bluuebunny/crossref_metadata_2025 huggingface dataset:
Deep learning facilitates rapid classification of human and veterinary clinical narratives
Authors: Pineda Arturo Lopez , Bear Don’t Walk Oliver J. , Venkataraman Guhan R. , Zehnder Ashley M. , Ayyar Sandeep , Page Rodney L. , Bustamante Carlos D. , Rivas Manuel A.
Published: October 2018

Objective

Currently, dedicated tagging staff spend considerable effort assigning clinical codes to patient summaries for public health purposes, and machine-learning automated tagging is bottlenecked by availability of electronic medical records. Veterinary medical records, a largely untapped data source that could benefit both human and non-human patients, could fill the gap.

Materials and Methods

In this retrospective study, we trained long short-term memory (LSTM) recurrent neural networks (RNNs) on 52,722 human and 89,591 veterinary records. We established relevant baselines by training Decision Trees (DT) and Random Forests (RF) on the same data. We finally investigated the effect of merging data across clinical settings and probed model portability.

Results

We show that the LSTM-RNNs accurately classify veterinary/human text narratives into top-level categories with an average weighted macro F1, score of 0.735/0.675 respectively. The evaluation metric for the LSTM was 7 and 8% higher than that of the DT and RF models respectively. We generally did not find evidence of model portability albeit moderate performance increases in select categories.

Discussion

We see a strong positive correlation between number of training samples and classification performance, which is promising for future efforts. The use of LSTM-RNN models represents a scalable structure that could prove useful in cohort selection, which could in turn better address emerging public health concerns.

Conclusion

Digitization of human and veterinary health information will continue to be a reality. Our approach is a step forward for these two domains to learn from, and inform, one another.
Evidence for the Scarr-Rowe effect on genetic expressivity in a large US sample
Authors: Woodley of Menie Michael A. , Pallesen Jonatan , Sarraf Matthew A.
Published: October 2018

Using the Continuous Parameter Estimation Method (CPEM), a large genotyped sample of the population of Wisconsin, USA (the Wisconsin Longitudinal Study, N=8,509) is examined for evidence of the Scarr-Rowe effect, an adverse gene x environment (GxE) interaction that reduces the heritability of IQ among those with low socioeconomic status. This method allows the differential expressivity of polygenic scores predictive of both educational attainment and IQ (EA3) on the phenotype of IQ to be operationalized throughout the full range of these variables. Utilizing a parental SES factor-weighted composite as a measure of childhood SES, evidence for the Scarr-Rowe effect was found, i.e. the genetic expressivity of EA3 on IQ increased with increasing parental SES (β=.064, p=3.82×10−9, df=8508). The effect was found for both the male and female samples separately (β(males)=.051, p=.002, df=4062; β(females)=.076, p=1.76×10−7, df=4445) — there were no significant sex differences in the effect magnitudes, however. The effects were furthermore robust to removing outlying values of parental SES.
Dual brain cortical calcium imaging reveals social interaction-specific correlated activity in mice
Authors: Michelson Nicholas J. , Bolaños Federico , Bolaños Luis A. , Balbi Matilde , LeDue Jeffrey M. , Murphy Timothy H.
Published: October 2018

We employ cortical mesoscale calcium-imaging to observe brain activity in two head-fixed mice in a staged social touch-like interaction. Using a rail system, mice are brought together to a distance where macrovibrissae of each mouse make contact. Cortical signals were recorded from both mice simultaneously before, during, and after the social contact period. When the mice were together, we observed bouts of mutual whisking and cross-mouse correlated cortical activity in the vibrissae cortex. This correlated activity was specific to individual interactions as the correlations fell in trial-shuffled mouse pairs. Whisk-related global GCAMP6s signals were greater in cagemate pairs during the together period. The effects of social interaction extend outside of regions associated with mutual touch and had global synchronizing effects on cortical activity. We present an open-source platform to investigate the neurobiology of social interaction by including mechanical drawings, protocols, and software necessary for others to extend this work.
Andaman mangrove sediments: source of nutrients and sink of heavy metals
Authors: Mishra A.K. , Manish K.
Published: October 2018

Andaman Islands (AI) of India is a biodiversity hotspot of mangroves but biogeochemical dynamics of AI is less understood. We collected sediment samples of four AI mangrove sites and one site without mangroves for nutrients and trace metal analysis. Samples were collected from each site at the inlet of seawater (Zone A) and the other 500m into the mangrove creek (Zone B). Nutrients (sulphate, ammonium, nitrite and nitrate) levels, organic matter (OM) and carbon content were higher at Zone B of mangrove ecosystem due to the higher OM content from mangrove leaf litter decomposition and microbial degradation. Metal (Pb &Cd) content of zones with and without mangroves were similar and Igeo values indicated moderate contamination of mangrove zones of AI due to lack of anthropogenic pollution. Our results suggest mangrove ecosystems of AI are uncontaminated from heavy metals and are source of nutrients to the oligotrophic coastal ecosystems of Andaman Sea.
Dissociable Cerebellar-Prefrontal Networks Underlying Executive Function: Evidence from the Human Connectome Project
Authors: Orr Joseph M. , Jackson Trevor B. , Imburgio Michael J. , Bernard Jessica A.
Published: October 2018

To date, investigations of executive function (EF) have focused on the prefrontal cortex (PFC), and prominent theories of EF are framed with respect to this brain region. Multiple theories describe a hierarchical functional organization for the lateral PFC. However, recent evidence has indicated that the cerebellum (CB) also plays a role in EF. Posterior CB regions (Crus I & II) show structural and functional connections with the PFC, and CB networks are associated with individual differences in EF in healthy adults. However, it is unclear whether the cerebellum shows a similar functional gradient as does the PFC. Here, we investigated high-resolution resting-state data from 225 participants in the Human Connectome Project. We compared resting-state connectivity from posterior cerebellar ROIs, and examined functional data from several tasks that activate the lateral PFC. Demonstrating preliminary evidence for parallel PFC and CB gradients, Crus I was functionally connected with rostrolateral PFC, Crus II with middle and ventral PFC, and Lobule VI with posterior PFC. Contrary to previous work, the activation of the task thought to activate rostrolateral PFC resembled the connectivity maps of Crus II, not Crus I; similarly, the activation of the task thought to activate middle PFC resembled the connectivity maps of Crus I, not Crus II. Nevertheless, there was evidence for dissociable CB-PFC networks. Further work is necessary to understand the functional role of these networks.
pH Gradient Mitigation in the Leaf Cell Secretory Pathway Alters the Defense Response ofNicotiana benthamianato Agroinfiltration
Authors: Jutras Philippe V. , Sainsbury Frank , Goulet Marie-Claire , Lavoie Pierre-Olivier , Tardif Rachel , Hamel Louis-Philippe , D’Aoust Marc-André , Michaud Dominique
Published: October 2018

Partial neutralization of the Golgi lumen pH by ectopic expression of influenza virus M2 proton channel stabilizes acid-labile and protease-susceptible recombinant proteins in the plant cell secretory pathway. Here, we assessed the impact of M2 channel expression on the proteome ofNicotiana benthamianaleaf tissue infiltrated with the bacterial gene vectorAgrobacterium tumefaciens, keeping in mind the key role of pH homeostasis on secreted protein processing and the involvement of protein secretion processes in plant cells upon microbial challenge. The proteomes of leaves agroinfiltrated with an empty vector or with an M2 channel-encoding vector were compared with the proteome of non-infiltrated leaves using a iTRAQ quantitative proteomics procedure. Leaves infiltrated with the empty vector had a low soluble protein content compared to non-infiltrated leaves, associated with a strong decrease of photosynthesis-associated proteins (including Rubisco) and a parallel increase of stress-related secreted proteins (including pathogenesis-related proteins, protease inhibitors and molecular chaperones). M2 expression partly compromised these alterations of the proteome to restore original soluble protein and Rubisco contents, associated with higher levels of translation-associated (ribosomal) proteins and reduced levels of stress-related proteins in the apoplast. Proteome changes in M2-expressing leaves were determined both transcriptionally and post-transcriptionally, to alter the steady-state levels of proteins not only along the secretory pathway but also in other cellular compartments including the chloroplast, the cytoplasm, the nucleus and the mitochondrion. These data illustrate the cell-wide influence of Golgi lumen pH homeostasis on the leaf proteome ofN. benthamianaplants responding to microbial challenge. They underline in practice the relevance of carefully considering the eventual off-target effects of accessory proteins used to modulate specific cellular or metabolic functions in plant protein biofactories.
Common and dissociable contributions of alexithymia and autism to domain-specific interoceptive dysregulations – a dimensional neuroimaging approach
Authors: Li Jialin , Xu Lei , Zheng Xiaoxiao , Fu Meina , Zhou Feng , Xu Xiaolei , Ma Xiaole , Li Keshuang , Kendrick Keith M. , Becker Benjamin
Published: October 2018

Alexithymia represents a transdiagnostic marker across psychiatric entities associated with emotional impairments, including autism spectrum disorders (ASD). Accumulating evidence suggests that interoceptive dysfunctions that underpin the core symptomatic emotion recognition and empathy deficits in ASD may be contributed to by high levels of alexithymia rather than autistic symptoms per se. However, previous findings are hampered by generally elevated alexithymia in ASD patients, and thus were not able to differentiate common and distinct contributions across the entire spectrum of variations of autism and alexithymia. Moreover, the multi-factorial nature of the domains affected, such as distinct neural reactivity towards perceiving physical and affective pain, has not been accounted for. Against this background the present fMRI study employed a dimensional trait approach in n = 242 healthy subjects to determine common and distinct associations between both traits and pain empathic responses towards physical and affective pain. Higher levels of alexithymia associated with increased left anterior insula pain empathic reactivity. Disentangling these effects revealed a positive association during perceived physical pain, but a negative one during affective pain. No significant associations with trait autism were found, but an interaction effect between the trait dimensions was observed in the mid-cingulate cortex. Moderation analysis demonstrated that trait autism only impacted mid-cingulate reactivity towards physical pain in high alexithymia subjects, whereas reactivity towards affective pain was specifically associated with trait autism in low alexithymia subjects. Findings confirm previous patient studies suggesting that alexithymia rather than autism per se may drive altered insula pain empathic reactivity. Importantly, the present approach allowed for the first time to demonstrate that the impact of alexithymia on insula reactivity varies as a function of the pain empathic domain and that effects on other core empathy nodes evolve in interaction with trait autism.
Endogenous retroviruses transcriptional modulation after severe infection, trauma and burn
Authors: Tabone Olivier , Mommert Marine , Jourdan Camille , Cerrato Elisabeth , Legrand Matthieu , Lepape Alain , Allaouchiche Bernard , Rimmelé Thomas , Pachot Alexandre , Monneret Guillaume , Venet Fabienne , Mallet François , Textoris Julien
Published: October 2018

Although human endogenous retroviruses (HERVs) expression is a growing subject of interest, no study focused before on specific endogenous retroviruses loci activation in severely injured patients. Yet, HERV reactivation is observed in immunity compromised settings like some cancers and auto-immune diseases. Our objective was to assess the transcriptional modulation of HERVs in burn, trauma and septic shock patients. We analyzed HERV transcriptome with microarray data from whole blood samples of a burn cohort (n=30), a trauma cohort (n=105) and 2 septic shock cohorts (n=28, n=51), and healthy volunteers (HV, n=60). We described expression of the 337 probesets targeting HERV from U133 plus 2.0 microarray in each dataset and then we compared HERVs transcriptional modulation of patients compared to healthy volunteers. Although all 4 cohorts contained very severe patients, the majority of the 337 HERVs was not expressed (around 74% in mean). Each cohort had differentially expressed probesets in patients compared to HV (from 19 to 46). Strikingly, 5 HERVs were in common in all types of severely injured patients, with 4 being up-modulated in patients. We highlighted co-expressed profiles between HERV and nearby gene as well as autonomous HERV expression. We suggest an inflammatory-specific HERV transcriptional response, and importantly, we introduce that the HERVs close to immunity-related genes might have a role on its expression.
Termination of non-coding transcription in yeast relies on both a CTD-interaction domain and a CTD-mimic in Sen1
Authors: Han Z , Jasnovidova O , Haidara N , Tudek A , Kubicek K , Libri D , Stefl R , Porrua O.
Published: October 2018

Pervasive transcription is a widespread phenomenon leading to the production of a plethora of non-coding RNAs (ncRNAs) without apparent function. Pervasive transcription poses a risk that needs to be controlled to prevent the perturbation of gene expression. In yeast, the highly conserved helicase Sen1 restricts pervasive transcription by inducing termination of non-coding transcription. However, the mechanisms underlying the specific function of Sen1 at ncRNAs are poorly understood. Here we identify a motif in an intrinsically disordered region of Sen1 that mimics the phosphorylated carboxy terminal domain (CTD) of RNA polymerase II and characterize structurally its recognition by the CTD-interacting domain of Nrd1, an RNA-binding protein that binds specific sequences in ncRNAs. In addition, we show that Sen1-dependent termination strictly requires the recognition of the CTD by the N-terminal domain of Sen1. We provide evidence that the Sen1-CTD interaction does not promote Sen1 initial recruitment but rather the capacity of Sen1 to induce the release of paused RNAPII from the DNA. Our results shed light onto the network of protein-protein interactions that control termination of non-coding transcription by Sen1.
Rationally designedmarinervectors to allow functional genomic analysis ofActinobacillus pleuropneumoniaeand other bacteria by transposon-directed insertion-site sequencing (TraDIS)
Authors: Bossé Janine T , Li Yanwen , Leanse Leon G. , Zhou Liqing , Chaudhuri Roy R , Peters Sarah E , Wang Jinhong , Maglennon Gareth A. , Holden Matthew TG , Maskell Duncan J , Tucker Alexander W , Wren Brendan W , Rycroft Andrew N , Langford Paul R ,   on behalf of the BRaDP1T consortium
Published: October 2018

Transposon Directed Insertion Sequencing (TraDIS) is a high-throughput method for mapping insertion sites in large libraries of transposon mutants. TheHimar1(mariner) transposon is ideal for generating near-saturating mutant libraries, especially in AT-rich chromosomes, as the requirement for integration is a TA dinucleotide. In this study, we generated two novelmarinervectors, pTsodCPC9 and pTlacPC9 (differing only in the promoter driving expression of the transposase gene), in order to facilitate TraDIS identification of conditionally essential genes inActinobacillus pleuropneumoniaeand other bacteria. Using the pTlacPC9 vector, we have generated, for the first time, saturatingmarinermutant libraries in bothA. pleuropneumoniaeandPasteurella multocidathat showed a near random distribution of insertions around the respective chromosomes. A preliminary screen of 5000 mutants each identified 8 and 15 genes, respectively, that are required for growth under anaerobic conditions.
TgCep250 is dynamically processed through the division cycle and essential for structural integrity of the Toxoplasma centrosome
Authors: Chen Chun-Ti , Gubbels Marc-Jan
Published: October 2018

The Toxoplasma centrosome is a unique bipartite structure comprising an inner- and outer-core responsible for the nuclear cycle (mitosis) and budding cycles (cytokinesis), respectively. These two cores remain associated during the cell cycle but have been proposed to function independently. Here, we describe the function of a large coiled-coil protein, TgCep250, in connecting the two centrosomal cores and promoting their structural integrity. Throughout the cell cycle TgCep250 localizes to the centrosome inner-core but resides on both inner- and outer-cores during the onset of cell division. This dynamic localization pattern is associated with proteolysis: the processed version residing on the inner-core. In the absence of TgCep250, stray centrosome inner- and outer-core foci were observed; detachment of the inner-outer-core connection resulted in nuclear partitioning defects. The detachment between centrosome inner- and outer-core was found in only one of the centrosomes during cell division, indicating distinct states of mother and daughter centrosomes. We further dissected the hierarchical organization of centrosome and kinetochore complex through depletion of kinetochore component TgNuf2, which resulted in dissociation of the intact bipolar centrosome from the nuclear periphery. Together, these data suggest that TgCep250 bridges the interaction between the centrosome cores but not between the inner-core and kinetochore.

Short Summary

The opportunistic apicomplexan parasite Toxoplasma gondii uses a bipartite centrosome to independently regulate mitosis and cytokinesis. Here we report a large coiled-coil protein that functions to integrate the two centrosomal cores for faithful cell division. This study also reveals the layered structural organization of the centrosome/kinetochore complex.
Improved DNA based storage capacity and fidelity using composite DNA letters
Authors: Anavy Leon , Vaknin Inbal , Atar Orna , Amit Roee , Yakhini Zohar
Published: October 2018

DNA, with its remarkable density and long-term stability, is an appealing potential next generation data storage medium, most notably for long-term archiving. Megabyte scale DNA based storage was first reported in 2012. The Shannon information capacity of DNA was recently demonstrated, using fountain codes, to be ∼1.57 bit per synthesized position. However, synthesis and sequencing technologies process multiple nominally identical molecules in parallel, leading to significant information redundancies. We introduce composite DNA alphabets, using mixed DNA base types, to leverage this redundancy, enabling higher density. We develop encoding and decoding for composite DNA based storage, including error correction. Using current DNA synthesis technologies, we code 6.4 Megabyte data into composite DNA, achieving ∼25% increase in capacity as compared to literature. We further demonstrate, on smaller scales, how flexible synthesis leads to 2.7 fold increased capacity per synthesized position. Composite DNA can thus reduce costs for DNA based storage and can also serve in other applications.
Neuronal adaptation reveals a suboptimal decoding of orientation tuned populations in the mouse visual cortex
Authors: Jin Miaomiao , Beck Jeffrey M. , Glickfeld Lindsey L.
Published: October 2018

Sensory information is encoded by populations of cortical neurons. Yet, it is unknown how this information is used for even simple perceptual choices such as discriminating orientation. To determine the computation underlying this perceptual choice, we took advantage of the robust adaptation in the mouse visual system. We find that adaptation increases animals’ thresholds for orientation discrimination. This was unexpected since optimal computations that take advantage of all available sensory information predict that the shift in tuning and increase in signal-to-noise ratio in the adapted condition should improve discrimination. Instead, we find that the effects of adaptation on behavior can be explained by the appropriate reliance of the perceptual choice circuits on target preferring neurons, but the failure to discount neurons that prefer the distractor. This suggests that to solve this task the circuit has adopted a suboptimal strategy that discards important task-related information to implement a feed-forward visual computation.
Applicability of the mutation-selection balance model to population genetics of heterozygous protein-truncating variants in humans
Authors: Weghorn Donate , Balick Daniel J. , Cassa Christopher , Kosmicki Jack , Daly Mark J. , Beier David R. , Sunyaev Shamil R.
Published: October 2018

The fate of alleles in the human population is believed to be highly affected by the stochastic force of genetic drift. Estimation of the strength of natural selection in humans generally necessitates a careful modeling of drift including complex effects of the population history and structure. Protein truncating variants (PTVs) are expected to evolve under strong purifying selection and to have a relatively high per-gene mutation rate. Thus, it is appealing to model the population genetics of PTVs under a simple deterministic mutation-selection balance, as has been proposed earlier [1]. Here, we investigated the limits of this approximation using both computer simulations and data-driven approaches. Our simulations rely on a model of demographic history estimated from 33,370 individual exomes of the Non-Finnish European subset of the ExAC dataset [2]. Additionally, we compared the African and European subset of the ExAC study and analyzed de novo PTVs. We show that the mutation-selection balance model is applicable to the majority of human genes, but not to genes under the weakest selection.
Using micro-CT techniques to explore the role of sex and hair in the functional morphology of bumblebee (Bombus terrestris) ocelli
Authors: Wilby David , Aarts Tobio , Tichit Pierre , Bodey Andrew , Rau Christoph , Taylor Gavin , Baird Emily
Published: October 2018

Many insects have triplets of camera type eyes, called ocelli, whose function remains unclear for most species. Here, we investigate the ocelli of the bumblebee,Bombus terrestris, using reconstructed 3D data from X-ray micro computed-tomography scans combined with computational ray-tracing simulations. This method enables us, not only to predict the visual fields of the ocelli, but to explore for the first time the effect that hair has on them as well as the difference between worker female and male ocelli.

We find that bumblebee ocellar fields of view are directed forward and dorsally, incorporating the horizon as well as the sky. There is substantial binocular overlap between the median and lateral ocelli, but no overlap between the two lateral ocelli. Hairs in both workers and males occlude the ocellar field of view, mostly laterally in the worker median ocellus and dorsally in the lateral ocelli. There is little to no sexual dimorphism in the ocellar visual field, suggesting that inB. terrestristhey confer no advantage to mating strategies.

We compare our results with published observations for the visual fields of compound eyes in the same species as well as with the ocellar vision of other bee and insect species.
An enhanced-sampling MD-based protocol for molecular docking
Authors: Basciu Andrea , Malloci Giuliano , Pietrucci Fabio , Bonvin Alexandre M. J. J. , Vargiu Attilio V.
Published: October 2018

Understanding molecular recognition of proteins by small molecules is key for drug design. Despite the number of experimental structures of ligand-protein complexes keeps growing, the number of available targets remains limited compared to the druggable genome, and structural diversity is generally low, which affects the chemical variance of putative lead compounds. From a computational perspective, molecular docking is widely used to mimic ligand-protein associationin silico. Ensemble-docking approaches include flexibility through a set of different conformations of the protein obtained either experimentally or from computer simulations, e.g. molecular dynamics. However, structures prone to host (the correct) ligands are generally poorly sampled by standard molecular dynamics simulations of the apo protein. In order to address this limitation, we introduce a computational approach based on metadynamics simulations (EDES -Ensemble-Docking withEnhanced-sampling of pocketShape) to generate druggable conformations of proteins only exploiting their apo structures. This is achieved by defining a set of collective variables that effectively sample different shapes of the binding site, ultimately mimicking the steric effect due to ligands to generate holo-like binding site geometries. We assessed the method on two challenging proteins undergoing different extents of conformational changes upon ligand binding. In both cases our protocol generated a significant fraction of structures featuring a low RMSD from the experimental holo conformation. Moreover, ensemble docking calculations using those conformations yielded native-like poses among the top ranked ones for both targets. This proof of concept study paves the route towards an automated workflow to generate druggable conformations of proteins, which should become a precious tool for structure-based drug design.
Silhouette width using generalized mean – a flexible method for assessing clustering efficiency
Authors: Lengyel Attila , Botta-Dukát Zoltán
Published: October 2018

Cluster analysis plays vital role in pattern recognition in several fields of science. Silhouette width is a widely used measure for assessing the fit of individual objects in the classification, as well as the quality of clusters and the entire classification. This index uses two clustering criteria, compactness (average within-cluster distances) and separation (average between-cluster distances), which implies that spherical cluster shapes are preferred over others – a property that can be seen as a disadvantage in the presence 22 of clusters with high internal heterogeneity, which is common in real situations.

We suggest a generalization of the silhouette width using the generalized mean. By changing the p parameter of the generalized mean between −∞ and +∞, several specific summary statistics, including the minimum, maximum, the arithmetic, harmonic, and geometric means, can be reproduced. Implementing the generalized mean in the calculation of silhouette width allows for changing the sensitivity of the index to compactness vs. connectedness. With higher sensitivity to connectedness instead of compactness the preference of silhouette width towards spherical clusters is expected to reduce. We test the performance of the generalized silhouette width on artificial data sets and on the Iris data set. We examine how classifications with different numbers of clusters prepared by single linkage, group average, and complete linkage algorithms are evaluated, if p is set to different values.

When p was negative, well separated clusters achieved high silhouette widths despite their elongated or circular shapes. Positive values of p increased the importance of compactness, hence the preference towards spherical clusters became even more detectable. With low p, single linkage clustering was deemed the most efficient clustering method, while with higher parameter values the performance of group average and complete linkage seemed better.

The generalized silhouette width is a promising tool for assessing clustering quality. It allows for adjusting the contribution of compactness and connectedness criteria to the index value, thus avoiding underestimation of clustering efficiency in the presence of clusters with high internal heterogeneity.
Cellular advective-diffusion drives the emergence of bacterial surface colonization patterns and heterogeneity
Authors: Rossy Tamara , Nadell Carey D. , Persat Alexandre
Published: October 2018

Microorganisms navigate and divide on surfaces to form multicellular structures called biofilms, the most widespread survival strategy found in the bacterial world1–4. One common assumption is that cellular components guide the spatial architecture and arrangement of multiple species in a biofilm. However, bacteria must contend with mechanical forces generated through contact with surfaces under fluid flow, whose contributions to colonization patterns are poorly understood. Here, we show how the balance between motility and flow promotes the emergence of morphological patterns in Caulobacter crescentus biofilms5. By modeling transport of single cells by flow and Brownian-like swimming, we show that the emergence of these patterns is guided by an effective Péclet number. By analogy with transport phenomena we show that, counter-intuitively, fluid flow represses mixing of distinct clonal lineages, thereby affecting the interaction landscapes between biofilm-dwelling bacteria. This demonstrates that hydrodynamics influence species interaction and evolution within surface-associated communities.
Multi-scale Imaging Reveals Aberrant Connectome Organization and Elevated Dorsal Striatal Arc Expression in Advanced Age
Authors: Colon-Perez Luis M. , Turner Sean M. , Lubke Katelyn N. , Febo Marcelo , Burke Sara N.
Published: October 2018

The functional connectome reflects a network architecture enabling adaptive behavior that becomes vulnerable in advanced age. The cellular mechanisms that contribute to altered functional connectivity in old age, however, are not known. Here we used a multi-scale imaging approach to link age-related changes in the functional connectome to altered expression of the activity-dependent immediate-early gene Arc as a function of training to multi-task. Aged behaviorally-impaired, but not young, rats had a subnetwork of increased connectivity between the anterior cingulate cortex and dorsal striatum. Moreover, the old rats had less stable rich club participation that increased with cognitive training. The altered functional connectome of aged rats was associated with a greater engagement of neurons in the dorsal striatum during cognitive multi-tasking. These findings point to aberrant large-scale functional connectivity in aged animals that is associated with altered cellular activity patterns within individual brain regions.
Electrospun Cellulose-Silk Composite Nanofibres Direct Mesenchymal Stem Cell Chondrogenesis in the Absence of Biological Stimulation
Authors: Begum Runa , Perriman Adam W. , Su Bo , Scarpa Fabrizio , Kafienah Wael
Published: October 2018

Smart biomaterials with an inherent stimulating capacity that elicit specific behavioursin lieuof biological prompts would prove advantageous for regenerative medicine applications. Specific blends of the natural polymers cellulose and silk cast as films can drive the chondrogenic differentiation of human bone marrow mesenchymal stem cells (hMSCs) uponin vitroculture. However, the true potential of such biomaterials for cartilage tissue engineering can be realised upon its three-dimensional fabrication. In this work we employ an electrospinning technique to model thein vivonanofibrous extracellular matrix (ECM). Cellulose and silk polymers at a mass ratio of 75:25 were regenerated using a trifluoroacetic acid and acetic acid cosolvent system. This natural polymer composite was directly electrospun for the first time, into nanofibers without post-spun treatment. The presence and size of fibre beading was influenced by environmental humidity. The regenerated composite retained the key chemical functionalities of its respective components. Biocompatibility of the natural polymer composite with hMSCs was demonstrated and its inherent capacity to direct chondrogenic stem cell differentiation, in the absence of stimulating growth factors, was confirmed. This physical chondrogenic stimulation was countered biochemically using fibroblast growth factor-2 (FGF-2), a growth factor used to enhance the proliferation of hMSCs. The newly fabricated scaffold provides the foundation for designing a robust, self-inductive, and cost-effective biomimetic biomaterial for cartilage tissue engineering.
No Cost of Complexity in Bacteriophages Adapting to a Complex Environment
Authors: Sackman Andrew M. , Rokyta Darin R.
Published: October 2018

A longstanding prediction in evolutionary biology is that organisms experience a so-called “cost of complexity” manifested as a decreasing rate of adaptation in populations as organisms or selective environments become increasingly complex. This theory assumes the ubiquity of antagonistic pleiotropy, or tradeoffs in fitness, for mutations affecting multiple traits or phenotypes. A particular manifestation of antagonism thought to be at play in adaptive dynamics involves the relationship between viral growth rate and capsid stability, an interaction that may impede the adaptation of viral pathogens to novel hosts and environments. Here, we present a comparison of the genetics of adaptation for populations of bacteriophages undergoing complete adaptive walks under both simple and complex selective conditions, with complexity being determined by the number of traits under directional selection. We found no evidence for a long-term cost of complexity in viruses experiencing complex selection, with on average at least as great a rate of adaptation under more complex conditions, and rampant evidence for synergistic, rather than antagonistic, pleiotropy. The lack of evident tradeoffs between multiple phenotypes implies that emerging pathogens may be able to improve their growth in many different hosts or environments simultaneously and to do so at a faster rate than previously anticipated.
GWAS using 2b-RAD sequencing identified three mastitis important SNPs via two-stage association analysis in Chinese Holstein cows
Authors: Yang Fan , Chen Fanghui , Li Lili , Yan Li , Badri Tarig , Lv Chenglong , Yu Daolun , Chen Jie , Xing Chaofeng , Li Jie , Wang Genlin , Li Honglin , Li Jun , Cai Yafei
Published: October 2018

Background

Bovine mastitis is a key disease restricting developing global dairy industry. Genomic wide association studies (GWAS) provided a convenient way to understand the biological basis of mastitis and better prevent or treat the disease. 2b-RADseq is a reduced-representation sequencing that offered a powerful method for genome-wide genetic marker development and genotyping. This study, GWAS using two-stage association analysis identified mastitis important genes’ single nucleotide polymorphisms (SNP) in Chinese Holstein cows.

Results

In the selected Chinese Holstein cows’ population, we identified 10,058 SNPs and predicted their allele frequencies. In stage I, 42 significant SNPs screened out in Chinese Holstein cows via Bayesian (P<0.001), while logistic regression model identified 51 SNPs (P<0.01). Twenty-seven significant SNPs appeared simultaneously in both analytical models, which of them only three significant SNPs (rs75762330, C>T, PIC=0.2999; rs88640083, A>G, PIC=0.1676; rs20438858, G>A, PIC=0.3366) located in non-coding region (introns and intergenic) screened out associated with inflammation or immune response. GO enrichment analysis showed that they annotated to three genes (PTK2B, SYK and TNFRSF21), respectively. Stage II? case-control study used to verify three important SNPs associated with dairy cows mastitis traits in independent population. Data suggested that the correlation between these three SNPs (rs75762330, P<0.025; rs88640083, P<0.005; rs20438858, P<0.001) and mastitis traits in dairy cows were consistent with stage I.

Conclusion

Two-stage association analysis approved that three significant SNPs associated with mastitis traits in Chinese Holstein cows. Gene function analysis indicated that three genes (PTK2B, SYK and TNFRSF21) involved in inflammation and immune response of dairy cows. Suggesting that they as new candidate genes have an impact on mastitis susceptibility (PTK2B and SYK, OR>1) or resistance (TNFRSF21, OR<1) in Chinese Holstein cows.
WindSTORM: Robust online image processing for high-throughput nanoscopy
Authors: Ma Hongqiang , Xu Jianquan , Liu Yang
Published: October 2018

High-throughput nanoscopy becomes increasingly important for unraveling complex biological processes from a large heterogeneous cell population at a nanoscale resolution. High-density emitter localization combined with a large field of view and fast imaging frame rate is commonly used to achieve a high imaging throughput, but the image processing speed in the dense emitter scenario remains a bottleneck. Here we present a simple non-iterative approach, referred to as WindSTORM, to achieve high-speed high-density emitter localization with robust performance for various image characteristics. We demonstrate that WindSTORM improves the computation speed by two orders of magnitude on CPU and three orders of magnitude upon GPU acceleration to realize online image processing, without compromising localization accuracy. Further, due to the embedded background correction, WindSTORM is highly robust in the presence of high and non-uniform background. WindSTORM paves the way for next generation of high-throughput nanoscopy.
Distinct gene-selective roles for a network of core promoter factors inDrosophilaneural stem cell identity
Authors: Neves Alexandre , Eisenman Robert N.
Published: October 2018

The transcriptional mechanisms that allow neural stem cells (NSC) to balance self-renewal with differentiation are not well understood. Employing an in vivo RNAi screen we identify here NSC-TAFs, a subset of nine TATA-binding protein associated factors (TAFs), as NSC identity genes inDrosophila. We found that depletion of NSC-TAFs results in decreased NSC clone size, reduced proliferation, defective cell polarity and increased hypersensitivity to cell cycle perturbation, without affecting NSC survival. Integrated gene expression and genomic binding analyses revealed that NSC-TAFs function with both TBP and TRF2, and that NSC-TAF-TBP and NSC-TAF-TRF2 shared target genes encode different subsets of transcription factors and RNA-binding proteins with established or emerging roles in NSC identity and brain development. Taken together, our results demonstrate that core promoter factors are selectively required for NSC identityin vivoby promoting cell cycle progression and NSC cell polarity as well as by restraining premature differentiation. Because pathogenic variants in a subset of TAFs have all been linked to human neurological disorders, this work may stimulate and inform future animal models of TAF-linked neurological disorders.

Author summary

The brains of many animal species are built with brain stem cells. Having too many brain stem cells can lead to brain tumors whereas too few can lead to birth defects such as microcephaly. A number of next generation sequencing studies have implicated proteins referred to as TATA-box-binding protein associated factors (TAFs) in human neurological disorders including microcephaly, but prior to this study, their function in brain development was unknown. Here we use brain stem cells, known as neural stem cells (NSCs), from the fruit flyDrosophila melanogasteras a model system to decipher how TAFs control brain stem cell identity. By combining genetics and low-input genomics, we show that TAFs directly control NSC cell division and cell polarity but do not appear to be required for NSC survival. We further show that TAFs accomplish these functions by associating either with their canonical partner TBP (TATA-binding protein) or the related protein TRF2. In summary, our study reveals unexpected and gene-selective functions of a unique subset of TAFs and their binding partners, which could inform future studies that seek to model human neurological disorders associated with TAFs.
Epithelial WNT2B and Desert Hedgehog are necessary for human colonoid regeneration after bacterial cytotoxin injury
Authors: In Julie G. , Yin Jianyi , Doucet Michele , Cole Robert N. , DeVine Lauren , Donowitz Mark , Zachos Nicholas C. , Blutt Sarah E. , Estes Mary K. , Kovbasnjuk Olga
Published: October 2018

Intestinal regeneration and crypt hyperplasia after radiation or pathogen injury relies on Wnt signaling to stimulate stem cell proliferation. Mesenchymal Wnts are essential for homeostasis and regeneration in mice, but the role of epithelial Wnts remains largely uncharacterized. Using the enterohemorrhagicE. colisecreted cytotoxin, EspP to induce injury to human colonoids, we evaluated a simplified, epithelial regeneration model that lacks mesenchymal Wnts. Here, we demonstrate that epithelial-produced WNT2B is upregulated following injury and essential for regeneration. Hedgehog signaling, specifically activation via the ligand Desert Hedgehog (DHH), but not Indian or Sonic Hedgehog, is another driver of regeneration and modulates WNT2B expression. These findings highlight the importance of epithelial WNT2B and DHH in regulating human colonic regeneration after injury.
Targeting neuronal and glial cell types with synthetic promoter AAVs in mice, non-human primates, and humans
Authors: Jüttner Josephine , Szabo Arnold , Gross-Scherf Brigitte , Morikawa Rei K. , Rompani Santiago B. , Teixeira Miguel , Hantz Peter , Szikra Tamas , Esposti Federico , Cowan Cameron S. , Bharioke Arjun , Patino-Alvarez Claudia P. , Keles Özkan , Roth Chiara N. , Kusnyerik Akos , Gerber-Hollbach Nadin , Azoulay Thierry , Hartl Dominik , Krebs Arnaud , Schübeler Dirk , Hajdu Rozina , Lukats Akos , Nemeth Janos , Nagy Zoltan Z. , Wu Kun-Chao , Wu Rong-Han , Xiang Lue , Fang Xiao-Long , Jin Zi-Bing , Goldblum David , Hasler Pascal W. , Scholl Hendrik , Krol Jacek , Roska Botond
Published: October 2018

Targeting genes to specific neuronal or glial cell types is valuable both for understanding and for repairing brain circuits. Adeno-associated viral vectors (AAVs) are frequently used for gene delivery, but targeting expression to specific cell types is a challenge. We created a library of 230 AAVs, each with a different synthetic promoter designed using four independent strategies. We show that ~11% of these AAVs specifically target expression to neuronal and glial cell types in the mouse retina, mouse brain, non-human primate retinain vivo, and in the human retinain vitro. We demonstrate applications for recording, stimulation, and molecular characterization, as well as the intersectional and combinatorial labeling of cell types. These resources and approaches allow economic, fast, and efficient cell-type targeting in a variety of species, both for fundamental science and for gene therapy.
Biphasic unbinding of Zur from DNA for transcription (de)repression in Live Bacteria
Authors: Jung Won , Chen Peng
Published: October 2018

Transcription regulator on-off binding to DNA constitutes a mechanistic paradigm in gene regulation, in which the repressors/activators bind to operator sites tightly while the corresponding non-repressors/non-activators do not. Another paradigm regards regulator unbinding from DNA to be a unimolecular process whose kinetics is independent of regulator concentration. Using single-molecule single-cell measurements, we find that the behaviors of the zinc-responsive uptake regulator Zur challenges these paradigms. Apo-Zur, a non-repressor and presumed non-DNA binder, can bind to chromosome tightly in live E. coli cells, likely at non-consensus sequence sites. Moreover, the unbinding from DNA of its apo-non-repressor and holo-repressor forms both show a biphasic, repressed-followed-by-facilitated kinetics with increasing cellular protein concentrations. The facilitated unbinding likely occurs via a ternary complex formation mechanism; the repressed unbinding is first-of-its-kind and likely results from protein oligomerization on chromosome, in which an inter-protein salt-bridge plays a key role. This biphasic unbinding could provide functional advantages in Zur's facile switching between repression and derepression.
Structural insight into TRPV5 channel function and modulation
Authors: Dang Shangyu , van Goor Mark K. , Wang YongQiang , Julius David , Cheng Yifan , van der Wijst Jenny
Published: October 2018

TRPV5 (transient receptor potential vanilloid) is a unique calcium-selective TRP channel that is essential for calcium homeostasis. TRPV5 and its close homologue TRPV6 do not exhibit thermosensitivity or ligand-dependent activation, unlike other TRPV channels, but are constitutively opened at physiological membrane potentials. Here, we report high resolution electron cryo-microscopy (cryo-EM) structures of truncated and full length TRPV5 in lipid nanodisc, as well as a TRPV5 W583A mutant structure and a complex structure of TRPV5 with calmodulin (CaM). These structures highlight and explain functional differences between the thermosensitive and calcium-selective TRPV channels. An extended S1-S2 linker folds on top of the channel that might shield it from modulation by extracellular factors. Resident lipid densities in the homologous vanilloid pocket are different from those previously found in TRPV1, supporting a comparatively more rigid architecture of TRPV5. A ring of tryptophan residues (W583) at the bottom of the pore coordinates a density and mutation of W583 resultes in opening of the lower gate. Moreover, we provide structural insight into the calcium-dependent channel inactivation and propose a flexible stoichiometry for TRPV5 and CaM binding.
Enhancing acute kidney injury regeneration by promoting cellular dedifferentiation in zebrafish
Authors: Skvarca Lauren Brilli , Han Hwa In , Espiritu Eugenel B. , Missinato Maria A. , Rochon Elizabeth R. , McDaniels Michael D. , Roman Beth L. , Waxman Joshua S. , Watkins Simon C. , Davidson Alan J. , Tsang Michael , Hukriede Neil A.
Published: October 2018

Acute kidney injury (AKI) is a serious disorder for which there is no approved pharmaceutical treatment. Following injury, native nephrons display limited regenerative capabilities, relying on the dedifferentiation and proliferation of renal tubular epithelial cells (RTECs) that survive the insult. Previously, we identified 4-(phenylthio)butanoic acid (PTBA), a histone deacetylase inhibitor (HDI) that enhances renal recovery and showed that PTBA treatment increased RTEC proliferation and reduced renal fibrosis. Here, we investigated the regenerative mechanisms of PTBA in zebrafish models of larval renal injury and adult cardiac injury. With respect to renal injury, we showed that delivery of PTBA using an esterified prodrug (UPHD25) increases the reactivation of the renal progenitor gene Pax2a, enhances dedifferentiation of RTECs, reduces Kidney injury molecule-1 expression, and lowers the number of infiltrating macrophages. Further, we find that the effects of PTBA on RTEC proliferation depend upon retinoic acid signaling and demonstrate the therapeutic properties of PTBA are not restricted to the kidney but also increase cardiomyocyte proliferation and decrease fibrosis following cardiac injury in adult zebrafish. These studies provide key mechanistic insights into how PTBA enhances tissue repair in models of acute injury and lay the groundwork for translating this novel HDI into the clinic.

SUMMARY STATEMENT

Mortality associated with acute kidney injury (AKI) is in part due to limited treatments available to ameliorate kidney injury. We identified a compound that enhances AKI recovery by promoting cellular dedifferentiation.