bluuebunny/crossref_metadata_2025 huggingface dataset:
A neural algorithm for a fundamental computing problem
Authors: Dasgupta Sanjoy , Stevens Charles F. , Navlakha Saket
Published: August 2017

Similarity search, such as identifying similar images in a database or similar documents on the Web, is a fundamental computing problem faced by many large-scale information retrieval systems. We discovered that the fly’s olfac-tory circuit solves this problem using a novel variant of a traditional computer science algorithm (calledlocality-sensitive hashing). The fly’s circuit assigns similar neural activity patterns to similar input stimuli (odors), so that behav-iors learned from one odor can be applied when a similar odor is experienced. The fly’s algorithm, however, uses three new computational ingredients that depart from traditional approaches. We show that these ingredients can be translated to improve the performance of similarity search compared to tra-ditional algorithms when evaluated on several benchmark datasets. Overall, this perspective helps illuminate the logic supporting an important sensory function (olfaction), and it provides a conceptually new algorithm for solving a fundamental computational problem.
The 10,000 Immunomes Project: A resource for human immunology
Authors: Zalocusky Kelly A. , Kan Matthew J. , Hu Zicheng , Dunn Patrick , Thomson Elizabeth , Wiser Jeffrey , Bhattacharya Sanchita , Butte Atul J.
Published: August 2017

New immunological assays now enable rich measurements of human immune function, but difficulty attaining enough measurements across sufficiently large and diverse cohorts has hindered describing normal human immune physiology on a large scale. Here we present the 10,000 Immunomes Project (10KIP), a diverse human immunology reference derived from over 44,000 individuals across 242 studies from ImmPort, a publicly available resource of raw immunology study data and protocols. We carefully curated datasets, aggregating subjects from healthy/control arms and harmonizing data across studies. We demonstrate 10KIP’s utility by describing variations in serum cytokines and leukocytes by age, race, and sex; defining a baseline cell-cytokine network; and using 10KIP as a common control to describe immunologic changes in pregnancy. Subject-level data is available for interactive visualization and download athttp://10kImmunomes.org/. We believe 10KIP can serve as a common control cohort and will accelerate hypothesis generation by clinical and basic immunologists across diverse populations.

One Sentence Summary

An open online resource of human immunology data from more than 10,000 normal subjects including interactive data visualization and download enables a new look at immune system differences across age and sex, rapid hypothesis generation, and creation of custom control cohorts.
MicroRNAs from the parasitic plantCuscuta campestristarget host messenger RNAs
Authors: Shahid Saima , Kim Gunjune , Johnson Nathan R. , Wafula Eric , Wang Feng , Coruh Ceyda , Bernal-Galeano Vivian , Phifer Tamia , dePamphilis Claude W. , Westwood James H. , Axtell Michael J.
Published: August 2017

First paragraph

Dodders (Cuscutaspp.) are obligate parasitic plants that obtain water and nutrients from the stems of host plants via specialized feeding structures called haustoria. Dodder haustoria facilitate bi-directional movement of viruses, proteins, and mRNAs between host and parasite1, but the functional effects of these movements are not clear. Here we show thatC. campestrishaustoria accumulate high levels of many novel microRNAs (miRNAs) while parasitizingArabidopsis thalianahosts. Many of these miRNAs are 22 nts long, a usually rare size of plant miRNA associated with amplification of target silencing through secondary small interfering RNA (siRNA) production2. SeveralA. thalianamRNAs are targeted byC. campestris22 nt miRNAs during parasitism, resulting in mRNA cleavage, secondary siRNA production, and decreased mRNA accumulation levels. Hosts with mutations in two of the targets supported significantly higher growth ofC. campestris.Homologs of target mRNAs from diverse plants also have predicted target sites to inducedC. campestrismiRNAs, and the same miRNAs are expressed and active against host targets whenC. campestrisparasitizes a different host,Nicotiana benthamiana. These data show thatC. campestrismiRNAs act astrans-species regulators of host gene expression, and suggest that they may act as virulence factors during parasitism.
Stable representation of sounds in the posterior striatum during flexible auditory decisions
Authors: Guo Lan , Walker William I. , Ponvert Nicholas D. , Penix Phoebe L. , Jaramillo Santiago
Published: August 2017

The neuronal pathways that link sounds to rewarded actions remain elusive. It is unclear whether neurons in the posterior tail of the dorsal striatum (which receive direct input from the auditory system) mediate action selection, as other striatal circuits do. Here, we examined the role of posterior striatal neurons in auditory decisions in mice. We found that, in contrast to the anterior dorsal striatum, activation of the posterior striatum did not elicit systematic movement. However, activation of posterior striatal neurons during sound presentation in an auditory discrimination task biased the animals’ choices, and transient inactivation of these neurons largely impaired sound discrimination. Moreover, the activity of these neurons reliably encoded stimulus features, but was only minimally influenced by the animals’ choices. Our results suggest that posterior striatal neurons play an essential role in auditory decisions, yet these neurons provide sensory information downstream rather than motor commands during well-learned sound-driven tasks.
Ventral hippocampal CA1 and CA3 differentially mediate learned approach-avoidance conflict processing
Authors: Schumacher Anett , Villaruel Franz R. , Riaz Sadia , Lee Andy C. H. , Ito Rutsuko
Published: August 2017

The ventral hippocampus is thought to play a key role in the resolution of approach-avoidance conflict, a scenario that arises when stimuli with opposing valences are present simultaneously. Little is known, however, about the contributions of specific hippocampal sub-regions in this process, a critical issue given the functional and anatomical heterogeneity of this structure. Using a non-spatial cue-based paradigm in rats, we found that transient pharmacological inactivation of ventral CA1 produced an avoidance of a conflict cue imbued with both learned positive and negative outcomes, whereas inactivation of the ventral CA3 resulted in the opposite pattern of behavior, with significant preference for the conflict cue. In contrast, dorsal CA1- and CA3- inactivated rats showed no change in conflict behavior. Our findings provide important insight into the functions and circuitry of the ventral hippocampus by demonstrating that the ventral CA1 and CA3 subserve distinct and opposing roles in approach-avoidance conflict processing.

Grant sponsor

Natural Science and Engineering Research Council (N.S.E.R.C) of Canada awarded to RI (402642) and ACHL (402651).
Low Perfusion Compartments in Glioblastoma Quantified by Advanced Magnetic Resonance Imaging and Correlated with Patient Survival
Authors: Li Chao , Yan Jiun-Lin , Torheim Turid , McLean Mary A. , Boonzaier Natalie R. , Huang Yuan , Yuan Jianmin , Van Dijken Bart RJ , Matys Tomasz , Markowetz Florian , Price Stephen J.
Published: August 2017

Background

Glioblastoma exhibits profound intratumoral heterogeneity in blood perfusion, which may cause inconsistent therapy response. Particularly, low perfusion may create hypoxic microenvironment and induce resistant clones. Thus, developing validated imaging approaches that define low perfusion compartments is crucial for clinical management.

Methods

A total of 112 newly-diagnosed supratentorial glioblastoma patients were prospectively recruited for maximal safe resection. Preoperative MRI included anatomical, dynamic susceptibility contrast (DSC), diffusion tensor imaging (DTI) and chemical shift imaging (CSI). The apparent diffusion coefficient (ADC) and relative cerebral blood volume (rCBV) were calculated from DTI and DSC respectively. Using thresholding methods, two low perfusion compartments (ADCH-rCBVLand ADCL-rCBVL) were identified. Volumetric analysis was performed. Lactate and macromolecule/lipid levels were determined from multivoxel spectroscopy. Progression-free survival (PFS) and overall survival (OS) were analysed using Kaplan-Meier and multivariate Cox regression analyses.

Results

Two compartments displayed higher lactate and macromolecule/lipid levels than normal controls (eachP< 0.001), suggesting hypoxic and pro-inflammatory microenvironment. The proportional volume of ADCL-rCBVLcompartment was associated with a larger infiltration area (P< 0.001, rho = 0.42). Lower lactate in this compartment was associated with a less invasive phenotype visualized on DTI. Multivariate Cox regression showed higher lactate level in the ADCL-rCBVLcompartment was associated with a worse survival (PFS: HR 2.995,P= 0.047; OS: HR 4.974,P= 0.005).

Conclusions

The ADCL-rCBVLcompartment represent a treatment resistant sub-region associated with glioblastoma invasiveness. This approach was based on clinically available imaging modalities and could thus provide crucial pretreatment information for clinical decision making.
Predictive feedback to V1 dynamically updates with sensory input
Authors: Edwards Grace , Vetter Petra , McGruer Fiona , Petro Lucy S. , Muckli Lars
Published: August 2017

Predictive coding theories propose that the brain creates internal models of the environment to predict upcoming sensory input. Hierarchical predictive coding models of vision postulate that higher visual areas generate predictions of sensory inputs and feed them back to early visual cortex. In V1, sensory inputs that do not match the predictions lead to amplified brain activation, but does this amplification process dynamically update to new retinotopic locations with eye-movements? We investigated the effect of eye-movements in predictive feedback using functional brain imaging and eye-tracking whilst presenting an apparent motion illusion. Apparent motion induces an internal model of motion, during which sensory predictions of the illusory motion feed back to V1. We observed attenuated BOLD responses to predicted stimuli at the new post-saccadic location in V1. Therefore, pre-saccadic predictions update their retinotopic location in time for post-saccadic input, validating dynamic predictive coding theories in V1.
Synthesis, secretion, and perception of abscisic acid regulates stress responses inChlorella sorokiniana
Authors: Khasin Maya , Cahoon Rebecca E. , Alvarez Sophie , Beckeris Richard , Eyun Seong-il , Jia Qidong , Riethoven Jean-Jack , Nickerson Kenneth W. , Riekhof Wayne R.
Published: August 2017

Abscisic acid (ABA) is a phytohormone that has been extensively characterized in higher plants for its roles in seed and bud dormancy, leaf abscission, and stress responses. Genomic studies have identified orthologs for ABA-related genes throughout theViridiplantae, including in unicellular algae; however, the role of ABA in algal physiology has not been characterized, and the existence of such a role has been a matter of dispute. In this study, we demonstrate that ABA is involved in regulating algal stress responses.Chlorella sorokinianastrain UTEX 1230 contains genes orthologous to those of higher plants which are essential for ABA biosynthesis, sensing, and degradation. RNAseq-based transcriptomic studies reveal that treatment with ABA induces dramatic changes in gene expression profiles, including the induction of a subset of genes involved in DNA replication and repair, a phenomenon which has been demonstrated in higher plants. Pretreatment ofC. sorokinianacultures with ABA exerts a protective effect on cell viability in response to ultraviolet radiation. Additionally,C. sorokinianaproduces and secretes biologically relevant amounts of both ABA and the oxylipin 12-oxo-phytodienoic acid (OPDA) into the growth medium in response to abiotic stressors. Taken together, these phenomena suggest that ABA signaling evolved as an intercellular stress response signaling molecule in eukaryotic microalgae prior to the evolution of multicellularity and colonization of land.
The influence of startReact on long-latency reflexive muscle activation during the transition from posture to movement
Authors: Honeycutt Claire F. , Ravichandran Vengateswaran J. , Perreault Eric J.
Published: August 2017

Many motor tasks involve transitions from posture to movement such as shifting from holding an object to setting it on a surface. Although many movements are voluntary processes, they are facilitated through motor pathways that span the continuum between reflexive and voluntary control. The mechanisms driving the long-latency stretch reflex (LLSR) have remained hotly contested. Recently, startReact has been shown to influence the fast muscular response to perturbations (Ravichandran et. al. 2013). The objective of this study was to evaluate how the LLSR and startReact impact the muscular response during the transition from posture to movement. We hypothesized that both the LLSR and startReact would be involved throughout the transition from posture to movement; however there would be a clear transition from LLSR dominance during posture to startReact dominance near/during movement. We tested this hypothesis using perturbations of elbow posture at various times before a fast ballistic extension movement. We found clear evidence that both the LLSR and startReact components were influenced changes in the late long-latency time window. The results provide insights on how the nervous system regulates involuntary responses to perturbations during the transition from maintenance of arm posture to movement.

New and Noteworthy

We recently demonstrated that the startReact effect, the startled release of a planned movement, can influence the muscular response during the LLSR. Here we observe how the influence of startReact can change from the transition from posture (no/little influence) to movement (strong influence). While not all paradigms trigger a startReact effect, this work demonstrates that when present startRect can have a profound effect on the overall muscle activity - even obscuring the traditional LLSR response.
Quasi-Periodic Patterns of Intrinsic Brain Activity in Individuals and their Relationship to Global Signal
Authors: Yousefi Behnaz , Shin Jaemin , Schumacher Eric H. , Keilholz Shella D.
Published: August 2017

Quasiperiodic patterns (QPPs) as reported by Majeed et al., 2011 are prominent features of the brain’s intrinsic activity that involve important large-scale networks (default mode, DMN; task positive, TPN) and are likely to be major contributors to widely used measures of functional connectivity. We examined the variability of these patterns in 470 individuals from the Human Connectome Project resting state functional MRI dataset. The QPPs from individuals can be coarsely categorized into two types: one where strong anti-correlation between the DMN and TPN is present, and another where most areas are strongly correlated. QPP type could be predicted by an individual’s global signal, with lower global signal corresponding to QPPs with strong anti-correlation. After regression of global signal, all QPPs showed strong anti-correlation between DMN and TPN. QPP occurrence and type was similar between a subgroup of individuals with extremely low motion (or even high motion) and the rest of the sample, which shows that motion is not a major contributor to the QPPs. After regression of estimates of slow respiratory and cardiac induced signal fluctuations, more QPPs showed strong anti-correlation between DMN and TPN, an indication that while physiological noise influences the QPP type, it is not the primary source of the QPP itself. QPPs were more similar for the same subjects scanned on different days than for different subjects. These results provide the first assessment of the variability in individual QPPs and their relationship to physiological parameters.
Insights into regeneration from the genome, transcriptome and metagenome analysis ofEisenia fetida
Authors: Bhambri Aksheev , Dhaunta Neeraj , Patel Surendra Singh , Hardikar Mitali , Srikakulam Nagesh , Shridhar Shruti , Vellarikkal Shamsudheen , Suryawanshi Hemant , Pandey Rajesh , Jayarajan Rijith , Verma Ankit , Kumar Vikram , Bhatt Abhishek , Gautam Pradeep , Rai Manish , Khan Jameel Ahmed , Fromm Bastian , Peterson Kevin J. , Scaria Vinod , Sivasubbu Sridhar , Pillai Beena
Published: August 2017

Earthworms show a wide spectrum of regenerative potential with certain species likeEisenia fetidacapable of regenerating more than two-thirds of their body while other closely related species, such asParanais litoralisseem to have lost this ability. Earthworms belong to the phylum annelida, in which the genomes of the marine oligochaeteCapitella telata, and the freshwater leechHelobdella robustahave been sequenced and studied. The terrestrial annelids, in spite of their ecological relevance and unique biochemical repertoire, are represented by a single rough genome draft ofEisenia fetida(North American isolate), which suggested that extensive duplications have led to a large number of HOX genes in this annelid. Herein, we report the draft genome sequence ofEisenia fetida(Indian isolate), a terrestrial redworm widely used for vermicomposting assembled using short reads and mate-pair reads. An in-depth analysis of the miRNome of the worm, showed that many miRNA gene families have also undergone extensive duplications. Genes for several important proteins such as sialidases and neurotrophins were identified by RNA sequencing of tissue samples. We also usedde novoassembled RNA-Seq data to identify genes that are differentially expressed during regeneration, both in the newly regenerating cells and in the adjacent tissue. Sox4, a master regulator of TGF-beta induced epithelial-mesenchymal transition was induced in the newly regenerated tissue. The regeneration of the ventral nerve cord was also accompanied by the induction of nerve growth factor and neurofilament genes. The metagenome of the worm, characterized using 16S rRNA sequencing, revealed the identity of several bacterial species that reside in the nephridia of the worm. Comparison of the bodywall and cocoon metagenomes showed exclusion of hereditary symbionts in the regenerated tissue. In summary, we present extensive genome, transcriptome and metagenome data to establish the transcriptome and metagenome dynamics during regeneration.
Systemic post-translational control of bacterial metabolism regulates adaptation in dynamic environments
Authors: Brunk Elizabeth , Chang Roger L. , Xia Jing , Hefzi Hooman , Yurkovich James T. , Kim Donghyuk , Buckmiller Evan , Wang Harris , Yang Chen , Palsson Bernhard O. , Church George M. , Lewis Nathan E.
Published: August 2017

Across all domains of life, elaborate control mechanisms regulate proteins, pathways, and cell phenotypes as organisms adapt to ever-changing environments. Post-translational modifications (PTMs) allow cells to rapidly and reversibly regulate molecular pathways, but it remains unclear how individual PTMs regulate fitness. Here, we studied >130 PTM sites inEscherichia colito unravel how PTMs regulate cell metabolism and fitness in response to environmental changes, such as the glucose-acetate diauxie. Using a new metabolic modeling approach, we found a significant fraction of post-translationally modified enzymes are predicted to control shifts in pathway usage following evolutionarily-important environmental changes. Genetic screens using Multiplex Automated Genome Engineering confirmed that these PTMs impact cellular fitness, especially under dynamically changing environments. Finally, mechanisms of how individual PTMs impact protein function were detailed using molecular dynamics simulations and enzyme assays for enolase, transaldolase, and serine hydroxymethyltransferase. Thus, by integrating whole-cell data and pathway modeling with detailed biochemical analysis, we unraveled how individual PTMs regulate enzymes, pathways, and phenotypes to adapt to sudden environmental changes.
A transgenic zebrafish model for thein vivostudy of the blood and choroid plexus brain barriers using claudin 5
Authors: van Leeuwen Lisanne Martine , Evans Robert J. , Jim Kin Ki , Verboom Theo , Fang Xiaoming , Bojarczuk Aleksandra , Malicki Jarema , Andrew Johnston Simon , Marijke van der Sar Astrid
Published: August 2017

The central nervous system (CNS) has specific barriers that protect the brain from potential threats and tightly regulate molecular transport. Despite the critical functions of the CNS barriers, the mechanisms underlying their development and function are not well understood, and there are very limited experimental models for their study. Claudin 5 is a tight junction protein required for blood brain barrier (BBB) and choroid plexus (CP) barrier structure and function in humans. Here, we show that the geneclaudin 5ais the zebrafish orthologue with high fidelity expression, in the BBB and CP barriers, that demonstrates the conservation of the BBB and CP between humans and zebrafish. Expression ofclaudin 5acorrelates with developmental tightening of the BBB and is restricted to a subset of the brain vasculature clearly delineating the BBB. We show thatclaudin 5aexpressing cells of the CP are ciliated ependymal cells that drive fluid flow in the brain ventricles. Finally, we find that CP development precedes BBB development and thatclaudin 5aexpression occurs simultaneously with angiogenesis. Thus, our novel transgenic zebrafish represents an ideal model to study CNS barrier development and function, critical in understanding the mechanisms underlying CNS barrier function in health and disease.
Determining the optimal number of independent components for reproducible transcriptomic data analysis
Authors: Kairov Ulykbek , Cantini Laura , Greco Alessandro , Molkenov Askhat , Czerwinska Urszula , Barillot Emmanuel , Zinovyev Andrei
Published: August 2017

Background

Independent Component Analysis (ICA) is a method that models gene expression data as an action of a set of statistically independent hidden factors. The output of ICA depends on a fundamental parameter: the number of components (factors) to compute. The optimal choice of this parameter, related to determining the effective data dimension, remains an open question in the application of blind source separation techniques to transcriptomic data.

Results

Here we address the question of optimizing the number of statistically independent components in the analysis of transcriptomic data for reproducibility of the components in multiple runs of ICA (within the same or within varying effective dimensions) and in multiple independent datasets. To this end, we introduce ranking of independent components based on their stability in multiple ICA computation runs and define a distinguished number of components (Most Stable Transcriptome Dimension, MSTD) corresponding to the point of the qualitative change of the stability profile. Based on a large body of data, we demonstrate that a sufficient number of dimensions is required for biological interpretability of the ICA decomposition and that the most stable components with ranks below MSTD have more chances to be reproduced in independent studies compared to the less stable ones. At the same time, we show that a transcriptomics dataset can be reduced to a relatively high number of dimensions without losing the interpretability of ICA, even though higher dimensions give rise to components driven by small gene sets.

Conclusions

We suggest a protocol of ICA application to transcriptomics data with a possibility of prioritizing components with respect to their reproducibility that strengthens the biological interpretation. Computing too few components (much less than MSTD) is not optimal for interpretability of the results. The components ranked within MSTD range have more chances to be reproduced in independent studies.
The psychological arrow of time and the human brain dynamics of event ordering
Authors: Gauthier Baptiste , Pestke Karin , Wassenhove Virginie van
Published: August 2017

When navigating the real-world, the spatiotemporal sequencing of events is intrinsically bound to one’s physical trajectory; when recollecting the past or imagining the future, the temporal and spatial dimension of events can be independently manipulated. Yet, the rules enabling the flexible use of spatial and temporal cognitive maps likely differ in one major way as time is directional (oriented from past-to-future) whereas space is not. Using combined magneto- and electroencephalography, we sought to capture such differences by characterizing time-resolved brain activity while participants mentally ordered memories from different mental perspectives in time (past/future) or space (west/east). We report two major neural dissociations underlying the mental ordering of events in time and in space: first, brain responses evoked by the temporal order and the temporal distance of events-to-self dissociated at early and late latencies, respectively whereas spatial order and distance of events-to-self elicited late brain responses simultaneously. Second, brain responses distinguishing self-position in time and the temporal order of events involved sources in the hippocampal formation; spatial perspective, order and distance did not. These results suggest that the neural dynamics evoked by the temporal ordering of a series of events retrieved from long-term memory, i.e. the psychological time arrow, entails dedicated cognitive processes in the hippocampal formation that are fundamentally distinct from the mapping of spatial location.
Asymmetric MukB ATPases are regulated independently by the N- and C-terminal domains of MukF kleisin
Authors: Zawadzka Katarzyna , Zawadzki Pawel , Baker Rachel , Rajasekar Karthik V. , Sherratt David J. , Arciszewska Lidia K.
Published: August 2017

TheEscherichia coliSMC complex, MukBEF, acts in chromosome segregation. MukBEF shares the distinctive architecture of other SMC complexes, with one prominent difference; unlike other kleisins, MukF forms dimers through its N-terminal domain. We show that a 4-helix bundle adjacent to the MukF dimerization domain interacts functionally with the MukB coiled-coiled ‘neck’ adjacent to the ATPase head, forming an asymmetric tripartite complex, as in other SMC complexes. Since MukF dimerization is preserved during this interaction, MukF directs the formation of dimer of dimers MukBEF complexes, observed previouslyin vivo. The MukF N- and C-terminal domains stimulate ATPase independently and additively, consistent with them each targeting only one of the two MukB ATPase active sites in the asymmetric complex. We demonstrate that MukF interaction with the MukB neck turns over during cycles of ATP binding and hydrolysisin vivoand that impairment of this interaction leads to MukBEF release from chromosomes.
Gene markers for exon capture and phylogenomics in ray-finned fishes
Authors: Jiang Jiamei , Yuan Hao , Zheng Xin , Wang Qian , Kuang Ting , Li Jingyan , Liu Junning , Song Shuli , Wang Weicai , Cheng Fangyaun , Li Hongjie , Huang Junman , Li Chenhong
Published: August 2017

Gene capture coupled with the next generation sequencing has become one of the favorable methods in subsampling genomes for phylogenomic studies. Many target gene markers have been developed in plants, sharks, frogs, reptiles and others, but few have been reported in the ray-finned fishes. Here, we identified a suite of “single-copy” protein coding sequence (CDS) markers through comparing eight fish genomes, and tested them empirically in 83 species (33 families and 11 orders) of ray-finned fishes. Sorting through the markers according to their completeness and phylogenetic decisiveness in taxa tested resulted in a selection of 4,434 markers, which were proven to be useful in reconstructing phylogenies of the ray-finned fishes at different taxonomic level. We also proposed a strategy of refining baits (probes) design a posteriori based on empirical data. The markers that we have developed may fill a gap in the tool kit of phylogenomic study in vertebrates.
The molecular mechanism of N-acetylglucosamine side-chain attachment to the Lancefield group A Carbohydrate inStreptococcus pyogenes
Authors: Rush Jeffrey S. , Edgar Rebecca J. , Deng Pan , Chen Jing , Zhu Haining , van Sorge Nina M. , Morris Andrew J. , Korotkov Konstantin V. , Korotkova Natalia
Published: August 2017

In many Lactobacillales species (i.e. lactic acid bacteria), peptidoglycan is decorated by polyrhamnose polysaccharides that are critical for cell envelope integrity and cell shape and also represent key antigenic determinants. Despite the biological importance of these polysaccharides, their biosynthetic pathways have received limited attention. The important human pathogen,Streptococcus pyogenes, synthesizes a key antigenic surface polymer—the Lancefield group A carbohydrate (GAC). GAC is covalently attached to peptidoglycan and consists of a polyrhamnose polymer, with N-acetylglucosamine (GlcNAc) side chains, which is an essential virulence determinant. The molecular details of the mechanism of polyrhamnose modification with GlcNAc are currently unknown. In this report, using molecular genetics, analytical chemistry and mass spectrometry analysis, we demonstrated that GAC biosynthesis requires two distinct undecaprenol-linked GlcNAc-lipid intermediates: GlcNAc-pyrophosphorylundecaprenol (GlcNAc-P-P-Und) produced by the GlcNAc-phosphate transferase GacO and GlcNAc-phosphate-undecaprenol (GlcNAc-P-Und) produced by the glycosyltransferase GacI. Further investigations revealed that the GAC polyrhamnose backbone is assembled on GlcNAc-P-P-Und. Our results also suggested that a GT-C glycosyltranferase, GacL, transfers GlcNAc from GlcNAc-P-Und to polyrhamnose. Moreover, GacJ, a small membrane-associated protein, formed a complex with GacI and significantly stimulated its catalytic activity. Of note, we observed that GacI homologs perform a similar function inStreptococcus agalactiaeandEnterococcus faecalis. In conclusion, the elucidation of GAC biosynthesis inS. pyogenesreported here enhances our understanding of how other Gram-positive bacteria produce essential components of their cell wall.
Intra-voxel incoherent motion magnetic resonance imaging of the living human fetus: the technique and within-subject reproducibility
Authors: Jakab András , Tuura Ruth , Kottke Raimund , Kellenberger Christian , Scheer Ianina
Published: August 2017

Our purpose was to test the within-subject repeatability of the perfusion fraction, diffusion coefficient and pseudo diffusion coefficient measurements in various fetal organs and in the placenta based on the intra-voxel incoherent motion imaging principle.In uterodiffusion-weighted magnetic resonance imaging was performed on 1.5T and 3.0T clinical scanners with b-factors ranging from 0 to 900 s/mm2 in 16 steps and a tetrahedral diffusion-weighting encoding scheme. Data from 16 pregnant women (maternal age: 34 ± 4.9 years, range: 24.6 −40.8) were included in this pilot study. For 15 cases, IVIM was repeated (maternal age: 33.7 ± 5.2 years, range: 24.6 – 40.8). A bi-exponential model was fitted on the volume-averaged diffusion values and the perfusion fraction (f), diffusion coefficient (d) and pseudo diffusion coefficient (D*) were calculated. Within-subject repeatability was given as the test-retest variability of the IVIM parameters in the fetal frontal cortex, frontal white matter, cerebellum, lungs, kidneys, liver and in the placenta. An in-house developed image processing script was utilized to remove the image frames with excessive motion, and to perform motion correction by using non-linear freeform deformations. For the fetal lungs, liver and the placenta, within-subject variability ranged from 14.4% to 20.4% for f, 12.2% to 14.1% for d and 16.8% to 25.3% for D*. The diffusion coefficients of the investigated brain regions were moderately to highly reproducible (4.8% to 15.2%), however, f and D* showed inferior reproducibility compared to corresponding measures derived for the lungs, liver and placenta. The IVIM-based parameters of the fetal kidney were revealed to be highly variable across scans. Our results indicate that in utero intra-voxel incoherent motion magnetic resonance imaging potentially provides a novel method for examining microvascular perfusion and diffusion in the developing human fetus. The reproducible quantification of the perfusion and diffusion parameters depend greatly upon data quality, fetal and maternal movements, and image post processing to detect and remove corrupted data before calculating the IVIM model.
Enhancement of non-specific immune responses in European sea bass (Dicentrarchus labrax, L. 1758) by geophyte extract injections (Urginea maritimaandMuscari comosum)
Authors: Uluköy Gülşen , Baba Esin , Mammadov Ramazan
Published: August 2017

The immunomodulatory effects of bulb extracts from the geophyte plantsMuscari comosum(MC) andUrginea maritima(UM) on a non-spesific immune responses of European sea bass were investigated. Ethanol extracts were administered via intraperitoneal injection at doses of 0.5mg/fish and 2mg/fish in PBS. Non-spesific immune parameters such as Nitro blue tetrazolium (NBT) positive cells, serum lysozyme, total protein, total number of leukocytes, leukocyte cell type percentages and specific growth rates were investigated on the 1st, 7th, 14th, 21st, 28th and 35th days following the injection. The results indicate that receiving injections with MC and UM enhances some non-specific immune parameters in European sea bass. Total protein in serum was not enhanced. Activation occured on the 14thday and 21stday and this positive effects started to decrease following days. The appropriate dosage to achieve this enhancement was determined to be 0.5 mg/fish for UM and 2 mg/fish for MC. This preliminary study indicates that these doses yield the best results to promote the health status of European sea bass in intensive aquaculture.
Spindle asymmetry drives non-Mendelian chromosome segregation
Authors: Akera Takashi , Chmátal Lukáš , Trimm Emily , Yang Karren , Aonbangkhen Chanat , Chenoweth David M. , Janke Carsten , Schultz Richard M. , Lampson Michael A.
Published: August 2017

Genetic elements compete for transmission through meiosis, when haploid gametes are created from a diploid parent. Selfish elements can enhance their transmission through meiotic drive, in violation of Mendel’s Law of Segregation. In female meiosis, selfish elements drive by preferentially attaching to the egg side of the spindle, which implies some asymmetry between the two sides of the spindle, but molecular mechanisms underlying spindle asymmetry are unknown. Here we show that CDC42 signaling from the cell cortex regulates microtubule tyrosination to induce spindle asymmetry, and non-Mendelian segregation depends on this asymmetry. These signals depend on cortical polarization directed by chromosomes, which are positioned near the cortex to allow the asymmetric cell division. Thus, selfish meiotic drivers exploit the asymmetry inherent in female meiosis to bias their transmission.
Optogenetic inhibition reveals distinct roles for basolateral amygdala activity at discrete timepoints during risky decision making
Authors: Orsini Caitlin A. , Hernandez Caesar M. , Singhal Sarthak , Kelly Kyle B. , Frazier Charles J. , Bizon Jennifer L. , Setlow Barry
Published: August 2017

Decision making is a multifaceted process, consisting of several distinct phases that likely require different cognitive operations. Previous work showed that the basolateral amygdala (BLA) is a critical substrate for decision making involving risk of punishment; however, it is unclear how the BLA is recruited at different stages of the decision process. To this end, the current study used optogenetics to inhibit the BLA during specific task phases in a model of risky decision making (Risky Decision-making Task; RDT) in which rats choose between a small, “safe” reward and a large reward accompanied by varying probabilities of footshock punishment. Rats received intra-BLA microinjections of viral vectors carrying either halorhodopsin (eNpHR3.0-mCherry) or mCherry alone (control) followed by optic fiber implants and were trained in the RDT. Laser stimulation during the task occurred during either intertrial interval, deliberation, or reward outcome phases, the latter of which was further divided into the three possible outcomes (small, safe; large, unpunished; large, punished). Inhibition of the BLA selectively during the deliberation phase decreased choice of the large, risky outcome (decreased risky choice). In contrast, BLA inhibition selectively during delivery of the large, punished outcome increased risky choice. Inhibition had no effect during the other phases, nor did it affect performance in control rats. Collectively, these data indicate that the BLA can either inhibit or promote choice of risky options, depending on the phase of the decision process in which it is active.

Significance Statement

To date, most behavioral neuroscience research on neural mechanisms of decision making has employed techniques that preclude assessment of distinct phases of the decision process. Here we show that optogenetic inhibition of the basolateral amygdala (BLA) has opposite effects on choice behavior in a rat model of risky decision making depending on the phase in which inhibition occurs. BLA inhibition during a period of deliberation between small, safe and large, risky outcomes decreased risky choice. In contrast, BLA inhibition during receipt of the large, punished outcome increased risky choice. These findings highlight the importance of temporally targeted approaches to understand neural substrates underlying complex cognitive processes. More importantly, they reveal novel information about dynamic BLA modulation of risky choice.
Contributions of different prefrontal cortical regions to abstract rule acquisition and reversal in monkeys
Authors: Camera Giancarlo La , Bouret Sebastien , Richmond Barry J.
Published: August 2017

The ability to learn and follow abstract rules relies on intact prefrontal regions including the lateral prefrontal cortex (LPFC) and the orbitofrontal cortex (OFC). Here, we investigate the specific roles of these brain regions in learning rules that depend critically on the formation of abstract concepts as opposed to simpler input-output associations. To this aim, we tested monkeys with bilateral removals of either LPFC or OFC on a rapidly learned task requiring the formation of the abstract concept of same vs. different. While monkeys with OFC removals were significantly slower than controls at both acquiring and reversing the concept-based rule, monkeys with LPFC removals were not impaired in acquiring the task, but were significantly slower at rule reversal. Neither group was impaired in the acquisition or reversal of a delayed visual cue-outcome association task without a concept-based rule. These results suggest that OFC is essential for the implementation of a concept-based rule, whereas LPFC seems essential for its modification once established.
Genome shuffling in a globalized bacterial plant pathogen: Recombination-mediated evolution inXanthomonas euvesicatoriaandX. perforans
Authors: Jibrin Mustafa O. , Potnis Neha , Timilsina Sujan , Minsavage Gerald V. , Vallad Gary E. , Roberts Pamela D. , Jones Jeffrey B. , Goss Erica M.
Published: August 2017

Bacterial recombination and clonality underly the evolution and epidemiology of pathogenic lineages as well as their cosmopolitan spread. While the spread of stable clonal bacterial pathotypes drives disease epidemics, recombination leads to the evolution of new bacterial lineages. Recombinant lineages of plant bacterial pathogens are typically associated with colonization of novel hosts and emergence of new diseases. Here, we show that recombination between evolutionarily and phenotypically distinct plant pathogenic lineages has generated new recombinant lineages with unique combinations of pathogenicity and virulence factors.X. euvesicatoria(Xe) andX. perforans(Xp) are two closely related monophyletic species causing bacterial spot disease on tomato and pepper worldwide. We sequenced the genomes of strains representing populations on tomato in Nigeria and found shuffling of secretion systems and effectors such that these strains contain genes from bothXeandXp. Multiple strains, from populations in Nigeria, Italy, and Florida, USA, exhibited extensive genomewide homologous recombination and both species exhibited dynamic open pangenomes. Our results show that recombination is generating new lineages of bacterial spot pathogens on tomato with consequences for disease management strategies.

Importance

TheXanthomonaspathogens that cause bacterial spot of tomato and pepper have been model systems for plant-microbe interactions. Two of these pathogens,X. euvesicatoriaandX. perforans, are very closely related. Genome sequences of bacterial spot field strains from Nigeria, Italy, and the United States showed varying levels of homologous recombination that changed the amino sequence of effectors, secretion systems, and other proteins. This shuffling of genome content occurred betweenX. euvesicatoriaandX. perforans, while a Nigerian lineage also contained the lipopolysaccharide cluster of a distantly relatedXanthomonasspecies. Gene content varied among strains and the affected genes are important in the establishment of disease, therefore our findings point to global variation in the host-pathogen interaction driven by gene exchange among evolutionarily distinct lineages.
Competition between microtubule-associated proteins directs motor transport
Authors: Monroy Brigette Y. , Sawyer Danielle L. , Ackermann Bryce E. , Borden Melissa M. , Tan Tracy C. , Ori-McKenney Kassandra M.
Published: August 2017

Within cells, numerous motor and non-motor microtubule-associated proteins (MAPs) simultaneously converge on the microtubule lattice. How the binding activities of non-motor MAPs are coordinated and how they contribute to the balance and distribution of microtubule motor transport is unknown. Here, we examine the relationship between MAP7 and tau due to their antagonistic effects on neuronal branch formation and kinesin motility in vivo1–8. We find that MAP7 and tau compete for binding to microtubules, and determine a mechanism by which MAP7 displaces tau from the lattice. In striking contrast to the inhibitory effect of tau, MAP7 promotes kinesin-based transport in vivo and strongly enhances kinesin-1 binding to the microtubule in vitro, providing evidence for direct enhancement of motor motility by a MAP. In contrast, both MAP7 and tau strongly inhibit kinesin-3 and have no effect on cytoplasmic dynein, demonstrating that MAPs exhibit differential control over distinct classes of motors. Overall, these results reveal a general principle for how MAP competition dictates access to the microtubule to determine the correct distribution and balance of molecular motor activity.
Inhibition of p53 improves CRISPR/Cas - mediated precision genome editing
Authors: Haapaniemi Emma , Botla Sandeep , Persson Jenna , Schmierer Bernhard , Taipale Jussi
Published: August 2017

We report here that genome editing by CRISPR/Cas9 induces a p53-mediated DNA damage response and cell cycle arrest. Transient inhibition of p53 prevents this response, and increases the rate of homologous recombination more than five-fold. This provides a way to improve precision genome editing of normal cells, but warrants caution in using CRISPR for human therapies until the mechanism of the activation of p53 is elucidated.
Induction of differentiation and metabolic reprogramming in human hepatoma cells by adult human serum
Authors: Steenbergen Rineke , Oti Martin , Horst Rob ter , Tat Wilson , Neufeldt Chris , Belovodskiy Alexandr , Chua Tiing Tiing , Cho Woo Jung , Joyce Michael , Dutilh Bas E. , Lorne Tyrrell D.
Published: August 2017

Tissue culture medium routinely contains fetal bovine serum (FBS). Here we show that culturing human hepatoma cells in their native, adult serum (human serum, HS) results in the restoration of key morphological and metabolic features of normal liver cells. When moved to HS, these cells show differential transcription of 22-32% of the genes, stop proliferating, and assume a hepatocyte-like morphology. Metabolic analysis shows that the Warburg-like metabolic profile, typical for FBS-cultured cells, is replaced by a diverse metabolic profile consistent within vivohepatocytes. We demonstrate the formation of large lipid and glycogen stores, increased glycogenesis, increased β-oxidation, increased ketogenesis, and decreased glycolysis. Finally, organ-specific functions are restored, including xenobiotics degradation and secretion of bile, very low density lipoprotein, and albumin. Thus, organ-specific functions are not necessarily lost in cell cultures, but might be merely suppressed in FBS. Together, we showed that cells that are representative of normal physiology can be produced from cancer cells simply by replacing FBS by HS in culture media. The effect of serum is often overseen in cell culture and we provide a detailed study in the changes that occur, provide insight in some of the serum components that may play a role in the establishment of the different phenotypes, and discuss how these finding might be beneficial to a variety of research fields.
The Geometry of Partial Fitness Orders and an Efficient Method for Detecting Genetic Interactions
Authors: Lienkaemper Caitlin , Lamberti Lisa , Drain James , Beerenwinkel Niko , Gavryushkin Alex
Published: August 2017

We present an efficient computational approach for detecting genetic interactions from fitness comparison data together with a geometric interpretation using polyhedral cones associated to partial orderings. Genetic interactions are defined by linear forms with integer coefficients in the fitness variables assigned to genotypes. These forms generalize several popular approaches to study interactions, including Fourier-Walsh coefficients, interaction coordinates, and circuits. We assume that fitness measurements come with high uncertainty or are even unavailable, as is the case for many empirical studies, and derive interactions only from comparisons of genotypes with respect to their fitness, i.e. from partial fitness orders. We present a characterization of the class of partial fitness orders that imply interactions, using a graph-theoretic approach. Our characterization then yields an efficient algorithm for testing the condition when certain genetic interactions, such as sign epistasis, are implied. This provides an exponential improvement of the best previously known method. We also present a geometric interpretation of our characterization, which provides the basis for statistical analysis of partial fitness orders and genetic interactions.
The lawful imprecision of human surface tilt estimation in natural scenes
Authors: Kim Seha , Burge Johannes
Published: August 2017

Estimating local surface orientation (slant and tilt) is fundamental to recovering the three-dimensional structure of the environment, but it is unknown how well humans perform this task in natural scenes. Here, with a high-fidelity database of natural stereo-images with groundtruth surface orientation at each pixel, we find dramatic differences in human tilt estimation with natural and artificial stimuli. With artificial stimuli, estimates are precise and unbiased. With natural stimuli, estimates are imprecise and strongly biased. An image-computable normative model grounded in natural scene statistics predicts human bias, precision, and trial-by-trial errors without fitting parameters to the human data. These similarities suggest that the complex human performance patterns with natural stimuli are lawful, and that human visual systems have internalized local image and scene statistics to optimally infer the three-dimensional structure of the environment. The current results help generalize our understanding of human vision from the lab to the real world.