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Rxivist combines preprints from bioRxiv with data from Twitter to help you find the papers being discussed in your field. Currently indexing 48,100 bioRxiv papers from 215,661 authors.

Most tweeted bioRxiv papers, last 24 hours

390 results found. For more information, click each entry to expand.

181: Osteocytes remodel bone by TGF-β-induced YAP/TAZ signaling
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Posted to bioRxiv 17 Apr 2019

Osteocytes remodel bone by TGF-β-induced YAP/TAZ signaling
1 tweet cell biology

Christopher D. Kegelman, Jennifer C Coulombe, Kelsey M Jordan, Daniel J Horan, Ling D Qin, Alexander G. Robling, Virginia L Ferguson, Teresita M. Bellido, Joel D. Boerckel

Osteocytes are bone matrix-entombed cells that form an interconnected network of processes called the lacunar/canalicular system, which enables osteocytes to coordinate bone formation and resorption. Osteocytes indirectly regulate osteoblast and osteoclast activity on bone surfaces but also directly resorb and deposit their surrounding bone matrix through perilacunar/canalicular remodeling. However, the molecular mechanisms by which osteocytes control bone remodeling remain unclear. We previously reported that the transcriptional regulators Yes-associated protein (YAP) and Transcriptional co-activator with PDZ-motif (TAZ) promote bone acquisition in osteoblast-lineage cells. Here, we tested the hypothesis that YAP and TAZ regulate osteocyte-mediated bone remodeling by conditional ablation of both YAP and TAZ from mouse osteocytes using 8kb-DMP1-Cre. Osteocyte conditional YAP/TAZ deletion reduced bone mass and dysregulated matrix collagen content and organization, which together impaired bone mechanical properties. YAP/TAZ deletion reduced osteoblast number and activity and increased osteoclast activity. In addition, YAP/TAZ deletion directly impaired osteocyte lacunar/canalicular network remodeling, reducing canalicular density, length, and branching, but did not alter lacunar size or shape. Further, consistent with recent studies identifying TGF-β signaling as a key inducer of perilacunar/canalicular remodeling through expression of matrix-remodeling enzymes, YAP/TAZ deletion in vivo decreased osteocyte expression of matrix proteases Mmp13, Mmp14, and Cathepsin K. In vitro, pharmacologic inhibition of YAP/TAZ transcriptional activity in osteocyte-like cells abrogated TGF-β-induced protease gene expression. Together, these data show that YAP and TAZ act downstream of TGF-β in osteocytes to control bone matrix accrual, organization, and mechanical properties indirectly by coordinating osteoblast/osteoclast activity and directly by regulating perilacunar/canalicular remodeling.

182: ANKLE2, a target of Zika virus, controls asymmetric cell division of neuroblasts and uncovers a novel microcephaly pathway
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Posted to bioRxiv 17 Apr 2019

ANKLE2, a target of Zika virus, controls asymmetric cell division of neuroblasts and uncovers a novel microcephaly pathway
1 tweet genetics

Nichole Link, Hyunglok Chung, Angad Jolly, Marjorie Withers, Burak Tepe, Benjamin R. Arenkiel, Priya S Shah, Nevan J. Krogan, Hatip Aydin, Bilgen B. Geckinli, Tulay Tos, Sedat Isikay, Beyhan Tuysuz, Ganesh H. Mochida, Ajay X. Thomas, Robin D. Clark, Ghayda M Mirzaa, James R. Lupski, Hugo J Bellen

Neuroblasts in flies divide asymmetrically by establishing polarity, distributing cell fate determinants asymmetrically, and positioning their spindle for cell division. The apical complex contains aPKC, Bazooka (Par3), and Par6, and its activity depends on L(2)gl. We show that Ankle2 interacts with L(2)gl and affects aPKC. Reducing Ankle2 levels disrupts ER and nuclear envelope morphology, releasing the kinase Ballchen/VRK1 into the cytosol. These defects are associated with reduced phosphorylation of aPKC, disruption of Par complex localization, and spindle alignment defects. Importantly, removal of one copy of ballchen/VRK1 or l(2)gl suppresses the loss of Ankle2 and restores viability and brain size. The Zika virus NS4A protein interacts with Drosophila Ankle2 and VRK1 in dividing neuroblasts. Human mutational studies implicate this neural cell division pathway in microcephaly and motor neuron disease. In summary, NS4A, ANKLE2, VRK1 and LLGL1 define a novel pathway that impinges on asymmetric determinants of neural stem cell division.

183: Exercise enhances motor skill learning by neurotransmitter switching in the adult midbrain
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Posted to bioRxiv 18 Apr 2019

Exercise enhances motor skill learning by neurotransmitter switching in the adult midbrain
1 tweet neuroscience

Hui-quan Li, Nicholas C Spitzer

Physical exercise promotes motor skill learning in normal individuals and those with neurological disorders but its mechanism of action is unclear. We found that one week of voluntary wheel running enhances the acquisition of motor skills in adult mice. One week of running also induces switching from ACh to GABA expression in neurons in the caudal pedunculopontine nucleus (cPPN). The switching neurons make projections to the substantia nigra (SN), ventral tegmental area (VTA) and ventrolateral-ventromedial nuclei of the thalamus (VL-VM), which regulate acquisition of motor skills. Use of viral vectors to override transmitter switching blocks the beneficial effect of running on motor skill learning. We suggest that neurotransmitter switching provides the basis by which sustained running benefits motor skill learning, presenting a new target for clinical treatment of movement disorders.

184: K-FIT: An accelerated kinetic parameterization algorithm using steady-state fluxomic data
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Posted to bioRxiv 18 Apr 2019

K-FIT: An accelerated kinetic parameterization algorithm using steady-state fluxomic data
1 tweet systems biology

Saratram Gopalakrishnan, Satyakam Dash, Costas Maranas

Kinetic models predict the metabolic flows by directly linking metabolite concentrations and enzyme levels to reaction fluxes. Robust parameterization of organism-level kinetic models that faithfully reproduce the effect of different genetic or environmental perturbations remains an open challenge due to the intractability of existing algorithms. This paper introduces K-FIT, an accelerated kinetic parameterization workflow that leverages a novel decomposition approach to identify steady-state fluxes in response to genetic perturbations followed by a gradient-based update of kinetic parameters until predictions simultaneously agree with the fluxomic data in all perturbed metabolic networks. The applicability of K-FIT to large-scale models is demonstrated by parameterizing an expanded kinetic model for E. coli (307 reactions and 258 metabolites) using fluxomic data from six mutants. The achieved thousand-fold speed-up afforded by K-FIT over meta-heuristic approaches is transformational enabling follow-up robustness of inference analyses and optimal design of experiments to inform metabolic engineering strategies.

185: ChIA-DropBox: a novel analysis and visualization pipeline for multiplex chromatin interactions
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Posted to bioRxiv 18 Apr 2019

ChIA-DropBox: a novel analysis and visualization pipeline for multiplex chromatin interactions
1 tweet bioinformatics

Simon Zhongyuan Tian, Daniel Capurso, Minji Kim, Byoungkoo Lee, Meizhen Zheng, Yijun Ruan

ChIA-Drop is a new experimental method for mapping multiplex chromatin interactions with single-molecule precision by barcoding chromatin complexes inside microfluidics droplets, followed by pooled DNA sequencing. The chromatin DNA reads with the same droplet-specific barcodes are inferred to be derived from the same chromatin interaction complex. Here, we describe an integrated computational pipeline, named ChIA-DropBox, that is specifically designed for reconstructing chromatin reads in each droplet and refining multiplex chromatin complexes from raw ChIA-Drop sequencing reads, and then visualizing the results. First, ChIA-DropBox maps and filters sequencing reads, and then reconstructs the chromatin droplets by parsing the barcode sequences and grouping together chromatin reads with the same barcode. Based on the concept of chromosome territories that most chromatin interactions take place within the same chromosome, potential mixing up of chromatin complexes derived from different chromosomes could be readily identified and separated. Accordingly, ChIA-DropBox refines these chromatin droplets into purely intra-chromosomal chromatin complexes, ready for downstream analysis. For visualization, ChIA-DropBox converts the ChIA-Drop data to pairwise format and automatically generates input files for viewing 2D contact maps in Juicebox and viewing loops in BASIC Browser. Finally, ChIA-DropBox introduces a new browser, named ChIA-View, for interactive visualization of multiplex chromatin interactions.

186: Hippocampal network reorganization underlies the formation of a temporal association memory
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Posted to bioRxiv 18 Apr 2019

Hippocampal network reorganization underlies the formation of a temporal association memory
1 tweet neuroscience

Mohsin S. Ahmed, James B Priestley, Angel Castro, Fabio Stefanini, Elizabeth M Balough, Erin Lavoie, Luca Mazzucato, Stefano Fusi, Attila Losonczy

Episodic memory requires linking events in time, a function dependent on the hippocampus. In ``trace'' fear conditioning, animals learn to associate a neutral cue with an aversive stimulus despite their separation in time by a delay period on the order of tens of seconds. But how this temporal association forms remains unclear. Here we use 2-photon calcium imaging to track neural population dynamics over the complete time-course of learning and show that, in contrast to previous theories, the hippocampus does not generate persistent activity to bridge the time delay. Instead, learning is concomitant with broad changes in the active neural population in CA1. While neural responses were highly stochastic in time, cue identity could be reliably read out from population activity rates over longer timescales after learning. These results question the ubiquity of neural sequences during temporal association learning, and suggest that trace fear conditioning relies on mechanisms that differ from persistent activity accounts of working memory.

187: Environmental variation mediates the evolution of anticipatory parental effects
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Posted to bioRxiv 18 Apr 2019

Environmental variation mediates the evolution of anticipatory parental effects
1 tweet evolutionary biology

Martin I Lind, Martyna K Zwoińska, Johan Andersson, Hanne Carlsson, Therese Krieg, Tuuli Larva, Alexei Maklakov

Environments vary over time and if this variation is predictable, environments that are similar across generations should favour evolution of anticipatory parental effects to benefit offspring. In contrast, the absence of correlation between parental and offspring environments should select against parental effects. However, experimental evidence is scarce. We investigated the evolution of maternal effects using experimental evolution. Populations of the nematode Caenorhabditis remanei, adapted to 20°C, were exposed to a novel temperature (25°C) for 30 generations with either positive or zero correlation between parent and offspring temperature. We found that populations evolving in environments with positive correlations had a positive maternal effect, since they required maternal exposure to 25°C to achieve maximum reproduction and fitness in 25°C. In contrast, populations evolving under zero correlation had lost this positive maternal effect. This shows that parental effects can aid population viability in warming environments. Correspondingly, ill-fitting parental effects can be rapidly lost.

188: Diversity begets diversity in microbiomes
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Posted to bioRxiv 18 Apr 2019

Diversity begets diversity in microbiomes
1 tweet evolutionary biology

Naïma Jesse Madi, Michiel Vos, Pierre Legendre, B. Jesse Shapiro

Microbes are embedded in complex microbiomes where they engage in a wide array of interspecific interactions. However, how these interactions shape diversification, and ultimately biodiversity, is not well understood. Two competing hypotheses have been put forward to explain how species interactions could influence diversification rates. Ecological Controls (EC) predicts a negative diversity-diversification relationship, where the evolution of novel types becomes constrained as available niches become filled. Diversity Begets Diversity (DBD) predicts a positive relationship, with diversity promoting diversification via niche construction and other species interactions. Using the Earth Microbiome Project, the largest standardized survey of global biodiversity to date, we provide support for DBD as the dominant driver of microbiome diversity. Only in the most diverse microbiomes does DBD reach a plateau, presumably because of increasingly saturated niche space. Genera that are strongly associated with particular biomes show a stronger DBD relationship than non-residents, consistent with prolonged evolutionary interactions driving diversification. Genera with larger genomes also experience a stronger DBD response, which could be due to a higher potential for metabolic interactions and niche construction. Our results provide evidence that microbiome diversity -- and its potential for future diversification -- is crucially shaped by species interactions.

189: Combined behavioral and electrophysiological evidence for a direct cortical effect of prefrontal tDCS on disorders of consciousness
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Posted to bioRxiv 18 Apr 2019

Combined behavioral and electrophysiological evidence for a direct cortical effect of prefrontal tDCS on disorders of consciousness
1 tweet neuroscience

Bertrand Hermann, Federico Raimondo, Lukas A Hirsch, Yu Huang, Melanie Denis-Valente, Pauline Perez, Denis-Alexander Engemann, Frederic Faugeras, Nicolas Weiss, Sophie Demeret, Benjamin Rohaut, Lucas C Parra, Jacobo D Sitt, Lionel Naccache

Severe brain injuries can lead to long-lasting disorders of consciousness (DoC) such as vegetative state/unresponsive wakefulness syndrome (VS/UWS) or minimally conscious state (MCS). While behavioral assessment remains the gold standard to determine conscious state, EEG has proven to be a promising complementary tool to monitor the effect of new therapeutics. Encouraging results have been obtained with invasive electrical stimulation of the brain, and recent studies identified transcranial direct current stimulation (tDCS) as an effective approach in randomized controlled trials. This non-invasive and inexpensive tool may turn out to be the preferred treatment option. However, its mechanisms of action and physiological effects on brain activity remain unclear and debated. Here, we stimulated 60 DoC patients with the anode placed over left-dorsolateral prefrontal cortex in an open-label study. Clinical behavioral assessment improved in twelve patients (20%) and none deteriorated. This behavioral response after tDCS coincided with an enhancement of putative EEG markers of consciousness: in comparison with non-responders, responders showed increases of power and long-range cortico-cortical functional connectivity in the theta-alpha band, and a larger and more sustained P300 suggesting improved conscious access to auditory novelty. The EEG changes correlated with electric fields strengths in prefrontal cortices, and no correlation was found on the scalp. Taken together, this prospective intervention in a large cohort of DoC patients strengthens the validity of the proposed EEG signatures of consciousness, and is suggestive of a direct causal effect of tDCS on consciousness.

190: Nerve Excitability Differences in Slow and Fast Motor Axons of the Rat: more than just Ih
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Posted to bioRxiv 18 Apr 2019

Nerve Excitability Differences in Slow and Fast Motor Axons of the Rat: more than just Ih
1 tweet neuroscience

James M Bell, Chad Lorenz, Kelvin E Jones

Objective: The objective was to determine if choice of anaesthetic confounded previous conclusions about the differences in nerve excitability indices between fast and slow motor axons. Methodology: Nerve excitability of the rat sciatic nerve was tested while measuring responses of motor axons innervating the slow-twitch soleus (SOL) and fast-twitch tibialis anterior (TA) muscles. The experiments were conducted with sodium pentobarbital (SP) anaesthetic and compared to previous results that used ketamine-xylazine (KX). Results and Conclusions: Previous conclusions about the differences in nerve excitability indices between TA and SOL motor axons using KX were corroborated and extended when experiments were done with SP. Nerve excitability indices sensitive to changes in hyperpolarization-activated inwardly rectifying cation current (I_h) indicated an increase in I_h in SOL axons compared to TA axons (e.g. S3 (-100%), t=7.949 (df=10),p<0.0001; TEh (90-100 ms), t=2.659 (df=20), p=0.0145; hyperpolarizing I/V slope, t=4.308 (df=19), p=0.0004). SOL axons also had a longer strength-duration time constant (t=3.35 (df=20), p=0.0032) and a longer and larger magnitude relative refractory period (RRP (ms) t=3.53 (df=12), p=0.0041; Refractoriness at 2 ms t=0.0055 (df=9), p=0.0055). Anaesthetic choice affected many measures of peripheral nerve excitability with differences most apparent in tests of threshold electrotonus and recovery cycle. For example, recovery cycle with KX lacked a clear superexcitable and late subexcitable period. We conclude that KX had a confounding effect on nerve excitability results consistent with ischaemic depolarization. Results using SP revealed the full extent of differences in nerve excitability measures between putative slow and fast motor axons of the rat. These differences have important implications for the use of nerve excitability measures during processes such as ageing where it is believed that there is a selective loss of fast axons.

191: Automated analysis of large-scale NMR data generates metabolomic signatures and links them to candidate metabolites
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Posted to bioRxiv 18 Apr 2019

Automated analysis of large-scale NMR data generates metabolomic signatures and links them to candidate metabolites
1 tweet bioinformatics

Bita Khalili, Mattia Tomasoni, Mirjam Mattei, Roger Mallol Parera, Reyhan Sonmez, Daniel Krefl, Rico Rueedi, Sven Bergmann

Identification of metabolites in large-scale 1H NMR data from human biofluids remains challenging due to the complexity of the spectra and their sensitivity to pH and ionic concentrations. In this work, we test the capacity of three analysis tools to extract metabolite signatures from 968 NMR profiles of human urine samples. Specifically, we studied sets of co-varying features derived from Principal Component Analysis (PCA), the Iterative Signature Algorithm (ISA) and Averaged Correlation Profiles (ACP), a new method we devised inspired by the STOCSY approach. We used our previously developed metabomatching method to match the sets generated by these algorithms to NMR spectra of individual metabolites available in public databases. Based on the number and quality of the matches we concluded that both ISA and ACP can robustly identify about a dozen metabolites, half of which were shared, while PCA did not produce any signatures with robust matches.

192: Lapses in perceptual judgments reflect exploration
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Posted to bioRxiv 19 Apr 2019

Lapses in perceptual judgments reflect exploration
1 tweet neuroscience

Sashank Pisupati, Lital Chartarifsky-Lynn, Anup Khanal, Anne K. Churchland

During perceptual decision making, subjects often display a constant rate of errors independent of evidence strength, referred to as lapses. Their proper treatment is crucial for accurate estimation of perceptual parameters, however they are often treated as a nuisance arising from motor errors or inattention. Here, we propose that lapses can instead reflect a dynamic form of exploration. We demonstrate that perceptual uncertainty modulates the probability of lapses both across and within modalities on a multisensory discrimination task in rats. These effects cannot be accounted for by inattention or motor error, however they are concisely explained by uncertainty-guided exploration. We confirm the predictions of the exploration model by showing that changing the magnitude or probability of reward associated with one of the decisions selectively affects the lapses associated with that decision in uncertain conditions, while leaving sure-bet decisions unchanged, as predicted by the model. Finally, we demonstrate that muscimol inactivations of secondary motor cortex and posterior striatum affect lapses asymmetrically across modalities. The inactivations can be captured by a devaluation of actions corresponding to the inactivated side, and do not affect sure-bet decisions. Together, our results suggest that far from being a nuisance, lapses are informative about subjects' action values, and deficits thereof, during perceptual decisions.

193: Organization of Associating or Crosslinked Actin Filaments in Confinement
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Posted to bioRxiv 19 Apr 2019

Organization of Associating or Crosslinked Actin Filaments in Confinement
1 tweet biophysics

Maral Adeli Koudehi, Dimitrios Vavylonis

A key factor of actin cytoskeleton organization in cells is the interplay between the dynamical properties of actin filaments and cell geometry, which restricts, confines and directs their orientation. Crosslinking interactions among actin filaments, together with geometrical cues and regulatory proteins can give rise to contractile rings in dividing cells and actin rings in neurons. Motivated by recent in vitro experiments, in this work we performed computer simulations to study basic aspects of the interplay between confinement and attractive interactions between actin filaments. We used a spring-bead model and Brownian dynamics to simulate semiflexible actin filaments that polymerize in a confining sphere with a rate proportional to the monomer concentration. We model crosslinking, or attraction through the depletion interaction, implicitly as an attractive short-range potential between filament beads. In confining geometries smaller than the persistence length of actin filaments, we show rings can form by curving of filaments of length comparable to, or longer than the confinement diameter. Rings form for optimal range of attractive interactions that exist in between open bundles, irregular loops, aggregated and unbunbulded morphologies. The probability of ring formation is promoted by attraction to the confining sphere boundary and decreases for large radii and initial monomer concentrations, in agreement with prior experimental data. The model reproduces ring formation along the flat axis of oblate ellipsoids.

194: Investigation of betaine as a novel psychotherapeutic for schizophrenia
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Posted to bioRxiv 19 Apr 2019

Investigation of betaine as a novel psychotherapeutic for schizophrenia
1 tweet neuroscience

Tetsuo Ohnishi, Shabeesh Balan, Manabu Toyoshima, Motoko Maekawa, Hisako Ohba, Akiko Watanabe, Yoshimi Iwayama, Chie Shimamoto-Mitsuyama, Yayoi Nozaki, Yasuko Hisano, Kayoko Esaki, Atsuko Nagaoka, Junya Matsumoto, Mizuki Hino, Nobuko Mataga, Akiko Hayashi-Takagi, Yasuto Kunii, Akiyoshi Kakita, Hirooki Yabe, Takeo Yoshikawa

Betaine is known to act against various biological stresses and its levels were reported to be decreased in schizophrenia patients. Using Chdh (a gene for betaine synthesis)-deficient mice and betaine-supplemented inbred mice, we assessed the role of betaine in psychiatric pathophysiology, and its potential as a novel psychotherapeutic, by leveraging metabolomics, behavioral-, transcriptomics and DNA methylation analyses. The Chdh-deficient mice revealed remnants of psychiatric behaviors along with schizophrenia-related molecular perturbations. Betaine supplementation elicited genetic background-dependent improvement in cognitive performance, and suppressed methamphetamine (MAP)-induced behavioral sensitization. Furthermore, betaine rectified the altered antioxidative and proinflammatory responses induced by MAP and in vitro phencyclidine treatments. Notably, betaine levels were decreased in the postmortem brains from schizophrenia, and a coexisting elevated carbonyl stress, a form of oxidative stress, demarcated a subset of schizophrenia with betaine deficit-oxidative stress pathology. We revealed the decrease of betaine levels in glyoxylase 1 (GLO1)-deficient hiPSCs, which shows elevated carbonyl stress, and the efficacy of betaine in alleviating it, thus supporting a causal link between betaine and oxidative stress conditions. Furthermore, a CHDH variant, rs35518479, was identified as a cis-expression quantitative trait locus (QTL) for CHDH expression in postmortem brains from schizophrenia, allowing genotype-based stratification of schizophrenia patients for betaine efficacy. In conclusion, the present study underscores the potential benefit of betaine in a subset of schizophrenia.

195: A Rab GTPase protein FvSec4 is necessary for fumonisin B1 biosynthesis and virulence in Fusarium verticillioides
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Posted to bioRxiv 19 Apr 2019

A Rab GTPase protein FvSec4 is necessary for fumonisin B1 biosynthesis and virulence in Fusarium verticillioides
1 tweet microbiology

Huijuan Yan, Jun Huang, Huan Zhang, Won Bo Shim

Rab GTPases are responsible for a variety of membrane trafficking and vesicular transportation in fungi. But the role of Rab GTPases in Fusarium verticillioides, one of the key corn pathogens worldwide, remains elusive. These Small GTPases in fungi, particularly those homologous to Saccharomyces cerevisiae Sec4, are known to be associated with protein secretion, vesicular trafficking, secondary metabolism and pathogenicity. Here, we characterized the molecular functions of FvSec4 by generating a null mutant and learned that it is important for vegetative growth, hyphal branching, and conidiation. Interestingly, the mutation did not impair the expression of key conidiation-related genes. Meanwhile, the mutant did not show any defect in sexual development, including perithecia production. GFP-FvSec4 localized to growing hyphal tips, and raised the possibility that FvSec4 is involved in protein trafficking and endocytosis. The mutant exhibited defect in corn stalk rot virulence and also significant alteration of fumonisn B1 production. The mutation led to more sensitivity to oxidative and cell wall stress agents, and defects in carbon utilization. Gene complementation fully restored the defects in the mutant demonstrating that FvSec4 plays important role in these functions. Taken together, our data indicate that FvSec4 plays important roles in F. verticillioides hyphal development, virulence, mycotoxin production and stresses response. Further study is needed to characterize whether the mutation in FvSec4 leads to altered vesicle trafficking and protein secretion, which ultimately impact F. verticillioides physiology and virulence.

196: Molecular signatures of non-typeable Haemophilus influenzae lung adaptation in paediatric chronic lung disease
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Posted to bioRxiv 19 Apr 2019

Molecular signatures of non-typeable Haemophilus influenzae lung adaptation in paediatric chronic lung disease
1 tweet microbiology

Ammar Aziz, Derek S. Sarovich, Elizabeth Nosworthy, Jemima Beissbarth, Anne Chang, Heidi Smith-Vaughan, Erin P. Price, Tegan M Harris

Non-typeable Haemophilus influenzae (NTHi), an opportunistic pathogen of the upper airways of healthy children, can infect the lower airways, driving chronic lung disease. However, the molecular basis underpinning NTHi transition from a commensal to a pathogen is not clearly understood. Here, we performed comparative genomic and transcriptomic analyses of 12 paired, isogenic NTHi strains, isolated from the nasopharynx (NP) and bronchoalveolar lavage (BAL) of 11 children with chronic lung disease, to identify convergent molecular signatures associated with lung adaptation. Comparative genomic analyses of the 12 NP-BAL pairs demonstrated that five were genetically identical, with the remaining seven differing by only 1 to 3 mutations. Within-patient transcriptomic analyses identified between 2 and 58 differentially expressed genes in 8 of the 12 NP-BAL pairs, including pairs with no observable genomic changes. Whilst no convergence was observed at the gene level, functional enrichment analysis revealed significant under-representation of differentially expressed genes belonging to Coenzyme metabolism, Function unknown, Translation, ribosomal structure and biogenesis Cluster of Orthologous Groups categories. In contrast, Carbohydrate transport and metabolism, Cell motility and secretion, Intracellular trafficking and secretion, and Energy production categories were over-represented. This observed trend amongst genetically-unrelated NTHi strains provides evidence of convergent transcriptional adaptation of NTHi to paediatric airways that deserves further exploration. Understanding the pathoadaptative mechanisms that NTHi employs to infect and persist in the lower paediatric airways is essential for devising targeted diagnostics and treatments aimed at minimising disease severity, and ultimately, preventing NTHi lung infections and subsequent chronic lung disease in children.

197: Engineering acetyl-CoA metabolic shortcut for eco-friendly production of polyketides triacetic acid lactone in Yarrowia lipolytica
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Posted to bioRxiv 19 Apr 2019

Engineering acetyl-CoA metabolic shortcut for eco-friendly production of polyketides triacetic acid lactone in Yarrowia lipolytica
1 tweet bioengineering

Huan Liu, Monireh Marsafari, Fang Wang, Li Deng, Peng Xu

Acetyl-CoA is the central metabolic node connecting glycolysis, Krebs cycle and fatty acids synthase. Plant-derived polyketides, are assembled from acetyl-CoA and malonyl-CoA, represent a large family of biological compounds with diversified bioactivity. Harnessing microbial bioconversion is considered as a feasible approach to large-scale production of polyketides from renewable feedstocks. Most of the current polyketide production platform relied on the lengthy glycolytic steps to provide acetyl-CoA, which inherently suffers from complex regulation with metabolically-costly cofactor/ATP requirements. Using the simplest polyketide triacetic acid lactone (TAL) as a target molecule, we demonstrate that acetate uptake pathway in oleaginous yeast (Yarrowia lipolytica) could function as an acetyl-CoA shortcut to achieve metabolic optimality in producing polyketides. We identified the metabolic bottlenecks to rewire acetate utilization for efficient TAL production in Y. lipolytica, including generation of the driving force for acetyl-CoA, malonyl-CoA and NADPH. The engineered strain, with the overexpression of endogenous acetyl-CoA carboxylase (ACC1), malic enzyme (MAE1) and a bacteria-derived cytosolic pyruvate dehydrogenase (PDH), affords robust TAL production with titer up to 4.76 g/L from industrial glacier acetic acid in shake flasks, representing 8.5-times improvement over the parental strain. The acetate-to-TAL conversion ratio (0.149 g/g) reaches 31.9% of the theoretical maximum yield. The carbon flux through this acetyl-CoA metabolic shortcut exceeds the carbon flux afforded by the native acetyl-CoA pathways. Potentially, acetic acid could be manufactured in large-quantity at low-cost from Syngas fermentation or heterogenous catalysis (methanol carbonylation). This alternative carbon sources present a metabolic advantage over glucose to unleash intrinsic pathway limitations and achieve high carbon conversion efficiency and cost-efficiency. This work also highlights that low-cost acetic acid could be sustainably upgraded to high-value polyketides by oleaginous yeast species in an eco-friendly and cost-efficient manner.

198: Creating reproducible pharmacogenomic analysis pipelines
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Posted to bioRxiv 19 Apr 2019

Creating reproducible pharmacogenomic analysis pipelines
1 tweet bioinformatics

Anthony Mammoliti, Petr Smirnov, Zhaleh Safikhani, Wail Ba-Alawi, Benjamin Haibe-Kains

The field of Pharmacogenomics presents great challenges for researchers that are willing to make their studies reproducible and shareable. This is attributed to the generation of large volumes of high-throughput multimodal data, and the lack of standardized workflows that are robust, scalable, and flexible to perform large-scale analyses. To address this issue, we developed pharmacogenomic workflows in the Common Workflow Language to process two breast cancer datasets in a reproducible and transparent manner. Our pipelines combine both pharmacological and molecular profiles into a portable data object that can be used for future analyses in cancer research. Our data objects and workflows are shared on Harvard Dataverse and Code Ocean where they have been assigned a unique Digital Object Identifier, providing a level of data provenance and a persistent location to access and share our data with the community.

199: CyMIRA: The Cytonuclear Molecular Interactions Reference for Arabidopsis
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Posted to bioRxiv 20 Apr 2019

CyMIRA: The Cytonuclear Molecular Interactions Reference for Arabidopsis
1 tweet genomics

Evan S Forsythe, Joel Sharbrough, Justin C Havird, Jessica M Warren, Daniel B. Sloan

The function and evolution of eukaryotic cells depends upon direct molecular interactions between gene products encoded in nuclear and cytoplasmic genomes. Understanding how these cytonuclear interactions drive molecular evolution and generate genetic incompatibilities between isolated populations and species is of central importance to eukaryotic biology. Plants are an outstanding system to investigate such effects because of their two different genomic compartments present in the cytoplasm (mitochondria and plastids) and the extensive resources detailing subcellular targeting of nuclear-encoded proteins. However, the field lacks a consistent classification scheme for mitochondrial- and plastid-targeted proteins based on their molecular interactions with cytoplasmic genomes and gene products, which hinders efforts to standardize and compare results across studies. Here, we take advantage of detailed knowledge about the model angiosperm Arabidopsis thaliana to provide a curated database of plant cytonuclear interactions at the molecular level. CyMIRA (Cytonuclear Molecular Interactions Reference for Arabidopsis) is available at http://cymira.colostate.edu/ and https://github.com/dbsloan/cymira and will serve as a resource to aid researchers in partitioning evolutionary genomic data into functional gene classes based on organelle targeting and direct molecular interaction with cytoplasmic genomes and gene products. It includes 11 categories (and 27 subcategories) of different cytonuclear complexes and types of molecular interactions, and it reports residue-level information for cytonuclear contact sites. We hope that this framework will make it easier to standardize, interpret and compare studies testing the functional and evolutionary consequences of cytonuclear interactions.

200: Modulating Fis and IHF binding specificity, crosstalk and regulatory logic through the engineering of complex promoters
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Posted to bioRxiv 20 Apr 2019

Modulating Fis and IHF binding specificity, crosstalk and regulatory logic through the engineering of complex promoters
1 tweet synthetic biology

Lummy Maria Oliveira Monteiro, Ananda Sanches-Medeiros, Caua Westmann, Rafael Silva-Rocha

Bacterial promoters are usually formed by multiple cis-regulatory elements recognized by a plethora of transcriptional factors (TFs). From those, global regulators are key elements since these TFs are responsible for the regulation of hundreds of genes in the bacterial genome. For instance, Fis and IHF are two global regulators which play a major role in gene expression control in Escherichia coli and usually multiple cis-regulatory elements for these proteins co-occur at target promoters. Here, we investigated the relationship between the architecture of the cis-regulatory elements for Fis and IHF in E. coli. For this, we constructed 42 synthetic promoter variants harboring consensus cis-elements for Fis and IHF at different distances from a core -35/-10 region and in different numbers and combinations. We first demonstrated that although Fis preferentially recognizes its consensus cis-element , it can also recognize, to some extent, the consensus binding site for IHF, and the same was true for IHF, which was also able of recognizing Fis binding sites. However, changing the arrangement of the cis-elements (i.e., the position or the number of sites) can completely abolish unspecific binding of both TFs. More remarkably, we demonstrate that combining cis-elements for both TFs could result in Fis and IHF repressed or activated promoters depending on the final architecture of the promoters in an unpredictable way. Taken together, the data presented here demonstrate how small changes in the architecture of bacterial promoters could result in drastic changes in the final regulatory logic of the system, with important implications for the understanding of natural complex promoters in bacteria and their engineering for novel applications. Importance The understanding of the regulatory complex in bacteria is a key issue in modern microbiology. Here, we constructed synthetic bacterial promoters in order to investigate how binding of transcriptional factors to multiple target sites at the promoters can influence gene expression. Our results demonstrate in a systematic way that the arrangement and number of these cis-regulatory elements are crucial for the final expression dynamics of the target promoters. In particular, we show that TF binding specificity or promiscuity can be modulated using different promoter architectures based on consensus cis-regulatory elements, and that transcriptional repression and activation can also be affected by promoter architecture. These results are relevant both for the understanding of natural systems and for the construction of synthetic circuits for biotechnological applications.

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