bluuebunny/crossref_metadata_2025 huggingface dataset:
The balance of interaction types determines the assembly and stability of ecological communities
Authors: Qian Jimmy J. , Akçay Erol
Published: May 2019

What determines the assembly and stability of complex communities is a central question in ecology. Past work has suggested that mutualistic interactions are inherently destabilizing. However, this conclusion relies on assuming that benefits from mutualisms never stop increasing. Furthermore, almost all theoretical work focuses on the internal (asymptotic) stability of communities assembled all-at-once. Here, we present a model with saturating benefits from mutualisms and sequentially assembled communities. We show that such communities are internally stable for any level of diversity and any combination of species interaction types. External stability, or resistance to invasion, is thus an important but overlooked measure of stability. We demonstrate that the balance of different interaction types governs community dynamics. Mutualisms may increase external stability and diversity of communities as well as species persistence, depending on how benefits saturate. Ecological selection increases the prevalence of mutualisms, and limits on biodiversity emerge from species interactions. Our results help resolve longstanding debates on the stability, saturation, and diversity of communities.
Signatures of selection in a recent invasion reveals adaptive divergence in a highly vagile invasive species
Authors: Cardilini Adam P. A. , Stuart Katarina C. , Cassey Phillip , Richardson Mark F. , Sherwin William , Rollins Lee A. , Sherman Craig D.H.
Published: May 2019

A detailed understanding of population genetics in invasive populations helps us to identify drivers of successful introductions. Here, we investigate putative signals of selection in Australian populations of invasive common starlings,Sturnus vulgaris, and seek to understand how these have been influenced by introduction history. We use reduced representation sequencing to determine population structure, and identity Single Nucleotide Polymorphisms (SNPs) that are putatively under selection. We found that since their introduction into Australia, starling populations have become genetically differentiated despite the potential for high levels of dispersal, and that selection has facilitated their adaptation to the wide range of environmental conditions across their geographic range. Isolation by distance appears to have played a strong role in determining genetic substructure across the starling’s Australian range. Analyses of candidate SNPs that are putatively under selection indicate that aridity, precipitation, and temperature may be important factors driving adaptive variation across the starling’s invasive range in Australia. However, we also note that the historic introduction regime may leave footprints on sites flagged as being under adaptive selection, and encourage critical interpretation of selection analyses.
Genome-wide identification of long non-coding RNAs and their regulatory networks involved in Apis mellifera ligustica response to Nosema ceranae infection
Authors: Guo Rui , Chen Huazhi , Du Yu , Zhou Dingding , Geng Sihai , Wang Haipeng , Zhu Zhiwei , Shi Caiyun , Wan Jieqi , Xiong Cuiling , Zheng Yanzhen , Chen Dafu
Published: May 2019

Long non-coding RNAs (lncRNAs) are a diverse class of transcripts that structurally resemble mRNAs but do not encode proteins, and lncRNAs have been proved to play pivotal roles in a wide range of biological processes in animals and plants. However, knowledge of expression pattern and potential role of honeybee lncRNAs response to Nosema ceranae infection is completely unknown. Here, we performed whole transcriptome strand-specific RNA sequencing of normal midguts of Apis mellifera ligustica workers (Am7CK, Am10CK) and N. ceranae-inoculated midguts (Am7T, Am10T), followed by comprehensive analyses using bioinformatic and molecular approaches. A total of 6353 A. m. ligustica lncRNAs were identified, including 4749 conserved lncRNAs and 1604 novel lncRNAs. These lncRNAs had low sequence similarities with other known lncRNAs in other species; however, their structural features were similar with counterparts in mammals and plants, including shorter exon and intron length, lower exon number, and lower expression level, compared with protein-coding transcripts. Further, 111 and 146 N. ceranae-responsive lncRNAs were identified from midguts at 7 day post inoculation (dpi) and 10 dpi compared with control midguts. 12 differentially expressed lncRNAs (DElncRNAs) were shared by Am7CK vs Am7T and Am10CK vs Am10T comparison groups, while the numbers of unique ones were 99 and 134, respectively. Functional annotation and pathway analysis showed the DElncRNAs may regulate the expression of neighboring genes by acting in cis. Moreover, we discovered 27 lncRNAs harboring eight known miRNA precursors and 513 lncRNAs harboring 2257 novel miRNA precursors. Additionally, hundreds of DElncRNAs and their target miRNAs were found to form complex competitive endogenous RNA (ceRNA) networks, suggesting these DElncRNAs may act as miRNA sponges. Furthermore, DElncRNA-miRNA-mRNA networks were constructed and investigated, the result demonstrated that part of DElncRNAs were likely to participate in regulating the material and energy metabolism as well as cellular and humoral immune during host responses to N. ceranae invasion. Finally, the expression pattern of 10 DElncRNAs was validated using RT-qPCR, confirming the reliability of our sequencing data. Our findings revealed here offer not only a rich genetic resource for further investigation of the functional roles of lncRNAs involved in A. m. ligustica response to N. ceranae infection, but also a novel insight into understanding host-pathogen interaction during microsporidiosis of honeybee.
Isolation of a novel strain of Lactic Acid Bacteria from traditionally fermented common lime (Citrus aurantifolia) of Assam, India and analysis of exopolymeric substances produced by the strain
Authors: Borah Nabajyoti , Barman Arindam , Baishya Debabrat
Published: May 2019

A gram positive, rod shaped and catalase negative strain of Lactic Acid Bacteria was isolated from traditionally fermented common lime (Citrus aurantifolia) of Assam, North-East India. Bacterial identification was done by using conventional morphological and biochemical methods as well as advanced molecular technique. Traditionally fermented lime juice was serially diluted on selective culture medium and growth of translucent, ropy bacterial colony was observed in the culture plate. Isolated bacteria were identified up to species level by using ribosomal RNA (rRNA) gene sequencing technique. Based on nucleotide homology and phylogenetic analysis the isolate was found to be a strain ofLactobacillus delbrueckii. This is the first report of finding this sub species of Lactic Acid Bacteria in citrus fruit product. The sequence determined in this study has been deposited in the GenBank database with sequential accession numberKT198973.The bacterial isolate also produced exopolysaccharide when grown in chemically defined medium. Fourier Transform Infrared Spectroscopy (FTIR) was done for chemical and compositional characterization of partially purified exopolysaccharide.
Reading-out task variables as a low-dimensional reconstruction of neural spike trains in single trials
Authors: Koren Veronika , Andrei Ariana R. , Hu Ming , Dragoi Valentin , Obermayer Klaus
Published: May 2019

We propose a new model of the read-out of spike trains that exploits the multivariate structure of responses of neural ensembles. Assuming the point of view of a read-out neuron that receives synaptic inputs from a population of projecting neurons, synaptic inputs are weighted with a heterogeneous set of weights. We propose that synaptic weights reflect the role of each neuron within the population for the computational task that the network has to solve. In our case, the computational task is discrimination of binary classes of stimuli, and weights are such as to maximize the discrimination capacity of the network. We compute synaptic weights as the feature weights of an optimal linear classifier. Once weights have been learned, they weight spike trains and allow to compute the post-synaptic current that modulates the spiking probability of the read-out unit in real time. We apply the model on parallel spike trains from V1 and V4 areas in the behaving monkey macaca mulatta, while the animal is engaged in a visual discrimination task with binary classes of stimuli. The read-out of spike trains with our model allows to discriminate the two classes of stimuli, while population PSTH entirely fails to do so. Splitting neurons in two subpopulations according to the sign of the weight, we show that population signals of the two functional subnetworks are negatively correlated. Disentangling the superficial, the middle and the deep layer of the cortex, we show that in both V1 and V4, superficial layers are the most important in discriminating binary classes of stimuli.
A prospectively validated machine learning model for the prediction of survival and tumor subtype in pancreatic ductal adenocarcinoma
Authors: Kaissis Georgios , Ziegelmayer Sebastian , Lohöfer Fabian , Algül Hana , Eiber Matthias , Weichert Wilko , Schmid Roland , Friess Helmut , Rummeny Ernst , Ankerst Donna , Siveke Jens , Braren Rickmer
Published: May 2019

Purpose

To develop a supervised machine learning algorithm capable of predicting above vs. below-median overall survival from medical imaging-derived radiomic features in a cohort of patients with pancreatic ductal adenocarcinoma (PDAC).

Materials and Methods

102 patients with histopathologically proven PDAC were retrospectively assessed as the training cohort and 30 prospectively enrolled patients served as the external validation cohort. Tumors were segmented in pre-operative diffusion weighted-(DW)-MRI derived ADC maps and radiomic features were extracted. A Random Forest machine learning algorithm was fit to the training cohort and tested in the external validation cohort. The histopathological subtype of the tumor samples was assessed by immunohistochemistry in 21/30 patients of the external validation cohort. Individual radiomic feature importance was evaluated.

Results

The machine learning algorithm achieved a sensitivity of 87% and a specificity of 80% (ROC-AUC 90%) for the prediction of above- vs. below-median survival on the unseen data of the external validation cohort. Heterogeneity-related features were highly ranked by the model. Of the 21 patients for whom the histopathological subtype was determined, 8/9 patients predicted by the model to experience below-median overall survival exhibited the quasi-mesenchymal subtype, while 11/12 patients predicted to experience above-median survival exhibited a non-quasi-mesenchymal subtype (Fisher’s exact test P<0.001).

Conclusion

The application of machine-learning to the radiomic analysis of DW-MRI-derived ADC maps allowed the prediction of overall survival with high diagnostic accuracy in a prospectively collected cohort. The high overlap of clinically relevant histopathological subtypes with model predictions underlines the potential of quantitative imaging workflows in pre-operative subtyping and risk assessment in PDAC.
Morphology of the nervous system of monogonont rotiferEpiphanes sentawith focus on sexual dimorphism between feeding females and dwarfed males
Authors: Gąsiorowski Ludwik , Furu Anlaug , Hejnol Andreas
Published: May 2019

Background

Monogononta is a large clade of rotifers comprised of diverse morphological forms found in a wide range of ecological habitats. Most of the monogonont species display a cyclical parthenogenesis, where generations of asexually reproducing females are interspaced by mixis events when sexual reproduction occurs between mictic females and dwarfed, haploid males. The morphology of monogonont feeding females is relatively well described, however data on male anatomy are very limited. Thus far, male musculature of only two species has been described with confocal laser scanning microscopy (CLSM) and it remained unknown how dwarfism influences neuroanatomy of males.

Results

Here, we provide a CLSM-based description of the nervous system of both sexes ofEpiphanes senta, a freshwater monogonont rotifer. The general nervous system architecture is similar between males and females and shows same level of complexity. However, the nervous system in males is more compact and lacks its stomatogastric part.

Conclusion

Comparison of the neuroanatomy between male and normal-sized feeding females provides better understanding of the nature of male dwarfism in Monogononta. We propose that dwarfism of monogonont non-feeding males is a specific case of progenesis as they, due to their inability to feed, retain a juvenile body size. Reduction of the stomatogastric nervous system in the males correlates with the loss of entire digestive tract and associated morphological structures.
Environmental correlates of genetic variation in the invasive and largely panmictic European starling in North America
Authors: Hofmeister Natalie R. , Werner Scott J. , Lovette Irby J.
Published: May 2019

Populations of invasive species that colonize and spread in novel environments may differentiate both through demographic processes and local selection. European starlings (Sturnus vulgaris) were introduced to New York in 1890 and subsequently spread throughout North America, becoming one of the most widespread and numerous bird species on the continent. Genome-wide comparisons across starling individuals and populations can identify demographic and/or selective factors that facilitated this rapid and successful expansion. We investigated patterns of genomic diversity and differentiation using reduced-representation genome sequencing (ddRADseq) of 17 winter-season starling populations. Consistent with this species’ high dispersal rate and rapid expansion history, we found low geographic differentiation and few FST outliers even at a continental scale. Despite starting from a founding population of approximately 180 individuals, North American starlings show only a moderate genetic bottleneck, and models suggest a dramatic increase in effective population size since introduction. In genotype-environment associations we found that ∼200 single-nucleotide polymorphisms are correlated with temperature and/or precipitation against a background of negligible genome- and range-wide divergence. Local adaptation in North American starlings may have evolved rapidly even in this wide-ranging and evolutionarily young population. This survey of genomic signatures of expansion in North American starlings is the most comprehensive to date and complements ongoing studies of world-wide local adaptation in these highly dispersive and invasive birds.
Delta phase resets mediate non-rhythmic temporal prediction
Authors: Daume Jonathan , Wang Peng , Maye Alexander , Zhang Dan , Engel Andreas K.
Published: May 2019

The phase of neural oscillatory activity aligns to the predicted onset of upcoming stimulation. Whether such phase alignments represent phase resets of underlying neural oscillations or just rhythmically evoked activity, and whether they can be observed in a rhythm-free visual context, however, remains unclear. Here, we recorded the magnetoencephalogram while participants were engaged in a temporal prediction task judging the visual or tactile reappearance of a uniformly moving stimulus. The prediction conditions were contrasted with a control condition to dissociate phase adjustments of neural oscillations from stimulus-driven activity. We observed stronger delta band inter-trial phase consistency (ITPC) in a network of sensory, parietal and frontal brain areas, but no power increase reflecting stimulus-driven or prediction-related processes. Delta ITPC further correlated with prediction performance in the cerebellum and visual cortex. Our results provide evidence that phase alignments of low-frequency neural oscillations underlie temporal predictions in a non-rhythmic visual and crossmodal context.
Influenza-specific effector memory B cells predict long-lived antibody responses to vaccination in humans
Authors: Nellore Anoma , Zumaquero Esther , Scharer Christopher D. , King Rodney G. , Tipton Christopher M. , Fucile Christopher F. , Mi Tian , Mousseau Betty , Bradley John E. , Zhou Fen , Goepfert Paul A. , Boss Jeremy M. , Randall Troy D. , Sanz Ignacio , Rosenberg Alexander F. , Lund Frances E.
Published: May 2019

Seasonal influenza vaccination elicits hemagglutinin (HA)-specific CD27+ memory B cells (Bmem) that differ in expression of T-bet, BACH2 and TCF7. T-bethiBACH2loTCF7lo Bmem are transcriptionally similar to effector-like memory cells while T-betloBACH2+TCF7+ Bmem exhibit stem-like central memory properties. T-bethi Bmem do not express plasma cell-specific transcription factors but do exhibit transcriptional, epigenetic, metabolic and functional changes that poise the cells for antibody production. Consistent with these changes, D7 HA+ T-bethi Bmem express intracellular immunoglobulin and T-bethi Bmem differentiate more rapidly into ASCs in vitro. The T-bethi Bmem response positively correlates with long-lived humoral immunity and clonotypes from T-bethi Bmem are represented in the early secondary ASC response to repeat vaccination, suggesting that this effector-like population can be used to predict vaccine durability and recall potential.
Nanoscale dynamics of cholesterol in the cell membrane
Authors: Pinkwart Kerstin , Schneider Falk , Lukoseviciute Martyna , Sauka-Spengler Tatjana , Lyman Edward , Eggeling Christian , Sezgin Erdinc
Published: May 2019

Cholesterol constitutes approximately 30-40% of the mammalian plasma membrane — a larger fraction than any other single component. It is a major player in numerous signalling processes as well as molecular membrane architecture. However, our knowledge on dynamics of cholesterol in the plasma membrane is limited which restricts our understanding of the mechanisms regulating its involvement in cell signalling. Here, advanced fluorescence imaging and spectroscopy approaches were applied on in vitro (model membranes) and in vivo (live cells and embryos) membranes to systematically study the nanoscale dynamics of cholesterol in biological membranes. The results show that cholesterol diffuses faster than phospholipids in live membranes, but not in model membranes. The data indicate that diffusion of cholesterol and phospholipids is not correlated with membrane domain partitioning. Instead, our data show that the fast diffusion of cholesterol is due to its nanoscale interactions and localization in the membrane.
An omnidirectional visualization model of personalized gene regulatory networks
Authors: Chen Chixiang , Jiang Libo , Wang Ming , Wang Yaqun , Shen Biyi , Liu Zhenqiu , Wang Zuoheng , Hou Wei , Berceli Scott A. , Wu Rongling
Published: May 2019

Gene regulatory networks (GRNs) have been widely used as a fundamental tool to reveal the genomic mechanisms that underlie the organism’s response to environmental and developmental cues. Standard approaches infer GRNs as holistic graphs of gene co-expression, but such graphs cannot quantify how gene-gene interactions differentiate among organisms and how they alter structurally across spatiotemporal gradients. Here, we develop a generalized framework for inferring informative, dynamic, omnidirectional, and personalized GRNs (idopGRNs) from routine transcriptional experiments. This framework is constructed by a system of quasi-dynamic ordinary differential equations (qdODEs) derived from the combination of ecological and evolutionary theories. We reconstruct idopGRNs from a clinical genomic study and illustrate how network structure and organization affect surgical response to infrainguinal vein bypass grafting and the outcome of grafting. idopGNRs may shed light on genotype-phenotype relationships and provide valuable information for personalized medicine.
A fast microfluidic device to measure the deformability of red blood cells
Authors: Mehendale Ninad , Mitra Dhrubaditya , Paul Debjani
Published: May 2019

We report a microfluidic device to determine the shear elastic modulus and the Young’s modulus of red blood cells (RBCs). Our device consists of a single channel opening into a funnel, with a semi-circular obstacle placed at the mouth of the funnel. As a RBC passes the obstacle, it deflects from its original path. Using populations of artificially-stiffened RBCs, we show that the stiffer RBCs deflect more compared to the normal RBCs. We use calibration curves obtained from numerical simulations to map a trajectory of each RBC to its elastic constants. Our estimates of the shear elastic modulus and the Young’s modulus of normal RBCs are within the same range of values reported in the literature using AFM, optical tweezers and micropipette measurements. We also estimate indirectly the elongation index of normal and artificially hardened RBCs from their tracks, without any direct observation of their shapes. Finally, we sort a mixed population of RBCs based on their deformability alone. Our device could potentially be further miniaturized to sort and obtain the elastic constants of nanoscale objects, whose shape change is difficult to monitor by optical microscopy.
Algorithmic differentiation improves the computational efficiency of OpenSim-based optimal control simulations of movement
Authors: Falisse Antoine , Serrancolí Gil , Dembia Christopher L. , Gillis Joris , De Groote Friedl
Published: May 2019

Algorithmic differentiation (AD) is an alternative to finite differences (FD) for evaluating function derivatives. The primarily aim of this study was to demonstrate the computational benefits of using AD instead of FD in OpenSim-based optimal control simulations. The secondary aim was to evaluate computational choices including different AD tools, different linear solvers, and the use of first- or second-order derivatives. First, we enabled the use of AD in OpenSim through a custom source code transformation tool and through the operator overloading tool ADOL-C. Second, we developed an interface between OpenSim and CasADi to perform optimal control simulations. Third, we evaluated computational choices through simulations of perturbed balance, two-dimensional predictive simulations of walking, and three-dimensional tracking simulations of walking. We performed all simulations using direct collocation and implicit differential equations. Using AD through our custom tool was between 1.8 ± 0.1 and 17.8 ± 4.9 times faster than using FD, and between 3.6 ± 0.3 and 12.3 ± 1.3 times faster than using AD through ADOL-C. The linear solver efficiency was problem-dependent and no solver was consistently more efficient. Using second-order derivatives was more efficient for balance simulations but less efficient for walking simulations. The walking simulations were physiologically realistic. These results highlight how the use of AD drastically decreases computational time of optimal control simulations as compared to more common FD. Overall, combining AD with direct collocation and implicit differential equations decreases the computational burden of optimal control simulations, which will facilitate their use for biomechanical applications.
Reversible Pulmonary Trunk Banding. XI: Myocardial Vascular Endothelial Growth Factor Expression in Young Goats Submitted to Ventricular Retraining
Authors: Assad Renato S. , Rocha Eduardo A. V. , Aiello Vera D. , Meniconi Tiago A. , Abduch Maria C. D. , Thomaz Petronio G. , Jatene Marcelo B. , Moreira Luiz F. P.
Published: May 2019

Background

Ventricle retraining has been extensively studied by our laboratory. Previous studies have demonstrated that intermittent overload causes a more efficient ventricular hypertrophy. The adaptive mechanisms involved in the ventricle retraining are not completely established. This study assessed vascular endothelial growth factor (VEGF) expression in the ventricles of goats submitted to systolic overload.

Methods

Twenty-one young goats were divided into 3 groups (7 animals each): control, 96-hour continuous systolic overload, and intermittent systolic overload (four 12-hour periods of systolic overload paired with 12-hour resting period). During the 96-hour protocol, systolic overload was adjusted to achieve a right ventricular (RV) / aortic pressure ratio of 0.7. Hemodynamic evaluations were performed daily before and after systolic overload. Echocardiograms were obtained preoperatively and at protocol end to measure cardiac masses thickness. At study end, the animals were killed for morphologic evaluation and immunohistochemical assessment of VEGF expression.

Results

RV-trained groups developed hypertrophy of RV and septal masses, confirmed by increased weight and thickness, as expected. In the study groups, there was a small but significantly increased water content of the RV and septum compared with those in the control group (p<0.002). VEGF expression in the RV myocardium was greater in the intermittent group (2.89% ± 0.41%) than in the continuous (1.80% ± 0.19%) and control (1.43% ± 0.18%) groups (p<0.023).

Conclusions

Intermittent systolic overload promotes greater upregulation of VEGF expression in the subpulmonary ventricle, an adaptation that provides a mechanism for increased myocardial perfusion during the rapid myocardial hypertrophy of young goats.
Actin protrusions push on E-cadherin to maintain epithelial cell-cell adhesion
Authors: Li John Xiao He , Tang Vivian W. , Brieher William M.
Published: May 2019

Cadherin mediated cell-cell adhesion is actin dependent, but the precise role of actin in maintaining cell-cell adhesion is not fully understood. Actin polymerization-dependent protrusive activity is required to push distally separated cells close enough together to initiate contact. Whether protrusive activity is required to maintain adhesion in confluent sheets of epithelial cells is not known. By electron microscopy as well as live cell imaging, we have identified a population of protruding actin microspikes that operate continuously near apical junctions of polarized MDCK cells. Live imaging shows that microspikes containing E-cadherin extend into gaps between E-cadherin clusters on neighboring cells while reformation of cadherin clusters across the cell-cell boundary triggers microspike withdrawal. We identify Arp2/3, EVL, and CRMP-1 as three actin assembly factors necessary for microspike formation. Depleting these factors from cells using RNAi results in myosin II-dependent unzipping of cadherin adhesive bonds. Therefore, actin polymerization-dependent protrusive activity operates continuously at cadherin cell-cell junctions to keep them shut and to prevent myosin II-dependent contractility from tearing cadherin adhesive contacts apart.
The molecular determinants of R-roscovitine block of hERG channels
Authors: Cernuda Bryan , Fernandes Christopher , Allam Salma , Orzillo Matthew , Suppa Gabrielle , Chia Chang Zuleen , Athanasopoulos Demosthenes , Buraei Zafir
Published: May 2019

Human ether-à-go-go-related gene (Kv11.1, or hERG) is a potassium channel that conducts the delayed rectifier potassium current (IKr) during the repolarization phase of cardiac action potentials. hERG channels have a larger pore than other K+channels and can trap many unintended drugs, often resulting in acquired LQTS (aLQTS). R-roscovitine, a cyclin-dependent kinase (CDK) inhibitor that also inhibits L-type calcium channels, inhibits open hERG channels but does not become trapped in the pore. Two-electrode voltage clamp recordings from Xenopus oocytes expressing wild-type (WT) or mutant (T623A, S624A, Y652A, F656A) hERG channels demonstrated that, compared to WT hERG, T623A, Y652A, and F656A inhibition by 200 μM R-roscovitine was ~ 48 %, 29 %, and 73 % weaker, respectively. In contrast, S624A hERG was inhibited more potently than WT hERG, with an ~ 34 % stronger inhibition. These findings were further supported by the IC50 values, which were increased for T623A, Y652A and F656A (by ~5.5, 2.75, and 42 fold respectively) and reduced 1.3 fold for the S624A mutant. Our data suggest that while T623, Y652, and F656 are critical for R-roscovitine-mediated inhibition, S624 may not be. This relatively unique feature, coupled with R-roscovitine’s tolerance in clinical trials, could guide future drug screens. We discuss our findings and how they lend support for the recent Comprehensive In Vitro Proarrhythmia Assay (CiPA) guidelines on the re-evaluation of potentially useful drugs that had failed testing due to unintended interactions with hERG.
Transplanted cells are essential for the induction but not the expression of cortical plasticity
Authors: Hoseini Mahmood S. , Rakela Benjamin , Flores-Ramirez Quetzal , Hasenstaub Andrea R. , Alvarez-Buylla Arturo , Stryker Michael P.
Published: May 2019

Transplantation of even a small number of embryonic inhibitory neurons from the medial ganglionic eminence (MGE) into postnatal visual cortex makes it lose responsiveness to an eye deprived of vision when the transplanted neurons reach the age of the normal critical period of activity-dependent ocular dominance (OD) plasticity. The transplant might induce OD plasticity in the host circuitry or might instead construct a parallel circuit of its own to suppress cortical responses to the deprived-eye. We transplanted MGE neurons expressing archaerhodopsin, closed one eyelid for 4-5 days, and, as expected, observed transplant-induced OD plasticity. This plasticity was evident even when the activity of the transplanted cells was suppressed optogenetically, demonstrating that the plasticity was produced by changes in the host visual cortex.

Significance Statement

Interneuron transplantation into mouse V1 creates a window of heightened plasticity which is quantitatively and qualitatively similar to the normal critical period, i.e. short-term occlusion of either eye markedly changes ocular dominance. The underlying mechanism of this process is not known. Transplanted interneurons might either form a separate circuit to maintain the ocular dominance shift or might instead trigger changes in the host circuity. We designed experiments to distinguish the two hypotheses. Our findings suggest that while inhibition produced by the transplanted cells triggers this form of plasticity, the host circuity is entirely responsible for maintaining the ocular dominance shift.

One Sentence Summary

Neuronal transplants do not just grow and connect—they induce plasticity in the adult brain.
A comparison of automatic cell identification methods for single-cell RNA-sequencing data
Authors: Abdelaal Tamim , Michielsen Lieke , Cats Davy , Hoogduin Dylan , Mei Hailiang , Reinders Marcel J.T. , Mahfouz Ahmed
Published: May 2019

Background

Single cell transcriptomics are rapidly advancing our understanding of the cellular composition of complex tissues and organisms. A major limitation in most analysis pipelines is the reliance on manual annotations to determine cell identities, which are time-consuming and irreproducible. The exponential growth in the number of cells and samples has prompted the adaptation and development of supervised classification methods for automatic cell identification.

Results

Here, we benchmarked 20 classification methods that automatically assign cell identities including single cell-specific and general-purpose classifiers. The methods were evaluated using eight publicly available single cell RNA-sequencing datasets of different sizes, technologies, species, and complexity. The performance of the methods was evaluated based on their accuracy, percentage of unclassified cells, and computation time. We further evaluated their sensitivity to the input features, their performance across different annotation levels and datasets. We found that most classifiers performed well on a variety of datasets with decreased accuracy for complex datasets with overlapping classes or deep annotations. The general-purpose SVM classifier has overall the best performance across the different experiments.

Conclusions

We present a comprehensive evaluation of automatic cell identification methods for single cell RNA-sequencing data. All the code used for the evaluation is available on GitHub (https://github.com/tabdelaal/scRNAseq_Benchmark). Additionally, we provide a Snakemake workflow to facilitate the benchmarking and to support extension of new methods and new datasets (https://github.com/tabdelaal/scRNAseq_Benchmark/tree/snakemake_and_docker).
Two different pathways for initiation ofTrichoderma reeseiRad51-only meiotic recombination
Authors: Li Wan-Chen , Chuang Yu-Chien , Chen Chia-Ling , Timofejeva Ljudmilla , Pong Wen-Li , Chen Yu-Jie , Wang Chih-Li , Wang Ting-Fang
Published: May 2019

Background

Meiotic recombination is mainly, but not exclusively, initiated by Spo11-induced double strand breaks (DSBs) in some sexual eukaryotes. DSBs are repaired by one or two RecA-like recombinases (ubiquitous Rad51 and meiosis-specific Dmc1). In yeast and mammals, Dmc1 is superior to Rad51 in tolerating mismatched sequences during highly polymorphic hybrid meiosis. The mechanisms underlying Rad51-only meiotic recombination remain less studied.

Results

The Rad51-only filamentous fungusTrichoderma reeseihas only onespo11gene. Removal ofspo11fromT. reeseigenome does not affect normal sexual development, meiosis or chromosome synapsis, but results in decrease of interhomolog recombination products to 70%, crossover homeostasis and lower genetic interference. Our results also suggest thatT. reeseiRad51, like yeast and mammalian Dmc1 (but not Rad51), can tolerate mismatched sequences during meiotic recombination. Moreover, Topoisomerase II might act redundantly (and predominantly) with Spo11 to initiate meiotic recombination.

Conclusion

We suggest thatT. reeseiis an emerging model for studying Spo11-independent and Rad51-only meiosis.
In vitrocharacterization of the yeast DcpS, a scavenger mRNA decapping enzyme
Authors: Wulf Madalee G. , Buswell John , Chan Siu-Hong , Dai Nan , Marks Katherine , Martin Evan R. , Tzertzinis George , Whipple Joseph M. , Corrêa Ivan R. , Schildkraut Ira
Published: May 2019

Eukaryotic mRNAs are modified at their 5’ end early during transcription by the addition ofN7-methylguanosine (m7G), which forms the “cap” on the first 5’ nucleotide. Identification of the 5’ nucleotide on mRNA is necessary for determination of the Transcription Start Site (TSS). We explored the effect of various reaction conditions on the activity of the yeast scavenger mRNA decapping enzyme DcpS (yDcpS) and examined decapping of 30 chemically distinct cap structures varying the state of methylation, sugar, phosphate linkage, and base composition on 25mer RNA oligonucleotides. Contrary to the generally accepted belief that DcpS enzymes only decap short oligonucleotides, we found that yDcpS efficiently decaps RNA transcripts as long as 1400 nucleotides. Further, we validated the application of yDcpS for enriching capped RNA using a strategy of specifically tagging the 5’ end of capped RNA by first decapping and then recapping it with an affinity-tagged guanosine nucleotide.
Genome-wide mapping and profiling of γH2AX binding hotspots in response to different replication stress inducers
Authors: Lyu Xinxing , Chastain Megan , Chai Weihang
Published: May 2019

Background

Replication stress (RS) gives rise to DNA damage that threatens genome stability. RS can originate from different sources that stall replication by diverse mechanisms. However, the mechanism underlying how different types of RS contribute to genome instability is unclear, in part due to the poor understanding of the distribution and characteristics of damage sites induced by different RS mechanisms.

Results

We use ChIP-seq to map γH2AX binding sites genome-wide caused by aphidicolin (APH), hydroxyurea (HU), and methyl methanesulfonate (MMS) treatments in human lymphocyte cells. Mapping of γH2AX ChIP-seq reveals that APH, HU, and MMS treatments induce non-random γH2AX chromatin binding at discrete regions, suggesting that there are γH2AX binding hotspots in the genome. Characterization of the distribution and sequence/epigenetic features of γH2AX binding sites reveals that the three treatments induce γH2AX binding at largely non-overlapping regions, suggesting that RS may cause damage at specific genomic loci in a manner dependent on the fork stalling mechanism. Nonetheless, γH2AX binding sites induced by the three treatments share common features including compact chromatin, coinciding with larger-than-average genes, and depletion of CpG islands and transcription start sites. Moreover, we observe significant enrichment of SINEs in γH2AX sites in all treatments, indicating that SINEs may be a common barrier for replication polymerases.

Conclusions

Our results identify the location and common features of genome instability hotspots induced by different types of RS, and help in deciphering the mechanisms underlying RS-induced genetic diseases and carcinogenesis.
Gating Mechanism of β-Ketoacyl-ACP Synthases
Authors: Mindrebo Jeffrey T. , Patel Ashay , Kim Woojoo E. , Davis Tony D. , Chen Aochiu , Bartholow Thomas G. , La Clair James J. , McCammon J. Andrew , Noel Joseph P. , Burkart Michael D.
Published: May 2019

Formation of carbon-carbon bonds via β-ketoacyl-acyl carrier protein (ACP) synthases (KS), are key reactions duringde novofatty acid and polyketide biosynthesis. KSs recognize multiple ACPs and choreograph ping-pong mechanisms often in an iterative fashion. Therefore, KSs must limit non-productive protein-protein interactions (PPIs) to achieve high degrees of reaction fidelity. To better understand the stereochemical features governing substrate discrimination during ACP•KS PPIs, we determined x-ray crystal structures complemented by molecular dynamic simulations ofE. coliAcpP in complex with the elongating KSs, FabF and FabB. Covalently trapped substrate analogs were used to interrogate critical catalytic events accompanying carbon-carbon bond formation revealing a previously unknown gating mechanism during the binding and delivery of acyl-AcpPs. Two active site loops undergo large conformational excursions during this dynamic gating mechanism and are likely evolutionarily conserved features generally in elongating KSs.
A theory of learning to infer
Authors: Dasgupta Ishita , Schulz Eric , Tenenbaum Joshua B. , Gershman Samuel J.
Published: May 2019

Bayesian theories of cognition assume that people can integrate probabilities rationally. However, several empirical findings contradict this proposition: human probabilistic inferences are prone to systematic deviations from optimality. Puzzlingly, these deviations sometimes go in opposite directions. Whereas some studies suggest that people under-react to prior probabilities (base rate neglect), other studies find that people under-react to the likelihood of the data (conservatism). We argue that these deviations arise because the human brain does not rely solely on a general-purpose mechanism for approximating Bayesian inference that is invariant across queries. Instead, the brain is equipped with a recognition model that maps queries to probability distributions. The parameters of this recognition model are optimized to get the output as close as possible, on average, to the true posterior. Because of our limited computational resources, the recognition model will allocate its resources so as to be more accurate for high probability queries than for low probability queries. By adapting to the query distribution, the recognition model “learns to infer.” We show that this theory can explain why and when people under-react to the data or the prior, and a new experiment demonstrates that these two forms of under-reaction can be systematically controlled by manipulating the query distribution. The theory also explains a range of related phenomena: memory effects, belief bias, and the structure of response variability in probabilistic reasoning. We also discuss how the theory can be integrated with prior sampling-based accounts of approximate inference.
Differential genomic and transcriptomic events associated with high-grade transformation of Chronic Lymphocytic Leukemia
Authors: Klintman Jenny , Stamatopoulos Basile , Ridout Katie , Eyre Toby A. , Pascua Laura Lopez , Appleby Niamh , Knight Samantha J. L. , Dreau Helene , Popitsch Niko ,   The HICF2 Consortium, Ehinger Mats , Martín-Subero Jose I. , Campo Elias , Månsson Robert , Rossi Davide , Taylor Jenny C. , Vavoulis Dimitrios V. , Schuh Anna
Published: May 2019

The transformation of chronic lymphocytic leukemia (CLL) to high-grade diffuse large B-cell lymphoma (DLBCL), also called Richter’s Syndrome (RS), is a rare cancer with dismal prognosis. Drug discovery for RS is hampered by the lack of suitable experimental models, and effective therapies remain elusive rendering RS an area of high unmet clinical need. We performed whole genome sequencing (WGS) to interrogate paired CLL and RS samples from 17 patients enrolled in a prospective multicenter Phase 2 clinical trial (CHOP-OR) and we found that subclones affected by mutations in MAPK and PI3K pathways show a high expansion probability during transformation. We also demonstrate for the first time that non-coding mutation clusters in aPAX5enhancer, situated 330kb upstream from the transcription initiation site, correlate with transformation. Finally, we confirm our findings by employing targeted DNA sequencing (TGS) and RNA expression profiling on an extended cohort of 38 patients.

Statement of significance

Through integrated analysis of WGS, TGS and RNA expression data, we identified drivers of transformation not previously implicated in RS, which can be targeted therapeutically and tested in the clinic. Our results have informed the design of a new clinical platform study, which is now open to recruitment in the UK.
Reproducible data management and analysis using R
Authors: Fjukstad Bjørn , Shvetsov Nikita , Nøst Therese H. , Bøvelstad Hege , Halbach Till , Holsbø Einar , Hansen Knut , Lund Eiliv , Bongo Lars Ailo
Published: May 2019

Background

Standardizing and documenting computational analyses are necessary to ensure reproducible results. It is especially important for large and complex projects where data collection, analysis, and interpretation may span decades. Our objective is therefore to provide methods, tools, and best practice guidelines adapted for analyses in epidemiological studies that use -omics data.

Results

We describe an R-based implementation of data management and preprocessing. The method is well-integrated with the analysis tools typically used for statistical analysis of -omics data. We document all datasets thoroughly and use version control to track changes to both datasets and code over time. We provide a web application to perform the standardized preprocessing steps for gene expression datasets. We provide best practices for reporting data analysis results and sharing analyses.

Conclusion

We have used these tools to organize data storage and documentation, and to standardize the analysis of gene expression data, in the Norwegian Women and Cancer (NOWAC) system epidemiology study. We believe our approach and lessons learned are applicable to analyses in other large and complex epidemiology projects.
Hybridization drives genetic erosion in sympatric desert fishes of western North America
Authors: Chafin Tyler K. , Douglas Marlis R. , Martin Bradley T. , Douglas Michael E.
Published: May 2019

Many species have evolved or currently coexist in sympatry due to differential adaptation in a heterogeneous environment. However, anthropogenic habitat modifications can either disrupt reproductive barriers or obscure environmental conditions which underlie fitness gradients. In this study, we evaluated the potential for an anthropogenically-mediated shift in reproductive boundaries that separate two historically sympatric fish species (Gila cyphaandG. robusta) endemic to the Colorado River Basin using ddRAD sequencing of 368 individuals. We first examined the integrity of reproductive isolation while in sympatry and allopatry, then characterized hybrid ancestries using genealogical assignment tests. We tested for localized erosion of reproductive isolation by comparing site-wise genomic clines against global patterns and identified a breakdown in the drainage-wide pattern of selection against interspecific heterozygotes. This, in turn, allowed for the formation of a hybrid swarm in one tributary, and asymmetric introgression where species co-occur. We also detected a weak but significant relationship between genetic purity and degree of consumptive water removal, suggesting a role for anthropogenic habitat modifications in undermining species boundaries. In addition, results from basin-wide genomic clines suggested that hybrids and parental forms are adaptively non-equivalent. If so, then a failure to manage for hybridization will exacerbate the long-term extinction risk in parental populations. These results reinforce the role of anthropogenic habitat modification in promoting interspecific introgression in sympatric species by relaxing divergent selection. This, in turn, underscores a broader role for hybridization in decreasing global biodiversity within rapidly deteriorating environments.
Npas1+-Nkx2.1+Neurons Are an Integral Part of the Cortico-pallido-cortical Loop
Authors: Abecassis Zachary A. , Berceau Brianna L. , Win Phyo H. , Garcia Daniela , Xenias Harry S. , Cui Qiaoling , Pamucku Arin , Cherian Suraj , Hernández Vivian M. , Chon Uree , Lim Byung Kook , Justice Nicholas J. , Awatramani Raj , Kim Yongsoo , Hooks Bryan M. , Gerfen Charles R. , Boca Simina M. , Chan C. Savio
Published: May 2019

Within the basal ganglia circuit, the external globus pallidus (GPe) is critically involved in motor control. Aside from Foxp2+neurons and ChAT+neurons that have been established as unique neuron types, there is little consensus on the classification of GPe neurons. Properties of the remaining neuron types are poorly-defined. In this study, we leverage new mouse lines, viral tools, and molecular markers to better define GPe neuron subtypes. We found that Sox6 represents a novel, defining marker for GPe neuron subtypes. Lhx6+neurons that lack the expression of Sox6 were devoid of both parvalbumin and Npas1. This result confirms previous assertions of the existence of a unique Lhx6+population. Neurons that arise from the Dbx1+lineage were similarly abundant in the GPe and displayed a heterogeneous makeup. Importantly, tracing experiments revealed that Npas1+-Nkx2.1+neurons represent the principal non-cholinergic, cortically-projecting neurons. In other words, they form the pallido-cortical arm of the cortico-pallido-cortical loop. Our data further described that pyramidal-tract neurons in the cortex collateralized within the GPe, forming a closed-loop system between the two brain structures. Overall, our findings reconcile some of the discrepancies that arose from differences in techniques or the reliance on pre-existing tools. While spatial distribution and electrophysiological properties of GPe neurons reaffirm the diversification of GPe subtypes, statistical analyses strongly support the notion that these neuron subtypes can be categorized under the two principal neuron classes—i.e., PV+neurons and Npas1+neurons.

Significance statement

The poor understanding of the neuronal composition in the GPe undermines our ability to interrogate its precise behavioral and disease involvements. In this study, twelve different genetic crosses were used, hundreds of neurons were electrophysiologically-characterized, and over 100,000 neurons were histologically- and/or anatomically-profiled. Our current study further establishes the segregation of GPe neuron classes and illustrates the complexity of GPe neurons in adult mice. Our results support the idea that Npas1+-Nkx2.1+neurons are a distinct GPe neuron subclass. By providing a detailed analysis of the organization of the cortico-pallidal-cortical projection, our findings establish the cellular and circuit substrates that can be important for motor function and dysfunction.