bluuebunny/crossref_metadata_2025_split huggingface dataset:
Reverse engineering neural networks to characterise their cost functions
Authors: Isomura Takuya , Friston Karl 
Published: May 2019

AbstractThis work considers a class of biologically plausible cost functions for neural networks, where the same cost function is minimised by both neural activity and plasticity. We show that such cost functions can be cast as a variational bound on model evidence under an implicit generative model. Using generative models based on Markov decision processes (MDP), we show, analytically, that neural activity and plasticity perform Bayesian inference and learning, respectively, by maximising model evidence. Using mathematical and numerical analyses, we then confirm that biologically plausible cost functions—used in neural networks—correspond to variational free energy under some prior beliefs about the prevalence of latent states that generate inputs. These prior beliefs are determined by particular constants (i.e., thresholds) that define the cost function. This means that the Bayes optimal encoding of latent or hidden states is achieved when, and only when, the network’s implicit priors match the process that generates the inputs. Our results suggest that when a neural network minimises its cost function, it is implicitly minimising variational free energy under optimal or sub-optimal prior beliefs. This insight is potentially important because it suggests that any free parameter of a neural network’s cost function can itself be optimised—by minimisation with respect to variational free energy.
PPPred: Classifying Protein-phenotype Co-mentions Extracted from Biomedical Literature
Authors: Shahri Morteza Pourreza , Roe Mandi M. , Reynolds Gillian , Kahanda Indika 
Published: May 2019

ABSTRACTThe MEDLINE database provides an extensive source of scientific articles and heterogeneous biomedical information in the form of unstructured text. One of the most important knowledge present within articles are the relations between human proteins and their phenotypes, which can stay hidden due to the exponential growth of publications. This has presented a range of opportunities for the development of computational methods to extract these biomedical relations from the articles. However, currently, no such method exists for the automated extraction of relations involving human proteins and human phenotype ontology (HPO) terms. In our previous work, we developed a comprehensive database composed of all co-mentions of proteins and phenotypes. In this study, we present a supervised machine learning approach called PPPred (Protein-Phenotype Predictor) for classifying the validity of a given sentence-level co-mention. Using an in-house developed gold standard dataset, we demonstrate that PPPred significantly outperforms several baseline methods. This two-step approach of co-mention extraction and classification constitutes a complete biomedical relation extraction pipeline for extracting protein-phenotype relations.CCS CONCEPTS•Computing methodologies → Information extraction; Supervised learning by classification; •Applied computing →Bioinformatics;
A deletion in theSTA1promoter determines maltotriose and starch utilization inSTA1+Saccharomyces cerevisiaestrains
Authors: Krogerus Kristoffer , Magalhães Frederico , Kuivanen Joosu , Gibson Brian 
Published: May 2019

AbstractDiastatic strains ofSaccharomyces cerevisiaeare common contaminants in beer fermentations and are capable of producing an extracellularSTA1-encoded glucoamylase. Recent studies have revealed variable diastatic ability in strains tested positive forSTA1,and here we elucidate genetic determinants behind this variation. We show that poorly diastatic strains have a 1162 bp deletion in the promoter ofSTA1. With CRISPR/Cas9-aided reverse engineering, we show that this deletion greatly decreases the ability to grow in beer and consume dextrin, and the expression ofSTA1. New PCR primers were designed for differentiation of highly and poorly diastatic strains based on the presence of the deletion in theSTA1promoter. In addition, using publically available whole genome sequence data, we show that theSTA1gene is prevalent in among the ‘Beer 2’/’Mosaic Beer’ brewing strains. These strains utilize maltotriose efficiently, but the mechanisms for this have been unknown. By deletingSTA1from a number of highly diastatic strains, we show here that extracellular hydrolysis of maltotriose throughSTA1appears to be the dominant mechanism enabling maltotriose use during wort fermentation inSTA1+strains. The formation and retention ofSTA1seems to be an alternative evolutionary strategy for efficient utilization of sugars present in brewer’s wort. The results of this study allow for the improved reliability of molecular detection methods for diastatic contaminants in beer, and can be exploited for strain development where maltotriose use is desired.
Tissue Engineered Axon Tracts Serve as Living Scaffolds to Accelerate Axonal Regeneration and Functional Recovery Following Peripheral Nerve Injury in Rats
Authors: Katiyar Kritika S. , Struzyna Laura A. , Morand Joseph P. , Burrell Justin C. , Clements Basak , Laimo Franco A. , Browne Kevin D. , Kohn Joachim , Ali Zarina , Ledebur Harry C. , Smith Douglas H. , Cullen D. Kacy 
Published: May 2019

AbstractAlthough regeneration of damaged axons in peripheral nerves has long been observed, the mechanisms facilitating this growth are not well characterized. Recently, we demonstrated that host axon regeneration could be greatly enhanced by transplanting engineered living axon tracts to guide outgrowth. Here, we used a model of rat sciatic nerve transection to explore potential mechanisms of this facilitated regeneration and its efficacy in comparison with nerve guidance tubes (NGTs) and autografts. Tissue engineered nerve grafts (TENGs) were developed via “stretch-growth” in mechanobioreactors and consisted of centimeter-scale aligned axonal tracts. Either TENGs, NGTs or autografts (reversed nerve) were then transplanted to bridge a 1 cm segmental gap in the sciatic nerve with the mechanisms of axonal regrowth assessed at 2 weeks and the extent of functional recovery assessed at 16 weeks. We observed numerous host axons growing directly along and intertwining with pre-formed axonal tracts in TENGs. This behavior appears to mimic the action of “pioneer” axons in developmental pathfinding by providing living cues for directed and accelerated outgrowth. Indeed, we found that the rates of axon regeneration were 3-4 fold faster than NGTs and equivalent to autografts. It was also observed that infiltration of host Schwann cells – traditional drivers of peripheral axon regeneration – was both accelerated and progressed directly along TENG axonal tracts. These TENG repairs resulted in levels of functional recovery equivalent to autografts, with each being several fold superior to NGT repairs. This new mechanism – which we term “axon-facilitated axon-regeneration” – may be further exploited to enhance axonal regeneration and functional recovery following neurotrauma.
Brain-synthesized estrogens regulate cortical migration in a sexually divergent manner
Authors: Sellers Katherine J. , Denley Matthew C.S. , Saito Atsushi , Kamiya Atsushi , Srivastava Deepak P. 
Published: May 2019

AbstractEstrogens play an important role in the sexual dimorphisms that occur during brain development, including the neural circuitry that underlies sex-typical and socio-aggressive behaviors. Aromatase, the enzyme responsible for the conversion of androgens to estrogens, is expressed at high levels during early development in both male and female cortices, suggesting a role for brain-synthesized estrogens during corticogenesis. This study investigated how the local synthesis of estrogens affects neurodevelopment of the cerebral cortex, and how this differs in males and females by knockdown expression of the Cyp19a1 gene, which encodes aromatase, between embryonic day 14.5 and postnatal day 0 (P0). The effects of Cyp19a1 knockdown on neural migration was then assessed. Aromatase was expressed in the developing cortex of both sexes, but at significantly higher levels in male than female mice. Under basal conditions, no obvious differences in cortical migration between male and female mice were observed. However, knockdown of Cyp19a1 increased the number GFP-positive cells in the cortical plate, with a concurrent decrease in the subventricular zone/ventricular zone in P0 male mice. The opposite effect was observed in females, with a significantly reduced number of GFP-positive cells migrating to the cortical plate. These findings have important implications for our understanding of the role of fetal steroids for neuronal migration during cerebral cortex development. Moreover, these data indicate that brain-synthesized estrogens regulate radial migration through distinct mechanisms in males and females.
Integrated Single-Cell Analysis of Multicellular Immune Dynamics during Hyper-Acute HIV-1 Infection
Authors: Kazer Samuel W. , Aicher Toby P. , Muema Daniel M. , Carroll Shaina L. , Ordovas-Montanes Jose , Ziegler Carly G. K. , Nyquist Sarah K. , Wong Emily B. , Ismail Nasreen , Dong Mary , Moodley Amber , Dong Krista L. , Ndhlovu Zaza M. , Ndung’u Thumbi , Walker Bruce D. , Shalek Alex K. 
Published: May 2019

ABSTRACTCellular immunity is critical for controlling intracellular pathogens, but the dynamics and cooperativity of the evolving host response to infection are not well defined. Here, we apply single-cell RNA-sequencing to longitudinally profile pre- and immediately post-HIV infection peripheral immune responses of multiple cell types in four untreated individuals. Onset of viremia induces a strong transcriptional interferon response integrated across most cell types, with subsequent pro-inflammatory T cell differentiation, monocyte MHC-II upregulation, and cytolytic killing. With longitudinal sampling, we nominate key intra- and extracellular drivers that induce these programs, and assign their multi-cellular targets, temporal ordering, and duration in acute infection. Two individuals studied developed spontaneous viral control, associated with initial elevated frequencies of proliferating cytotoxic cells, inclusive of a previously unappreciated proliferating natural killer (NK) cell subset. Our study presents a unified framework for characterizing immune evolution during a persistent human viral infection at single-cell resolution, and highlights programs that may drive response coordination and influence clinical trajectory.
Codon Pairs are Phylogenetically Conserved: Codon pairing as a new class of phylogenetic characters
Authors: Miller Justin B. , McKinnon Lauren M. , Whiting Michael F. , Ridge Perry G. 
Published: May 2019

AbstractIdentical codon pairing and co-tRNA codon pairing increase translational efficiency within genes when two codons that encode the same amino acid are located within a ribosomal window. By examining both identical and co-tRNA codon pairing across 23 423 species, we determined that both pairing techniques are phylogenetically informative across all domains of life using either an alignment-free or parsimony framework. We also determined that conserved codon pairing typically has a smaller window size than the length of a ribosome. We also analyzed frequencies of codon pairing for each codon to determine which codons are most likely to pair. The alignment-free method does not require orthologous gene annotations and recovers species relationships that are comparable to other alignment-free techniques. Parsimony generally recovers phylogenies that are more congruent with the established phylogenies than the alignment-free method. However, four of the ten taxonomic groups do not have sufficient ortholog annotations and are therefore recoverable using only the alignment-free methods. Since the recovered phylogenies using only codon pairing largely match established phylogenies and are comparable to other algorithms, we propose that codon pairing biases are phylogenetically conserved and should be considered in conjunction with current techniques in future phylogenomic studies. Furthermore, the phylogenetic conservation of codon pairing indicates that codon pairing plays a greater role in the speciation process than previously acknowledged.AvailabilityAll scripts used to recover and compare phylogenies, including documentation and test files, are freely available on GitHub athttps://github.com/ridgelab/codon_pairing.
Timescales of spontaneous fMRI fluctuations relate to structural connectivity in the brain
Authors: Fallon John , Ward Phil , Parkes Linden , Oldham Stuart , Arnatkevic̆iūtė Aurina , Fornito Alex , Fulcher Ben D. 
Published: May 2019

AbstractIntrinsic timescales of activity fluctuations vary hierarchically across the brain. This variation reflects a broad gradient of functional specialization in information storage and processing, with integrative association areas displaying slower timescales that are thought to reflect longer temporal processing windows. The organization of timescales is associated with cognitive function, distinctive between individuals, and disrupted in disease, but we do not yet understand how the temporal properties of activity dynamics are shaped by the brain’s underlying structural-connectivity network. Using resting-state fMRI and diffusion MRI data from 100 healthy individuals from the Human Connectome Project, here we show that the timescale of resting-state fMRI dynamics increases with structural-connectivity strength, matching recent results in the mouse brain. Our results hold at the level of individuals, are robust to parcellation schemes, and are conserved across a range of different timescale-related statistics. We establish a comprehensive BOLD dynamical signature of structural connectivity strength by comparing over 6000 time-series features, highlighting a range of new temporal features for characterizing BOLD dynamics, including measures of stationarity and symbolic motif frequencies. Our findings indicate a conserved property of mouse and human brain organization in which a brain region’s spontaneous activity fluctuations are closely related to their surrounding structural scaffold.
Enzymatic degradation of biofilm by metalloprotease fromMicrobacteriumsp. SKS10
Authors: Saggu Sandeep Kaur , Jha Gopaljee , Mishra Prakash Chandra 
Published: May 2019

AbstractEnzymes have replaced or decreased usage of toxic chemicals for industrial and medical applications leading towards sustainable chemistry. In this study, we report purification and characterization of a biofilm degrading protease secreted byMicrobacteriumsp. SKS10. The protease was identified as a metalloprotease, Peptidase M16 using mass spectrometry. It showed optimum activity at 60 °C, pH 12 and retained its activity in the presence of various salts and organic solvents. The enzyme was able to degrade biofilms efficiently at enzyme concentration lower than other known enzymes such as papain, trypsin and □-amylase. The presence of this protease increased the accessibility of antibiotics inside the biofilm, and was found to be non-cytotoxic towards human epidermoid carcinoma cells (A431) at the effective concentration for biofilm degradation. Thus, this protease may serve as an effective tool for management of biofilms.
(p)ppGpp and CodY promoteEnterococcus faecalisvirulence in a murine model of catheter-associated urinary tract infection
Authors: Colomer-Winter C , Flores-Mireles AL , Kundra S , Hultgren SJ , Lemos JA 
Published: May 2019

AbstractIn Firmicutes, the nutrient-sensing regulators (p)ppGpp, the effector molecule of the stringent response, and CodY work in tandem to maintain bacterial fitness during infection. Here, we tested (p)ppGpp andcodYmutant strains ofEnterococcus faecalisin a catheter-associated urinary tract infections (CAUTI) mouse model and used global transcriptional analysis to investigate the (p)ppGpp and CodY relationship. Absence of (p)ppGpp or single inactivation ofcodYled to lower bacterial loads in catheterized bladders, and diminished biofilm formation on fibrinogen-coated surfaces underin vitroandin vivoconditions. Single inactivation of the bifunctional (p)ppGpp synthetase/hydrolasereldid not affect virulence supporting previous evidence that association of (p)ppGpp with enterococcal virulence is not dependent on activation of the stringent response. Inactivation ofcodYin the (p)ppGpp0strain restoredE. faecalisvirulence in the CAUTI model as well as the ability to form biofilmsin vitro. Transcriptome analysis revealed that inactivation ofcodYrestores, for the most part, the dysregulated metabolism of (p)ppGpp0cells. While a clear linkage between (p)ppGpp and CodY with expression of virulence factors could not be established, targeted transcriptional analysis indicate that a possible association between (p)ppGpp and c-di-AMP signaling pathways in response to the conditions found in the bladder may plays a role in enterococcal CAUTI. Collectively, this study identifies the (p)ppGpp-CodY network as an important contributor to enterococcal virulence in catheterized mouse bladder and supports that basal (p)ppGpp pools and CodY promote virulence through maintenance of a balanced metabolism during adverse conditions.ImportanceCatheter-associated urinary tract infections (CAUTI) are one of the most frequent types of infection found in the hospital setting that can develop into serious and potentially fatal bloodstream infections. One of the infectious agents that frequently cause complicated CAUTI is the bacteriumEnterococcus faecalis, a leading cause of hospital-acquired infections that are often difficult to treat due to the exceptional multidrug resistance of some isolates. Understanding the mechanisms by whichE. faecaliscauses CAUTI will aid in the discovery of new druggable targets to treat these infections. In this study, we report the importance of two nutrient-sensing bacterial regulators, named (p)ppGpp and CodY, for the ability ofE. faecalisto infect the catheterized bladder of mice.
Novel inducers of the expression of multidrug efflux pumps that triggerPseudomonas aeruginosatransient antibiotic resistance
Authors: Laborda Pablo , Alcalde-Rico Manuel , Blanco Paula , Martínez José Luis , Hernando-Amado Sara 
Published: May 2019

ABSTRACTThe study of the acquisition of antibiotic resistance (AR) has mainly focused in inherited processes, namely mutations and acquisition of AR genes. However, inducible, non-inheritable AR has received less attention and most information in this field derives from the study of antibiotics as inducers of their associated resistance mechanisms. Less is known about non-antibiotic compounds or situations that can induce AR during infection. Multidrug resistance efflux pumps are a category of AR determinants characterized by the tightly regulation of their expression. Their contribution to acquired AR relies in their overexpression. Herein we analyzed potential inducers of the expression of the chromosomally-encodedPseudomonas aeruginosaclinically-relevant efflux pumps, MexCD-OprJ and MexAB-OprM. For this purpose, we developed a set ofluxCDABE-basedP. aeruginosabiosensor strains, which allows the high-throughput analysis of compounds able of modifying the expression of these efflux pumps. Using these strains, we analyzed a set of 240 compounds present in Biolog Phenotype Microarrays. Several inducers of the expression of the genes that encode these efflux pumps were found. The study focused in dequalinium chloride, procaine and atropine, compounds that can be found in clinical settings. Using real-time PCR, we confirmed that these compounds indeed induce the expression ofmexCD-oprJ.In addition,P. aeruginosapresents lower susceptibility to ciprofloxacin (a MexCD-OprJ substrate) when dequalinium chloride, procaine or atropine are present. This work emphasizes the need of studying compounds that can trigger transient AR during antibiotic treatment, a phenotype difficult to discover using classical susceptibility tests.
Genome-resolved viral and cellular metagenomes revealed potential key virus-host interactions in a deep freshwater lake
Authors: Okazaki Yusuke , Nishimura Yosuke , Yoshida Takashi , Ogata Hiroyuki , Nakano Shin-ichi 
Published: May 2019

SummaryMetagenomics has dramatically expanded the known virosphere, but freshwater viral diversity and their ecological interaction with hosts remain poorly understood. Here, we conducted a metagenomic exploration of planktonic dsDNA prokaryotic viruses by sequencing both virion (<0.22 μm) and cellular (0.22–5.0 μm) fractions collected spatiotemporally from a deep freshwater lake (Lake Biwa, Japan). This simultaneously reconstructed 183 complete (i.e., circular) viral genomes and 57 bacterioplankton metagenome-assembled genomes. Analysis of metagenomic read coverage revealed vertical partitioning of the viral community analogous to the vertically stratified bacterioplankton community. The hypolimnetic community was generally stable during stratification, but occasionally shifted abruptly, presumably due to lysogenic induction. Genes involved in assimilatory sulfate reduction were encoded in 20 (10.9%) viral genomes, including those of dominant viruses, and may aid viral propagation in sulfur-limited freshwater systems. Hosts were predicted for 40 (21.9%) viral genomes, encompassing 10 phyla (or classes of Proteobacteria) including ubiquitous freshwater bacterioplankton lineages (e.g., Ca. Fonsibacter and Ca. Nitrosoarchaeum). Comparison with viral genomes derived from published metagenomes revealed viral phylogeographic connectivity in geographically isolated habitats. Notably, analogous to their hosts, actinobacterial viruses were among the most diverse, ubiquitous, and abundant viral groups in freshwater systems, with potential high lytic activity in surface waters.
Taurine promotes axonal regeneration after a complete spinal cord injury in lampreys
Authors: Sobrido-Cameán Daniel , Fernández-López Blanca , Pereiro Natividad , Lafuente Anunciación , Rodicio María Celina , Barreiro-Iglesias Antón 
Published: May 2019

AbstractTaurine is one of the most abundant free amino acids in the brain. It is well known that taurine protects the brain from further damage after a traumatic event. However, only a few ex vivo studies have looked at the possible role of taurine in the regulation of axon regeneration after injury. Here, we aimed to reveal the possible role for taurine in the modulation of axonal regeneration following a complete spinal cord injury (SCI) using lampreys as an animal model. The brainstem of lampreys contains several individually identifiable descending neurons that differ greatly in their capacity for axonal regeneration after SCI. This offers a convenient model to promote or inhibit axonal regrowth in the same in vivo preparation. First, we carried out high performance liquid chromatography experiments to measure taurine levels in the spinal cord following SCI. Our results revealed a statistically significant increase in taurine levels 4 weeks post lesion, which suggested that taurine might have a positive effect on axonal regrowth. Based on these results, we decided to apply an acute taurine treatment at the site of injury to study its effect on axon regeneration. Results from these experiments show that an acute taurine treatment enhances axonal regeneration following SCI in lampreys. This offers a novel way to try to promote axon regeneration after nervous system injuries in mammalian models.