bluuebunny/crossref_metadata_2025_split huggingface dataset:
Exploration of alcohol use disorder-associated brain miRNA-mRNA regulatory networks
Authors: Lim Yolpanhchana , Beane-Ebel Jennifer E. , Tanaka Yoshiaki , Ning Boting , Husted Christopher R. , Henderson David C. , Xiang Yangfei , Park In-Hyun , Farrer Lindsay A. , Zhang Huiping 
Published: July 2021

AbstractAlcohol use disorder (AUD) is due to gene expression changes in specific brain regions, but the underlying mechanism is not fully understood. We investigated AUD-associated miRNA-mRNA regulatory networks in multiple brain regions by analyzing transcriptomic changes in two sets of postmortem brain tissue samples and ethanol-exposed human embryonic stem cell (hESC)-derived cortical interneurons. miRNA and mRNA transcriptomes were profiled in 192 postmortem tissue samples (Set 1) from eight brain regions (amygdala, caudate nucleus, cerebellum, hippocampus, nucleus accumbens, prefrontal cortex, putamen, and ventral tegmental area) of 12 AUD and 12 control Caucasians. Nineteen differentially expressed miRNAs (fold-change>2.0 &P<0.05) and 97 differentially expressed mRNAs (fold-change>2.0 &P<0.001) were identified in one or multiple brain regions of AUD subjects. AUD-associated miRNA-mRNA regulatory networks in each brain region were constructed using differentially expressed and negatively correlated miRNA-mRNA pairs. AUD-relevant pathways (includingCREB Signaling, IL-8 Signaling, andAxonal Guidance Signaling) were potentially regulated by AUD-associated brain miRNA-mRNA pairs. Moreover, miRNA and mRNA transcriptomes were mapped in additional 96 postmortem tissue samples (Set 2) from six of the above eight brain regions of eight AUD and eight control Caucasians, and some of the AUD-associated miRNA-mRNA regulatory networks were confirmed. Additionally, miRNA and mRNA transcriptomes were analyzed in hESC-derived cortical interneurons with and without ethanol exposure, and ethanol-influenced miRNA-mRNA regulatory networks were constructed. This study provided evidence that alcohol could induce concerted miRNA and mRNA expression changes in reward-related or alcohol-responsive brain regions. We concluded that altered brain miRNA-mRNA regulatory networks might contribute to AUD development.
CFTR-mediated monocyte-macrophage dysfunction revealed by cystic fibrosis proband- parent comparisons
Authors: Zhang Xi , Moore Camille , Harmacek Laura , Domenico Joanne , Rangaraj Vittobai , Ideozu Justin E. , Knapp Jennifer R. , Woods Kate A. , Jump Stephanie , Jia Shuang , Prokop Jeremy W. , Bowler Russel , Hessner Martin J. , Gelfand Erwin W. , Levy Hara 
Published: July 2021

ABSTRACTCystic fibrosis (CF) is an inherited disorder caused by biallelic mutations of the cystic fibrosis transmembrane conductance regulator gene (CFTR). Converging lines of evidence suggest that CF carriers with only one defective CFTR copy are at increased risk for CF-related conditions and pulmonary infections, but the molecular mechanisms underpinning this effect remain unknown. Here, we performed transcriptomic profiling of peripheral blood mononuclear cells (PBMCs) of CF child-parent trios (proband, father, and mother) and healthy control PBMCs or THP-1 cells incubated with the plasma of these subjects. Transcriptomic analyses revealed suppression of cytokine-enriched immune-related genes (IL-1β, CXCL8, CREM) implicating lipopolysaccharide tolerance in innate immune cells (monocytes) of CF probands and their parents and in the control innate immune cells incubated with proband or parent plasma. These data suggest that not only a homozygous but also a heterozygous CFTR mutation can modulate the immune/inflammatory system. This conclusion is further supported by the findings of lower numbers of circulating monocytes in CF probands and their parents compared to healthy controls, the abundance of mononuclear phagocyte subsets (macrophages, monocytes, and activated dendritic cells) which correlated with Pseudomonas aeruginosa infection, lung disease severity, and CF progression in the probands. This study provides insight into demonstrated CFTR-related innate immune dysfunction in individuals with CF and carriers of a CFTR mutation that may serve as a target for personalized therapy.
Partners in space: Discordant population structure between legume hosts and rhizobium symbionts in their native range
Authors: Riley Alex B. , Grillo Michael A. , Epstein Brendan , Tiffin Peter , Heath Katy D. 
Published: July 2021

AbstractCoevolution is predicted to depend on how the genetic diversity of interacting species is geographically structured. Plant-microbe symbioses such as the legume-rhizobium mutualism are ecologically and economically important, but distinct life history and dispersal mechanisms for these host and microbial partners, plus dynamic genome composition in bacteria, present challenges for understanding spatial genetic processes in these systems. Here we study the model rhizobium Ensifer meliloti using a hierarchically-structured sample of 191 strains from 21 sites in the native range and compare its population structure to that of its host plant Medicago truncatula. We find high local genomic variation and minimal isolation by distance across the rhizobium genome, particularly at the two symbiosis elements pSymA and pSymB, which have evolutionary histories and population structures that are similar to each other but distinct from both the chromosome and the host. While the chromosome displays weak isolation by distance, it is uncorrelated with hosts. Patterns of discordant population structure among elements with the bacterial genome has implications for bacterial adaptation to life in the soil versus symbiosis, while discordant population genetic structure of hosts and microbes might restrict local adaptation of species to each other and give rise to phenotypic mismatches in coevolutionary traits.
Isolation and characterization of novel phages targeting pathogenic Klebsiella pneumoniae
Authors: Li Na , Zeng Yigang , Bao Rong , Zhu Tongyu , Tan Demeng , Hu Bijie 
Published: July 2021

AbstractKlebsiella pneumoniae is a dominant cause of community-acquired and nosocomial infections, specifically among immunocompromised individuals. The increasing occurrence of multidrug-resistant (MDR) isolates has significantly impacted the effectiveness of antimicrobial agents. As antibiotic resistance is becoming prevalent, the use of bacteriophages to treat pathogenic bacterial infections is becoming revitalized. Elucidating the details of phage-bacteria interactions will provide insights into phage biology and the better development of phage therapies. In this study, a total of 22 K. pneumoniae isolates were assessed for their genetic and phenotypic relatedness by multi-locus sequence typing (MLST), endonuclease S1 nuclease pulsed-field gel electrophoresis (S1-PFGE), and in vitro antibiotic susceptibility testing. In addition, the beta-lactamase gene (blaKPC) was characterized to determine the spread and outbreak of K. pneumoniae carbapenemase (KPC)-producing enterobacterial pathogens. Using these K. pneumoniae isolates, three phages were isolated and characterized to evaluate the application of lytic phages against these 22 ST11 K. pneumoniae isolates. In vitro inhibition assays with three phages and K. pneumoniae strain ZS15 demonstrated the strong lytic potential of the phages, however, followed by the rapid growth of phage-resistant mutants. Together, this data adds more comprehensive knowledge to known phage biology and further emphasizes their complexity and future challenges to overcome prior to using phages for controlling this important MDR bacterium.
Inconsistent patterns of microbial diversity and composition between highly similar sequencing protocols: a case study with reef-building corals
Authors: Epstein Hannah E. , Hernandez-Agreda Alejandra , Starko Samuel , Baum Julia K. , Thurber Rebecca Vega 
Published: July 2021

Abstract16S rRNA gene profiling (amplicon sequencing) is a popular technique for understanding host-associated and environmental microbial communities. Most protocols for sequencing amplicon libraries follow a standardized pipeline that can differ slightly depending on laboratory facility and user. Given that the same variable region of the 16S gene is targeted, it is generally accepted that sequencing output from differing protocols are comparable and this assumption underlies our ability to identify universal patterns in microbial dynamics through meta-analyses. However, discrepant results from a combined 16S rRNA dataset prepared by two labs whose protocols differed only in DNA polymerase and sequencing platform led us to scrutinize the outputs and challenge the idea of confidently combining them for standard microbiome analysis. Using technical replicates of reef-building coral samples from two species, Montipora aequituberculata and Porites lobata, we evaluated the consistency of alpha and beta diversity metrics between data resulting from these highly similar protocols. While we found minimal variation in alpha diversity between platform, significant differences were revealed with most beta diversity metrics, dependent on host species. These inconsistencies persisted following removal of low abundance taxa and when comparing across higher taxonomic levels, suggesting that bacterial community differences associated with sequencing protocol are likely to be context dependent and difficult to correct without extensive validation work. The results of this study encourage caution in the statistical comparison and interpretation of studies that combine rRNA sequence data from distinct protocols and point to a need for further work identifying mechanistic causes of these observed differences.ImportanceAmplicon sequencing remains a popular technique for characterizing organism and environmental microbiomes. The publication of sequence data from microbiome studies on open-access repositories provides an opportunity to identify universal patterns in microbial dynamics. To this end, it has been widely accepted that sequencing output from differing protocols are comparable and can be combined for analysis, so long as the same gene region is targeted. While most protocols for amplicon sequencing follow standardized pipelines, they can differ slightly between laboratory facility and user. In this study, we compared technical replicates of coral samples to evaluate the efficacy of combining organism-associated microbial datasets derived from two differing protocols. We found inconsistencies in the differences between bacterial communities, which persisted following data manipulations intended to increase comparability. These results suggest caution must be taken in the statistical comparison and interpretation of studies that combine data derived from distinct protocols.
Activation of Adipocyte mTORC1 Increases Milk Lipids in a Mouse Model of Lactation
Authors: Habbal Noura El , Meyer Allison C. , Hafner Hannah , Redd JeAnna R. , Carlson Zach , Mulcahy Molly C. , Gregg Brigid , Bridges Dave 
Published: July 2021

AbstractHuman milk is the recommended nutrient source for newborns. The mammary gland comprises multiple cell types including epithelial cells and adipocytes. The contributions of mammary adipocytes to breast milk composition and the intersections between mammary nutrient sensing and milk lipids are not fully understood. A major nutrient sensor in most tissues is the mechanistic target of rapamycin 1 (mTORC1). To assess the role of excess nutrient sensing on mammary gland structure, function, milk composition, and offspring weights, we used an Adiponectin-Cre driven Tsc1 knockout model of adipocyte mTORC1 hyperactivation. Our results show that the knockout dams have higher milk fat contributing to higher milk caloric density and heavier offspring weight during lactation. Additionally, milk of knockout dams displayed a lower percentage of saturated fatty acids, higher percentage of monounsaturated fatty acids, and a lower milk ω6: ω3 ratio driven by increases in docosahexaenoic acid (DHA). Mammary gland gene expression analyses identified changes in eicosanoid metabolism, adaptive immune function, and contractile gene expression. Together, these results suggest a novel role of adipocyte mTORC1 in mammary gland function and morphology, milk composition, and offspring growth.
Drosophila larval models of invasive tumourigenesis for in vivo studies on tumour/peripheral host tissue interactions during cancer cachexia
Authors: Hodgson Joseph A. , Parvy Jean-Philippe , Yu Yachuan , Vidal Marcos , Cordero Julia B. 
Published: July 2021

AbstractCancer cachexia is a common deleterious paraneoplastic syndrome that represents an area of unmet clinical need, partly due to its poorly understood aetiology and complex multifactorial nature. We have interrogated multiple genetically defined larval Drosophila models of tumourigenesis against key features of human cancer cachexia. Our results indicate that cachectic tissue wasting is dependent on the genetic characteristics of the tumour and demonstrate that host malnutrition or tumour burden are not sufficient to drive wasting. We show that JAK/STAT and TNF-α/Egr signalling are elevated in cachectic muscle and promote tissue wasting. Furthermore, we introduce a dual driver system that allows independent genetic manipulation of tumour and host skeletal muscle. Overall, we present a novel Drosophila larval paradigm to study tumour/host tissue crosstalk in vivo, which may contribute to future research in cancer cachexia and impact the design of therapeutic approaches for this pathology.
Ad26.COV2.S elicited neutralizing activity against Delta and other SARS-CoV-2 variants of concern
Authors: Jongeneelen Mandy , Kaszas Krisztian , Veldman Daniel , Huizingh Jeroen , van der Vlugt Remko , Schouten Theo , Zuijdgeest David , Uil Taco , van Roey Griet , Guimera Nuria , Navis Marjon , Bos Rinke , le Gars Mathieu , Sadoff Jerald , Muchene Leacky , Juraszek Jarek , Langedijk Johannes PM , Vogels Ronald , Custers Jerome , Schuitemaker Hanneke , Brandenburg Boerries 
Published: July 2021

AbstractSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to evolve and recently emerging variants with substitutions in the Spike protein have led to growing concerns over increased transmissibility and decreased vaccine coverage due to immune evasion. Here, sera from recipients of a single dose of our Ad26.COV2.S COVID-19 vaccine were tested for neutralizing activity against several SARS-CoV-2 variants of concern. All tested variants demonstrated susceptibility to Ad26.COV2.S-induced serum neutralization albeit mainly reduced as compared to the B.1 strain. Most pronounced reduction was observed for the B.1.351 (Beta; 3.6-fold) and P.1 (Gamma; 3.4-fold) variants that contain similar mutations in the receptor-binding domain (RBD) while only a 1.6-fold reduction was observed for the widely spreading B.1.617.2 (Delta) variant.
Effects of High-Volume versus High-Load Resistance Training on Skeletal Muscle Growth and Molecular Adaptations
Authors: Vann Christopher G. , Sexton Casey L. , Osburn Shelby C. , Smith Morgan A. , Haun Cody T. , Rumbley Melissa N. , Mumford Petey W. , Ferguson Brian K. , Montgomery Nathan T. , Fox Carlton D. , Ruple Bradley A. , McKendry James , Mcleod Jonathan , Bashir Adil , Beyers Ronald J. , Brook Matthew S. , Smith Kenneth , Atherton Philip J , Beck Darren T. , McDonald James R. , Young Kaelin C. , Phillips Stuart M. , Roberts Michael D. 
Published: July 2021

ABSTRACTAimWe evaluated the effects of higher-load (HL) versus (lower-load) higher-volume (HV) resistance training on skeletal muscle hypertrophy, strength, and muscle-level molecular markers.MethodsTrained men (n=15, age: 23±3 y; training experience: 7±3 y) performed unilateral lower body training for 6 weeks (3x weekly), where single legs were assigned to HV and HL paradigms. Vastus lateralis (VL) biopsies were obtained prior to study initiation (PRE) as well as 3 days (POST) and 10 days following the last bout (POSTPR). Body composition and strength tests were performed at each testing session, and biochemical assays were performed on muscle tissue after study completion. Two-way within subjects repeated measures ANOVAs were performed on all dependent variables except tracer data, which was compared using dependent samples t-tests.ResultsA significant (p<0.05) interaction existed for unilateral leg extension 1RM (HV<HL at POST and POSTPR). Six-week integrated sarcoplasmic protein synthesis (iSarcoPS) rates were higher in the HV versus HL leg, while no difference between legs existed for integrated myofibrillar protein synthesis rates. Main time effects existed for unilateral leg press strength (PRE<POST and POSTPR), knee extensor peak torque (PRE and POST<POSTPR), dual-energy x-ray absorptiometry (DXA)-derived upper leg lean mass (PRE<POST and POSTPR), ultrasound-derived VL thickness (PRE and POSTPR<POST), sarcoplasmic protein concentrations (POST and POSTPR<PRE), and tropomyosin and troponin protein abundances (POST and POSTPR<PRE).ConclusionsWith the exception of differences in leg extensor strength and iSarcoPS between legs, our data suggest that short-term (6 weeks) HV and HL training elicit similar hypertrophic, strength, and molecular-level adaptations.
Spectro-temporal neural dynamics during sentence completion
Authors: Coolen Tim , Dumitrescu Alexandru Mihai , Wens Vincent , Bourguignon Mathieu , Gómez Gustavo Lucena , Rovai Antonin , Sadeghi Niloufar , Urbain Charline , Goldman Serge , De Tiège Xavier 
Published: July 2021

AbstractThis magnetoencephalography (MEG) study aimed at characterizing the spectro-temporal dynamics of brain oscillatory activity elicited by sentence completion (SC). For that purpose, we adapted a version of the SC experimental paradigm typically used in functional magnetic resonance imaging to MEG investigation constraints. Twenty right-handed healthy young adults underwent MEG recordings while they were sequentially presented with short sentences divided in three parts: the first two giving context and the last requiring completion. MEG data were then analysed using a prior-free, non-parametric statistical approach with stringent control of the family-wise error rate. We identified three successive significant neural response patterns associated with distinct spatial and spectro-temporal characteristics: (i) an early (<300 ms) bioccipital 4-10-Hz event-related synchronization (ERS); (ii) an intermediate (at about 400 ms) 8-30-Hz event-related desynchronization (ERD) in an extended semantic network involving the ventral language stream as well as bilateral posterior nodes of the default mode network (DMN) in both hemispheres; (iii) a late (>800 ms) 8-30 Hz ERD involving the left dorsal language stream. Furthermore, the left component of the ventral language stream displayed prolonged ERD after 800 ms compared to the right which showed signs of inhibition in the form of ERS. Overall, this study elucidates the dynamics of the recruitment of the language network that accompany SC and the spectro-temporal signature of an extended semantic network. This MEG adaptation of an SC paradigm also paves the way for novel approaches in presurgical language mapping and may help to understand the neural underpinnings of the alterations of sentence completion in various neurologic disorders affecting language.
Modeling site-specific nucleotide biases affecting Himar1 transposon insertion frequencies in TnSeq datasets
Authors: Choudhery Sanjeevani , Brown A. Jacob , Akusobi Chidiebere , Rubin Eric J. , Sassetti Christopher M. , Ioerger Thomas R. 
Published: July 2021

AbstractIn bacterial TnSeq experiments, a library of transposons insertion mutants is generated, selected under various growth conditions, and sequenced to determine the profile of insertions at different sites in the genome, from which the fitness of mutant strains can be inferred. The widely used Himar1 transposon is known to be restricted to insertions at TA dinucleotides, but otherwise, few site-specific biases have been identified. As a result, most analytical approaches assume that insertion counts are expected a priori to be randomly distributed among TA sites in non-essential regions. However, recent analyses of independent Himar1 Tn libraries in M. tuberculosis have identified a local sequence pattern that is non-permissive for Himar1 insertion. This suggests there are site-specific biases that affect the frequency of insertions of the Himar1 transposon at different TA sites. In this paper, we use statistical and machine learning models to characterize patterns in the nucleotides surrounding TA sites associated with high and low insertion counts. We not only affirm that the previously discovered non-permissive pattern (CG)GnTAnC(CG) suppresses insertions, but conversely show that an A in the -3 position or T in the +3 position from the TA site encourages them. We demonstrate that these insertion preferences exist in Himar1 TnSeq datasets other than M. tuberculosis, including mycobacterial and non-mycobacterial species. We build predictive models of Himar1 insertion preferences as a function of surrounding nucleotides. The final predictive model explains about half of the variance in insertion counts, presuming the rest comes from stochastic variability between libraries or due to sampling differences during sequencing. Based on this model, we present a new method, called the TTN-Fitness method, to improve the identification of conditionally essential genes or genetic interactions, i.e., to better distinguish true biological fitness effects by comparing the observed counts to expected counts using a site-specific model of insertion preferences. Compared to previous methods like Hidden Markov Models, the TTN-Fitness method can make finer distinctions among genes whose disruption causes a fitness defect (or advantage), separating them out from the large pool of non-essentials, and is able to classify the essentiality of many smaller genes (with few TA sites) that were previously characterized as uncertain.
Flavonols and dihydroflavonols inhibit the main protease activity of SARS-CoV-2 and the replication of human coronavirus 229E
Authors: Zhu Yue , Scholle Frank , Kisthardt Samantha C. , Xie De-Yu 
Published: July 2021

AbstractSince December 2019, the deadly novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused the current COVID-19 pandemic. To date, vaccines are available in the developed countries to prevent the infection of this virus, however, medicines are necessary to help control COVID-19. Human coronavirus 229E (HCoV-229E) causes the common cold. The main protease (Mpro) is an essential enzyme required for the multiplication of these two viruses in the host cells, and thus is an appropriate candidate to screen potential medicinal compounds. Flavonols and dihydroflavonols are two groups of plant flavonoids. In this study, we report docking simulation with two Mpro enzymes and five flavonols and three dihydroflavonols, in vitro inhibition of the SARS-CoV-2 Mpro, and in vitro inhibition of the HCoV 229E replication. The docking simulation results predicted that (+)-dihydrokaempferol, (+)-dihydroquercetin, (+)-dihydromyricetin, kaempferol, quercetin, myricentin, isoquercetin, and rutin could bind to at least two subsites (S1, S1’, S2, and S4) in the binding pocket and inhibit the activity of SARS-CoV-2 Mpro. Their affinity scores ranged from −8.8 to −7.4. Likewise, these compounds were predicted to bind and inhibit the HCoV-229E Mpro activity with affinity scores ranging from −7.1 to −7.8. In vitro inhibition assays showed that seven available compounds effectively inhibited the SARS-CoV-2 Mpro activity and their IC50 values ranged from 0.125 to 12.9 µM. Five compounds inhibited the replication of HCoV-229E in Huh-7 cells. These findings indicate that these antioxidative flavonols and dihydroflavonols are promising candidates for curbing the two viruses.