bluuebunny/crossref_metadata_2025_split huggingface dataset:
Primate fetal hepatic responses to maternal obesity: epigenetic signalling pathways and lipid accumulation
Authors: Puppala Sobha , Li Cun , Glenn Jeremy P. , Saxena Romil , Gawrieh Samer , Quinn Amy , Palarczyk Jennifer , Dick Edward J. , Nathanielsz Peter W. , Cox Laura A. 
Published: March 2018

Key points
Maternal obesity (MO) and exposure to a high‐fat, high‐simple‐carbohydrate diet during pregnancy predisposes offspring to obesity, metabolic and cardiovascular disorders in later life.
Underlying molecular pathways and potential epigenetic factors that are dysregulated in MO were identified using unbiased transcriptomic methods.
There was increased lipid accumulation and severe steatosis in the MO baboon fetal liver suggesting that these offspring are on an early trajectory of non‐alcoholic fatty liver disease and non‐alcoholic steatohepatitis.
AbstractMaternal obesity (MO) increases offspring cardiometabolic disease risk. Altered fetal liver development in response to the challenge of MO has metabolic consequences underlying adverse offspring life‐course health outcomes. Little is known about the molecular pathways and potential epigenetic changes regulating primate fetal liver responses to MO. We hypothesized that MO would induce fetal baboon liver epigenetic changes resulting in dysregulation of key metabolic pathways that impact lipid metabolism. MO was induced prior to pregnancy by a high‐fat, high‐fructose diet. Unbiased gene and microRNA (small RNA Seq) abundance analyses were performed on fetal baboon livers at 0.9 gestation and subjected to pathway analyses to identify fetal liver molecular responses to MO. Fetal baboon liver lipid and glycogen content were quantified by the Computer Assisted Stereology Toolbox. In response to MO, fetal livers revealed dysregulation of TCA cycle, proteasome, oxidative phosphorylation, glycolysis and Wnt/β‐catenin signalling pathways together with marked lipid accumulation supporting our hypothesis that multiple pathway dysregulation detrimentally impacts lipid management. This is the first study of MO programming of the non‐human primate fetal liver using unbiased transcriptome analysis to detect changes in hepatic gene expression levels and identify potential microRNA epigenetic regulators of metabolic disruption.
Nascent DNA methylome mapping reveals inheritance of hemimethylation at CTCF/cohesin sites
Authors: Xu Chenhuan , Corces Victor G. 
Published: March 2018

Hemimethylation drives chromatin assembly
Cytosine DNA methylation is a heritable and essential epigenetic mark. During DNA replication, cytosines on mother strands remain methylated, but those on daughter strands are initially unmethylated. These hemimethylated sites are rapidly methylated to maintain faithful methylation patterns. Xu and Corces mapped genome-wide strand-specific DNA methylation sites on nascent chromatin, confirming such maintenance in the vast majority of the DNA methylome (see the Perspective by Sharif and Koseki). However, they also identified a small fraction of sites that were stably hemimethylated and showed their inheritance at CTCF (CCCTC-binding factor)/cohesin binding sites. These inherited hemimethylation sites were required for CTCF and cohesin to establish proper chromatin interactions.

Science
, this issue p.
1166
; see also p.
1102
Imidazolopiperazines Kill both Rings and Dormant Rings in Wild-Type and K13 Artemisinin-Resistant Plasmodium falciparum In Vitro
Authors: Dembele Laurent , Gupta Devendra Kumar , Lim Michelle Yi-Xiu , Ang Xiaoman , Selva Jeremy J. , Chotivanich Kesinee , Nguon Chea , Dondorp Arjen M. , Bonamy Ghislain M. C. , Diagana Thierry T. , Bifani Pablo 
Published: March 2018

ABSTRACT

Artemisinin (ART) resistance has spread through Southeast Asia, posing a serious threat to the control and elimination of malaria. ART resistance has been associated with mutations in the
Plasmodium falciparum
kelch-13 (
Pfk13
) propeller domain. Phenotypically, ART resistance is defined as delayed parasite clearance in patients due to the reduced susceptibility of early ring-stage parasites to the active metabolite of ART dihydroartemisinin (DHA). Early rings can enter a state of quiescence upon DHA exposure and resume growth in its absence. These quiescent rings are referred to as dormant rings or DHA-pretreated rings (here called dormant rings). The imidazolopiperazines (IPZ) are a novel class of antimalarial drugs that have demonstrated efficacy in early clinical trials. Here, we characterized the stage of action of the IPZ GNF179 and evaluated its activity against rings and dormant rings in wild-type and ART-resistant parasites. Unlike DHA, GNF179 does not induce dormancy. We show that GNF179 is more rapidly cidal against schizonts than against ring and trophozoite stages. However, with 12 h of exposure, the compound effectively kills rings and dormant rings of both susceptible and ART-resistant parasites within 72 h. We further demonstrate that in combination with ART, GNF179 effectively prevents recrudescence of dormant rings, including those bearing
pfk13
propeller mutations.
Population Pharmacokinetics of Meropenem in Plasma and Subcutis from Patients on Extracorporeal Membrane Oxygenation Treatment
Authors: Hanberg Pelle , Öbrink-Hansen Kristina , Thorsted Anders , Bue Mats , Tøttrup Mikkel , Friberg Lena E. , Hardlei Tore Forsingdal , Søballe Kjeld , Gjedsted Jakob 
Published: March 2018

ABSTRACT

The objectives of this study were to describe meropenem pharmacokinetics (PK) in plasma and/or subcutaneous adipose tissue (SCT) in critically ill patients receiving extracorporeal membrane oxygenation (ECMO) treatment and to develop a population PK model to simulate alternative dosing regimens and modes of administration. We conducted a prospective observational study. Ten patients on ECMO treatment received meropenem (1 or 2 g) intravenously over 5 min every 8 h. Serial SCT concentrations were determined using microdialysis and compared with plasma concentrations. A population PK model of SCT and plasma data was developed using NONMEM. Time above clinical breakpoint MIC for
Pseudomonas aeruginosa
(8 mg/liter) was predicted for each patient. The following targets were evaluated: time for which the free (unbound) concentration is maintained above the MIC of at least 40% (40%
f
T>MIC), 100%
f
T>MIC, and 100%
f
T>4×MIC. For all dosing regimens simulated in both plasma and SCT, 40%
f
T>MIC was attained. However, prolonged meropenem infusion would be needed for 100%
f
T>MIC and 100%
f
T>4×MIC to be obtained. Meropenem plasma and SCT concentrations were associated with estimated creatinine clearance (eCL
Cr
). Simulations showed that in patients with increased eCL
Cr
, dose increment or continuous infusion may be needed to obtain therapeutic meropenem concentrations. In conclusion, our results show that using traditional targets of 40%
f
T>MIC for standard meropenem dosing of 1 g intravenously every 8 h is likely to provide sufficient meropenem concentration to treat the problematic pathogen
P. aeruginosa
for patients receiving ECMO treatment. However, for patients with an increased eCL
Cr
, or if more aggressive targets, like 100%
f
T>MIC or 100%
f
T>4×MIC, are adopted, incremental dosing or continuous infusion may be needed.
Inactivation of the Pseudomonas-Derived Cephalosporinase-3 (PDC-3) by Relebactam
Authors: Barnes Melissa D. , Bethel Christopher R. , Alsop Jim , Becka Scott A. , Rutter Joseph D. , Papp-Wallace Krisztina M. , Bonomo Robert A. 
Published: March 2018

ABSTRACT

Pseudomonas aeruginosa
is a prevalent and life-threatening Gram-negative pathogen.
Pseudomonas
-derived cephlosporinase (PDC) is the major inducible cephalosporinase in
P. aeruginosa
. In this investigation, we show that relebactam, a diazabicyclooctane β-lactamase inhibitor, potently inactivates PDC-3, with a
k
2
/
K
of 41,400 M
−1
s
−1
and a
k
off
of 0.00095 s
−1
. Relebactam restored susceptibility to imipenem in 62% of multidrug-resistant
P. aeruginosa
clinical isolates, while only 21% of isolates were susceptible to imipenem-cilastatin alone. Relebactam promises to increase the efficacy of imipenem-cilastatin against
P. aeruginosa
.
Microbiome Dynamics in a Large Artificial Seawater Aquarium
Authors: Patin Nastassia V. , Pratte Zoe A. , Regensburger Matthew , Hall Eric , Gilde Kailen , Dove Alistair D. M. , Stewart Frank J. 
Published: March 2018

ABSTRACT

Artificial habitats for animals have high commercial and societal value. Microbial communities (microbiomes) in such habitats may play ecological roles similar to those in nature. However, this hypothesis remains largely untested. Georgia Aquarium's
Ocean Voyager
(OV) exhibit is a closed-system aquatic habitat that mimics the oligotrophic open ocean and houses thousands of large marine animals, including fish, sea turtles, and whale sharks. We present a 14-month time series characterizing the OV water column microbiome. The composition and stability of the microbiome differed from those of natural marine environments with similar chemical features. The composition shifted dramatically over the span of 2 weeks and was characterized by bloom events featuring members of two heterotrophic bacterial lineages with cosmopolitan distributions in the oceans. The relative abundances of these lineages were inversely correlated, suggesting an overlap in ecological niches. Transcript mapping to metagenome-assembled genomes (MAGs) of these taxa identified unique characteristics, including the presence and activity of genes for the synthesis and degradation of cyanophycin, an amino acid polymer linked to environmental stress and found frequently in cyanobacteria but rarely in heterotrophic bacteria. The dominant MAGs also contained and transcribed plasmid-associated sequences, suggesting a role for conjugation in adaptation to the OV environment. These findings indicate a highly dynamic microbiome despite the stability of the physical and chemical parameters of the water column. Characterizing how such fluctuations affect microbial function may inform our understanding of animal health in closed aquaculture systems.

IMPORTANCE
Public aquariums play important societal roles, for example, by promoting science education and helping conserve biodiversity. The health of aquarium animals depends on interactions with the surrounding microbiome. However, the extent to which aquariums recreate a stable and natural microbial ecosystem is uncertain. This study describes the taxonomic composition of the water column microbiome over 14 months in a large indoor aquatic habitat, the
Ocean Voyager
exhibit at the Georgia Aquarium. Despite stable water column conditions, the exhibit experienced blooms in which the abundance of a single bacterial strain increased to over 65% of the community. Genome analysis indicated that the OV's dominant strains share unique adaptations, notably genes for storage polymers associated with environmental stress. These results, interpreted alongside data from natural ocean systems and another artificial seawater aquarium, suggest a highly dynamic aquarium microbiome and raise questions of how microbiome stability may affect the ecological health of the habitat.
Landscape-Scale Factors Affecting the Prevalence of Escherichia coli in Surface Soil Include Land Cover Type, Edge Interactions, and Soil pH
Authors: Dusek Nicholas , Hewitt Austin J. , Schmidt Kaycie N. , Bergholz Peter W. 
Published: March 2018

ABSTRACT

Escherichia coli
is deposited into soil with feces and exhibits subsequent population decline with concomitant environmental selection. Environmentally persistent strains exhibit longer survival times during this selection process, and some strains have adapted to soil and sediments. A georeferenced collection of
E. coli
isolates was developed comprising 3,329 isolates from 1,428 soil samples that were collected from a landscape spanning the transition from the grasslands to the eastern deciduous forest biomes. The isolate collection and sample database were analyzed together to discover how land cover, site characteristics, and soil chemistry influence the prevalence of cultivable
E. coli
in surface soil. Soils from forests and pasture lands had equally high prevalences of
E. coli
. Edge interactions were also observed among land cover types, with proximity to forests and pastures affecting the likelihood of
E. coli
isolation from surrounding soils.
E. coli
is thought to be more prevalent in sediments with high moisture, but this was observed only in grass- or crop-dominated lands in this study. Because differing
E. coli
phylogroups are thought to have differing ecology profiles, isolates were also typed using a novel single-nucleotide polymorphism (SNP) genotyping assay. Phylogroup B1 was the dominant group isolated from soil, as has been reported in all other surveys of environmental
E. coli
. Although differences were small, isolates belonging to phylogroups B2 and D were associated with wooded areas, slightly more acidic soils, and soil sampling after rainfall events. In contrast, isolates from phylogroups B1 and E were associated with pasture lands.

IMPORTANCE
The consensus is that complex niches or life cycles should select for complex genomes in organisms. There is much unexplained biodiversity in
E. coli
, and its cycling through complex extrahost environments may be a cause. In order to understand the evolutionary processes that lead to adaptation for survival and growth in soil, an isolate collection that associates soil conditions and isolate genome sequences is required. An equally important question is whether traits selected in soil or other extrahost habitats can be transmitted to
E. coli
residing in hosts via gene flow. The new findings about the distribution of
E. coli
in soil at the landscape scale (i) enhance our capability to study how extrahost environments influence the evolution of
E. coli
and other bacteria, (ii) advance our knowledge of the environmental biology of this microbe, and (iii) further affirm the emerging scientific consensus that
E. coli
in waterways originates from nonpoint sources not associated with human activity or livestock farming.
Two Phytoplasmas Elicit Different Responses in the Insect Vector Euscelidius variegatus Kirschbaum
Authors: Galetto Luciana , Abbà Simona , Rossi Marika , Vallino Marta , Pesando Massimo , Arricau-Bouvery Nathalie , Dubrana Marie-Pierre , Chitarra Walter , Pegoraro Mattia , Bosco Domenico , Marzachì Cristina 
Published: March 2018

ABSTRACT

Phytoplasmas are plant-pathogenic bacteria transmitted by hemipteran insects. The leafhopper
Euscelidius variegatus
is a natural vector of chrysanthemum yellows phytoplasma (CYp) and a laboratory vector of flavescence dorée phytoplasma (FDp). The two phytoplasmas induce different effects on this species: CYp slightly improves whereas FDp negatively affects insect fitness. To investigate the molecular bases of these different responses, transcriptome sequencing (RNA-seq) analysis of
E. variegatus
infected with either CYp or FDp was performed. The sequencing provided the first
de novo
transcriptome assembly for a phytoplasma vector and a starting point for further analyses on differentially regulated genes, mainly related to immune system and energy metabolism. Insect phenoloxidase activity, immunocompetence, and body pigmentation were measured to investigate the immune response, while respiration and movement rates were quantified to confirm the effects on energy metabolism. The activation of the insect immune response upon infection with FDp, which is not naturally transmitted by
E. variegatus
, confirmed that this bacterium is mostly perceived as a potential pathogen. Conversely, the acquisition of CYp, which is naturally transmitted by
E. variegatus
, seems to increase the insect fitness by inducing a prompt response to stress. This long-term relationship is likely to improve survival and dispersal of the infected insect, thus enhancing the opportunity of phytoplasma transmission.
Serum Amyloid P and IgG Exhibit Differential Capabilities in the Activation of the Innate Immune System in Response to Bacillus anthracis Peptidoglycan
Authors: Girton Alanson W. , Popescu Narcis I. , Keshari Ravi S. , Burgett Tarea , Lupu Florea , Coggeshall K. Mark 
Published: March 2018

ABSTRACTWe showed that human IgG supported the response by human innate immune cells to peptidoglycan (PGN) fromBacillus anthracisand PGN-induced complement activation. However, other serum constituents have been shown to interact with peptidoglycan, including the IgG-like soluble pattern recognition receptor serum amyloid P (SAP). Here, we compared the abilities of SAP and of IgG to support monocyte and complement responses to PGN. Utilizingin vitromethods, we demonstrate that SAP is superior to IgG in supporting monocyte production of cytokines in response to PGN. Like IgG, the response supported by SAP was enhanced by phagocytosis and signaling kinases, such as Syk, Src, and phosphatidylinositol 3-kinase, that are involved in various cellular processes, including Fc receptor signaling. Unlike IgG, SAP had no effect on the activation of complement in response to PGN. These data demonstrate an opsonophagocytic role for SAP in response to PGN that propagates a cellular response without propagating the formation of the terminal complement complex.
Visible DNA Microarray System as an Adjunctive Molecular Test in Identification of Pathogenic Fungi Directly from a Blood Culture Bottle
Authors: Sturaro Lais Lovison , Gonoi Tohru , Busso-Lopes Ariane Fidelis , Tararam Cibele Aparecida , Levy Carlos Emilio , Lyra Luzia , Trabasso Plinio , Schreiber Angélica Zaninelli , Kamei Katsuhiko , Moretti Maria Luiza 
Published: March 2018

ABSTRACT

A DNA microarray platform, based on the nucleotide sequences of the internal transcribed spacer regions (ITS1 and ITS2) of the rRNA gene, was developed to identify 32 fungal pathogens at the species level. The probe sequences were spotted onto polycarbonate slides with a mini-microarray printer, and after the hybridization, the results were visible with the naked eye. The performance of the microarray platform was evaluated against the commercial automated systems (Vitek 2 and BD Phoenix systems) and DNA sequencing (gold standard). A total of 461 blood culture bottles were tested: 127 positive for fungi, 302 positive for bacteria, and 32 that were negative. Once the microorganisms were identified by automated systems, fungal DNA was extracted directly from the blood culture bottles. The DNA products were tested using the microarray platform, and DNA sequencing was performed. The results of the microarray and DNA sequencing were concordant in 96.7% of cases, and the results from the automated systems and DNA sequencing were concordant in 98.4%. Of all the nucleotide sequences contained in the microarray platform, the microarray failed to identify four fungal isolates (one
Candida parapsilosis
, two
Candida tropicalis
, and one
Cryptococcus neoformans
). Of note, the microarray detected
Candida krusei
DNA in two blood cultures from the same patient, whereas the automated system was only positive for
Enterococcus faecium
. Our microarray system provided reliable and fast fungal identification compared to that from DNA sequencing and the automated systems. The simplicity of reading the results by the naked eye made this DNA platform a suitable method for fungal molecular diagnosis.
Identification of H209 as Essential for pH 8-Triggered Receptor-Independent Syncytium Formation by S Protein of Mouse Hepatitis Virus A59
Authors: Li Pei , Shan Yiwei , Zheng Wangliang , Ou Xiuyuan , Mi Dan , Mu Zhixia , Holmes Kathryn V. , Qian Zhaohui 
Published: March 2018

ABSTRACT
The spike glycoprotein (S) of murine coronavirus mouse hepatitis virus (MHV) strain A59 uses murine carcinoembryonic antigen-related cell adhesion molecule 1a as its receptor for cell entry, but S protein can also be triggered in the absence of receptor by pH 8.0 alone at 37°C. The mechanism by which conformational changes of this S glycoprotein can be triggered by pH 8.0 has not yet been determined. Here, we show that MHV-A59 S protein is triggered by pH 8.0 at 37°C to induce receptor-independent syncytium (RIS) formation on 293T cells, and that the conformational changes in S proteins triggered by pH 8.0 are very similar to those triggered by receptor binding. We systemically mutated each of 15 histidine residues in S protein and found that H209 is essential for pH 8.0-triggered RIS formation, while H179, H441, H643, and H759 also play important roles in this process. Replacement of H209 with Ala had no effect on receptor binding, but in murine 17Cl.1 cells mutant H209A MHV-A59 showed delayed growth kinetics and was readily outcompeted by wild-type virus when mixed together, indicating that the H209A mutation caused a defect in virus fitness. Finally, the H209A mutation significantly increased the thermostability of S protein in its prefusion conformation, which may raise the energy barrier for conformational change of S protein required for membrane fusion and lead to a decrease in virus fitness in cell culture. Thus, MHV-A59 may have evolved to lower the stability of its S protein in order to increase virus fitness.

IMPORTANCE
Enveloped viruses enter cells through fusion of viral and cellular membranes, and the process is mediated by interactions between viral envelope proteins and their host receptors. In the prefusion conformation, viral envelope proteins are metastable, and activation to the fusion conformation is tightly regulated, since premature activation would lead to loss of viral infectivity. The stability of viral envelope proteins greatly influences their activation and virus fitness. Here, we report that, similar to the A82V mutation in Ebola glycoprotein, in the S glycoprotein of murine coronavirus MHV-A59, the histidine residue at position of 209 significantly affects the thermal stability of the S protein, determines whether S protein can be activated at 37°C by either pH 8.0 alone or by receptor binding, and affects viral fitness in cell culture. Thus, the spike glycoprotein of MHV-A59 has evolved to retain histidine at position 209 to optimize virus fitness.