bluuebunny/crossref_metadata_2025_split huggingface dataset:
Overproduction of the AlgT sigma factor is lethal to mucoidPseudomonas aeruginosa
Authors: Cross Ashley R. , Raghuram Vishnu , Wang Zihuan , Dey Debayan , Goldberg Joanna B. 
Published: June 2020

ABSTRACTPseudomonas aeruginosaisolates from chronic lung infections often overproduce alginate, giving rise to the mucoid phenotype. Isolation of mucoid strains from chronic lung infections correlates with a poor patient outcome. The most common mutation that causes the mucoid phenotype is calledmucA22and results in a truncated form of the anti-sigma factor MucA that is continuously subjected to proteolysis. When a functional MucA is absent, the cognate sigma factor, AlgT, is no longer sequestered and continuously transcribes the alginate biosynthesis operon leading to alginate overproduction. In this work, we report that in the absence of wild-type MucA, providing exogenous AlgT is toxic. This is intriguing since mucoid strains endogenously possess high levels of AlgT. Furthermore, we show that suppressors of toxic AlgT production have mutations inmucP, a protease involved in MucA degradation, and provide the first atomistic model of MucP. Our findings support a model where mutations inmucPstabilize the truncated form of MucA22 rendering it functional and therefore able to reduce toxicity by properly sequestering AlgT.IMPORTANCEPseudomonas aeruginosais an opportunistic bacterial pathogen capable of causing chronic lung infections. Phenotypes important for the long-term persistence and adaption to this unique lung ecosystem are largely regulated by the AlgT sigma factor. Chronic infection isolates often contain mutations in the anti-sigma factormucAresulting in uncontrolled AlgT and continuous production of alginate, in addition to the expression of ~300 additional genes includingalgTitself. Here we report that in the absence of wild-type MucA, AlgT overproduction is lethal and that suppressors of toxic AlgT production have mutations in the MucA protease, MucP. Since AlgT contributes to the establishment of chronic infections, understanding how AlgT is regulated will provide vital information on howP. aeruginosais capable of causing long-term infections.
Comparison of different linear-combination modelling algorithms for short-TE proton spectra
Authors: Zöllner Helge J. , Považan Michal , Hui Steve C. N. , Tapper Sofie , Edden Richard A. E. , Oeltzschner Georg 
Published: June 2020

AbstractShort-TE proton MRS is used to study metabolism in the human brain. Common analysis methods model the data as linear combination of metabolite basis spectra. This large-scale multi-site study compares the levels of the four major metabolite complexes in short-TE spectra estimated by three linear-combination modelling (LCM) algorithms.277 medial parietal lobe short-TE PRESS spectra (TE = 35 ms) from a recent 3T multi-site study were pre-processed with the Osprey software. The resulting spectra were modelled with Osprey, Tarquin and LCModel, using the same three vendor-specific basis sets (GE, Philips, and Siemens) for each algorithm. Levels of total N-acetylaspartate (tNAA), total choline (tCho), myoinositol (mI), and glutamate+glutamine (Glx) were quantified with respect to total creatine (tCr).Group means and CVs of metabolite estimates agreed well for tNAA and tCho across vendors and algorithms, but substantially less so for Glx and mI, with mI systematically estimated lower by Tarquin. The cohort mean coefficient of determination for all pairs of LCM algorithms across all datasets and metabolites was, indicating generally only moderate agreement of individual metabolite estimates between algorithms. There was a significant correlation between local baseline amplitude and metabolite estimates (cohort mean).While mean estimates of major metabolite complexes broadly agree between linear-combination modelling algorithms at group level, correlations between algorithms are only weak-to-moderate, despite standardized pre-processing, a large sample of young, healthy and cooperative subjects, and high spectral quality. These findings raise concerns about the comparability of MRS studies, which typically use one LCM software and much smaller sample sizes.Graphical AbstractThree linear-combination algorithms (Osprey, Tarquin and LCMode) were used to quantify the levels of tNAA, tCho, mI, and Glx in 277 short-TE PRESS. Group means and CVs of metabolite estimates agreed well for tNAA and tCho, but substantially less so for Glx and mI with a cohort mean correlation coefficient of, indicating moderate agreement between algorithms. These findings raise concerns about the comparability of MRS studies, which typically use one LCM software and much smaller sample sizes.
Speech perception under the tent: A domain-general predictive role for the cerebellum
Authors: Skipper Jeremy I , Lametti Daniel R 
Published: June 2020

AbstractThe role of the cerebellum in speech perception remains a mystery. Given its uniform architecture, we tested the hypothesis that it implements a domain-general mechanism whose role in speech is determined by connectivity. We collated all neuroimaging studies reporting cerebellar activity in the Neurosynth database (n = 8,206). From this set, we found all studies involving passive speech and sound perception (n = 72, 64% speech, 12.5% sounds, 12.5% music, and 11% tones) and speech production and articulation (n = 175). Standard and coactivation neuroimaging meta-analyses were used to compare cerebellar and associated cortical activations between passive perception and production. We found distinct regions of perception-and production-related activity in the cerebellum and regions of perception-production overlap. Each of these regions had distinct patterns of cortico-cerebellar connectivity. To test for domain generality versus specificity, we identified all psychological and task-related terms in the Neurosynth database that predicted activity in cerebellar regions associated with passive perception and production. Regions in the cerebellum activated by speech perception were associated with domain-general terms related to prediction. One hallmark of predictive processing is metabolic savings (i.e., decreases in neural activity when events are predicted). To test the hypothesis that the cerebellum plays a predictive role in speech perception, we examined cortical activation between studies reporting cerebellar activation and those without cerebellar activation during speech perception. When the cerebellum was active during speech perception there was far less cortical activation than when it was inactive. The results suggest that the cerebellum implements a domain-general mechanism related to prediction during speech perception.
Protein covariance networks reveal interactions important to the emergence of SARS coronaviruses as human pathogens
Authors: Robins William P. , Mekalanos John J. 
Published: June 2020

AbstractSARS-CoV-2 is one of three recognized coronaviruses (CoVs) that have caused epidemics or pandemics in the 21stcentury and that have likely emerged from animal reservoirs based on genomic similarities to bat and other animal viruses. Here we report the analysis of conserved interactions between amino acid residues in proteins encoded by SARS-CoV-related viruses. We identified pairs and networks of residue variants that exhibited statistically high frequencies of covariance with each other. While these interactions are likely key to both protein structure and other protein-protein interactions, we have also found that they can be used to provide a new computational approach (CoVariance-based Phylogeny Analysis) for understanding viral evolution and adaptation. Our data provide evidence that the evolutionary processes that converted a bat virus into human pathogen occurred through recombination with other viruses in combination with new adaptive mutations important for entry into human cells.
Allergen-induced dendritic cell migration is controlled through Substance P release by sensory neurons
Authors: Aderhold Pamela A. , Dewan Zaynah N. A. , Perner Caroline , Flayer Cameron H. , Zhu Xueping , Voisin Tiphaine , Camire Ryan B. , Chiu Isaac M. , Chow Ohn A. , Sokol Caroline L. 
Published: June 2020

SUMMARYDendritic cells (DCs) of the cDC2 lineage are necessary for the initiation of the allergic immune response and in the dermis are marked by their expression of CD301b. CD301b+dermal DCs respond to allergens encountered in vivo, but not in vitro. This suggests that another cell in the dermis may sense allergens and relay that information to activate and induce the migration of CD301b+DCs to the draining lymph node. Using a model of cutaneous allergen exposure, we show that allergens directly activate TRPV1+sensory neurons leading to itch and pain behaviors. Allergen-activated sensory neurons release the neuropeptide Substance P, which stimulates proximally located CD301b+DCs through MRGPRA1. Substance P induces CD301b+DC migration to the draining lymph node where they initiate Th2 differentiation. Thus, sensory neurons act as primary sensors of allergens, linking exposure to activation of allergic-skewing DCs and the initiation of the allergic immune response.
Multi-Locus Molecular Phylogeny ofSolenopsis(Hymenoptera: Formicidae)
Authors: Shreve Scott , Achury Rafael , Johnson Kevin , Suarez Andrew , Gotzek Dietrich 
Published: June 2020

AbstractThe myrmicine ant genusSolenopsisis species-rich, globally distributed, and is often a common and ecologically important faunal element of the leaf litter. The genus is also well-known for containing several widely distributed tramp species and some of the worst invasive species in the World (the Red Imported Fire Ant,S. invicta, and the Tropical Fire Ant,S. geminata). Although not hyper-diverse and despite its ecological and economic importance,Solenopsishas long frustrated systematists due its lack of reliable diagnostic characters and no phylogenetic hypothesis exists to date. We present a preliminary multi-locus molecular phylogenetic analysis ofSolenopsisto address this knowledge gap. Our analyses recover mostly well-supported phylogenetic hypothesis, which suggestsSolenopsisarose in the Neotropics and spread to all other continents (except Antarctica). Importantly, it demonstrates problems with current systematic understanding of the genus, but provides an evolutionary framework upon which to build future research.
Induction of RNA interference byC. elegansmitochondrial dysfunction via the DRH-1/RIG-I homologue RNA helicase and the EOL-1/RNA decapping enzyme
Authors: Mao Kai , Breen Peter , Ruvkun Gary 
Published: June 2020

AbstractRNA interference (RNAi) is an antiviral pathway common to many eukaryotes that detects and cleaves foreign nucleic acids. In mammals, mitochondrially localized proteins such as MAVS, RIG-I, and MDA5 mediate antiviral responses. Here, we report that mitochondrial dysfunction inCaenorhabditis elegansactivates RNAi-directed silencing via induction of a pathway homologous to the mammalian RIG-I helicase viral response pathway. The induction of RNAi also requires the conserved RNA decapping enzyme EOL-1/DXO. The transcriptional induction ofeol-1requires DRH-1 as well as the mitochondrial unfolded protein response (UPRmt). Upon mitochondrial dysfunction, EOL-1 is concentrated into foci that depend on the transcription of mitochondrial RNAs that may form dsRNA, as has been observed in mammalian antiviral responses. The enhanced RNAi triggered by mitochondrial dysfunction contributes to the increase in longevity that is induced by mitochondrial dysfunction.
Temporal proteomic profiling reveals insight into critical developmental processes and temperature-influenced physiological response differences in a bivalve mollusc
Authors: Trigg Shelly A. , Mitchell Kaitlyn R. , Thompson Rhonda Elliott , Eudeline Benoit , Vadopalas Brent , Timmins-Schiffman Emma B. , Roberts Steven B. 
Published: June 2020

ABSTRACTBackgroundProtein expression patterns underlie physiological processes and phenotypic differences including those occurring during early development. The Pacific oyster (Crassostrea gigas) undergoes a major phenotypic change in early development from free-swimming larval form to sessile benthic dweller while proliferating in environments with broad temperature ranges. Despite the economic and ecological importance of the species, physiological processes occurring throughout metamorphosis and the impact of temperature on these processes have not yet been mapped out.ResultsTowards this, we comprehensively characterized protein abundance patterns for 7978 proteins throughout metamorphosis in the Pacific oyster at different temperature regimes. We used a multi-statistical approach including principal component analysis, ANOVA-simultaneous component analysis, and hierarchical clustering coupled with functional enrichment analysis to characterize these data. We identified distinct sets of proteins with time-dependent abundances generally not affected by temperature. Over 12 days, adhesion and calcification related proteins acutely decreased, organogenesis and extracellular matrix related proteins gradually decreased, proteins related to signaling showed sinusoidal abundance patterns, and proteins related to metabolic and growth processes gradually increased. Contrastingly, different sets of proteins showed temperature-dependent abundance patterns with proteins related to immune response showing lower abundance and catabolic pro-growth processes showing higher abundance in animals reared at 29°C relative to 23°C.ConclusionAlthough time was a stronger driver than temperature of metamorphic proteome changes, temperature-induced proteome differences led to pro-growth physiology corresponding to larger oyster size at 29°C, and to altered specific metamorphic processes and possible pathogen presence at 23°C. These findings offer high resolution insight into why oysters may experience high mortality rates during this life transition in both field and culture settings. The proteome resource generated by this study provides data-driven guidance for future work on developmental changes in molluscs. Furthermore, the analytical approach taken here provides a foundation for effective shotgun proteomic analyses across a variety of taxa.
Limited inhibition of multiple nodes in a driver network blocks metastasis
Authors: Yesilkanal Ali E. , Yang Dongbo , Tiwari Payal , Sabino Alan U. , Lee Jiyoung , Xie Xiao-He , Sun Siqi , Dann Christopher , Steinberg Ethan , Stuhlmiller Timothy , Frankenberger Casey , Goldsmith Elizabeth , Johnson Gary L. , Ramos Alexandre F. , Rosner Marsha R. 
Published: June 2020

ABSTRACTMetastasis suppression by high-dose, multi-drug targeting is largely unsuccessful due to network heterogeneity and compensatory network activation. Here we show that targeting driver network signaling capacity by limited inhibition of its core pathways is a more effective anti-metastatic strategy. This principle underlies the action of a physiological metastasis suppressor, Raf Kinase Inhibitory Protein, which moderately decreases stress-regulated MAP kinase network activity, reducing the output to metastatic transcription factor BACH1 and motility-related target genes. We developed a low-dose four-drug mimic that blocks metastatic colonization in mouse breast cancer models and increases survival. Experiments and network flow modeling show: 1) limited inhibition of multiple pathways is required to overcome variation in MAPK network topology and suppress signaling output across heterogeneous tumor cells, and 2) restricting inhibition of individual kinases dissipates surplus signal, preventing threshold activation of compensatory kinase networks. This low-dose multi-drug approach to decrease signaling capacity of driver networks represents a transformative, clinically-relevant strategy for anti-metastatic treatment.
Differences in metabolic and liver pathobiology induced by two dietary mouse models of nonalcoholic fatty liver disease
Authors: Zhang Hannah , Léveillé Mélissa , Courty Emilie , Gunes Aysim , Nguyen Bich , Estall Jennifer L. 
Published: June 2020

ABSTRACTNon-alcoholic fatty liver disease (NAFLD) is a growing epidemic associated with key aspects of metabolic disease such as obesity and diabetes. The first stage of NAFLD is characterized by lipid accumulation in hepatocytes, but this can further progress into non-alcoholic steatohepatitis (NASH), fibrosis or cirrhosis, and hepatocellular carcinoma (HCC). A western diet, high in fats, sugars and cholesterol is linked to NAFLD development. Murine models are often used to experimentally study NAFLD, as they can display similar histopathological features as humans; however, there remains debate on which diet-induced model most appropriately and consistently mimics both human disease progression and pathogenesis. In this study, we performed a side-by-side comparison of two popular diet models of murine NAFLD/NASH and associated HCC: a high fat diet supplemented with 30% fructose water (HFHF) and a western diet high in cholesterol (WDHC), comparing them to a common grain-based chow diet (GBD). Mice on both experimental diets developed liver steatosis, while WDHC-fed mice had greater levels of hepatic inflammation and fibrosis than HFHF-fed mice. In contrast, HFHF-fed mice were more obese and developed more severe metabolic syndrome, with less pronounced liver disease. Despite these differences, WDHC-fed and HFHF-fed mice had similar tumour burdens in a model of diet-potentiated liver cancer. Response to diet and resulting phenotypes were generally similar between sexes, albeit delayed in females. Notably, although metabolic and liver disease phenotypes are often thought to progress in parallel, this study shows that modest differences in diet can significantly uncouple glucose homeostasis and liver damage. In conclusion, long-term feeding of either HFHF or WDHC are reliable methods to induce NASH and diet-potentiated liver cancer in mice of both sexes; however, the choice of diet involves a trade-off between severity of metabolic syndrome and liver damage.
X-linked meiotic drive boosts population size and persistence
Authors: Mackintosh Carl , Pomiankowski Andrew , Scott Michael F 
Published: June 2020

ABSTRACTX-linked meiotic drivers cause X-bearing sperm to be produced in excess by male carriers, leading to female-biased sex ratios. Selection for these selfish sex chromosomes can lead to completely female populations, which cannot produce offspring and go extinct. However, at the population level, moderately female-biased sex ratios are optimal because relatively few males are required to fertilise all the females. We develop eco-evolutionary models for sex-linked meiotic drive alleles to investigate their full range of demographic effects. We find general conditions for the spread and fixation of X-drivers, accounting for transmission bias and other factors associated with the spread of X-drivers such as sperm competition and polyandry. Our results suggest driving X-alleles that do not reach fixation (or do not bias segregation excessively) will boost population sizes and persistence times by increasing population productivity, demonstrating the potential for selfish genetic elements to move sex ratios closer to the population-level optimum. We suggest that researchers should look beyond extinction risk and consider the potential for ecologically beneficial side effects of selfish genetic elements, especially in light of proposals to use meiotic drive for biological control.
Structural variation affecting DNA backbone interactions underlies adaptation of B3 DNA binding domains to constraints imposed by protein architecture
Authors: Jia Haiyan , Suzuki Masaharu , McCarty Donald R. 
Published: June 2020

ABSTRACTFunctional diversification of transcription factor families through variation in modular domain architectures has played a central role in the independent evolution of gene regulatory networks underlying complex development in plants and animals. Here we show that architecture has in turn constrained evolution of B3 DNA binding domains in the B3 network regulating embryo formation in plants. B3 domains of ABI3, FUS3, LEC2 and VAL1 proteins recognize the same cis-element. ABI3 and VAL1 have complex architectures that physically integrate cis-element recognition with other signals, whereas LEC2 and FUS3 have reduced architectures conducive to their roles as pioneer activators. Qualitatively different activities of LEC2 and ABI3 B3 domains measured in vivo and in vitro are attributed in part to clade-specific substitutions in three amino acids that interact with the DNA backbone. Activities of FUS3 and VAL1 B3 domains show a similar correlation with architectural complexity. Domain-swap analyses in planta show that in a complex architecture setting the attenuated activities of ABI3 and VAL1 B3 domains are required for proper integration of ciselement recognition with hormone signalling. These results highlight modes of structural variation affecting non-specific, electrostatic interactions with the DNA backbone as a general mechanism allowing adaptation of DNA binding affinity to architectural constraints while preserving DNA sequence specificity.
Synthetic antibodies neutralize SARS-CoV-2 infection of mammalian cells
Authors: Miersch Shane , Ustav Mart , Li Zhijie , Case James B. , Ganaie Safder , Matusali Giulia , Colavita Francesca , Lapa Daniele , Capobianchi Maria R. , Novelli Giuseppe , Gupta Jang B. , Jain Suresh , Pandolfi Pier Paolo , Diamond Michael S. , Amarasinghe Gaya , Rini James M. , Sidhu Sachdev S. 
Published: June 2020

ABSTRACTCoronaviruses (CoV) are a large family of enveloped, RNA viruses that circulate in mammals and birds. Three highly pathogenic strains have caused zoonotic infections in humans that result in severe respiratory syndromes including the Middle East Respiratory Syndrome CoV (MERS), Severe Acute Respiratory Syndrome CoV (SARS), and the ongoing Coronavirus Disease 2019 (COVID-19) pandemic. Here, we describe a panel of synthetic monoclonal antibodies, built on a human IgG framework, that bind to the spike protein of SARS-CoV-2 (the causative agent of COVID-19), compete for ACE2 binding, and potently inhibit SARS-CoV-2. All antibodies that exhibited neutralization potencies at sub-nanomolar concentrations against SARS-CoV-2/USA/WA1 in Vero E6 cells, also bound to the receptor binding domain (RBD), suggesting competition for the host receptor ACE2. These antibodies represent strong immunotherapeutic candidates for treatment of COVID-19.
Phylogenetic and evolutionary analysis reveals the recent dominance of ciprofloxacin resistant S. sonnei and local persistence of S. flexneri clones in India
Authors: Sethuvel Dhiviya Prabaa Muthuirulandi , Mutreja Ankur , Pragasam Agila Kumari , Vasudevan Karthick , Murugan Dhivya , Anandan Shalini , Michael Joy Sarojini , Walia Kamini , Veeraraghavan Balaji 
Published: June 2020

AbstractShigella is the second leading cause of bacterial diarrhea worldwide. Recently S. sonnei seems to be replacing S. flexneri in low and middle-income countries undergoing economic development. Despite this, studies focusing on these species at genomic level remain largely unexplored. Here we compared the genome sequences of S. flexneri and S. sonnei isolated from India with the publically available genomes of global strains. Our analysis provide evidence for the long term persistence of all PGs of S. flexneri and the recent dominance of ciprofloxacin-resistant S. sonnei lineage in India. Within S. flexneri PGs, majority of the study isolates belonged to PG3 within the predominance of serotype 2. For S. sonnei, the current pandemic involves globally distributed MDR clones that belong to Central Asia lineage III. The presence of such epidemiologically-dominant lineages in association with stable AMR determinants results in the successful survival in the community.