bluuebunny/crossref_metadata_2025_split huggingface dataset:
Global transcriptional regulators fine-tune the translational and metabolic machinery inEscherichia coliunder anaerobic fermentation
Authors: Iyer Mahesh S. , Pal Ankita , Srinivasan Sumana , Somvanshi Pramod R. , Venkatesh K.V. 
Published: July 2020

AbstractComplex regulatory interactions between genetic and metabolic networks together confer robustness against external and internal perturbations in an organism such asEscherichia coli. In balanced exponential growth, this robustness is attributed to cost-effective metabolism by means of efficient resource allocation coordinated by the interplay of global transcriptional regulators with growth-rate dependent machinery. Here, we reappraise the role of global transcriptional regulators FNR, ArcA and IHF, integral to sustaining proteome-efficiency in anaerobic fermentative conditions, fundamental for optimal growth ofE. coli. We reveal at the transcriptome and metabolome level, that absence of these global regulators ensued a disruption of nitrogen homeostasis, overexpression of otherwise unnecessary or hedging genes and impairment in core bottleneck steps and amino acid metabolism. Notably, our findings emphasize their importance in optimizing the metabolic proteome resources essential for rapid exponential growth. Consequentially, the perturbations in the metabolic proteome as a result of deletion of global regulators unbalances the ribosomal proteome share imposing a high translation program, though at the expense of lowered efficiency. We illustrate that disruption of this inherent trade-off between metabolic and ribosomal proteomic investment eventually culminate to lowered growth rates. Despite no changes in gene expression related to glucose import, our findings elucidate that the accumulations of intracellular metabolites directly modulated by growth rate, negatively impacts the glucose uptake. Our results employing the proteome allocation theory and quantitative experimental measurements, suffices to explain the physiological consequences of altered translational and metabolic efficiency in the cell, driven by the loss of these global regulators.
Precision long-read metagenomics sequencing for food safety by detection and assembly of Shiga toxin-producingEscherichia coliin irrigation water
Authors: Maguire Meghan , Kase Julie A. , Roberson Dwayne , Muruvanda Tim , Brown Eric W. , Allard Marc , Musser Steven M. , González-Escalona Narjol 
Published: July 2020

ABSTRACTShiga toxin-producingEscherichia coli(STEC) contamination of agricultural water might be an important factor to recent foodborne illness and outbreaks involving leafy greens. Whole genome sequencing generation of closed bacterial genomes plays an important role in source tracking. We aimed to determine the limits of detection and classification of STECs by qPCR and nanopore sequencing using enriched irrigation water artificially contaminated withE. coliO157:H7 (EDL933). We determined the limit of STEC detection by qPCR to be 30 CFU/reaction, which is equivalent to 105CFU/ml in the enrichment. By using Oxford Nanopore’s EPI2ME WIMP workflow andde novoassembly with Flye followed by taxon classification with a k-mer analysis software (Kraken),E. coliO157:H7 could be detected at 103CFU/ml (68 reads) and a complete fragmentedE. coliO157:H7 metagenome-assembled genome (MAG) was obtained at 105-108CFU/ml. Using a custom script to extract theE. colireads, a completely closed MAG was obtained at 107-108CFU/ml and a complete, fragmented MAG was obtained at 105-106CFU/ml.In silicovirulence detection forE. coliMAGs for 105-108CFU/ml showed that the virulotype was indistinguishable from the spikedE. coliO157:H7 strain. We further identified the bacterial species in the un-spiked enrichment, including antimicrobial resistance genes, which could have important implications to food safety. We propose this workflow could be used for detection and complete genomic characterization of STEC from a complex microbial sample and could be applied to determine the limit of detection and assembly of other foodborne bacterial pathogens.IMPORTANCEFoodborne illness caused by Shiga toxin-producingE. coli(STEC) ranges in severity from diarrhea to hemolytic uremic syndrome and produce-related incidence is increasing. The pervasive nature ofE.colirequires not only detection, but also a complete genome to determine potential pathogenicity based onstxandeaegenes, serotype, and other virulence factors. We have developed a pipeline to determine the limits of nanopore sequencing for STECs in a metagenomic sample. By utilizing the current qPCR in the FDA Bacteriological Analytical Manual (BAM) Chapter 4A, we can quantify the amount of STEC in the enrichment and then sequence and classify the STEC in less than half the time as current protocols that require a single isolate. These methods have wide implications for food safety, including decreased time to STEC identification during outbreaks, characterization of the microbial community, and the potential to use these methods to determine the limits for other foodborne pathogens.
Disparate effects of metformin onMycobacterium tuberculosisinfection in diabetic and non-diabetic mice
Authors: Sathkumara Harindra D. , Hansen Karyna , Miranda-Hernandez Socorro , Govan Brenda , Rush Catherine M. , Henning Lars , Ketheesan Natkunam , Kupz Andreas 
Published: July 2020

AbstractComorbid type 2 diabetes poses a great challenge to the global control of tuberculosis. Here we assessed the efficacy of metformin (MET); an anti-diabetic drug, in mice infected with a very-low dose ofMycobacterium tuberculosis. In contrast to diabetic mice, infected non-diabetic mice that received the same therapeutic concentration of MET presented with significantly higher disease burden. This warrants further studies to investigate the disparate efficacy of MET against tuberculosis in diabetic and non-diabetic individuals.
Extratubular polymerized uromodulin induces leukocyte recruitment and inflammationin vivo
Authors: Immler Roland , Lange-Sperandio Bärbel , Steffen Tobias , Beck Heike , Roth Jonas , Hupel Georg , Pfister Frederik , Popper Bastian , Uhl Bernd , Mannell Hanna , Reichel Christoph A. , Vielhauer Volker , Scherberich Jürgen , Sperandio Markus , Pruenster Monika 
Published: July 2020

ABSTRACTUromodulin (UMOD) is produced and secreted by tubular epithelial cells. Secreted UMOD polymerizes (pUMOD) within the lumen, where it regulates salt transport and protects the kidney from bacteria and stone formation. Under various pathological conditions, pUMOD accumulates within the tubular lumen and reaches extratubular sites where it may interact with renal interstitial cells. Here, we investigated the potential of extratubular pUMOD to act as a damage associated molecular pattern (DAMP) molecule thereby creating local inflammation. We found that intrascrotal and intraperitoneal injection of pUMOD induced leukocyte recruitmentin vivoand led to TNF-α secretion by F4/80 positive macrophages. Additionally, pUMOD directly affected vascular permeability and increased neutrophil extravasation independent of macrophage-released TNF-α. Interestingly, pUMOD did not directly upregulate adhesion molecules on endothelial cells and did not directly activate β2 integrins on neutrophils. In obstructed neonatal murine kidneys, we observed extratubular UMOD accumulation with tubular atrophy and leukocyte infiltrates. Finally, we found extratubular UMOD deposits associated with peritubular leukocyte infiltration in kidneys from patients with inflammatory kidney diseases. Taken together, we identified extratubular pUMOD as a strong inducer of leukocyte recruitment, underlining its critical role in mounting an inflammatory response in various kidneys pathologies.
Regulatory roles of 5′ UTR and ORF-internal RNAs detected by 3′ end mapping
Authors: Adams Philip P. , Baniulyte Gabriele , Esnault Caroline , Chegireddy Kavya , Singh Navjot , Monge Molly , Dale Ryan K. , Storz Gisela , Wade Joseph T. 
Published: July 2020

AbstractMany bacterial genes are regulated by RNA elements in their 5′ untranslated regions (UTRs). However, the full complement of these elements is not known even in the model bacteriumEscherichia coli. Using complementary RNA-sequencing approaches, we detected large numbers of 3′ ends in 5′ UTRs and open reading frames (ORFs), suggesting extensive regulation by premature transcription termination. We documented regulation for multiple transcripts, including spermidine induction involving Rho and translation of an upstream ORF for an mRNA encoding a spermidine efflux pump. In addition to discovering novel sites of regulation, we detected short, stable RNA fragments derived from 5′ UTRs and sequences internal to ORFs. Characterization of three of these transcripts, including an RNA internal to an essential cell division gene, revealed that they have independent functions as sRNA sponges. Thus, these data uncover an abundance ofcis- andtrans-acting RNA regulators in bacterial 5′ UTRs and internal to ORFs.
Cortical recycling in high-level visual cortex during childhood development
Authors: Nordt Marisa , Gomez Jesse , Natu Vaidehi , Rezai Alex A. , Finzi Dawn , Kular Holly , Grill-Spector Kalanit 
Published: July 2020

AbstractHuman ventral temporal cortex (VTC) contains category-selective regions that respond preferentially to ecologically-relevant categories such as faces, bodies, places, and words, which are causally involved in the perception of these categories. How do these regions develop during childhood? We used functional MRI to measure longitudinal development of category-selectivity in school-age children over 1 to 5 years. We discovered that from young childhood to the teens, face- and word-selective regions in VTC expand and become more category-selective, but limb-selective regions shrink and lose their preference for limbs. Critically, as a child develops, increases in face- and word-selectivity are directly linked to decreases in limb-selectivity, revealing that during childhood limb-selectivity in VTC is repurposed into word- and face-selectivity. These data provide evidence for cortical recycling during childhood development. This has important implications for understanding typical as well as atypical brain development and necessitates a rethinking of how cortical function develops during childhood.
Computational and Molecular Dynamics Simulation Approach To Analyze the Impact ofXPDGene Mutation on Protein Stability and Function
Authors: Panchal Nagesh Kishan , Bhale Aishwarya , Verma Vinod Kumar , Beevi Syed Sultan 
Published: July 2020

AbstractXPDacts as a functional helicase and aids in unwinding double helix around damaged DNA, leading to efficient DNA repair. Mutations ofXPDgive rise to DNA-repair deficiency diseases and cancer proneness. In this study, cancer-causing missense mutation that could inactivate helicase function and hinder its binding with other complexes were analysed using bioinformatics approach. Rigorous computational methods were employed to understand the molecular pathogenic profile of mutation. The mutant model with the desired mutation was built with I-TASSER. GROMACS 5.0.1 was used to evaluate the effect of a mutation on protein stability and function. Of the 276 missense mutations, 64 were found to be disease-causing. Out of these 64, seven were of cancer-causing mutations. Among these, we evaluated K48R mutation in a computational simulated environment to determine its impact on protein stability and function since K48 position was ascertained to be highly conserved and substitution with arginine could impair theXPDactivity. Molecular Dynamic Simulation and Essential Dynamics analysis showed that K48R mutation altered protein structural stability and produced conformational drift. Our predictions thus revealed that K48R mutation could impair theXPDhelicase activity and affect its ability to repair the damaged DNA, thus augmenting the risk for cancer.
Generalized Hidden Markov Models for Phylogenetic Comparative Datasets
Authors: Boyko James D. , Beaulieu Jeremy M. 
Published: July 2020

AbstractHidden Markov models (HMM) have emerged as an important tool for understanding the evolution of characters that take on discrete states. Their flexibility and biological sensibility make them appealing for many phylogenetic comparative applications.Previously available packages placed unnecessary limits on the number of observed and hidden states that can be considered when estimating transition rates and inferring ancestral states on a phylogeny.To address these issues, we expanded the capabilities of the R packagecorHMMto handlen-state andn-character problems and provide users with a streamlined set of functions to create custom HMMs for any biological question of arbitrary complexity.We show that increasing the number of observed states increases the accuracy of ancestral state reconstruction. We also explore the conditions for when an HMM is most effective, finding that an HMM is an appropriate model when the degree of rate heterogeneity is moderate to high.Finally, we demonstrate the importance of these generalizations by reconstructing the phyllotaxy of the ancestral angiosperm flower. Partially contradicting previous results, we find the most likely state to be a whorled perianth, whorled androecium, whorled gynoecium. The difference between our analysis and previous studies was that our modeling explicitly allowed for the correlated evolution of several flower characters.
Novel mechanisms of efflux-mediated levofloxacin resistance and reduced amikacin susceptibility inStenotrophomonas maltophilia
Authors: Dulyayangkul Punyawee , Calvopiña Karina , Heesom Kate J. , Avison Matthew B. 
Published: July 2020

AbstractFluoroquinolone resistance inStenotrophomonas maltophiliais multi-factorial, but the most significant factor is production of efflux pumps, particularly SmeDEF. Here we report that mutations in the glycosyl transferase genesmlt0622inS. maltophiliaK279a mutant K M6 cause constitutive activation of SmeDEF production, leading to elevated levofloxacin MIC. Selection of a levofloxacin-resistant K M6 derivative, K M6 LEVR, allowed identification of a novel two-component regulatory system, Smlt2645/6 (renamed as SmaRS). The sensor kinase Smlt2646 (SmaS) is activated by mutation in K M6 LEVRcausing over-production of two novel ABC transporters and the known aminoglycoside efflux pump SmeYZ. Over-production of one ABC transporter, Smlt1651-4 (renamed as SmaCDEF) causes levofloxacin resistance in K M6 LEVR. Over-production of the other ABC transporter, Smlt2642/3 (renamed SmaAB) and SmeYZ both contribute to the elevated amikacin MIC against K M6 LEVR. Accordingly, we have identified two novel ABC transporters associated with antimicrobial drug resistance inS. maltophilia, and two novel regulatory systems whose mutation causes resistance to levofloxacin, clinically important as a promising drug for monotherapy against this highly resistant pathogen.
Probing the dissonance among the diagnostic outputs of multiple approaches used for detection of Methicillin-resistant Staphylococcus aureus (MRSA)
Authors: Dahiya Ujjwal Ranjan , Sikidar Arnab , Sharma Priyanka , Rawat Chitra , Dhawan Benu , Kapil Arti , Elangovan Ravikrishnan , Kalyanasundaram Dinesh 
Published: July 2020

AbstractMethicillin resistant staphylococcus aureus (MRSA) is an extremely infectious hospital acquired bacterial pathogen often found in post-surgical patients globally. Early detection of such pathogens is a critical requirement to eliminate or reduce the incidence of anti-microbial resistance as well as for effective management of the disease. Despite the development of multiple biochemical, microbiological and nucleic acid amplifications techniques (NAATs), conventional culture methods are widely used clinically owing to high variability between the methods, technical skills and infrastructural needs. Further, multiple reports suggest significant variation among diagnostic output for MRSA detection. This work attempts to probe the discordance among the diagnostic output of three commonly used methods, while trying to understand the underlying cause of variability. MRSA detection on 217 clinical pus isolates was carried out using three different methods namely, conventional culture method, qPCR-based amplification and a modern LAMP based detection approach. Also, to confirm the presence of MRSA and distinguish from coagulase-negative staphylococci (CoNS), as well as to investigate the observed differences between qPCR and LAMP outputs, melt curve analysis was performed on discordant samples. LAMP based MRSA detection was found to be the optimum method. In summary, this study evaluates the diagnostic efficiency of the different detection methods, while probing for possible explanations for the observed differences.
Timing of mating, reproductive status and resource availability in relation to migration in the painted lady butterfly,Vanessa cardui
Authors: Stefanescu Constantí , Ubach Andreu , Wiklund Christer 
Published: July 2020

AbstractIn many migratory insects, migration occurs during the pre-reproductive phase of the life cycle. This trait probably arises from a trade-off between migration and reproduction and in females has been termed as the ‘oogenesis-flight syndrome’. However, the generality of this syndrome has been questioned, especially for monomorphic insects. We studied the relationship between migration and reproduction in the highly cosmopolitan painted lady butterfly, which in the Palaearctic undertakes the longest known multi-generational migration circuit of any insect. We tested for the oogenesis-flight syndrome in both spring and autumn migrants in two regions linked by migration, North Africa and northern Spain. Field observations were combined with laboratory experiments to determine the lifespan and the age at first mating to unravel the reproductive strategy observed in individuals captured in the wild. Females and males wait on average around 5–6 days before mating, and field data revealed that mating frequencies increase rapidly once females reach a medium wing wear category. There were seasonal differences in mating frequencies in the study regions depending on whether the region acted as a source or as a destination for migrants, and in the latter case there were almost twice as many mated females. Moreover, about 80% of females collected during migratory flights were unmated, the remaining females having mated only very recently. Our results thus strongly indicate that the painted lady fulfils the oogenesis-flight syndrome, as migration is concentrated in its relatively short pre-reproductive period. Field data also showed a high positive correlation between mating frequency and host plant abundance, which suggests that mated females have the ability to locate potential breeding areas. This, together with the very high fecundity estimated from over 1000 eggs in laboratory trials, makes the painted lady one of the most successful migratory insects on Earth.
Phenotypical predictors of Restless Legs Syndrome in pregnancy and their association with basal ganglia and the limbic circuits
Authors: Chechko Natalia , Lefort-Besnard Jeremy , Goecke Tamme W. , Frensch Markus , Schnakenberg Patricia , Stickel Susanne , Bzdok Danilo 
Published: July 2020

ABSTRACTThe pregnancy-related restless legs syndrome (RLS) is thought to have a multifactorial etiology. However, the reason behind the manifestation of RLS during pregnancy remains largely elusive.A neurological and obstetrical cohort of 308 postpartum women was screened for RLS symptoms twice: 1 to 6 days (T0) and 12 weeks postpartum (T1). 57 participants were identified as affected by pregnancy-associated RLS. The clinical and anamnestic indicators of the condition were assessed by a pattern-learning classifier trained to predict the RLS status. Structural MRI was obtained from 25 of the 57 participants with RLS history in pregnancy. In this sample, a multivariate two-window algorithm was employed to systematically chart the relationship between brain structures and phenotypical predictors.The RLS prevalence rate in our sample was 19% (n=57), with the women suffering from RLS being older, more often unmarried, affected by gestational diabetes and having been more exposed to stressful life events. A history of RLS and the severity and frequency of repetitive compulsive movements were found to be the strongest predictors of RLS manifestation. In the RLS group, high cortisol levels, being married and receiving iron supplements were found to be associated with increased volumes in the bilateral striatum.Investigating pregnancy-related RLS in a frame of brain phenotype modes may help shed light on the heterogeneity of the condition.
FOXP1 negatively regulates intrinsic excitability in D2 striatal projection neurons by promoting inwardly rectifying and leak potassium currents
Authors: Khandelwal Nitin , Cavalier Sheridan , Rybalchenko Volodymyr , Kulkarni Ashwinikumar , Anderson Ashley G. , Konopka Genevieve , Gibson Jay R. 
Published: July 2020

AbstractHeterozygous loss-of-function mutations in the transcription factorFOXP1are strongly associated with autism. Dopamine receptor 2 expressing (D2) striatal projection neurons (SPNs) in heterozygousFoxp1(Foxp1+/−) mice have higher intrinsic excitability. To understand the mechanisms underlying this alteration, we examined SPNs with cell-type specific homozygousFoxp1deletion to study cell-autonomous regulation byFoxp1. As inFoxp1+/−mice, D2 SPNs had increased intrinsic excitability with homozygousFoxp1deletion. This effect involved postnatal mechanisms. The hyperexcitability was mainly due to down-regulation of two classes of potassium currents: inwardly rectifying (KIR) and leak (KLeak). Single-cell RNA sequencing data from D2 SPNs withFoxp1deletion indicated the down-regulation of transcripts of candidate ion channels that may underlie these currents:Kcnj2andKcnj4for KIRandKcnk2for KLeak. ThisFoxp1-dependent regulation was neuron-type specific since these same currents and transcripts were either unchanged, or very little changed, in D1 SPNs with cell-specificFoxp1deletion. Our data are consistent with a model where FOXP1 negatively regulates the excitability of D2 SPNs through KIRand KLeakby transcriptionally activating their corresponding transcripts. This, in turn, provides a novel example of how a transcription factor may regulate multiple genes to impact neuronal electrophysiological function that depends on the integration of multiple current types – and do this in a cell-specific fashion. Our findings provide initial clues to altered neuronal function and possible therapeutic strategies not only for FOXP1-associated autism but also for other autism forms associated with transcription factor dysfunction.
A biaryl-linked tripeptide fromPlanomonosporaleads to widespread class of minimal RiPP gene clusters
Authors: Zdouc Mitja M. , Alanjary Mohammad M. , Zarazúa Guadalupe S. , Maffioli Sonia I. , Crüsemann Max , Medema Marnix H. , Donadio Stefano , Sosio Margherita 
Published: July 2020

AbstractMicrobial natural products impress by their bioactivity, structural diversity and ingenious biosynthesis. While screening the rare actinobacterial genusPlanomonospora,cyclopeptides1Aand1Bwere discovered, featuring an unusual Tyr-His biaryl-bridging across a tripeptide scaffold, with the sequencesN-acetyl-Tyr-Tyr-His (1A) andN-acetyl-Tyr-Phe-His (1B). Genome analysis of the1Aproducing strain pointed to-wards a ribosomal synthesis of1A, from a pentapeptide precursor encoded by the tiny 18-nucleotide genebycA,to our knowledge the smallest gene ever reported. Further, biaryl instalment is performed by the closely linked genebycB,encoding a cytochrome P450 monooxygenase. Biosynthesis of1Awas confirmed by heterologous production inStreptomyces,yielding the mature product. Bioinformatic analysis of related cytochrome P450 monooxygenases indicated that they constitute a widespread family of pathways, associated to 5-aa coding sequences in approximately 200 (actino)bacterial genomes, all with potential for a biaryl linkage between amino acids 1 and 3. We propose the name biarylicins for this newly discovered family of RiPPs.