bluuebunny/crossref_metadata_2025 huggingface dataset:
Developmental chromatin restriction of pro-growth gene networks acts as an epigenetic barrier to axon regeneration in cortical neurons
Authors: Venkatesh Ishwariya , Mehra Vatsal , Wang Zimei , Califf Ben , Blackmore Murray G.
Published: February 2018

Axon regeneration in the central nervous system is prevented in part by a developmental decline in the intrinsic regenerative ability of maturing neurons. This loss of axon growth ability likely reflects widespread changes in gene expression, but the mechanisms that drive this shift remain unclear. Chromatin accessibility has emerged as a key regulatory mechanism in other cellular contexts, raising the possibility that chromatin structure may contribute to the age-dependent loss of regenerative potential. Here we establish an integrated bioinformatic pipeline that combines analysis of developmentally dynamic gene networks with transcription factor regulation and genome-wide maps of chromatin accessibility. When applied to the developing cortex, this pipeline detected overall closure of chromatin in sub-networks of genes associated with axon growth. We next analyzed mature CNS neurons that were supplied with various pro-regenerative transcription factors. Unlike prior results with SOX11 and KLF7, here we found that neither JUN nor an activated form of STAT3 promoted substantial corticospinal tract regeneration. Correspondingly, chromatin accessibility in JUN or STAT3 target genes was substantially lower than in predicted targets of SOX11 and KLF7. Finally, we used the pipeline to predict pioneer factors that could potentially relieve chromatin constraints at growth-associated loci. Overall this integrated analysis substantiates the hypothesis that dynamic chromatin accessibility contributes to the developmental decline in axon growth ability and influences the efficacy of pro-regenerative interventions in the adult, while also pointing toward selected pioneer factors as high-priority candidates for future combinatorial experiments.
The origin of the odorant receptor gene family in insects
Authors: Brand Philipp , Robertson Hugh M. , Lin Wei , Pothula Ratnasri , Klingeman William E. , Jurat-Fuentes Juan Luis , Johnson Brian R.
Published: February 2018

The sense of smell enables the detection and discrimination of airborne chemicals via chemosensory receptors that have evolved independently multiple times throughout the tree of life. In insects, the odorant receptor (OR) gene family is the major chemosensory gene family involved in olfaction and its origin has been hypothesized to coincide with the evolution of a terrestrial lifestyle in hexapods. Missbach et al. (2014) challenged this view and suggested that ORs evolved with an ancestral OR co-receptor (Orco) after the origin of terrestriality, hypothesizing that the OR/Orco system is an adaptation to winged flight in insects instead. Building upon this work, we investigated the genomes of basal hexapod and insect lineages including Collembola, Diplura, Archaeognatha, Zygentoma, Odonata, and Ephemeroptera in an effort to identify the origin of the insect OR gene family. While absent from all non-insect hexapod lineages analyzed, ORs are present in all insect genomes. Orco is absent only in the most ancient insect lineage Archaeognatha. A fully functional OR/Orco system was present in our newly generated genome data of the Zygentoma Thermobia domestica. We suggest that ORs did evolve as adaptation to a terrestrial lifestyle outside high-humidity habitats, and not winged flight, representing a key evolutionary novelty in the ancestor of all insects. The OR family is therefore the first known molecular synapomorphy for the Class Insecta.
Laminin heparin-binding peptides promiscuously bind growth factors and enhance diabetic wound healing
Authors: Ishihara Jun , Ishihara Ako , Fukunaga Kazuto , Briquez Priscilla S. , Hubbell Jeffrey A.
Published: February 2018

Laminin, as a key component of the basement membrane extracellular matrix (ECM), regulates tissue morphogenesis. We show that multiple laminin isoforms promiscuously bind to growth factors (GFs) with high affinity, through their heparin binding domains (HBDs) located in the a chain LG domains. Interestingly, these domains also bind to syndecan cell-surface receptors, promoting attachment of fibroblasts and endothelial cells. We next explore application of these multifunctional laminin HBDs in skin healing in the type 2 diabetic mouse. We demonstrate that covalent incorporation of laminin HBDs into fibrin matrix enables the slow-release of GFs. Incorporation of the α33043-3067 laminin HBD significantly enhances in vivo wound-healing efficacy of vascular endothelial cell growth factor (VEGF)-A165 and platelet-derived growth factor (PDGF)-BB, under conditions where the GFs alone in fibrin are inefficacious. This laminin HBD peptide may be clinically useful by improving biomaterials as both GF reservoirs and cell scaffolds, leading to effective tissue regeneration.
Temperature drives Zika virus transmission: evidence from empirical and mathematical models
Authors: Tesla Blanka , Demakovsky Leah R. , Mordecai Erin A. , Ryan Sadie J. , Bonds Matthew H. , Ngonghala Calistus N. , Brindley Melinda A. , Murdock Courtney C.
Published: February 2018

Temperature is a strong driver of vector-borne disease transmission. Yet, for emerging arboviruses we lack fundamental knowledge on the relationship between transmission and temperature. Current models rely on the untested assumption that Zika virus responds similarly to dengue virus, potentially limiting our ability to accurately predict the spread of Zika. We conducted experiments to estimate the thermal performance of Zika virus (ZIKV) in field-derived Aedes aegypti across eight constant temperatures. We observed strong, unimodal effects of temperature on vector competence, extrinsic incubation period, and mosquito survival. We used thermal responses of these traits to update an existing temperature-dependent model to infer temperature effects on ZIKV transmission. ZIKV transmission was optimized at 29°C, and had a thermal range of 22.7°C - 34.7°C. Thus, as temperatures move toward the predicted thermal optimum (29°C) due to climate change, urbanization, or seasonally, Zika could expand north and into longer seasons. In contrast, areas that are near the thermal optimum were predicted to experience a decrease in overall environmental suitability. We also demonstrate that the predicted thermal minimum for Zika transmission is 5°C warmer than that of dengue, and current global estimates on the environmental suitability for Zika are greatly over-predicting its possible range.
Dopamine Detection using Mercaptopropionic Acid and Cysteamine for Electrodes Surface Modiﬁcation
Authors: Khan Muhammad Salman , Asif Afia , Khawaldeh Saed , Tekin Ahmet
Published: February 2018

Gold electrodes are often not suitable for the dopamine measurements as dopamine creates a non-conducting polymer layer on the surface of the electrodes, which leads to the increased amount of electrode passivity with the gradual increase in voltammograms measurement. This work presents the impedance spectroscopy and cyclic-voltammetry comparitive study for dopamine detection with two modiﬁcations for the surface of Au electrodes i.e., (1) Cysteamine and (2) Mercaptopropionic Acid (MPA) for thermally bonded and ultrasonically welded microﬂuidic chips respectively. The effects of optimized tubing selection, bonding techniques, and cleaning methods of the devices with KOH solution played crucial role for improvements in dopamine detection which are observed in results. Furthermore, comparison for the modiﬁcation with unmodiﬁed chips, and ﬁnding the unknown concentration of dopamine solution using ﬂow injection techniques is also illustrated.
Transcranial direct current stimulation over left inferior frontal cortex improves speech fluency in adults who stutter
Authors: Chesters Jennifer , Möttönen Riikka , Watkins Kate E.
Published: February 2018

Stuttering is a neurodevelopmental disorder affecting 5% of children, and persisting in 1% of adults. Promoting lasting fluency improvement in adults who stutter is a particular challenge. Novel interventions to improve outcomes are required, therefore. Previous work in patients with acquired motor and language disorders reported enhanced benefits of behavioural therapies when paired with transcranial direct current stimulation (tDCS). Here, we report the results of the first trial investigating whether tDCS can improve speech fluency in adults who stutter. Thirty adult men who stutter completed a randomized, double-blind, controlled trial of anodal tDCS over left inferior frontal cortex. Fifteen men received 20 minutes of 1-mA tDCS on five consecutive days while speech fluency was temporarily induced using choral and metronome-timed speech. The other 15 men received the same speech fluency intervention with sham stimulation. We predicted that applying anodal tDCS to the left inferior frontal cortex during speech production with temporary fluency inducers would result in longer-lasting fluency improvements. Speech fluency during reading and conversation was assessed at baseline, before and after the stimulation on each day of the five-day intervention, and at 1 and 6 weeks after the end of the intervention. TDCS combined with speech fluency training significantly reduced the percentage of disfluent speech measured 1 week after the intervention compared with fluency intervention alone. At 6 weeks after the intervention, this improvement was maintained during reading but not during conversation. Outcome scores at both post-intervention time points on a clinical assessment tool (the Stuttering Severity Instrument – version 4) also showed significant improvement in the group receiving tDCS compared with the sham group, in whom fluency was unchanged from baseline. We conclude that tDCS combined with behavioural fluency intervention has the capacity to improve fluency in adults who stutter. tDCS thereby offers a potentially useful adjunct to future speech therapy interventions for this population, for whom therapy outcomes are currently limited.
Kaptive Web: user-friendly capsule and lipopolysaccharide serotype prediction forKlebsiellagenomes
Authors: Wick Ryan R , Heinz Eva , Holt Kathryn E , Wyres Kelly L
Published: February 2018

As whole genome sequencing becomes an established component of the microbiologist’s toolbox, it is imperative that researchers, clinical microbiologists and public health professionals have access to genomic analysis tools for rapid extraction of epidemiologically and clinically relevant information. For the gram-negative hospital pathogens such asKlebsiella pneumoniae, initial efforts have focused on detection and surveillance of antimicrobial resistance genes and clones. However, with the resurgence of interest in alternative infection control strategies targetingKlebsiellasurface polysaccharides, the ability to extract information about these antigens is increasingly important.

Here we present Kaptive Web, an online tool for rapid typing ofKlebsiellaK and O loci, which encode the polysaccharide capsule and lipopolysaccharide O antigen, respectively. Kaptive Web enables users to upload and analyse genome assemblies in a web browser. Results can be downloaded in tabular format or explored in detail via the graphical interface, making it accessible for users at all levels of computational expertise.

We demonstrate Kaptive Web’s utility by analysis of >500K. pneumoniaegenomes. We identify extensive K and O locus diversity among 201 genomes belonging to the carbapenemase- associated clonal group 258 (25 K and six O loci). Characterisation of a further 309 genomes indicates that such diversity is common among the multi-drug resistant clones and that these loci represent useful epidemiological markers for strain subtyping. These findings reinforce the need for rapid, reliable and accessible typing methods such as Kaptive Web.

Kaptive Web is available for use at kaptive.holtlab.net and source code is available at github.com/kelwyres/Kaptive-Web.
Metabolic pairing of aerobic and anaerobic production in a one-pot batch cultivation
Authors: Salmela Milla , Lehtinen Tapio , Efimova Elena , Santala Suvi , Mangayil Rahul
Published: February 2018

Background

The versatility of microbial metabolic pathways enables their utilization in vast number of applications. However, the electron and carbon recovery rates, essentially constrained by limitations of cell energetics, are often too low in terms of process feasibility. Cocultivation of divergent microbial species in a single process broadens the metabolic landscape and thus, the possibilities for more complete carbon and energy utilization.

Results

In this study, we integrated the metabolisms of two bacteria, an obligate anaerobeClostridium butyricumand an obligate aerobeAcinetobacter baylyiADP1. In the process, a glucose-negative mutant ofA. baylyiADP1 first deoxidized the culture allowingC. butyricumto grow and produce hydrogen from glucose. In the next phase, ADP1 produced long chain alkyl esters utilizing the by-products ofC. butyricum, namely acetate and butyrate.

Conclusions

The cocultivation of strictly anaerobic and aerobic bacteria allowed the production of both hydrogen gas and long-chain alkyl esters in a simple one-pot batch process. The study demonstrates the potential of ‘metabolic pairing’ using designed microbial consortia for optimal electron and carbon recovery.
The formation of chromatin domains: a new model
Authors: Bernardi Giorgio
Published: February 2018

In spite of the recent advances in the field of chromatin architecture1,2, the formation mechanism of chromatin domains, TADs, the topologically associating domains, and LADs, the lamina associated domains, is still an open problem. While previous models only dealt with TADs and essentially relied on the architectural proteins CTCF and cohesin, the model presented here concerns both TADs and LADs and is primarily based on the corresponding DNA sequences, the GC-rich and GC-poor isochores, more specifically on their newly discovered 3-D structures. Indeed, the compositionally homogeneous GC-poor isochores were shown to be locally stiff because of the presence of interspersed oligo- Adenines4,5, whereas the compositionally heterogeneous GC-rich isochores were found to be peak-shaped and characterized by increasing gradients of GC and of interspersed oligo- Guanines. In LADs, oligo-Adenines induce local nucleosome depletions4,5 that are responsible for a wavy structure well adapted for interaction with the lamina. In TADs, the increasing GC levels and increasing oligo-Guanines of the isochore peaks are responsible for a decreasing nucleosome density5,6, a decreasing supercoiling7 and an increasing accessibility8. These factors mould the loops of “primary TADs”, that lack self-interactions since they are CTCF/cohesin-free, yet transcriptionally functional structures9-11. This “moulding step” is followed by a second step, in which the cohesin rings bind to the tips of the “primary TADs” and slide down the loops. This process is very likely due to Scc2/Nipbl, an essential factor not only for loading cohesin, but also for stimulating its translocation12 and its ATPase activity13. This “sliding step” creates self-interactions in the loops and stops at the CTCF binding sites located at the base of the loops that are thus closed and insulated.
Modulation of defence and iron homeostasis genes in rice roots by the diazotrophic endophyte: Herbaspirillum seropedicae
Authors: Brusamarello-Santos L. C. C , Alberton D. , Valdameri G. , Camilios-Neto D. , Covre R. , Lopes K. , Tadra-Sfeir M. Z. , Faoro H. , Monteiro R. A. , Silva A. B. , Broughton W. J. , Pedrosa F. O. , Wassem R. , Souza E. M.
Published: February 2018

Rice is staple food of nearly half the world’s population. Rice yields must therefore increase to feed ever larger populations. By colonising rice and other plants,Herbaspirillumspp. stimulate plant growth and productivity. However the molecular factors involved are largely unknown. To further explore this interaction, the transcription profiles of Nipponbare rice roots inoculated withHerbaspirillum seropedicaewere determined by RNA-seq. Mapping the 104 million reads against theOryza sativacv. Nipponbare genome produced 65 million unique mapped reads that represented 13,840 transcripts each with at least two-times coverage. About 7.4 % (1,019) genes were differentially regulated and of these 256 changed expression levels more than two times. Several of the modulated genes encoded proteins related to plant defence (e.g. a putative probenazole inducible protein), plant disease resistance as well as enzymes involved in flavonoid and isoprenoid synthesis. Genes related to the synthesis and efflux of phytosiderophores (PS) and transport of PS-iron complexes were also induced by the bacteria. These data suggest that the bacterium represses the rice defence system while concomitantly activating iron uptake. Transcripts ofH. seropedicaewere also detected amongst which genes involved in nitrogen fixation, cell motility and cell wall synthesis were the most expressed.

Highlights

RNASeq ofH. seropedicaecolonised rice roots showed remarkable regulation of defence, metal transport, stress and signalling genes. Fe-uptake genes were highly induced with implications in plant nutrition and immunity.
Selective increases in inter-individual variability in response to environmental enrichment
Authors: Körholz Julia , Zocher Sara , Grzyb Anna N. , Morisse Benjamin , Poetzsch Alexandra , Ehret Fanny , Schmied Christopher , Kempermann Gerd
Published: February 2018

One manifestation of individualization is a progressively differential response of individuals to the non-shared components of the same environment. Individualization has practical implications in clinical setting, where subtle differences between patients are often decisive for the success of an intervention, yet there has been no suitable animal model to study its underlying biological mechanisms. Here we show that enriched environment (ENR) can serve as a model of brain individualization. We kept 40 isogenic mice for 3 months in ENR and compared the effects on a wide range of phenotypes on both mean and variance to an equally sized group of standard-housed control animals. While ENR influenced multiple parameters and restructured correlation patterns between them, it only increased differences among individuals in traits related to brain and behavior (adult hippocampal neurogenesis, motor cortex thickness, open field and object exploration, rotarod performance), in agreement with the hypothesis of a specific activity-dependent development of brain individuality.
Molecular Typing with COI - DNA Barcode of mosquitoes with medical importance from rural area of La Pintada, Antioquia, Colombia
Authors: Hoyos-López Richard
Published: February 2018

DNA barcode is a methodology that allows the identification of species using a short fragment of cytochrome oxidase I and library sequences stored in the barcode of life database (bold>), make up an alternative tool for mosquito identification in areas epidemiologically active for arboviruses, protozoa and bacteria. In our study, we collected 114 adult mosquitoes in a rural area in the municipality of La Pintada (Antioquia, Colombia), and were separate for genus and species using morphological keys. Two Legs were taken of specimens mounted, and these were used for DNA extraction, amplification of COI-Barcode through PCR and sequencing. 38 sequences were characterized of seven mosquito species and used in bold> for molecular identification, subsequent characterization of genetic distances intra/interspecies, and MOTUs grouping by neighbor-joining analyses. Seven MOTUs were separate corresponding to seven species identify by morphological keys. bold> was able to identify five species, and two were identified to the genre. The following medically important mosquitoes were recorded in the rural area from La Pintada(Antioquia): Aedes aegypti, Anopheles triannulatus, Coquillettidia nigricans, Mansonia titillans, Ochlerotatus angustivitatus, Psorophora ferox and Psorophora (Grabhamia)sp.
Structure and mutagenic analysis of the lipid II flippase MurJ from Escherichia coli
Authors: Zheng Sanduo , Sham Lok-To , Rubino Frederick A. , Brock Kelly , Robins William P. , Mekelanos John J. , Marks Debora S. , Bernhardt Thomas G. , Kruse Andrew C.
Published: February 2018

The peptidoglycan cell wall provides an essential protective barrier in almost all bacteria, defining cellular morphology and conferring resistance to osmotic stress and other environmental hazards. The precursor to peptidoglycan, lipid II, is assembled on the inner leaflet of the plasma membrane. However, peptidoglycan polymerization occurs on the outer face of the plasma membrane, and lipid II must be flipped across the membrane by the MurJ protein prior to its use in peptidoglycan synthesis. Due to its central role in cell wall assembly, MurJ is of fundamental importance in microbial cell biology and is a prime target for novel antibiotic development. However, relatively little is known regarding the mechanisms of MurJ function, and structural data are only available for MurJ from the extremophile Thermosipho africanus. Here, we report the crystal structure of substrate-free MurJ from the Gram-negative model organism Escherichia coli, revealing an inward-open conformation. Taking advantage of the genetic tractability of E. coli, we performed high-throughput mutagenesis and next-generation sequencing to assess mutational tolerance at every amino acid in the protein, providing a detailed functional and structural map for the enzyme and identifying sites for inhibitor development. Finally, through the use of sequence co-evolution analysis we identify functionally important interactions in the outward-open state of the protein, supporting a rocker-switch model for lipid II transport.
Protein-ligand interfaces are polarized: Discovery of a strong trend for intermolecular hydrogen bonds to favor donors on the protein side with implications for predicting and designing ligand complexes
Authors: Raschka Sebastian , Wolf Alex J. , Bemister-Buffington Joseph , Kuhn Leslie A.
Published: February 2018

Understanding how proteins encode ligand specificity is fascinating and similar in importance to deciphering the genetic code. For protein-ligand recognition, the combination of an almost infinite variety of interfacial shapes and patterns of chemical groups makes the problem especially challenging. Here we analyze data across non-homologous proteins in complex with small biological ligands to address observations made in our inhibitor discovery projects: that proteins favor donating H-bonds to ligands and avoid using groups with both H-bond donor and acceptor capacity. The resulting clear and significant chemical group matching preferences elucidate the code for protein-native ligand binding, similar to the dominant patterns found in nucleic acid base-pairing. On average, 90% of the keto and carboxylate oxygens occurring in the biological ligands formed direct H-bonds to the protein. A two-fold preference was found for protein atoms to act as H-bond donors and ligand atoms to act as acceptors, and 76% of all intermolecular H-bonds involved an amine donor. Together, the tight chemical and geometric constraints associated with satisfying donor groups generate a hydrogen-bonding lock that can be matched only by ligands bearing the right acceptor-rich key. Measuring an index of H-bond preference based on the observed chemical trends proved sufficient to predict other protein-ligand complexes and can be used to guide molecular design. The resulting Hbind and Protein Recognition Index software packages are being made available for rigorously defining intermolecular H-bonds and measuring the extent to which H-bonding patterns in a given complex match the preference key.

Abbreviations

3D

three-dimensional

CATH

Class Architecture Topology Homologous superfamily

H-bonds

hydrogen bonds

MMFF94

Merck Molecular Force Field

PDB

Protein Data Bank

PRI

Protein Recognition Index
A proteolytic complex targets multiple cell wall hydrolases inPseudomonas aeruginosa
Authors: Srivastava Disha , Seo Jin , Rimal Binayak , Kim Sung Joon , Darwin Andrew J.
Published: February 2018

Carboxy-terminal processing proteases (CTPs) occur in all three domains of life. In bacteria some of them have been associated with virulence. However, the precise roles of bacterial CTPs are poorly understood and few direct proteolytic substrates have been identified. One bacterial CTP is the CtpA protease ofPseudomonas aeruginosa, which is required for type III secretion system function, and for virulence in a mouse model of acute pneumonia. Here, we have investigated the function of CtpA inP. aeruginosaand identified some of the proteins it cleaves. We discovered that CtpA forms a complex with a previously uncharacterized protein, which we have named LbcA (lipoproteinbinding partner ofCtpA). LbcA is required for CtpA activityin vivoand promotes its activityin vitro. We have also identified four proteolytic substrates of CtpA, all of which are uncharacterized proteins predicted to cleave the peptide cross-links within peptidoglycan. Consistent with this, actpAnull mutant was found to have fewer peptidoglycan cross-links than the wild type and grew slowly in salt-free medium. Intriguingly, the accumulation of just one of the CtpA substrates was required for some ΔctpAmutant phenotypes, including the defective T3SS. We propose that LbcA•CtpA is a proteolytic complex in theP. aeruginosacell envelope, which controls the activity of several peptidoglycan cross-link hydrolases by degrading them. Furthermore, based on these and other findings we suggest that many bacterial CTPs might be similarly controlled by partner proteins as part of a widespread mechanism to control peptidoglycan hydrolase activity.

IMPORTANCE

Bacterial carboxy-terminal processing proteases (CTPs) are widely conserved and have been associated with the virulence of several species. However, their roles are poorly understood and few direct substrates have been identified in any species.Pseudomonas aeruginosais an important human pathogen in which one CTP, known as CtpA, is required for type III secretion system function, and for virulence. This work provides an important advance by showing that CtpA works with a previously uncharacterized binding partner to degrade four substrates. These substrates are all predicted to hydrolyze peptidoglycan cross-links, suggesting that the CtpA complex is an important control mechanism for peptidoglycan hydrolysis. This is likely to emerge as a widespread mechanism used by diverse bacteria to control some of their peptidoglycan hydrolases. This is significant, given the links between CTPs and virulence in several pathogens, and the importance of peptidoglycan remodeling to almost all bacterial cells.
Behaviors of individual microtubules and microtubule populations relative to critical concentrations: Dynamic instability occurs when critical concentrations are driven apart by nucleotide hydrolysis
Authors: Jonasson Erin M. , Mauro Ava J. , Li Chunlei , Norby Ellen C. , Mahserejian Shant M. , Scripture Jared P. , Gregoretti Ivan V. , Alber Mark S. , Goodson Holly V.
Published: February 2018

The concept of critical concentration (CC) is central to understanding behaviors of microtubules and other cytoskeletal polymers. Traditionally, these polymers are understood to have one CC, measured multiple ways and assumed to be the subunit concentration necessary for polymer assembly. However, this framework does not incorporate dynamic instability (DI), and there is work indicating that microtubules have two CCs. We use our previously established simulations to confirm that microtubules have (at least) two experimentally relevant CCs and to clarify the behaviors of individuals and populations relative to the CCs. At free subunit concentrations above the lower CC (CCIndGrow), growth phases of individual filaments can occurtransiently; above the higher CC (CCPopGrow), the population’s polymer mass will increasepersistently. Our results demonstrate that most experimental CC measurements correspond to CCPopGrow, meaning “typical” DI occurs below the concentration traditionally considered necessary for polymer assembly. We report that [free tubulin] at steady state does not equal CCPopGrow, but instead approaches CCPopGrowasymptotically as [total tubulin] increases and depends on the number of stable microtubule seeds. We show that the degree of separation between CCIndGrowand CCPopGrowdepends on the rate of nucleotide hydrolysis. This clarified framework helps explain and unify many experimental observations.
Phylogeny Recapitulates Learning: Self-Optimization of Genetic Code
Authors: Attie Oliver , Sulkow Brian , Di Chong , Qiu Wei-Gang
Published: February 2018

Learning algorithms have been proposed as a non-selective mechanism capable of creating complex adaptive systems in life. Evolutionary learning however has not been demonstrated to be a plausible cause for the origin of a specific molecular system. Here we show that genetic codes as optimal as the Standard Genetic Code (SGC) emerge readily by following a molecular analog of the Hebb’s rule (“neurons fire together, wire together”). Specifically, error-minimizing genetic codes are obtained by maximizing the number of physio-chemically similar amino acids assigned to evolutionarily similar codons. Formulating genetic code as a Traveling Salesman Problem (TSP) with amino acids as “cities” and codons as “tour positions” and implemented with a Hopfield neural network, the unsupervised learning algorithm efficiently finds an abundance of genetic codes that are more error-minimizing than SGC. Drawing evidence from molecular phylogenies of contemporary tRNAs and aminoacyl-tRNA synthetases, we show that co-diversification between gene sequences and gene functions, which cumulatively captures functional differences with sequence differences and creates a genomic “memory” of the living environment, provides the biological basis for the Hebbian learning algorithm. Like the Hebb’s rule, the locally acting phylogenetic learning rule, which may simply be stated as increasing phylogenetic divergence for increasing functional difference, could lead to complex and robust life systems. Natural selection, while essential for maintaining gene function, is not necessary to act at system levels. For molecular systems that are self-organizing through phylogenetic learning, the TSP model and its Hopfield network solution offer a promising framework for simulating emerging behavior, forecasting evolutionary trajectories, and designing optimal synthetic systems.
Adaptive stimulus selection for multi-alternative psychometric functions with lapses
Authors: Bak Ji Hyun , Pillow Jonathan W.
Published: February 2018

Psychometric functions (PFs) quantify how external stimuli affect behavior and play an important role in building models of sensory and cognitive processes. Adaptive stimulus selection methods seek to select stimuli that are maximally informative about the PF given data observed so far in an experiment and thereby reduce the number of trials required to estimate the PF. Here we develop new adaptive stimulus selection methods for flexible PF models in tasks with two or more alternatives. We model the PF with a multinomial logistic regression mixture model that incorporates realistic aspects of psychophysical behavior, including lapses and multiple alternatives for the response. We propose an information-theoretic criterion for stimulus selection and develop computationally efficient methods for inference and stimulus selection based on semi-adaptive Markov Chain Monte Carlo (MCMC) sampling. We apply these methods to data from macaque monkeys performing a multi-alternative motion discrimination task, and show in simulated experiments that our method can achieve a substantial speed-up over random designs. These advances will reduce the data needed to build accurate models of multi-alternative PFs and can be extended to high-dimensional PFs that would be infeasible to characterize with standard methods.
Inferring and validating mechanistic models of neural microcircuits based on spike-train data
Authors: Ladenbauer Josef , McKenzie Sam , English Daniel Fine , Hagens Olivier , Ostojic Srdjan
Published: February 2018

The interpretation of neuronal spike train recordings often relies on abstract statistical models that allow for principled parameter estimation and model selection but provide only limited insights into underlying microcircuits. In contrast, mechanistic models are useful to interpret microcircuit dynamics, but are rarely quantitatively matched to experimental data due to methodological challenges. Here we present analytical methods to efficiently fit spiking circuit models to single-trial spike trains. Using derived likelihood functions, we statistically infer the mean and variance of hidden inputs, neuronal adaptation properties and connectivity for coupled integrate-and-fire neurons. Comprehensive evaluations on synthetic data, validations using ground truth in-vitro and in-vivo recordings, and comparisons with existing techniques demonstrate that parameter estimation is very accurate and efficient, even for highly subsampled networks. Our methods bridge statistical, data-driven and theoretical, model-based neurosciences at the level of spiking circuits, for the purpose of a quantitative, mechanistic interpretation of recorded neuronal population activity.
Engineering Lipid Droplet Assembly Mechanisms for Improved Triacylglycerols Accumulation in S. cerevisiae
Authors: Teixeira Paulo Gonçalves , David Florian , Siewers Verena , Nielsen Jens
Published: February 2018

Production of triacylglycerols (TAGs) through microbial fermentation is an emerging alternative to plant and animal-derived sources. The yeast Saccharomyces cerevisiae is a preferred organism for industrial use but has natively a very poor capacity of TAG production and storage. Here, we engineered S. cerevisiae for accumulation of high TAG levels through the use of structural and physiological factors that influence assembly and biogenesis of lipid droplets. First, human and fungal perilipin genes were expressed, increasing TAG content by up to 36% when expressing the human perilipin gene PLIN3. Secondly, expression of the FIT2 homologue YFT2 resulted in a 26% increase in TAG content. Lastly, the genes ERD1 and PMR1 were deleted in order to induce an ER stress response and stimulate lipid droplet formation, increasing TAG content by 72% for Δerd1, with an additive effect for both YFT2 and PLIN3 expression. These new approaches were implemented in previously engineered strains that carry high flux of fatty acid biosynthesis and conversion of acyl-CoA into TAG, resulting in improvements of up to 138% over those high-producing strains without any substantial growth effects or abnormal cell morphology. We find that these approaches are not only a major advancement in engineering S. cerevisiae for TAG production, but also highlight the importance of lipid droplet dynamics for high lipid accumulation in yeast.
Temperature-induced changes in wheat phosphoproteome reveal temperature-regulated interconversion of phosphoforms
Authors: Vu Lam Dai , Zhu Tingting , Verstraeten Inge , van de Cotte Brigitte ,   IWGSC, Gevaert Kris , Smet Ive De
Published: February 2018

Wheat (Triticum ssp.) is one of the most important human food sources. However, this crop is very sensitive to temperature changes. Specifically, processes during wheat leaf, flower and seed development and photosynthesis, which all contribute to the yield of this crop, are affected by high temperature. While this has to some extent been investigated on physiological, developmental and molecular levels, very little is known about early signalling events associated with an increase in temperature. Phosphorylation-mediated signalling mechanisms, which are quick and dynamic, are associated with plant growth and development, also under abiotic stress conditions. Therefore, we probed the impact of a short-term increase in temperature on the wheat leaf and spikelet phosphoproteome. The resulting data set provides the scientific community with a first large-scale plant phosphoproteome under the control of higher ambient temperature, which will be valuable for future studies. Our analyses also revealed a core set of common proteins between leaf and spikelet, suggesting some level of conserved regulatory mechanisms. Furthermore, we observed temperature-regulated interconversion of phosphoforms, which likely impacts protein activity.
Concentration of 2’C-methyladenosine triphosphate byLeishmania guyanensisenables specific inhibition ofLeishmaniaRNA virus 1 via its RNA polymerase
Authors: Robinson John I. , Beverley Stephen M.
Published: February 2018

Leishmaniais a widespread trypanosomatid protozoan parasite causing significant morbidity and mortality in humans. The endobiont dsRNA virusLeishmaniaRNA virus 1 (LRV1) chronically infects some strains, where it increases parasite numbers and virulence in murine leishmaniasis models, and correlates with increased treatment failure in human disease. Previously, we reported that 2’-C-methyladenosine (2CMA) potently inhibited LRV1 inLeishmania guyanensis(Lgy) andL. braziliensis, leading to viral eradication at concentrations above 10 µM. Here we probed the cellular mechanisms of 2CMA inhibition, involving metabolism, accumulation and inhibition of the viral RNA dependent RNA polymerase (RDRP). Activation to 2CMA triphosphate (2CMATP) was required, as 2CMA showed no inhibition of RDRP activity from virions purified on cesium chloride gradients. In contrast, 2CMA-TP showed IC50s ranging from 150 to 910 µM, depending on the CsCl density of the virion (empty, ssRNA- and dsRNA-containing).Lgyparasites incubatedin vitrowith 10 µM 2CMA accumulated 2CMA-TP to 410 µM, greater than the most sensitive RDRP IC50 measured. Quantitative modeling showed good agreement between the degree of LRV1 RDRP inhibition and LRV1 levels. These results establish that 2CMA activity is due to its conversion to 2CMA-TP, which accumulates to levels that inhibit RDRP and cause LRV1 loss. This attests to the impact of the Leishmania purine uptake and metabolism pathways, which allow even a weak RDRP inhibitor to effectively eradicate LRV1 at micromolar concentrations. Future RDRP inhibitors with increased potency may have potential therapeutic applications for ameliorating the increased Leishmania pathogenicity conferred by LRV1.
DROSHA associates to DNA damage sites and is required for DNA repair
Authors: Cabrini Matteo , Roncador Marco , Galbiati Alessandro , Cipolla Lina , Iannelli Fabio , Sabbioneda Simone , Fagagna Fabrizio d’Adda di , Francia Sofia
Published: February 2018

The DNA damage response (DDR) is the signaling cascade through which a cell recognizes DNA lesions, and promotes their resolution via the repair pathways of Non-Homologous End Joining (NHEJ), or Homologous Recombination (HR). We recently demonstrated that DROSHA boosts DDR signaling by processing damage-induced long non-coding RNAs into smaller DNA damage response RNAs (DDRNAs). However, the location at which DROSHA exerts its DDR functions, relative to sites of DNA damage, remains unknown.

To investigate DROSHA’s localization during DDR activation, we used the DiVA cellular system, which allows the controlled induction of several DNA double strand breaks (DSBs) in the human genome. Indeed, by genome wide chromatin immunoprecipitation followed by next generation sequencing, we demonstrate that DROSHA associates with DSBs. In support of this, DSB-recruitment of DROSHA is detectable at the single-cell level by Proximity Ligation Assay between DROSHA and known DDR markers, and by DNA damage in situ ligation followed by Proximity Ligation Assay (DI-PLA), which demonstrates proximity of DROSHA to DNA ends. DROSHA recruitment occurs at both genic and inter-genic DSBs, suggesting that its recruitment is independent from ongoing transcription preceding damage generation. DROSHA’s recruitment to DNA lesions occurs throughout the cell cycle, and with a preference for NHEJ-prone DSBs. Consistently, inhibition of the HR pathway increases DROSHA recruitment, and DROSHA knock down strongly impairs NHEJ efficiency in a GFP-reporter cellular system for monitoring NHEJ DNA repair. Overall, these results demonstrate that DROSHA acts locally at sites of DNA damage to promote NHEJ DNA repair.
Multiplexed enrichment and genomic profiling of peripheral immune cell subsets on a microfluidic chip
Authors: Reyes Miguel , Vickers Dwayne , Billman Kianna , Eisenhaure Thomas , Hoover Paul , Browne Edward , Rao Deepak A. , Hacohen Nir , Blainey Paul C.
Published: February 2018

The human immune system consists of many specialized cell subsets that simultaneously carry out a diverse range of functions using overlapping pathways and signals. Subset-specific immune profiling can resolve immune activity in autoimmune disease, cancer immunity, and infectious disease that may not be discoverable or detectable in analyses of crude blood samples. The activity of specific subsets may help predict the course of disease and response to therapy in certain patient populations. Here, we present a low-input microfluidic system for sorting immune cells into subsets and profiling their cellular states by gene expression analysis using full-length RNA-seq. Our system is robust and has the potential to make multiplexed subset-specific analysis routine in many research laboratories and clinical settings. We validate the device’s technical performance by benchmarking its subset enrichment and genomic profiling performance against standard protocols. We make the added value of subset-resolved profiling over crude samples clear throughex vivoexperiments that show subset-specific stimulated responses. Finally, we demonstrate the scalability of our device by profiling four immune cell subsets in blood from systemic lupus erythematosus (SLE) patients and matched controls enrolled in a clinical study. The results from our initial cohort confirm the role of type I interferons in lupus pathogenesis and further show that the canonical interferon signature for SLE is prominent in B cells, demonstrating the ability of our integrated analytical platform to identify cell-specific disease signatures.
Emergence of Human Amygdala Functional Networks: 3 Months to 5 Years of Age
Authors: Gabard-Durnam L.J. , O’Muircheartaigh J. , Dirks H. , Dean D.C. , Tottenham N. , Deoni S.
Published: February 2018

Although the amygdala’s role in shaping social behavior is especially important during early post-natal development, very little is known of human amygdala functional development before childhood. To address this important gap, this study used resting-state fMRI to examine early functional network development of the amygdala and its subregions in 80 participants from 3-months to 5-years of age. Whole brain functional connectivity with the whole amygdala and its laterobasal and superficial nuclear groups were largely similar to those seen in older children and adults, and functional distinctions between subregion networks exist already. These patterns suggest many amygdala functional circuits are intact from infancy, especially those that are part of larger motor, visual, auditory and subcortical (basal ganglia especially) networks. Notably, these observed robust amygdala functional networks in infancy precede reports to date of elicited amygdala reactivity in development. Developmental changes in connectivity were observed between the laterobasal nucleus and bilateral ventral temporal and motor cortex as well as between the superficial nuclei and medial thalamus, occipital cortex and a different region of motor cortex. These results show amygdala-subcortical and sensory-cortex connectivity begins refinement prior to childhood, though connectivity changes with associative and frontal cortical areas, seen after early childhood, were not evident in this age range. These findings represent early steps in understanding amygdala network dynamics across infancy through early childhood, an important period of emotional and cognitive development.
NeoDTI: Neural integration of neighbor information from a heterogeneous network for discovering new drug-target interactions
Authors: Wan Fangping , Hong Lixiang , Xiao An , Jiang Tao , Zeng Jianyang
Published: February 2018

Motivation

Accurately predicting drug-target interactions (DTIs) in silico can guide the drug discovery process and thus facilitate drug development. Computational approaches for DTI prediction that adopt the systems biology perspective generally exploit the rationale that the properties of drugs and targets can be characterized by their functional roles in biological networks.

Results

Inspired by recent advance of information passing and aggregation techniques that generalize the convolution neural networks (CNNs) to mine large-scale graph data and greatly improve the performance of many network-related prediction tasks, we develop a new nonlinear end-to-end learning model, called NeoDTI, that integrates diverse information from heterogeneous network data and automatically learns topology-preserving representations of drugs and targets to facilitate DTI prediction. The substantial prediction performance improvement over other state-of-the-art DTI prediction methods as well as several novel predicted DTIs with evidence supports from previous studies have demonstrated the superior predictive power of NeoDTI. In addition, NeoDTI is robust against a wide range of choices of hyperparameters and is ready to integrate more drug and target related information (e.g., compound-protein binding affinity data). All these results suggest that NeoDTI can offer a powerful and robust tool for drug development and drug repositioning.

Availability and implementation

The source code and data used in NeoDTI are available at: https://github.com/FangpingWan/NeoDTI.

Contact

zengjy321@tsinghua.edu.cn

Supplementary information

Supplementary data are available at Bioinformatics online.
Reversing Glial Scar Back To Neural Tissue Through NeuroD1-Mediated Astrocyte-To-Neuron Conversion
Authors: Zhang Lei , Lei Zhuofan , Guo Ziyuan , Pei Zifei , Chen Yuchen , Zhang Fengyu , Cai Alice , Mok Yung Kin , Lee Grace , Swaminnathan Vishal , Wang Fan , Bai Yuting , Chen Gong
Published: February 2018

Nerve injury often causes neuronal loss and glial proliferation, disrupting the delicate balance between neurons and glial cells in the brain. Recently, we have developed an innovative technology to convert internal reactive glial cells into functional neurons inside the mouse brain. Here, we further demonstrate that such glia-to-neuron conversion can rebalance neuron-glia ratio and reverse glial scar back to neural tissue. Specifically, using a severe stab injury model in the mouse cortex, we demonstrated that ectopic expression of NeuroD1 in reactive astrocytes significantly reduced glial reactivity and transformed toxic A1 astrocytes into less harmful astrocytes before neuronal conversion. Importantly, astrocytes were not depleted after neuronal conversion but rather repopulated due to its intrinsic proliferation capability. Remarkably, converting reactive astrocytes into neurons also significantly reduced microglia-mediated neuroinflammation. Moreover, accompanying regeneration of new neurons together with repopulation of new astrocytes, blood-brain-barrier was restored and synaptic density was rescued in the injury sites. Together, these results demonstrate that glial scar can be reversed back to neural tissue through rebalancing neuron:glia ratio after glia-to-neuron conversion.