bluuebunny/crossref_metadata_2025_split huggingface dataset:
Gene networks with transcriptional bursting recapitulate rare transient coordinated expression states in cancer
Authors: Schuh Lea , Saint-Antoine Michael , Sanford Eric , Emert Benjamin L. , Singh Abhyudai , Marr Carsten , Goyal Yogesh , Raj Arjun 
Published: July 2019

SUMMARYNon-genetic transcriptional variability at the single-cell level is a potential mechanism for therapy resistance in melanoma. Specifically, rare subpopulations of melanoma cells occupy a transient pre-resistant state characterized by coordinated high expression of several genes. Importantly, these rare cells are able to survive drug treatment and develop resistance. How might these extremely rare states arise and disappear within the population? It is unclear whether the canonical stochastic models of probabilistic transcriptional pulsing can explain this behavior, or if it requires special, hitherto unidentified molecular mechanisms. Here we use mathematical modeling to show that a minimal network comprising of transcriptional bursting and interactions between genes can give rise to rare coordinated high states. We next show that although these states occur across networks of different sizes, they depend strongly on three (out of seven) model parameters and require network connectivity to be ≤ 6. Interestingly, we find that while entry into the rare coordinated high state is initiated by a long transcriptional burst that also triggers entry of other genes, the exit from it occurs through the independent inactivation of individual genes. Finally, our model predicts that increased network connectivity can lead to transcriptionally stable states, which we verify using network inference analysis of experimental data. In sum, we demonstrate that established principles of gene regulation are sufficient to describe this new class of rare cell variability and argue for its general existence in other biological contexts.
Adult dentate gyrus neurogenesis: a functional model
Authors: Gozel Olivia , Gerstner Wulfram 
Published: July 2019

SummaryIn adult dentate gyrus neurogenesis, the link between maturation of newborn neurons and their function, such as behavioral pattern separation, has remained puzzling. By analyzing a theoretical model, we show that the switch from excitation to inhibition of the GABAergic input onto maturing newborn cells is crucial for their proper functional integration. When the GABAergic input is excitatory, cooperativity drives the growth of synapses such that newborn cells become sensitive to stimuli similar to those that activate mature cells. When GABAergic input switches to inhibitory, competition pushes the configuration of synapses onto newborn cells towards stimuli that are different from previously stored ones. This enables the maturing newborn cells to code for concepts that are novel, yet similar to familiar ones. Our theory of newborn cell maturation explains both how adult-born dentate granule cells integrate into the preexisting network and why they promote separation of similar but not distinct patterns.
Self-immunity guided identification of threonyl-tRNA synthetase as the molecular target of obafluorin, a β-lactone antibiotic
Authors: Scott Thomas A. , Batey Sibyl F. , Wiencek Patrick , Chandra Govind , Alt Silke , Franklyn Christopher S. , Wilkinson Barrie 
Published: July 2019

AbstractTo meet the ever-growing demand of antibiotic discovery, new chemical matter and antibiotic targets are urgently needed. Many potent natural product antibiotics which were previously discarded can also provide lead molecules and drug targets. One such example is the structurally unique β-lactone obafluorin, produced by Pseudomonas fluorescens ATCC 39502. Obafluorin is active against both Grampositive and -negative pathogens, however the biological target was unknown. We now report that obafluorin targets threonyl-tRNA-synthetase and we identify a homologue, ObaO, which confers self-immunity to the obafluorin producer. Disruption of obaO in P. fluorescens ATCC 39502 results in obafluorin sensitivity, whereas expression in sensitive E. coli strains confers resistance. Enzyme assays demonstrate that E. coli threonyl-tRNA synthetase is fully inhibited by obafluorin, whereas ObaO is only partly susceptible, exhibiting a very unusual partial inhibition mechanism. Altogether, our data highlight the utility of a self-immunity guided approach for the identification of an antibiotic target de novo and will ultimately enable the generation of improved obafluorin variants.
Lorcaserin maintenance fails to attenuate heroin vs. food choice in rhesus monkeys
Authors: Townsend E. Andrew , Negus S. Stevens , Poklis Justin L. , Banks Matthew L. 
Published: July 2019

AbstractBackgroundThe current opioid crisis has reinvigorated preclinical research in the evaluation of non-opioid candidate treatments for opioid use disorder (OUD). Emerging evidence suggests 5-HT2C receptor agonists may attenuate the abuse-related effects of opioids. This study evaluated effectiveness of 7-day treatment with the clinically available 5-HT2C agonist lorcaserin on heroin-vs.-food choice in rhesus monkeys. Lorcaserin effects were compared to effects produced by saline substitution and by 7-day treatment with the opioid antagonist naltrexone.MethodsAdult male (1) and female (6) rhesus monkeys were trained to respond under a concurrent schedule of food delivery (1g pellets, fixed-ratio 100 schedule) and intravenous heroin injections (0-0.032 mg/kg/injection, fixed-ratio 10 schedule) during daily 2h sessions. Heroin choice dose-effect functions were determined daily before and following 7-day saline substitution or 7-day continuous treatment with naltrexone (0.0032-0.032 mg/kg/h, IV) or lorcaserin (0.032-0.32 mg/kg/h, IV).ResultsUnder baseline conditions, increasing heroin doses maintained a dose-dependent increase in heroin choice. Both saline substitution and 7-day naltrexone treatment significantly attenuated heroin choice and produced a reciprocal increase in food choice. Continuous lorcaserin treatment significantly increased heroin choice.ConclusionsIn contrast to saline substitution and naltrexone, lorcaserin treatment was ineffective to reduce heroin-vs.-food choice. These preclinical results do not support the therapeutic potential of lorcaserin as a candidate OUD treatment.
Distinct neural markers for intentional and unintentional task unrelated thought
Authors: Martel Adrien , Arvaneh Mahnaz , Robertson Ian , Smallwood Jonathan , Dockree Paul 
Published: July 2019

AbstractStudies suggest that generating thought unrelated to the task in hand is accompanied by a reduction of attention to external task-relevant information. This observations led contemporary theory to suggest multiple component processes contribute to patterns of ongoing thought. The present study used EEG to seek support for these component-process accounts by examining the neural correlates of deliberate and spontaneous task unrelated thought. EEG activity was compared prior to reports of ongoing thought during a test of sustained attention. Event-related potentials, such as the P3, were attenuated during off-task states, regardless of whether they were intentional or not. In contrast, increased alpha power and cortical phase-locking were linked to deliberate off-task thoughts, while reductions of evoked sensory response were prevalent in spontaneous off-task episodes. These data suggest off-task thought shares common and distinct neural features that are differentiated through their relationship to intention, supporting component process accounts of ongoing thought.
Differences in unity: the go/no-go and stop signal tasks rely on different inhibitory mechanisms
Authors: Raud Liisa , Westerhausen René , Dooley Niamh , Huster René J. 
Published: July 2019

AbstractResponse inhibition refers to the suppression of prepared or initiated actions. Typically, the go/no-go task (GNGT) or the stop signal task (SST) are used interchangeably to capture individual differences in response inhibition. Yet, there is some controversy if these tasks assess similar inhibitory processes. We extracted the time-courses of sensory, motor, attentional, and cognitive control networks by group independent component (G-ICA) analysis of electroencephalography (EEG) data from both tasks. Additionally, electromyography (EMG) from the responding effector muscles was recorded to detect the timing of response inhibition. The results indicated that inhibitory performance in the GNGT may be comparable to response selection mechanisms, reaching peripheral muscles at around 316 ms. In contrast, inhibitory performance in the SST is achieved via biasing of the sensory-motor system in preparation for stopping, followed by fast sensory, motor and frontal integration during outright stopping. Inhibition can be detected at the peripheral level at 140 ms after stop stimulus presentation. The GNGT and the SST therefore seem to recruit widely different neural dynamics, implying that the interchangeable use of superficially similar inhibition tasks in both basic and clinical research is unwarranted.
Illuminating microbial species-specific effects on organic matter remineralization in marine sediments
Authors: Mahmoudi Nagissa , Enke Tim N. , Beaupré Steven R. , Teske Andreas P. , Cordero Otto X. , Pearson Ann 
Published: July 2019

SummaryMarine microorganisms play a fundamental role in the global carbon cycle by mediating the sequestration of organic matter in ocean waters and sediments. A better understanding of how biological factors, such as microbial community composition, influence the lability and fate of organic matter is needed. Here, we explored the extent to which organic matter remineralization is influenced by species-specific metabolic capabilities. We carried out aerobic time-series incubations of Guaymas basin sediments to quantify the dynamics of carbon utilization by two different heterotrophic marine isolates. Continuous measurement of respiratory CO2 production and its carbon isotopic compositions (13C and 14C) shows species-specific differences in the rate, quantity, and type of organic matter remineralized. Each species was incubated with hydrothermally-influenced vs. unimpacted sediments, resulting in a ~3-fold difference in respiratory CO2 yield across the experiments. Genomic analysis indicated that the observed carbon utilization patterns may be attributed in part to the number of gene copies encoding for extracellular hydrolytic enzymes. Our results demonstrate that the lability and remineralization of organic matter in marine environments is not only a function of chemical composition and/or environmental conditions, but also a function of the microorganisms that are present and active.
Hyperinsulinemia promotes HMGB1 release leading to inflammation induced systemic insulin resistance: An interplay between pancreatic beta-cell and peripheral organs
Authors: Choubey Abhinav , Kar Aditya K , Girdhar Khyati , Chattopadhyay Tandrika , Dogra Surbhi , Kushwaha Shaivya , Medhi Bikash , Bhansali Anil , Mantri Chinmay Kumar , Kolthur-Seetharam Ullas , Ghosh Debabrata , Mondal Prosenjit 
Published: July 2019

SummaryInsulin resistance results from several pathophysiologic mechanisms, including chronic tissue inflammation and defective insulin signaling. Pancreatic β-cells hypersecretion (hyperinsulinemia), is a central hallmark of peripheral insulin resistance. However, the underlying mechanism by which hyperinsulinemia perpetuates towards the development of insulin resistance remains unclear and is still a bigger therapeutic challenge. Here, we found hyperinsulinemia triggers inflammation and insulin resistance by stimulating TLR4-driven inflammatory cascades. We show that hyperinsulinemia activates the TLR4 signaling through HMGB1, an endogenous TLR4 ligand emanating from hyperinsulinemia exposed immune cells and peripheral organs like adipose tissue and liver. Further, our observation suggests hyperinsulinemia ensuring hyperacetylation, nuclear-to-cytoplasmic shuttling and release of HMGB1 into the extracellular space. HMGB1 was also found to be elevated in serum of T2DM patients. We found that extracellular HMGB1 plays a crucial role to promote proinflammatory responses and provokes systemic insulin resistance. Importantly, in-vitro and in-vivo treatment with naltrexone, a TLR4 antagonist led to an anti-inflammatory phenotype with protection from hyperinsulinemia mediated insulin resistance. In-vitro treatment with naltrexone directly enhanced SIRT1 activity, blocked the release of HMGB1 into extracellular milieu, suppressed release of proinflammatory cytokines and ultimately led to insulin-sensitizing effects. These observations elucidate a regulatory network between pancreatic β-cells, macrophage and hepatocytes and assign an unexpected role of TLR4 - HMGB1 signaling axis in hyperinsulinemia mediated systemic insulin resistance.Graphical Abstract
The potential for gas-free measurements of absolute oxygen metabolism during both baseline and activation states in the human brain
Authors: Liu Eulanca Y. , Guo Jia , Simon Aaron B. , Haist Frank , Dubowitz David J. , Buxton Richard B. 
Published: July 2019

AbstractQuantitative functional magnetic resonance imaging methods make it possible to measure cerebral oxygen metabolism (CMRO2) in the human brain. Current methods require the subject to breathe special gas mixtures (hypercapnia and hyperoxia). We tested a noninvasive suite of methods to measure absolute CMRO2in both baseline and dynamic activation states without the use of special gases: arterial spin labeling (ASL) to measure baseline and activation cerebral blood flow (CBF), with concurrent measurement of the blood oxygenation level dependent (BOLD) signal as a dynamic change in tissue R2*; VSEAN to estimate baseline O2extraction fraction (OEF) from a measurement of venous blood R2, which in combination with the baseline CBF measurement yields an estimate of baseline CMRO2; and FLAIR-GESSE to measure tissue R2′to estimate the scaling parameter needed for calculating the change in CMRO2in response to a stimulus with the calibrated BOLD method. Here we describe results for a study sample of 17 subjects (8 female, mean age=25.3 years, range 21-31 years). The primary findings were that OEF values measured with the VSEAN method were in good agreement with previous PET findings, while estimates of the dynamic change in CMRO2in response to a visual stimulus were in good agreement between the traditional hypercapnia calibration and calibration based on R2′. These results support the potential of gas-free methods for quantitative physiological measurements.SynopsisWe tested noninvasive methods to measure absolute oxygen metabolism (CMRO2) in both baseline and activation states without the use of special gases: VSEAN to measure baseline O2extraction fraction (OEF), and FLAIR-GESSE to measure R2′to estimate the scaling parameterM. Primary findings were: CMRO2changes to visual stimulation derived from R2′were similar to estimates based on hypercapnia-derivedM; OEF values were in good agreement with previous PET findings; and, variation of baseline CBF/CMRO2coupling across subjects does not follow activation coupling, suggesting different mechanisms may be involved. These results support the potential of gas-free methods for quantitative physiological measurements.PurposeTo demonstrate the potential for two non-invasive techniques, VSEAN and FLAIR-GESSE, for absolute measurements of CMRO2during both baseline and activation states.
The functional connectivity of the human claustrum according to the Human Connectome Project database
Authors: Rodríguez-Vidal Lluviana , Alcauter Sarael , Barrios Fernando A 
Published: July 2019

AbstractThe claustrum is an irregular and fine sheet of grey matter in the basolateral telencephalon present in almost all mammals. The claustrum has been the object of several studies using animal models and more recently in human beings using neuroimaging. Believed to be involved in cognition and disease such as fear recognition, suppression of natural urges, multisensory integration, conceptual integration, seizures, multiple sclerosis, and Parkinson’s disease. Nevertheless, the function of the claustrum still remains unclear. We present a functional connectivity study of the claustrum in order to identify its main networks. Resting state functional and anatomical MRI data from 100 healthy subjects were analyzed; taken from the Human Connectome Project (HCP, NIH Blueprint: The Human Connectome Project), with 2×2×2 mm3 voxel resolution. Positive functional connectivity was found (p<0.05, FDR corrected) between the claustrum and the insula, anterior cingulate cortex, pre-central and postcentral gyrus, superior temporal gyrus, and subcortical areas. Our findings coincide with the results previously reported in both animal models and studies with humans. Showing the claustrum as a well-connected structure not only structurally but also functionally. Evidencing the claustrum as a node participating in different neural networks.
Towards a state-space geometry of neural responses to natural scenes: A steady-state approach
Authors: Hansen Bruce C. , Field David J. , Greene Michelle R. , Olson Cassady , Miskovic Vladimir 
Published: July 2019

AbstractOur understanding of information processing by the mammalian visual system has come through a variety of techniques ranging from psychophysics and fMRI to single unit recording and EEG. Each technique provides unique insights into the processing framework of the early visual system. Here, we focus on the nature of the information that is carried by steady state visual evoked potentials (SSVEPs). To study the information provided by SSVEPs, we presented human participants with a population of natural scenes and measured the relative SSVEP response. Rather than focus on particular features of this signal, we focused on the full state-space of possible responses and investigated how the evoked responses are mapped onto this space. Our results show that it is possible to map the relatively high-dimensional signal carried by SSVEPs onto a 2-dimensional space with little loss. We also show that a simple biologically plausible model can account for a high proportion of the explainable variance (∼73%) in that space. Finally, we describe a technique for measuring the mutual information that is available about images from SSVEPs. The techniques introduced here represent a new approach to understanding the nature of the information carried by SSVEPs. Crucially, this approach is general and can provide a means of comparing results across different neural recording methods. Altogether, our study sheds light on the encoding principles of early vision and provides a much needed reference point for understanding subsequent transformations of the early visual response space to deeper knowledge structures that link different visual environments.
The double-edge sword of heterogeneous ripening pattern in winter wheat cultivar mixtures: A case study under post-anthesis water stress
Authors: Haghshenas Abbas , Emam Yahya , Sepaskhah Ali Reza , Edalat Mohsen 
Published: July 2019

AbstractWheat cultivar mixtures with heterogeneous phenology has a less-explored potential to improve crop diversity, yield stability, and agronomic features particularly in response to the currently increased environmental stresses and uncertainties. To investigate the option of using wheat cultivar mixtures with different ripening patterns for mitigating the adverse effects of post-anthesis water stress, a two-year field experiment was conducted during 2014-15 and 2015-16 growing seasons at the research field of School of Agriculture, Shiraz University, Iran. The factorial experiment was a Randomized Complete Block Design with 3 replicates, in which 15 mixture treatments including monocultures and every 11 possible mixtures of four early- to middle-ripening wheat cultivars were grown under two normal and post-anthesis deficit-irrigation conditions. Measured traits and estimated indices included grain yield and its components, canopy temperature, soil water content, water productivity, susceptibility index, and water use efficiency. The results indicated that under the stressful condition of post-anthesis deficit-irrigation, heterogeneity in the ripening pattern of mixtures was declined. Consequently, dissimilarities in grain yields as well as various agronomic characters of mixture treatments were also lessened. This may be an evidence for the negative effect of water shortage stress on heterogeneity within agroecosystems. Although cultivar mixtures showed some casual advantages in some traits, such beneficial effects were not consistent across all conditions. Moreover, no cultivar mixture produced higher grain yield than the maximum monoculture. Despite the general expectation for beneficial ecological services from cultivar mixtures, in many cases disadvantageous blends were found which led to a considerable reduction in grain yield and water productivity. Therefore, it is suggested that unless the performance, and preferably the involved mechanisms, of cultivar mixtures are not fully understood, use of blends as an alternative for conventional high-input wheat cropping systems may lead to adverse results.
Dissecting the first phased dikaryotic genomes of the wheat rust pathogenPuccinia triticinareveals the mechanisms of somatic exchange in nature
Authors: Wu Jing Qin , Dong Chongmei , Song Long , Cuomo Christina A. , Park Robert F. 
Published: July 2019

AbstractAlthough somatic hybridization (SH) has been proposed as a means of accelerating rust pathogen virulence evolution in the absence of sexual recombination, previous studies are limited to the laboratory and none have revealed how this process happens. Using long-read sequencing, we generated dikaryotic phased genomes and annotations for three Australian field-collected isolates of the wheat leaf rust pathogen (Puccinia triticina; Pt), including a putative asexual hybrid (Pt64) and two putative parental isolates (Pt104 and Pt53; 132-141 Mb,155-176 contigs, N50of 1.9-2.1 Mb). The genetic dissection based on the high-quality phased genomes including whole-genome alignments, phylogenetic and syntenic analyses along with short-read sequencing of 27 additionalPtisolates convergently demonstrated that Pt64, which rendered several commercial hybrid wheat cultivars susceptible to leaf rust, arose from SH between isolates within the Pt53 and Pt104 lineages. Parentage analysis demonstrated the role of mitotic crossover in the derivation of both nuclei of Pt64. Within HD mating type genes, the distinct specificity regions in Pt64 and the distinct phylogenetic pattern of the remaining admixed isolates suggested high genetic variation in specificity-related regions on theblocus intrinsically associated with the SH. This study not only provided a fundamental platform for investigating genomic variation underlying virulence evolution in one of the most devastating wheat pathogens, but also offered an in-depth understanding of the mechanisms of naturally occurring SH. This asexual mechanism can be broadly exploited by any dikaryotic pathogen to accelerate virulence evolution, and understanding this process is both urgent and crucial for sustainable pathogen control.ImportanceStrategies to manage plant rust pathogens are challenged by the constant emergence of new virulence. Although somatic hybridization has been proposed as a means by which rusts could overcome host resistance rapidly and cause crop loss, there is very little evidence of this process in nature and the mechanisms underlying it are not known. This study generated and analysed the first dikaryotic phased genomes of the wheat leaf rust pathogen, identifying an isolate as a hybrid and for the first time unveiling parasexuality via mitotic crossover in a rust pathogen. The erosion of the resistance of several hybrid wheat cultivars in agriculture by the hybrid rust has important implications for breeding efforts targeting durable resistance and sustained rust control.