bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prefrontal cortex represents heuristics that shape choice bias and its integration into future behavior
Authors: Mochol Gabriela , Kiani Roozbeh , Moreno-Bote Rubén 
Published: March 2020

SummaryGoal-directed behavior requires integrating sensory information with prior knowledge about the environment. Behavioral biases that arise from these priors could increase positive outcomes when the priors match the true structure of the environment, but mismatches also happen frequently and could cause unfavorable outcomes. Biases that reduce gains and fail to vanish with training indicate fundamental suboptimalities arising from ingrained heuristics of the brain. Here, we report systematic, gain-reducing choice biases in highly-trained monkeys performing a motion direction discrimination task where only the current stimulus is behaviorally relevant. The monkey’s bias fluctuated at two distinct time scales: slow, spanning tens to hundreds of trials, and fast, arising from choices and outcomes of the most recent trials. Our finding enabled single trial prediction of biases, which influenced the choice especially on trials with weak stimuli. The pre-stimulus activity of neuronal ensembles in the monkey prearcuate gyrus represented these biases as an offset along the decision axis in the state space. This offset persisted throughout the stimulus viewing period, when sensory information was integrated, leading to a biased choice. The pre-stimulus representation of history-dependent bias was functionally indistinguishable from the neural representation of upcoming choice before stimulus onset, validating our model of single-trial biases and suggesting that pre-stimulus representation of choice could be fully defined by biases inferred from behavioral history. Our results indicate that the prearcuate gyrus reflects intrinsic heuristics that compute bias signals, as well as the mechanisms that integrate them into the oculomotor decision-making process.
The small DdrR protein directly interacts with the UmuDAb regulator to inhibit the mutagenic DNA damage response inAcinetobacter baumannii
Authors: Pavlin Anja , Bajc Gregor , Fornelos Nadine , Browning Douglas F. , Butala Matej 
Published: March 2020

Disclaimer statement:The authors have withdrawn their manuscript due to observed inconsistent results regarding the DdrR effect on the enhanced binding of UmuDAb to its promoter regions. Further experiments are needed to unravel the biology of DdrR. Therefore, the authors do not wish this work to be cited as a reference for the project. If you have any questions, please contact the corresponding author.
Electrostatic and bending energies predict staggering and splaying in nonmuscle myosin II minifilaments
Authors: Kaufmann Tom , Schwarz Ulrich S. 
Published: March 2020

AbstractRecent experiments with super-resolution live cell microscopy revealed that nonmuscle myosin II minifilaments are much more dynamic than formerly appreciated, often showing plastic processes such as splitting, concatenation and stacking. Here we combine sequence information, electrostatics and elasticity theory to demonstrate that the parallel staggers at 14.3, 43.2 and 72 nm have a strong tendency to splay their heads away from the minifilament, thus potentially initiating the diverse processes seen in live cells. In contrast, the straight antiparallel stagger with an overlap of 43 nm is very stable and likely initiates minifilament nucleation. Using stochastic dynamics in a newly defined energy landscape, we predict that the optimal parallel staggers between the myosin rods are obtained by a trial-and-error process in which two rods attach and re-attach at different staggers by rolling and zipping motion. The experimentally observed staggers emerge as the configurations with the largest contact times. We find that contact times increase from isoforms C to B to A, that A-B-heterodimers are surprisingly stable and that myosin 18A should incorporate into mixed filaments with a small stagger. Our findings suggest that nonmuscle myosin II minifilaments in the cell are first formed by isoform A and then convert to mixed A-B-filaments, as observed experimentally.Author summaryNonmuscle myosin II (NM2) is a non-processive molecular motor that assembles into minifilaments with a typical size of 300 nm to generate force and motion in the actin cytoskeleton. This process is essential for many cellular processes such as adhesion, migration, division and mechanosensing. Due to their small size below the resolution limit, minifilaments are a challenge for imaging with traditional light microscopy. With the advent of super-resolution microscopy, however, it has become apparent that the formation of NM2-minifilaments is much more dynamic than formerly appreciated. Modeling the electrostatic interaction between the rigid rods of the myosin monomers has confirmed the main staggers observed in experiments, but cannot explain these high dynamics. Here we complement electrostatics by elasticity theory and stochastic dynamics to show that the parallel staggers are likely to splay away from the main axis of the minifilament and that monomers attach and deattach with rolling and zipping motions. Based on the sequences of the different NM2-isoforms, we predict that isoform A forms the most stable homofilaments and that A-B-heterofilaments are also very stable.
Reconstruction of the urinary tract at the appropriate time reduces fibrosis of the metanephros in rats as judged by imaging
Authors: Nishi Kotaro , Haji Takafumi , Matsumoto Takuya , Hayakawa Chisato , Maeda Kenichi , Okano Shozo , Yokoo Takashi , Iwai Satomi 
Published: March 2020

AbstractChronic kidney disease leads to high morbidity rates among humans. It is a serious disease that requires curative treatments other than kidney transplantation. Recently, we successfully established the iPS-derived generated kidney, which might produce urine. The urine can be directed to the native bladder with a stepwise peristaltic ureter system, followed by anastomosis with the recipient ureter for reconstruction of the urinary tract. However, the growth of the regenerated kidney varies significantly, whereas the time window of the anastomosis is quite narrow. Therefore, this study was conducted to evaluate the growth of transplanted metanephros with bladder periodically and noninvasively using computed tomography and ultrasonography. Ultrasonographic findings showed high correlations with computed tomographic findings and clearly evaluated metanephros with bladder. We found that the degree of growth of the metanephros with bladder after the transplantation differed in each individual. However, most of them reached the appropriate period for urinary tract reconstruction within 3 weeks after transplantation. Optimizing the stepwise peristaltic ureter system anastomosis by ultrasonography reduced long-term tubular dilation of the metanephros, thereby decreasing fibrosis caused by transforming growth factor-β. This may be significantly related to long-term maturation of fetal grafts. These results provide new insights into transplanting regenerated kidneys in higher animals. We are one step closer to the first human trial of kidney generation.
Behavioral response of insecticide-resistant mosquitoes against spatial repellent: a modified self-propelled particle model simulation
Authors: Zhou Guofa , Yu Leonard , Wang Xiaoming , Zhong Daibin , Lee Ming-chieh , Kibret Solomon , Yan Guiyun 
Published: March 2020

AbstractRapidly increasing pyrethroid insecticide resistance and changes in vector biting and resting behavior pose serious challenges in malaria control. Mosquito repellents, especially spatial repellents, have received much attention from industry. Many of these repellents contain the same or similar chemicals as those used in insecticides. Does resistance to insecticides affect the efficacy of spatial repellents? We attempted to simulate interactions between mosquitoes and repellents using a machine learning method, the self-propelled particle (SPP) model, which we modified to include attractiveness/repellency effects. We simulated a random walk scenario and scenarios with insecticide susceptible/resistant mosquitoes against repellent alone and against repellent plus attractant (to mimic a human host). We assumed attractant odors and repellent chemicals diffused randomly and omnidirectionally, and that mosquitoes were confined in a cubic cage. We modified the velocity and direction components of SPP using attraction/repulsion rates and concentrations. Simulation results indicated that without attractant/repellent, mosquitoes would fly anywhere in the cage at random. With attractant, mosquitoes might or might not fly toward the source (i.e., the human), depending on the simulation time (and thus the attractant concentration distribution). Eventually, however, all mosquitoes were attracted to the source of the odor. With repellent, results depended on the amount of chemical used and the level of mosquito insecticide resistance. All insecticide-susceptible mosquitoes eventually moved to the corner of the cage farthest from the repellent release point. Surprisingly, a high proportion of highly resistant mosquitoes might reach the attractant release point (the human) earlier in the simulation when repellent was present compare to no repellent was present. At fixed concentration, a high proportion of mosquitoes could be able to reach the host when the relative repellency efficacy (compare to attractant efficacy) was <1, whereas, no mosquitoes reached the host when the relative repellency efficacy was > 1. This result implies that repellent may not be sufficient against highly physiologically insecticide resistant mosquitoes, since very high concentrations of repellent are neither practically feasible nor cost-effective.
The genetic structure of Norway
Authors: Mattingsdal Morten , Ebenesersdóttir S. Sunna , Moore Kristjan H. S. , Andreassen Ole A. , Hansen Thomas F. , Werge Thomas , Kockum Ingrid , Olsson Tomas , Alfredsson Lars , Helgason Agnar , Stefánsson Kári , Hovig Eivind 
Published: March 2020

AbstractThe aim of the present study was to describe the genetic structure of the Norwegian population using genotypes from 6369 unrelated individuals with detailed information about places of residence. Using standard single marker- and haplotype-based approaches, we report evidence of two regions with distinctive patterns of genetic variation, one in the far northeast, and another in the south of Norway, as indicated by fixation indices, haplotype sharing, homozygosity and effective population size. We detect and quantify a component of Uralic Sami ancestry that is enriched in the North. On a finer scale, we find that rates of migration have been affected by topography like mountain ridges. In the broader Scandinavian context, we detect elevated relatedness between the mid- and northern border areas towards Sweden. The main finding of this study is that despite Norway’s long maritime history and as a former Danish territory, the region closest to mainland Europe in the south appears to have been the most isolated region in Norway, highlighting the open sea as a barrier to gene flow.
Arrayed CRISPRi and Quantitative Imaging Describe the Morphotypic Landscape of Essential Mycobacterial Genes
Authors: de Wet Timothy J. , Winkler Kristin R. , Mhlanga Musa M. , Mizrahi Valerie , Warner Digby F. 
Published: March 2020

ABSTRACTMycobacterium tuberculosispossesses a large number of genes of unknown or merely predicted function, undermining fundamental understanding of pathogenicity and drug susceptibility. To address this challenge, we developed a high-throughput functional genomics approach combining inducible CRISPR-interference and image-based analyses of morphological features and sub-cellular molecular localizations in the related non-pathogen,M. smegmatis. Applying automated imaging and analysis to an arrayed library of 272 essential gene knockdown mutants, we derive robust, quantitative descriptions of bacillary morphologies consequent on gene silencing. Leveraging statistical-learning, we demonstrate that functionally related genes cluster by morphotypic similarity and that this information can be used to infer gene function. Exploiting this observation, we reveal a previously unknown restriction-modification system, and identify filamentation as a defining mycobacterial response to histidine starvation. Our results support the application of large-scale image-based analyses for mycobacterial functional genomics, simultaneously establishing the utility of this approach for drug mechanism-of-action studies.
Mechanism-based inhibitors of SIRT2: structure–activity relationship, X-ray structures, target engagement, regulation of α-tubulin acetylation and inhibition of breast cancer cell migration
Authors: Nielsen Alexander L. , Rajabi Nima , Kudo Norio , Lundø Kathrine , Moreno-Yruela Carlos , Bæk Michael , Fontenas Martin , Lucidi Alessia , Madsen Andreas S. , Yoshida Minoru , Olsen Christian A. 
Published: March 2020

ABSTRACTSirtuin 2 (SIRT2) is a protein deacylase enzyme that removes acetyl groups and longer chain acyl groups from post-translationally modified lysine residues. It affects diverse biological functions in the cell and has been considered a drug target in relation to both neurodegenerative diseases and cancer. Therefore, access to well-characterized and robust tool compounds is essential for the continued investigation of the complex functions of this enzyme. Here, we report a collection of probes that are potent, selective, stable in serum, water-soluble, amenable to cell culture experiments, and inhibit both SIRT2 deacetylation and demyristoylation. Compared to the current landscape of SIRT2 inhibitors, this is a unique ensemble of features built into a single compound. We expect the developed chemotypes to find broad application in the interrogation of SIRT2 functions in both healthy and diseased cells, and to provide a foundation for the development of future therapeutics.
IDH1 Mutations Induce Organelle Defects Via Dysregulated Phospholipids
Authors: Lita Adrian , Pliss Artem , Kuzmin Andrey , Yamasaki Tomohiro , Zhang Lumin , Dowdy Tyrone , Burks Christina , de Val Natalia , Celiku Orieta , Ruiz-Rodado Victor , Nicoli Elena-Raluca , Kruhlak Michael , Andresson Thorkell , Das Sudipto , Yang Chunzhang , Schmitt Rebecca , Herold-Mende Christel , Gilbert Mark R. , Prasad Paras N. , Larion Mioara 
Published: March 2020

SummaryCytosolic IDH1 enzyme plays a key, but currently unexplored, role in lipid biosynthesis. Using Raman imaging microscopy, we identified heterogeneous lipid profiles in cellular organelles attributed uniquely to IDH1 mutations. Via organelle lipidomics, we found an increase in saturated and monounsaturated fatty acids in the endoplasmic reticulum of IDH1mutcells compared with IDHWTglioma. We showed that these fatty acids incorporate into phospholipids and induce organelle dysfunctions, with prominent dilation of Golgi apparatus, which can be restored by transient knockdown of stearyl-CoA desaturase or inhibition of D-2-hydroxyglutarate (D-2HG) formation. We validated these findings using tissue from patients with glioma. Oleic acid addition led to increased sensitivity to apoptosis of IDH1mutcells compared with IDHWT. Addition of D-2HG to U251WTcells lead in increased ER and Golgi apparatus dilation. Collectively, these studies provide clinically relevant insights into the functional link between IDH1mut-induced lipid alterations and organelle dysfunction, with therapeutic implications.SignificanceGliomas are devastating tumors, with the most aggressive form—glioblastoma multiforme— correlated with a mean patient survival of 14.5 months. No curative treatment exists to date. Low-grade glioma (LGG) with the isocitrate dehydrogenase 1 (IDH1) mutation, R132H, provides a survival benefit to patients. Understanding the unique metabolic profile of IDH1mutcould provide clues regarding its association with longer survival and information about therapeutic targets. Herein, we identified lipid imbalances in organelles, generated by IDHmutin cells and patient tissue, that were responsible for Golgi dilation and that correlated with increased survival. Addition of oleic acid, which tilted the balance towards elevated levels of monounsaturated fatty acids produced IDH1mut-specific cellular apoptosis.HighlightsSingle-organelle omics revealed unique alterations in lipid metabolism due to IDH1-mutations.IDH mutation leads to organelle-wide structural defects.IDH1 mutation leads to increased monounsaturated fatty acids levels in glioma cells and oligodendroglioma patient samples.Lipid alterations affect the membrane integrity of the Golgi apparatus.Increased D-2HG induced SCD expression and elevated monounsaturated fatty acidsTilting the balance toward more-abundant monounsaturated fatty acids leads to specific IDH1mutglioma apoptosis.
Metabolite Quantitative Trait Loci for flavonoids provide new insights into the genetic architecture of strawberry (Fragariaxananassa) fruit quality
Authors: Labadie Marc , Vallin Guillaume , Petit Aurélie , Ring Ludwig , Hoffmann Thomas , Gaston Amèlia , Potier Aline , Schwab Wilfried , Rothan Christophe , Denoyes Béatrice 
Published: March 2020

AbstractFlavonoids are products from specialized metabolism that contribute to fruit sensorial (colour) and nutritional (antioxidant properties) quality. Here, using a pseudo full-sibling F1progeny previously studied for fruit sensorial quality of cultivated strawberry (Fragariaxananassa), we explored over two successive years the genetic architecture of flavonoid-related traits using LC-ESI-MS (13 compounds including anthocyanins, flavonols and flavan-3-ols) and colorimetric assays (anthocyanins, flavonoids, phenolics, FRAP and TEAC antioxidant capacity). Network correlation analysis highlighted the high connectivity of flavonoid compounds within each chemical class and low correlation with colorimetric traits except anthocyanins. Mapping onto the female and male linkage maps of 152 flavonoid metabolic QTLs (mQTLs) and of 26 colorimetric QTLs indicated co-localization on few linkage groups of major flavonoid- and taste-related QTLs previously uncovered. These results pave the way for the discovery of genetic variations underlying flavonoid mQTLs and for marker-assisted selection of strawberry varieties with improved sensorial and nutritional quality.
The influence of the phylogenetic inference pipeline on murine antibody repertoire sequencing data following viral infection
Authors: Yermanos Alexander , Greiff Victor , Stadler Tanja , Oxenius Annette , Reddy Sai T. 
Published: March 2020

AbstractUnderstanding B cell evolution following vaccination or infection is crucial for instructing targeted immunotherapies when searching for potential therapeutic or virus-neutralizing antibodies. Antibody phylogenetics holds the potential to quantify both clonal selection and somatic hypermutation, two key players shaping B cell evolution. A wide range of bioinformatic pipelines and phylogenetic inference methods have been utilized on antibody repertoire sequencing datasets to delineate B cell evolution. Although the majority of B cell repertoire studies incorporate some aspect of antibody evolution, how the chosen computational methods affect the results is largely ignored. Therefore, we performed an extensive computational analysis on time-resolved antibody repertoire sequencing data to better characterize how commonly employed bioinformatic practices influence conclusions regarding antibody selection and evolution. Our findings reveal that different combinations of clonal lineage assignment strategies, phylogenetic inference methods, and biological sampling affect the inferred size, mutation rates, and topologies of B cell lineages in response to virus infection.
Area from image analyses accurately estimates dry-weight biomass of juvenile moss tissue
Authors: Burtscher Wesley P. , List Marna A. , Payton Adam C. , McDaniel Stuart F. , Carey Sarah B. 
Published: March 2020

SummaryMosses have long served as models for studying many areas of plant biology. Investigators have used two-dimensional measurements of juvenile growth from photographs as a surrogate for dry-weight biomass. The relationship between area and biomass, however, has not been critically evaluated.Here we grew axenic tissue cultures of tenCeratodon purpureusisolates to study the relationship between these parameters. We measured area and biomass on replicate cultures with two distinct starting inoculum sizes each week for three weeks and examined the correlation between area and biomass as well as the influence of variation in inoculum size on both parameters.We found a strong correlation between area and biomass after two weeks of growth. Furthermore, we found inoculum size affected biomass during the first week of growth but not subsequent weeks and inoculum size had no detectible effect on area.These analyses provide experimental confirmation that area is a suitable proxy for biomass and provide clear guidelines for when inoculum size variation may affect downstream growth estimates.
Motor neurons involved in fine motor control are labeled by tracingAtoh1-lineage neurons in the spinal cord
Authors: Ogujiofor Osita W. , Pop Iliodora V. , Espinosa Felipe , Durodoye Razaq O. , Viacheslavov Michael L. , Jarvis Rachel , Landy Mark A. , Fishell Gordon , Machold Robert P. , Lai Helen C. 
Published: March 2020

AbstractMotor neurons (MNs) innervating the digit muscles of the intrinsic hand and foot (IH and IF) control fine motor movements. Previous studies suggest that the IH and IF MN pools have a unique developmental history in comparison to limb MN pools. Consistent with having this unique development, we find that the IH and IF MN pools are labeled postnatally using a CRE knock-in mouse line ofAtoh1, a developmentally expressed basic helix-loop-helix (bHLH) transcription factor, while limb-innervating MN pools are not. Approximately 60% of the IH and IF MN pools are labeled and are a mixture of alpha and gamma-MNs. In addition, becauseAtoh1is known developmentally to specify many cerebellar-projecting neurons, we tested the hypothesis that IH and IF MNs can send axon collaterals to the cerebellum as a mechanism of corollary discharge. Using intersectional genetic, viral labeling, and retrograde labeling strategies, we were unable to provide evidence in support of this idea. As a secondary finding of our viral labeling experiments, we report here that injection of both AAV and Lentiviruses in the periphery can cross the blood-brain barrier to infect Purkinje cells within the central nervous system. Altogether, though, we find that labeling of the IH and IF motor neurons using theAtoh1CRE knock-in mouse suggests that IH and IF MNs have a unique developmental history and that this mouse strain might be a useful tool to target these specific sets of neurons allowing for functional studies of fine motor control.Significance StatementMotor neurons (MNs) of the intrinsic hand and foot (IH and IF) are labeled postnatally using a CRE knock-in mouse line of the basic helix-loop-helix (bHLH) transcription factorAtoh1indicating a unique developmental history. We tested whether IH and IF MNs send axon collaterals rostrally to the cerebellum as a mechanism of direct corollary discharge from MNs, but the question remains unresolved. As a resource for the community, we report that injection of both AAV and Lentiviruses in the periphery can cross the blood-brain barrier and infect Purkinje cells within the central nervous system.