridget P. , Vedithi Sundeep C. , Júlvez Jorge , Torres Pedro , Waman Vaishali P. , Munir Asma , Mendes Vitor , Malhotra Sony , Skwark Marcin J. , Oliver Stephen G. , Blundell Tom L. 
Published: January 2019

AbstractThree related mycobacteria are the cause of widespread infections in man and are the focus of intense research and drug-discovery efforts in the face of growing antimicrobial resistance.Mycobacterium tuberculosis, the causative agent of tuberculosis, is currently one of the top ten causes of death in the world according to WHO;M.abscessus, a group of non-tuberculous mycobacteria causes lung infections and other opportunistic infections in humans; andM.leprae, the causative agent of leprosy, remains endemic in tropical countries. There is an urgent need to design alternatives to conventional treatment strategies, due to the increase in resistance to standard antibacterials. In this study, we present a comparative analysis of chokepoint and essentiality datasets that will provide insight into the development of new treatment regimes. We illustrate the key metabolic pathways shared between these three organisms and identify drug targets with a wide metabolic impact that are common to the three species. We demonstrate that 72% of the chokepoint enzymes are proteins essential toMycobacterium tuberculosis. We show also that 78% of the drug targets, prioritized based on their presence in multiple paths on the metabolic network, are present in pathways shared byM. tuberculosis, M.lepraeandM.abscessus, including biosynthesis of amino acids, carbohydrates, cell structures, fatty acid and lipid biosynthesis. A further 17% is found in the prioritised pathways shared betweenM. tuberculosisandM.abscessus. We have performed comparative structure modelling of potential drug targets identified using our analysis in order to assess druggability and demonstrate the importance of chokepoint analysis in terms of drug target identification.AUTHOR SUMMARYComputer simulation studies to design new drugs against mycobacteria
Genome-Wide Association Study and Pathway-Level Analysis of Kernel Color in Maize
Authors: Owens Brenda F. , Mathew Deepu , Diepenbrock Christine H. , Tiede Tyler , Wu Di , Mateos-Hernandez Maria , Gore Michael A. , Rocheford Torbert 
Published: January 2019

ABSTRACTRapid development and adoption of biofortified, provitamin A-dense orange maize (Zea maysL.) varieties could be facilitated by a greater understanding of the natural variation underlying kernel color, including as relates to carotenoid biosynthesis and retention in maize grain. Greater abundance of carotenoids in maize kernels is generally accompanied by deeper orange color, useful for distinguishing provitamin A-dense varieties to consumers. While kernel color can be scored and selected with high-throughput, low-cost phenotypic methods within breeding selection programs, it remains to be well established as to what would be the logical genetic loci to target for selection for kernel color. We conducted a genome-wide association study of maize kernel color, as determined by colorimetry, in 1,651 yellow and orange inbreds from the Ames maize inbred panel. Associations were found withy1, encoding the first committed step in carotenoid biosynthesis, and withdxs2, which encodes the enzyme responsible for the first committed step in the biosynthesis of the isoprenoid precursors of carotenoids. These genes logically could contribute to overall carotenoid abundance and thus kernel color. ThelcyEandzep1genes, which can affect carotenoid composition, were also found to be associated with colorimeter values. A pathway-level analysis, focused on genes witha priorievidence of involvement in carotenoid biosynthesis and retention, revealed associations fordxs3anddmes1, involved in isoprenoid biosynthesis;ps1andvp5, within the core carotenoid pathway; andvp14, involved in cleavage of carotenoids. Collectively, these identified genes appear relevant to the accumulation of kernel color.
Genome-Scale reconstruction ofPaenarthrobacter aurescensTC1 metabolic model towards the study of atrazine bioremediation
Authors: Ofaim Shany , Zarecki Raphy , Porob Seema , Gat Daniella , Lahav Tamar , Xu Xihui , Kashi Yechezkel , Aly Radi , Jiang Jiandong , Eizenberg Hanan , Ronen Zeev , Freilich Shiri 
Published: January 2019

ABSTRACTAtrazine is an herbicide and pollutant of great environmental concern that is naturally biodegraded by microbial communities. The efficiency of biodegradation can be improved through the stimulating addition of fertilizers, electron acceptors, etc. In recent years, metabolic modelling approaches have become widely used as anin silicotool for organism-level phenotyping and the subsequent development of metabolic engineering strategies including biodegradation improvement. Here, we constructed a genome scale metabolic model,iRZ960, forPaenarthrobacter aurescensTC1 – a widely studied atrazine degrader - aiming at simulating its degradation activity. A mathematical stoichiometric metabolic model was constructed based on a published genome sequence ofP. aurescensTC1. An Initial draft model was automatically constructed using the RAST and KBase servers. The draft was developed into a predictive model through semi-automatic gap-filling procedures including manual curation. In addition to growth predictions under different conditions, model simulations were used to identify optimized media for enhancing the natural degradation of atrazine without a need in strain design via genetic modifications. Model predictions for growth and atrazine degradation efficiency were tested in myriad of media supplemented with different combinations of carbon and nitrogen sources that were verifiedin vitro. Experimental validations support the reliability of the model’s predictions for both bacterial growth (biomass accumulation) and atrazine degradation. Predictive tools, such as the presented model, can be applied for achieving optimal biodegradation efficiencies and for the development of ecologically friendly solutions for pollutant degradation in changing environments.
Variation in assembly stoichiometry in non-metazoan homologs of the hub domain of Ca2+/Calmodulin-dependent protein kinase II
Authors: McSpadden Ethan D. , Xia Zijie , Chi Chris C. , Susa Anna C. , Shah Neel H. , Gee Christine L. , Williams Evan R. , Kuriyan John 
Published: January 2019

AbstractThe multi-subunit Ca2+/calmodulin-dependent protein kinase II (CaMKII) holoenzyme plays a critical role in animal learning and memory. The kinase domain of CaMKII is connected by a flexible linker to a C-terminal hub domain that assembles into a 12- or 14-subunit scaffold that displays the kinase domains around it. Studies on CaMKII suggest that the stoichiometry and dynamic assembly/disassembly of hub oligomers may be important for CaMKII regulation. Although CaMKII is a metazoan protein, genes encoding predicted CaMKII-like hub domains, without associated kinase domains, are found in the genomes of some green plants and bacteria. We show that the hub domains encoded by three related green algae, Chlamydomonas reinhardtii, Volvox carteri f. nagarensis, and Gonium pectoral, assemble into 16-, 18-, and 20-subunit oligomers, as assayed by native protein mass spectrometry. These are the largest known CaMKII hub domain assemblies. A crystal structure of the hub domain from Chlamydomonas reinhardtii reveals an 18-subunit organization. We identified four intra-subunit hydrogen bonds in the core of the fold that are present in the Chlamydomonas hub domain, but not in metazoan hubs. When six point mutations designed to recapitulate these hydrogen bonds were introduced into the human CaMKII-α hub domain, the mutant protein formed assemblies with 14 and 16 subunits, instead of the normal 12- and 14-subunit assemblies. Our results show that the stoichiometric balance of CaMKII hub assemblies can be shifted readily by small changes in sequence.
Imprinted gene expression at theDlk1-Dio3cluster is controlled by both maternal and paternalIG-DMRs in a tissue-specific fashion
Authors: Alexander Katherine A. , García-García María J. 
Published: January 2019

ABSTRACTImprinting at theDlk1-Dio3cluster is controlled by theIG-DMR, an imprinting control region differentially methylated between maternal and paternal chromosomes. The maternalIG-DMRis essential for imprinting control, functioning as acisenhancer element. Meanwhile, DNA methylation at the paternalIG-DMRis thought to prevent enhancer activity. To explore whether suppression of enhancer activity at the methylatedIG-DMRrequires the transcriptional repressor TRIM28, we analyzedTrim28chatwoembryos and performed epistatic experiments withIG-DMRdeletion mutants. We found that while TRIM28 regulates the enhancer properties of the paternalIG-DMR, it also controls imprinting through other mechanisms. Additionally, we found that the paternalIG-DMR, previously deemed dispensable for imprinting, is required in certain tissues, demonstrating that imprinting is regulated in a tissue-specific manner. Using PRO-seq to analyze nascent transcription, we identified 30 novel transcribed regulatory elements, including 23 that are tissue-specific. These results demonstrate that different tissues have a distinctive regulatory landscape at theDlk1-Dio3cluster and provide insight into potential mechanisms of tissue-specific imprinting control. Together, our findings challenge the premise thatDlk1-Dio3imprinting is regulated through a single mechanism and demonstrate that different tissues use distinct strategies to accomplish imprinted gene expression.