bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of Re, W and Co on dislocation nucleation at the crack tip in the
γ
-phase of Ni-based single-crystal superalloys by atomistic simulation
Authors: Wang Dianwu , Wang Chongyu , Yu Tao
Published: July 2019

The effects of Re, W and Co on dislocation nucleation at the crack tip in Ni have been studied by the molecular dynamics method. The results show that the activation energy of dislocation nucleation is lowered by the addition of Re, W and Co; moreover, the activation energy decreases when the alloying element increases from 1 at.% to 2 at.%. The energy landscapes of the atoms are studied to elucidate these effects. Quantification analyses of the bonding strength between Ni and X (X = Re, W or Co) reveal that strong bonding between Ni and X (X = Re, W or Co) in the dislocation nucleation process can suppress the cleavage process and enhance the ability of dislocation nucleation. The surface energy and unstable stacking fault energy are also calculated to understand the alloying effects on the dislocation nucleation process. The results imply that interaction between alloying elements and Ni atoms plays a role in promoting the dislocation nucleation process at the crack tip. The ability of Re, W and Co in improving the ductility of the Ni crack system is in the order W > Re > Co. The results could provide useful information in the design of Ni-based superalloys.
Study on synthesis and application of tetrabasic lead sulfate as the positive active material additive for lead-acid batteries
Authors: Kim Myonghak , Kim Mungi , Ri Cholnam , Jong Songchol , Pak Ilman , Kim Ganghyok , Ri Mun
Published: July 2019

Tetrabasic lead sulfate (4BS) was used as a positive active material additive for lead-acid batteries, which affirmatively affected the performance of the battery. Herein, tetrabasic lead sulfate was synthesized from scrap lead paste that was formed through the production process of the lead-acid batteries. This solves the disposing problem of the scrap lead paste that is challenging in the production of the lead-acid batteries. Scrap lead paste was first pre-treated and the 4BS with high purity and crystalline was synthesized by sintering at the temperature of 450°C and hold time of 7 h. As demonstrated by X-ray diffraction and scanning electron microscopy test and Material Studio software calculation, the purity of synthesized 4BS is higher than 98 wt%, small particles have pillar forms and are evenly distributed. Moreover, the synthesized 4BS of 1 wt% was added to the positive lead paste and then valve-regulated lead-acid battery was made after the pasting, curing and formation processes. The effectiveness of the lead-acid batteries after adding 4BS as crystal seeds was evaluated, and the 100% charge–discharge cycle life of the new battery (523 times) was about 1.4 times higher than that of general lead-acid batteries (365 times).
Two-point wavepacket modelling of jet noise
Authors: Maia I. A. , Jordan P. , Cavalieri A. V. G. , Jaunet V.
Published: July 2019

This paper is focused on the study of a kinematic wavepacket model for jet noise based on two-point statistics. The model contains physical parameters that define its structure in terms of wavenumber, envelope shape and coherence decay. These parameters, which are necessary to estimate the sound pressure levels radiated by the source, were educed from a large-eddy simulation database of a Mach 0.4, fully turbulent jet. The sound pressure levels predicted by the model were compared with acoustic data and the results show that when the parameters are carefully educed from the data, the sound pressure levels generated are in good agreement with experimentally measured values for low Strouhal numbers and polar angles. Furthermore, here we show that a correct representation of both coherence decay and wavepacket envelope shape are key aspects to an accurate sound prediction. A Spectral Proper Orthogonal Decomposition (SPOD) of the model source was also performed motivated by the search for a low-rank model capable of capturing the acoustic efficiency of the full source. It is shown that only a few SPOD modes are necessary to recover acoustically important wavepacket traits.
Synergistic third-party rewarding and punishment in the public goods game
Authors: Fang Yinhai , Benko Tina P. , Perc Matjaž , Xu Haiyan , Tan Qingmei
Published: July 2019

We study the evolution of cooperation in the spatial public goods game in the presence of third-party rewarding and punishment. The third party executes public intervention, punishing groups where cooperation is weak and rewarding groups where cooperation is strong. We consider four different scenarios to determine what works best for cooperation, in particular, neither rewarding nor punishment, only rewarding, only punishment or both rewarding and punishment. We observe strong synergistic effects when rewarding and punishment are simultaneously applied, which are absent if neither of the two incentives or just each individual incentive is applied by the third party. We find that public cooperation can be sustained at comparatively low third-party costs under adverse conditions, which is impossible if just positive or negative incentives are applied. We also examine the impact of defection tolerance and application frequency, showing that the higher the tolerance and the frequency of rewarding and punishment, the more cooperation thrives. Phase diagrams and characteristic spatial distributions of strategies are presented to corroborate these results, which will hopefully prove useful for more efficient public policies in support of cooperation in social dilemmas.
Chimpanzees flexibly update working memory contents and show susceptibility to distraction in the self-ordered search task
Authors: Völter Christoph J. , Mundry Roger , Call Josep , Seed Amanda M.
Published: July 2019

Working memory (WM) is a core executive function that allows individuals to hold, process and manipulate information. WM capacity has been repeatedly nominated as a key factor in human cognitive evolution; nevertheless, little is known about the WM abilities of our closest primate relatives. In this study, we examined signatures of WM ability in chimpanzees (
Pan troglodytes
). Standard WM tasks for humans (
Homo sapiens
) often require participants to continuously update their WM. In Experiment 1, we implemented this updating requirement in a foraging situation: zoo-housed chimpanzees (
n
= 13) searched for food in an array of containers. To avoid redundant searches, they needed to continuously update which containers they had already visited (similar to WM paradigms for human children) with 15 s retention intervals in between each choice. We examined chimpanzees' WM capacity and to what extent they used spatial cues and object features to memorize their previous choices. In Experiment 2, we investigated how susceptible their WM was to attentional interference, an important signature, setting WM in humans apart from long-term memory. We found large individual differences with some individuals remembering at least their last four choices. Chimpanzees used a combination of spatial cues and object features to remember which boxes they had chosen already. Moreover, their performance decreased specifically when competing memory information was introduced. Finally, we found that individual differences in task performance were highly reliable over time. Together, these findings show remarkable similarities between human and chimpanzee WM abilities despite evolutionary and life-history differences.
Development of homeothermic endothermy is delayed in high-altitude native deer mice (
Peromyscus maniculatus)
Authors: Robertson Cayleih E. , Tattersall Glenn J. , McClelland Grant B.
Published: July 2019

Altricial mammals begin to independently thermoregulate during the first few weeks of postnatal development. In wild rodent populations, this is also a time of high mortality (50–95%), making the physiological systems that mature during this period potential targets for selection. High altitude (HA) is a particularly challenging environment for small endotherms owing to unremitting low O
2
and ambient temperatures. While superior thermogenic capacities have been demonstrated in adults of some HA species, it is unclear if selection has occurred to survive these unique challenges early in development. We used deer mice (
Peromyscus maniculatus
) native to high and low altitude (LA), and a strictly LA species (
Peromyscus leucopus
), raised under common garden conditions, to determine if postnatal onset of endothermy and maturation of brown adipose tissue (BAT) is affected by altitude ancestry. We found that the onset of endothermy corresponds with the maturation and activation of BAT at an equivalent age in LA natives, with 10-day-old pups able to thermoregulate in response to acute cold in both species. However, the onset of endothermy in HA pups was substantially delayed (by approx. 2 days), possibly driven by delayed sympathetic regulation of BAT. We suggest that this delay may be part of an evolved cost-saving measure to allow pups to maintain growth rates under the O
2
-limited conditions at HA.
Seismic air guns damage rock lobster mechanosensory organs and impair righting reflex
Authors: Day Ryan D. , McCauley Robert D. , Fitzgibbon Quinn P. , Hartmann Klaas , Semmens Jayson M.
Published: July 2019

The effects of anthropogenic aquatic noise on marine invertebrates are poorly understood. We investigated the impact of seismic surveys on the righting reflex and statocyst morphology of the palinurid rock lobster,Jasus edwardsii, using field-based exposure to air gun signals. Following exposure equivalent to a full-scale commercial assay passing within 100–500 m, lobsters showed impaired righting and significant damage to the sensory hairs of the statocyst. Reflex impairment and statocyst damage persisted over the course of the experiments—up to 365 days post-exposure and did not improved following moulting. These results indicate that exposure to air gun signals caused morphological damage to the statocyst of rock lobsters, which can in turn impair complex reflexes. This damage and impairment adds further evidence that anthropogenic aquatic noise has the potential to harm invertebrates, necessitating a better understanding of possible ecological and economic impacts.
Nonlinear changes in selection on a mating display across a continuous thermal gradient
Authors: Rosenthal Malcolm Fogelin , Elias Damian O.
Published: July 2019

Understanding how animal communication varies across time and space is critical to understanding how animal signals have evolved and how they function. Changes in temperature, which occur across both time and space, can alter both the courtship and mate choice behaviour of ectothermic animals. In this study, we examine the effect of daily thermal variation on courtship and mate choice in the wolf spiderSchizocosa floridana, which produces a complex song with vibrations from three distinct body parts. We test the hypothesis that different components ofS. floridana's courtship respond differently to daily changes in temperature and that corresponding mate choice patterns lead to complex, overlapping shifts in selection on the display itself. By manipulating the thermal environment of courting and choosing pairs, we found that several song components increased in production rate with increased temperature, whereas others decreased, or did not respond at all. We also found evidence that selection on courtship shifts with temperature in several ways, with some display components experiencing directional selection at higher temperatures, but not at lower temperatures. Our findings make it clear that understanding the effect of environmental variation on communication is critical to understanding how selection operates on mate choice and how signals, particularly complex signals, evolve.
Metagenomic identification of severe pneumonia pathogens with rapid Nanopore sequencing in mechanically-ventilated patients
Authors: Yang Libing , Haidar Ghady , Zia Haris , Nettles Rachel , Qin Shulin , Wang Xiaohong , Shah Faraaz , Rapport Sarah F. , Charalampous Themoula , Methé Barbara , Fitch Adam , Alison Morris MS , McVerry Bryan J. , O’Grady Justin , D. Kitsios Georgios
Published: July 2019

Background

Metagenomic sequencing of respiratory microbial communities for etiologic pathogen identification in pneumonia may help overcome the limitations of current culture-based methods. We examined the feasibility and clinical validity of rapid-turnaround metagenomics with Nanopore™ sequencing of respiratory samples for severe pneumonia diagnosis.

Methods and Findings

We conducted a case-control study of mechanically-ventilated patients with pneumonia (nine culture-positive and five culture-negative) and without pneumonia (eight controls). We collected endotracheal aspirate samples (ETAs) and applied a microbial DNA enrichment method prior to performing metagenomic sequencing with the Oxford Nanopore MinION device. We compared Nanopore results against clinical microbiologic cultures and bacterial 16S rRNA gene sequencing. In nine culture-positive cases, Nanopore revealed communities with low alpha diversity and high abundance of the bacterial (n=8) or fungal (n=1) species isolated by clinical cultures. In four culture-positive cases with resistant organisms, Nanopore detected antibiotic resistance genes corresponding to the phenotypic resistance identified by clinical antibiograms. In culture-negative pneumonia, Nanopore revealed probable bacterial pathogens in 1/5 cases and airway colonization by Candida species in 3/5 cases. In controls, Nanopore showed high abundance of oral bacteria in 5/8 subjects, and identified colonizing respiratory pathogens in the three other subjects. Nanopore and 16S sequencing showed excellent concordance for the most abundant bacterial taxa.

Conclusion

We demonstrated technical feasibility and proof-of-concept clinical validity of Nanopore metagenomics for severe pneumonia diagnosis, with striking concordance with positive microbiologic cultures and clinically actionable information offered from the sequencing profiles of culture-negative samples. Prospective studies with real-time metagenomics are warranted to examine the impact on antimicrobial decision-making and clinical outcomes.
Genomic Retargeting of Tumor Suppressors p53 and CTCF Promotes Oncogenesis
Authors: Schwartz Michal , Portugez Avital Sarusi , Attia Bracha Zukerman , Tannenbaum Miriam , Loza Olga , Chase Aliza , Turman Yousef , Kaplan Tommy , Salah Zaidoun , Hakim Ofir
Published: July 2019

Gene transcription is substantially regulated by distant regulatory elements via combinatorial binding of transcription factors. It is more and more recognized that alterations in chromatin state and transcription factor binding in these distant regulatory elements may have key roles in cancer development. Here we focused on the first stages of oncogene induced carcinogenic transformation, and characterized the regulatory network underlying transcriptional reprogramming associated with this process. Using Hi-C data, we couple between differentially expressed genes and their differentially active regulatory elements and reveal two candidate transcription factors, p53 and CTCF, as major determinants of transcriptional reprogramming at early stages of HRas-induced transformation. Strikingly, the malignant transcriptional reprograming is promoted by redistribution of chromatin binding of these factors without major variation in their expression level. Our results demonstrate that alterations in the regulatory landscape have a major role in driving oncogene-induced transcriptional reprogramming.
Reaching around obstacles accounts for uncertainty in coordinate transformations
Authors: Abedi Khoozani Parisa , Voudouris Dimitris , Blohm Gunnar , Fiehler Katja
Published: July 2019

When reaching to a visual target, humans need to transform the spatial target representation into the coordinate system of their moving arm. It has been shown that increased uncertainty in such coordinate transformations, for instance when the head is rolled toward one shoulder, leads to higher movement variability and influence movement decisions. However, it is unknown whether the brain incorporates such added variability in planning and executing movements. We designed an obstacle avoidance task in which participants had to reach with or without visual feedback of the hand to a visual target while avoiding collisions with an obstacle. We varied coordinate transformation uncertainty by varying head roll (straight, 30° clockwise and 30° counterclockwise). In agreement with previous studies, we observed that the reaching variability increased when the head was tilted. Indeed, head roll did not influence the number of collisions during reaching compared to the head straight condition, but it did systematically change the obstacle avoidance behavior. Participants changed the preferred direction of passing the obstacle and increased the safety margins indicated by stronger movement curvature. These results suggest that the brain takes the added movement variability during head roll into account and compensates for it by adjusting the reaching trajectories.
Molecular mechanism of sulfur chemolithotrophy in the betaproteobacterium Pusillimonas ginsengisoli
Authors: Mandal Subhrangshu , Rameez Moidu Jameela , Pyne Prosenjit , Bhattacharya Sabyasachi , Sarkar Jagannath , Ghosh Wriddhiman
Published: July 2019

Molecular mechanism of chemolithotrophic sulfur oxidation in Betaproteobacteria is less explored than that in Alphaproteobacteria. Here we carried out whole genome sequencing and analysis of a new betaproteobacterial isolate Pusillimonas ginsengisoli SBSA which oxidizes thiosulfate via formation tetrathionate as an intermediate. The 4.7-Mb SBSA genome was found to encompass a complete soxCDYZAXOB operon, plus one thiosulfate dehydrogenase (tsdA) and sulfite:acceptor oxidoreductase (sorAB) genes. Recombination-based knock-out of tsdA revealed that the entire thiosulfate oxidized by SBSA is first converted to tetrathionate, and no thiosulfate is directly converted to sulfate as typical of the Alphaproteobacterial Sox pathway whereas its tetrathionate-oxidizing ability was as good as that of the wild-type. The ∆soxYZ knock-out mutant exhibited wild-type-like phenotype for thiosulfate/tetrathionate oxidation, whereas ∆soxB oxidized thiosulfate only up to tetrathionate and had complete impairment of tetrathionate oxidation. However, substrate-dependent O2-consumption rate of whole cells, and sulfur-oxidizing enzyme activities of cell-free extracts, measured in the presence/absence of thiol-inhibitors/glutathione, indicated that glutathione plays a key role in SBSA tetrathionate oxidation. All the present findings collectively indicated that glutathione:tetrathionate coupling in Pusillimonas ginsengisoli may involve some unknown proteins other than thiol dehydrotransferase(ThdT), while subsequent oxidation of the potential glutathione:sulfodisulfane and sulfite molecules produced may proceed via soxBCD action.
Negative plant-microbiome feedback limits productivity in aquaponics
Authors: Day Jessica A. , Otwell Anne E. , Diener Christian , Tams Kourtney E. , Bebout Brad , Detweiler Angela M. , Lee Michael D. , Scott Madeline T. , Ta Wilson , Ha Monica , Carreon Shienna A. , Tong Kenny , Ali Abdirizak A. , Gibbons Sean M. , Baliga Nitin S.
Published: July 2019

The demand for food will outpace productivity of conventional agriculture due to projected growth of the human population, concomitant with shrinkage of arable land, increasing scarcity of freshwater, and a rapidly changing climate. Efforts to increase conventional agricultural output come with significant environmental impacts stemming from deforestation and excessive use of chemicals, including soil salinization, erosion, and nutrient runoffs. While aquaponics has potential to sustainably supplement food production with minimal environmental impact, there is a need to better characterize the complex interplay between the various components (fish, plant, microbiome) of these systems to optimize scale up and productivity. For instance, much of our knowledge of beneficial and detrimental microbial communities vis-à-vis crop productivity comes from studies on plant-microbiome interactions in soil. Here, we investigated how the practice of continued transfer of microbial communities from pre-existing systems might promote or impede productivity of aquaponics. Specifically, we monitored plant growth phenotypes, water chemistry, and microbiome composition of rhizospheres, biofilters, and fish feces over 61-days of lettuce (Lactuca sativa) growth in aquaponic systems inoculated with bacteria that were either commercially sourced or originating from a pre-existing aquaponic system. Strikingly, L. sativa plant and root growth was significantly reduced across all replicates inoculated with the established microbiome. Further analyses revealed the reduced productivity was potentially a consequence of plant-specific pathogen enrichment, including Pseudomonas, through transfer of microbiomes from pre-existing systems – a phenomenon consistent with negative feedbacks in soil ecology. These findings underscore the need for diagnostic tools to monitor microbiome composition, detect negative feedbacks early, and minimize pathogen accumulation in aquaponic systems.
Innovations in Primate Interneuron Repertoire
Authors: Krienen Fenna M. , Goldman Melissa , Zhang Qiangge , del Rosario Ricardo , Florio Marta , Machold Robert , Saunders Arpiar , Levandowski Kirsten , Zaniewski Heather , Schuman Benjamin , Wu Carolyn , Lutservitz Alyssa , Mullally Christopher D. , Reed Nora , Bien Elizabeth , Bortolin Laura , Fernandez-Otero Marian , Lin Jessica , Wysoker Alec , Nemesh James , Kulp David , Burns Monika , Tkachev Victor , Smith Richard , Walsh Christopher A. , Dimidschstein Jordane , Rudy Bernardo , Kean Leslie , Berretta Sabina , Fishell Gord , Feng Guoping , McCarroll Steven A.
Published: July 2019

Primates and rodents, which descended from a common ancestor more than 90 million years ago, exhibit profound differences in behavior and cognitive capacity. Modifications, specializations, and innovations to brain cell types may have occurred along each lineage. We used Drop-seq to profile RNA expression in more than 184,000 individual telencephalic interneurons from humans, macaques, marmosets, and mice. Conserved interneuron types varied significantly in abundance and RNA expression between mice and primates, but varied much more modestly among primates. In adult primates, the expression patterns of dozens of genes exhibited spatial expression gradients among neocortical interneurons, suggesting that adult neocortical interneurons are imprinted by their local cortical context. In addition, we found that an interneuron type previously associated with the mouse hippocampus—the “ivy cell”, which has neurogliaform characteristics—has become abundant across the neocortex of humans, macaques, and marmosets. The most striking innovation was subcortical: we identified an abundant striatal interneuron type in primates that had no molecularly homologous cell population in mouse striatum, cortex, thalamus, or hippocampus. These interneurons, which expressed a unique combination of transcription factors, receptors, and neuropeptides, including the neuropeptide TAC3, constituted almost 30% of striatal interneurons in marmosets and humans. Understanding how gene and cell-type attributes changed or persisted over the evolutionary divergence of primates and rodents will guide the choice of models for human brain disorders and mutations and help to identify the cellular substrates of expanded cognition in humans and other primates.
Probiotic strains improve high-fat diet-induced hypercholesterolemia through modulating gut microbiota in ways different from atorvastatin
Authors: Sudun  , Liu Songling , Xiao Chen , Peng Can , Liang Lifeng , He Xiaofen , Zhao Shancen , Zhang Gengyun
Published: July 2019

Hypercholesterolemia is a major risk factor for cardiovascular disease (CVD). Probiotics is one of the most popular dietary supplements for hypercholesterolemia, but there are questions as to whether there are differences between probiotics and cholesterol-lowering drugs as like atorvastatin (ATO) both in effectiveness and the underlying mechanisms. In this study, the hypocholesterolemia effects of 4 probiotic strains were investigated and compared with ATO, focusing on their impacts on gut microbiota. Hypercholesterolemia model was established via high-fat diet (HFD) in golden hamsters after which ATO and the 4 probiotics were orally administered individually for 8 weeks. All probiotics were effective, but less than ATO, both on body weight, serum parameters (TG, TC, LDL, INS, HbA1c) and expression of inflammatory factors (TNF-α, IL-1β, CRP), with strain JQII-5 most significant. Besides, these effects were associated with restoration of the microbiota dysbiosis induced by HFD. It was worth noting that ATO and probiotics induced different shifts of gut microbiota in both structure and key phylotypes. Most interestingly, Allobaculum, a HFD-suppressed genus, reported to be involved in alleviating oxidative stress, was enriched by all tested probiotic strains, but not by ATO. Furthermore, Prevotella, also a HFD-suppressed genus, was uniquely reversed by JQII-5. Importantly, most of the alerted genus and reversed genus was found to be correlated to inflammatory state and serum lipid level. Compared with ATO, probiotic strains were less effective on body weight, hypercholesterolemia, and inflammation. However, probiotics exert additional favorable effects on gut microbiota, making them excellent potential complements to cholesterol-lowering drugs like ATO.
Hydrogen peroxide as regeneration-initiation signal that activates pERK to trigger planarian regeneration
Authors: Jaenen Vincent , Fraguas Susanna , Bijnens Karolien , Vaca Mireia , Artois Tom , Romero Rafael , Smeets Karen , Cebrià Francesc
Published: July 2019

Despite the extensive research on molecular pathways controlling the process of regeneration in planarians and other regeneration models, little is known about the actual initiation signals necessary to induce regeneration. Previously the involvement of ROS, EGFR and MAPK/ERK has been demonstrated during planarian regeneration, however the exact interplay has not been yet described. By selectively interfering with major mediators in all three key parts (ROS, EGFR & MAPK/ERK), we were able to identify amputation/wound-induced ROS, and H2O2specifically, as upstream cue in activating regeneration-initiation. In addition, our results demonstrate new relationships between regeneration related ROS production and MAPK/ERK activation at early regeneration stages, as well as the involvement of the EGFR-signaling pathway. In summary, our results suggest a new and more extensive signaling model with ROS, and H2O2, highlighted as upstream initiation-factor and its important functions in the downstream EGFR-MAPK/ERK pathway during planarian regeneration.
Continuous transcription initiation guarantees robust repair of transcribed genes and regulatory regions in response to DNA damage
Authors: Liakos Anastasios , Konstantopoulos Dimitris , Lavigne Matthieu D. , Fousteri Maria
Published: July 2019

Inhibition of RNA synthesis caused by DNA damage-impaired RNA polymerase II (Pol II) elongation is found to conceal a local increase inde novotranscription, slowly progressing from Transcription Start Sites (TSSs) to gene ends. Although associated with accelerated repair of Pol II-encountered lesions and limited mutagenesis, it is still unclear how this mechanism is maintained during recovery from genotoxic stress. Here we uncover a surprising widespread gain in chromatin accessibility and preservation of the active histone mark H3K27ac after UV-irradiation. We show that the concomitant increase in Pol II release from promoter-proximal pause (PPP) sites of most active genes, PROMoter uPstream Transcripts (PROMPTs) and enhancer RNAs (eRNAs) favors unrestrained initiation, as demonstrated by the synthesis of short nascent RNAs, including TSS-associated RNAs (start-RNAs). In accordance, drug-inhibition of the transition into elongation replenished the post-UV reduced levels of pre-initiating pol II at TSSs. Continuous engagement of new Pol II thus ensures maximal transcription-driven DNA repair of active genes and non-coding regulatory loci. Together, our results reveal an unanticipated layer regulating the UV-triggered transcriptional-response and provide physiologically relevant traction to the emerging concept that transcription initiation rate is determined by pol II pause-release dynamics.
Regulation of thymocyte β-selection, development and positive selection by glycogen synthase kinase-3
Authors: Parsons Michael J. , Patel Satish , Doble Bradley W. , Ohashi Pamela S. , Woodgett James R.
Published: July 2019

Glycogen synthase kinase-3 (GSK-3) is a ubiquitously expressed serine/threonine kinase, that exists as two isoforms in mammals, GSK-3α and GSK-3β, that are key downstream mediators of the phosphatidylinositol 3’ kinase, Wnt, Notch and other pathways. Here, we report that simultaneous inactivation of both GSK-3α and GSK-3β during early thymocyte ontogeny has profound effects on both β-selection and positive selection, key checkpoints essential to producing functionally mature αβ T cells. Conditional GSK-3α/β knockout animals (LckCre+ GSK-3αβfl/fl) possessed pre-double positive (pre-DP) thymocytes (CD4−CD8−CD117−CD25−) with compromised TCRβ chain expression along with elevated levels of β-catenin and reduced Notch activity. β-selection was impaired allowing pre-DP thymocytes to differentiate to DP thymocytes (CD4+CD8+) while bypassing strict requirements for productive TCRβ chain rearrangements and functional expression. Also impaired was the requisite pre-TCR and Notch-mediated expansion that normally precedes differentiation to the DP stage. Consequently, LckCre+ GSK-3αβfl/fl mice initially generated fewer DP thymocytes that expressed significantly reduced levels of mature TCR. The aberrant DP thymocytes expressed high levels of the pro-survival Bcl-2 family member Mcl-1, failed positive selection and accumulated as CD4hiCD8lo positive selection intermediates resulting in loss of both mature CD4 and CD8 lineages. LckCre+ GSK-3αβfl/fl mice succumbed to oligoclonal peripheral lymphomas with high penetrance. These data reveal essential roles for GSK-3 in several checkpoints of early T cell development.
Parameters and determinants of responses to selection in antibody libraries
Authors: Schulz Steven , Boyer Sébastien , Smerlak Matteo , Cocco Simona , Monasson Rémi , Nizak Clément , Rivoire Olivier
Published: July 2019

Antibody repertoires contain binders to nearly any target antigen. The sequences of these antibodies differ mostly at few sites located on the surface of a scaffold that itself consists of much less varied amino acids. What is the impact of this scaffold on the response to selection of a repertoire? To gauge this impact, we carried out quantitative phage display experiments with three antibody libraries based on distinct scaffolds harboring the same diversity at randomized sites, which we selected for binding to four arbitrary targets. We first show that the response to selection of an antibody library is captured by a simple and measurable parameter with direct physical and information-theoretic interpretations. Second, we identify a major determinant of this parameter which is encoded in the scaffold, its degree of evolutionary maturation. Antibodies undergo an accelerated evolutionary process, called affinity maturation, to improve their affinity to a given target antigen as part of the adaptive immune response. We find that libraries of antibodies built around such maturated scaffolds have a lower response to selection to other arbitrary targets than libraries built around naïve scaffolds of germline origin. Our results are a first step towards quantifying and controlling the evolutionary potential of biomolecules.
Diurnal variation in xylem water isotopic signature biases depth of root-water uptake estimates
Authors: De Deurwaerder Hannes , Visser Marco D. , Detto Matteo , Boeckx Pascal , Meunier Félicien , Zhao Liangju , Wang Lixin , Verbeeck Hans
Published: July 2019

Stable water isotopes are a powerful and widely used tool to derive the depth of root water uptake (RWU) in lignified plants. Uniform xylem water isotopic signature (i-H2O-xyl) along the length of a lignified plant is a central assumption, which has never been properly evaluated.

Here we studied the effects of diurnal variation in RWU, sap flow velocity and various other soil and plant parameters oni-H2O-xylsignature within a plant using a mechanistic plant hydraulic model.

Our model predicts significant variation ini-H2O-xylalong the full length of an individual plant arising from diurnal RWU fluctuations and vertical soil water heterogeneity. Moreover, significant differences ini-H2O-xylemerge between individuals with different sap flow velocities. We corroborated our model predictions with field observations from French Guiana and northwestern China. Modelledi-H2O-xylvaried considerably along stem length ranging up to 18.3‰ in δ2H and 2.2‰ in δ18O, largely exceeding the range of measurement error.

Our results show clear violation of the fundamental assumption of uniformi-H2O-xyland occurrence of significant biases when using stable isotopes to assess RWU. As a solution, we propose to include monitoring of sap flow and soil water potential for more robust RWU depth estimates.
In vivo characterization of neurophysiological diversity in the lateral supramammillary nucleus during hippocampal sharp-wave ripples of adult rats
Authors: Vicente Ana F , Slézia Andrea , Ghestem Antoine , Bernard Christophe , Quilichini Pascale P
Published: July 2019

The extent of the networks that control the genesis and modulation of hippocampal sharp wave ripples (SPW-Rs), which are involved in memory consolidation, remains incompletely understood. Here, we performed a detailed in vivo analysis of single cell firing in the lateral supramammillary nucleus (lSuM) during theta and slow oscillations, including SPW-Rs, in anesthetized rats. We classified neurons as SPW-R-active and SPW-R unchanged according to whether or not they increased their firing during SPW-Rs. We show that lSuM SPW-R-active neurons increase their firing prior SPW-Rs peak power and prior hippocampal pyramidal cell activation. Moreover, lSuM SPW-R-active neurons show increased firing activity during theta and slow oscillations as compared to unchanged-neurons. SPW-R-active neurons are more active during high peak power SPW-Rs, whereas SPW-R-unchanged neurons are more active during long SPW-Rs. These results suggest that a sub-population of lSuM neurons can interact with the hippocampus during SPW-Rs, raising the possibility that the lSuM may modulate memory consolidation.
Genome-scale profiling reveals higher proportions of phylogenetic signal in non-coding data
Authors: Literman Robert , Schwartz Rachel S.
Published: July 2019

Accurate estimates of species relationships are integral to our understanding of evolution, yet many relationships remain controversial despite whole-genome sequence data. These controversies are due in part to complex patterns of phylogenetic and non-phylogenetic signal coming from regions of the genome experiencing distinct evolutionary forces, which can be difficult to disentangle. Here we profile the amounts and proportions of phylogenetic and non-phylogenetic signal derived from loci spread across mammalian genomes. We identified orthologous sequences from primates, rodents, and pecora, annotated sites as one or more of nine locus types (e.g. coding, intronic, intergenic), and profiled the phylogenetic information contained within locus types across evolutionary timescales associated with each clade. In all cases, non-coding loci provided more overall signal and a higher proportion of phylogenetic signal compared to coding loci. This suggests potential benefits of shifting away from primarily targeting genes or coding regions for phylogenetic studies, particularly in this era of accessible whole genome sequence data. In contrast to long-held assumptions about the phylogenetic utility of more variable genomic regions, most locus types provided relatively consistent phylogenetic information across timescales, although we find evidence that coding and intronic regions may, respectively and to a limited degree, inform disproportionately about older and younger splits. As part of this work we also validate the SISRS pipeline as an annotation-free ortholog discovery pipeline capable of identifying millions of phylogenetically informative sites directly from raw sequencing reads.
Neural systems for memory-based value judgment and decision-making
Authors: Vaidya Avinash R. , Badre David
Published: July 2019

Real life choices often require that we draw inferences about the value of options based on structured, schematic knowledge about their utility for our current goals. Other times, value information may be retrieved directly from a specific prior experience with an option. In a functional magnetic resonance imaging (fMRI) experiment, we investigated the neural systems involved in retrieving and assessing information from different memory sources to support value-based choice. Participants completed a task in which items could be conferred positive or negative value based on schematic associations (i.e. schema value), or learned directly from experience via deterministic feedback (i.e. experienced value). We found that ventromedial prefrontal cortex (vmPFC) activity correlated with the influence of both experience- and schema-based values on participants’ decisions. Connectivity between vmPFC and middle temporal cortex also tracked the inferred value of items based on schematic associations on the first presentation of ingredients, prior to any feedback. In contrast, the striatum responded to participants’ willingness to bet on ingredients as a function of the unsigned strength of their memory for those options’ values. These results argue that striatum and vmPFC play distinct roles in memory-based value judgment and decision-making. Specifically, the vmPFC assesses the value of options based on information inferred from schematic knowledge and retrieved from prior direct experience, while the striatum controls a decision to act on options based on memory strength.
Global analysis of protein degradation in prion infected cells
Authors: Hutti Charles , Welle Kevin A. , Hryhorenko Jennifer R. , Ghaemmaghami Sina
Published: July 2019

Prion diseases are rare neurological disorders caused by the misfolding of the cellular prion protein (PrPC) into cytotoxic fibrils (PrPSc). Intracellular PrPScaggregates primarily accumulate within late endosomes and lysosomes, organelles that participate in the degradation and turnover of a large subset of the proteome. Thus, intracellular accumulation of PrPScaggregates have the potential to globally influence protein degradation kinetics within an infected cell. We analyzed the proteome-wide effect of prion infection on protein degradation rates in N2a neuroblastoma cells by dynamic stable isotopic labeling with amino acids in cell culture (dSILAC) and bottom-up proteomics. The analysis quantified the degradation rates of more than 4,700 proteins in prion-infected and uninfected cells. As expected, the degradation rate of the prion protein is significantly decreased upon aggregation in infected cells. In contrast, the degradation kinetics of the remainder of the N2a proteome generally increases upon prion infection. This effect occurs concurrently with increases in the cellular activities of autophagy and lysosomal hydrolases. The resulting enhancement in proteome flux may play a role in the survival of N2a cells upon prion infection.
Differentiation of Pluripotent Synthetic Minimal Cells via Genetic Circuits and Programmable Mating
Authors: Gaut Nathaniel J. , Gomez-Garcia Jose , Heili Joseph M. , Cash Brock , Han Qiyuan , Engelhart Aaron E. , Adamala Katarzyna P.
Published: July 2019

Synthetic minimal cells, here defined as liposomal bioreactors synthesizing protein, are a recent technology that models the intricate gene and protein networks of live cells, without the noise inherent to natural systems. Here we show a toolset for engineering combinatorial genetic circuits in synthetic cells, where distinct populations of synthetic cells control single-gene components, and those populations are assembled via programmable fusion to construct complex biological pathways. We utilize this technology to demonstrate that progenitor populations can mimic differentiation into new lineages in response to small molecule stimuli or as an effect of “mating” with another synthetic cell population. This provides a practical tool for metabolic engineering and natural pathway study, as well as paving the way towards the construction of live synthetic cells with complex gene pathways and the ability to form distinct lineages.
SCelVis: Powerful explorative single cell data analysis on the desktop and in the cloud
Authors: Obermayer Benedikt , Holtgrewe Manuel , Nieminen Mikko , Messerschmidt Clemens , Beule Dieter
Published: July 2019

Background

Single cell omics technologies present unique opportunities for biomedical and life sciences from lab to clinic, but the high dimensional nature of such data poses challenges for computational analysis and interpretation. Furthermore, FAIR data management as well as data privacy and security become crucial when working with clinical data, especially in cross-institutional and translational settings. Existing solutions are either bound to the desktop of one researcher or come with dependencies on vendor-specific technology for cloud storage or user authentication.

Results

To facilitate analysis and interpretation of single-cell data by users without bioinformatics expertise, we present SCelVis, a flexible, interactive and user-friendly app for web-based visualization of pre-processed single-cell data. Users can survey multiple interactive visualizations of their single cell expression data and cell annotation, and download raw or processed data for further offline analysis. SCelVis can be run both on the desktop and cloud systems, accepts input from local and various remote sources using standard and open protocols, and allows for hosting data in the cloud and locally.

Methods

SCelVis is implemented in Python using Dash by Plotly. It is available as a standalone application as a Python package, via Conda/Bioconda and as a Docker image. All components are available as open source under the permissive MIT license and are based on open standards and interfaces, enabling further development and integration with third party pipelines and analysis components. The GitHub repository is https://github.com/bihealth/scelvis.
EuRBPDB: a comprehensive resource for annotation, functional and oncological investigation of eukaryotic RNA binding proteins (RBPs)
Authors: Liao Jian-You , Yang Bing , Zhang Yu-Chan , Wang Xiao-Juan , Ye Yushan , Peng Jing-Wen , Yang Zhi-Zhi , He Jie-Hua , Zhang Yin , Hu KaiShun , Lin De-Chen , Yin Dong
Published: July 2019

RNA binding proteins (RBPs) are a large protein family that plays important roles at almost all levels of gene regulation through interacting with RNAs, and contributes to numerous biological processes. However, the complete list of eukaryotic RBPs including human is still unavailable. In this study, we systematically identified RBPs in 162 eukaryotic species based on both computational analysis of RNA binding domains (RBDs) and large-scale RNA binding proteomic (RBPome) data, and established a comprehensive eukaryotic RBP database, EuRBPDB (http://EuRBPDB.syshospital.org:8081). We identified a total of 311,571 RBPs with RBDs and 3,639 non-canonical RBPs without known RBDs. EuRBPDB provides detailed annotations for each RBP, including basic information and functional annotation. Moreover, we systematically investigated RBPs in the context of cancer biology based on published literatures and large-scale omics data. To facilitate the exploration of the clinical relevance of RBPs, we additionally designed a cancer web interface to systematically and interactively display the biological features of RBPs in various types of cancers. EuRBPDB has a user-friendly web interface with browse and search functions, as well as data downloading function. We expect that EuRBPDB will be a widely-used resource and platform for the RNA biology community.
Temporal integration of narrative information in a hippocampal amnesic patient
Authors: Zuo Xiaoye , Honey Christopher J. , Barense Morgan D. , Crombie Davide , Norman Kenneth A. , Hasson Uri , Chen Janice
Published: July 2019

Default network regions appear to integrate information over time windows of 30 seconds or more during narrative listening. Does this long-timescale capability require the hippocampus? Amnesic behavior suggests that the hippocampus may not be needed for online processing when input is continuous and semantically rich: amnesics can participate in conversations and tell stories spanning minutes, and when tested immediately on recently heard prose their performance is relatively preserved. We hypothesized that default network regions can integrate the semantically coherent information of a narrative across long time windows, even in the absence of the hippocampus. To test this prediction, we measured BOLD activity in the brain of a hippocampal amnesic patient (D. A.) and healthy control participants while they listened to a seven-minute narrative. The narrative was played either in its intact form, or as a paragraph-scrambled version, which has been previously shown to interfere with the long-range temporal dependencies in default network activity. In the intact story condition, D. A.’s moment-by-moment BOLD activity spatial patterns were similar to those of controls in low-level auditory cortex as well as in some high-level default network regions (including lateral and medial posterior parietal cortex). Moreover, as in controls, D. A.’s response patterns in medial and lateral posterior parietal cortex were disrupted when paragraphs of the story were presented in a shuffled order, suggesting that activity in these areas did depend on information from 30 seconds or more in the past. Together, these results suggest that some default network cortical areas can integrate information across long timescales, even in the absence of the hippocampus.