bluuebunny/crossref_metadata_2025_split huggingface dataset:
Epigenetic intersection of BDNF Val66Met genotype with premenstrual dysphoric disorder transcriptome in a cross-species model of estradiol add-back
Authors: Marrocco Jordan , Einhorn Nathan R. , Petty Gordon H. , Li Howard , Dubey Neelima , Hoffman Jessica , Berman Karen F. , Goldman David , Lee Francis S. , Schmidt Peter J. , McEwen Bruce S. 
Published: October 2018

AbstractPremenstrual dysphoric disorder (PMDD) affects over 5% of women, with symptoms similar to anxiety and major depression, and is associated with differential sensitivity to circulating ovarian hormones. Little is known about the genetic and epigenetic factors that increase the risk to develop PMDD. We report that 17β-estradiol (E2) affects the behavior and the epigenome in a mouse model carrying a single-nucleotide polymorphism of the brain-derived neurotrophic factor gene (BDNF Val66Met), in a way that recapitulates the hallmarks of PMDD. Ovariectomized mice heterozygous for the BDNF Met allele (Het-Met) and their matched wild-type (WT) mice were administered estradiol or vehicle in drinking water for 6 weeks. Using the open field and the splash test, we show that E2 add-back induces anxiety-like and depression-like behavior in Het-Met mice, but not in WT mice. RNA-seq of the ventral hippocampus (vHpc) highlights that E2-dependent gene expression is markedly different between WT mice and Het-Met mice. Through a comparative whole-genome RNA-seq analysis between mouse vHpc and lymphoblastoid cell line cultures from control women and women with PMDD, we discovered common epigenetic biomarkers that transcend species and cell types. Those genes include epigenetic modifiers of the ESC/E(Z) complex, an effector of response to ovarian steroids. Although the BDNF Met genotype intersects the behavioral and transcriptional traits of women with PMDD, we suggest that these similarities speak to the epigenetic factors by which ovarian steroids produce negative behavioral effects.
Structural reorganization of SHP2 by oncogenic mutations and implications for oncoprotein resistance to allosteric inhibition
Authors: LaRochelle Jonathan R. , Fodor Michelle , Vemulapalli Vidyasiri , Mohseni Morvarid , Wang Ping , Stams Travis , LaMarche Matthew J. , Chopra Rajiv , Acker Michael G. , Blacklow Stephen C. 
Published: October 2018

AbstractActivating mutations in PTPN11, encoding the cytosolic protein tyrosine phosphatase SHP2, result in developmental disorders and act as oncogenic drivers in patients with hematologic cancers. The allosteric inhibitor SHP099 stabilizes the wild-type SHP2 enzyme in an autoinhibited conformation that is itself destabilized by oncogenic mutations. Here, we report the impact of the highly activated and most frequently observed mutation, E76K, on the structure of SHP2, and investigate the effect of E76K and other oncogenic mutations on allosteric inhibition by SHP099. SHP2E76K adopts an open conformation but can be restored to the closed, autoinhibited conformation, near-identical to the unoccupied wild-type enzyme, when complexed with SHP099. SHP099 inhibitory activity against oncogenic SHP2 variants in vitro and in cells scales inversely with the activating strength of the mutation, indicating that either oncoselective or vastly more potent inhibitors will be necessary to suppress oncogenic signaling by the most strongly activating SHP2 mutations in cancer.
Differential active site requirements for NDM-1 β-lactamase hydrolysis of carbapenem versus penicillin and cephalosporin antibiotics
Authors: Sun Zhizeng , Hu Liya , Sankaran Banumathi , Prasad B. V. Venkataram , Palzkill Timothy 
Published: October 2018

AbstractNew Delhi metallo-β-lactamase-1 exhibits a broad substrate profile for hydrolysis of the penicillin, cephalosporin and ‘last resort’ carbapenems, and thus confers bacterial resistance to nearly all β-lactam antibiotics. Here we address whether the high catalytic efficiency for hydrolysis of these diverse substrates is reflected by similar sequence and structural requirements for catalysis, i.e., whether the same catalytic machinery is used to achieve hydrolysis of each class. Deep sequencing of randomized single codon mutation libraries that were selected for resistance to representative antibiotics reveal stringent sequence requirements for carbapenem versus penicillin or cephalosporin hydrolysis. Further, the residue positions required for hydrolysis of penicillins and cephalosporins are a subset of those required for carbapenem hydrolysis. Thus, while a common core of residues is used for catalysis of all substrates, carbapenem hydrolysis requires an additional set of residues to achieve catalytic efficiency comparable to that for penicillins and cephalosporins.
Prefrontal projections to the thalamic nucleus reuniens mediate fear extinction
Authors: Ramanathan Karthik R. , Jin Jingji , Giustino Thomas F. , Payne Martin R. , Maren Stephen 
Published: October 2018

AbstractThe thalamic nucleus reuniens (RE) receives dense projections from the medial prefrontal cortex (mPFC), interconnects the mPFC and hippocampus, and may serve a pivotal role in regulating emotional learning and memory. Here we show that the RE and its mPFC afferents are critical for the extinction of Pavlovian fear memories in rats. Pharmacological inactivation of the RE during extinction learning or retrieval increases freezing to an extinguished conditioned stimulus (CS); renewal of fear outside the extinction context was unaffected. Suppression of fear in the extinction context is associated with an increase in c-fos expression and spike firing in RE neurons to the extinguished CS. The role for the RE in suppressing extinguished fear requires the mPFC, insofar as pharmacogenetically silencing mPFC to RE projections impairs the expression of extinction memory. These results reveal that mPFC-RE circuits inhibit the expression of fear, a function that is essential for adaptive emotional regulation.
The DNA binding landscape of the maize AUXIN RESPONSE FACTOR family
Authors: Galli Mary , Khakhar Arjun , Lu Zefu , Chen Zongliang , Sen Sidharth , Joshi Trupti , Nemhauser Jennifer L. , Schmitz Robert J. , Gallavotti Andrea 
Published: October 2018

AbstractAUXIN RESPONSE FACTORS (ARFs) are plant-specific transcription factors (TFs) that couple perception of the hormone auxin to gene expression programs essential to all land plants. As with many large TF families, a key question is whether individual members determine developmental specificity by binding distinct target genes. We use DAP-seq to generate genome-wide in vitro TF:DNA interaction maps for fourteen maize ARFs from the evolutionarily conserved A and B clades. Comparative analysis reveal a high degree of binding site overlap for ARFs of the same clade, but largely distinct clade A and B binding. Many sites are however co-occupied by ARFs from both clades, suggesting transcriptional coordination for many genes. Among these, we investigate known QTLs and use machine learning to predict the impact of cis-regulatory variation. Overall, large-scale comparative analysis of ARF binding suggests that auxin response specificity may be determined by factors other than individual ARF binding site selection.
A modeling study of the Danish HIV epidemic in men who have sex with men: travel, pre-exposure prophylaxis and elimination
Authors: Palk Laurence , Gerstoft Jan , Obel Niels , Blower Sally 
Published: October 2018

AbstractUNAIDS has identified the Danish HIV epidemic in men who have sex with men (MSM) as a priority for elimination. Incidence is close to the elimination threshold of one new infection per year per 1,000 individuals. However, surveillance data show that HIV strains are being imported into Denmark, mainly due to travel. We use a transmission model to predict (from 2018 to 2030) the impact of pre-exposure prophylaxis (PrEP) on incidence. Our model reflects the current epidemic and diagnosis rates in the Danish MSM community. We conduct a sensitivity analysis based on 20,000 simulations, and assume that PrEP coverage could range from zero to 50% and diagnosis rates increase up to three-fold. We predict that incidence will fall below the elimination threshold, even without the introduction of PrEP, reaching 0.87 (median, 95% Confidence Interval: 0.65–1.23) new infections per 1,000 MSM by 2030. PrEP could reduce incidence to well below the threshold, if it results in a significant increase in diagnosis rates and reduces the number of infections occurring abroad. The Danish Medicine Agency and Danish Health Authority have recommended introducing PrEP. Our study provides strong support for this recommendation, and shows the importance of Danish MSM using PrEP when abroad.
A task-experienced partner does not help dogs be as successful as wolves in a cooperative string-pulling task
Authors: Marshall-Pescini Sarah , Basin Camille , Range Friederike 
Published: October 2018

AbstractAlthough theories of domestication have suggested that dogs evolved a greater capacity for tolerant and cooperative behaviour compared to their wild wolf cousins, the differences between wolves’ and free-ranging dogs’ social ecology, with wolves relying more on conspecific cooperation than dogs, would rather predict the opposite. In a cooperative task involving joint action on a rope to pull a tray forward, wolves systematically outperformed dogs. The dogs’ failure appeared largely due to tolerance issues, i.e. one partner avoiding interacting with the apparatus, when the other was engaged with it, rather than cognitive limitations. To verify this, in the current study we trained the dominant partner to become an ‘expert’ on the task thereby potentially enhancing their understanding that they ‘needed the partner to succeed’. Indeed both the duration of co-action on the apparatus and the success rate of dyads composed of an expert and an inexperienced dog was higher than dyads composed of two inexperienced partners. Nevertheless the dogs’ performance was substantially poorer than that of wolf dyads with equivalent experience, highlighting that despite the facilitating effect of the ‘expert’, cooperation on this task did not come easily to dogs. For both dogs and wolves, cooperation was facilitated by the closeness of the affiliative bond between individuals, but opposite rank effects emerged. Dogs further apart in rank were more successful co-operators, whereas in wolves, animals closer in rank had a higher cooperative success. The results further highlight the importance of the different socio-ecologies of wolves and dogs in understanding their behaviour.
Robust sensing suite for measuring temporal dynamics of surface temperature in sewers
Authors: Thiyagarajan Karthick , Kodagoda Sarath , Ranasinghe Ravindra , Vitanage Dammika , Iori Gino 
Published: October 2018

AbstractSewerage systems are paramount underground infrastructure assets for any nation. In most cities, they are old and have been exposed to significant microbial induced corrosion. It is a serious global problem as they pose threats to public health and economic repercussions to water utilities. For managing sewer assets efficaciously, it is vital to predict the rate of corrosion. Predictive models of sewer corrosion incorporate concrete surface temperature measurements as an observation. However, currently, it has not been fully utilized due to unavailability of a proven sensor. This study reports the feasibility of infrared radiometer for measuring the surface temperature dynamics in the aggressive sewer conditions. The infrared sensor was comprehensively evaluated in the laboratory at different environmental conditions. Then, the sensor suite was deployed in a Sydney based sewer for three months to perform continuous measurements of surface temperature variations. The field study revealed the suitability of the developed sensor suite for non-contact surface temperature measurements in hostile sewer conditions. Further, the accuracy of the sensor measurements was improved by calibrating the sensor with emissivity coefficient of the sewer concrete. Overall, this study will ameliorate the present sewer corrosion monitoring capabilities by providing new data to models predicting sewer corrosion.
Body ownership shapes self-orientation perception
Authors: Preuss Nora , Brynjarsdóttir B. Laufey , Ehrsson H. Henrik 
Published: October 2018

AbstractSelf-orientation perception is a necessary ability for everyday life that heavily depends on visual and vestibular information. To perceive the orientation of oneself with respect to the external environment would seem to first require that one has a clear sense of one’s own body (‘sense of body ownership’). However, the experimental evidence for this is sparse. Therefore, the aim of the present study was to investigate how the sense of body ownership affects perceived self-orientation. We combined a self-orientation illusion – where the visual scene, i.e., a fully furnished room, was rotated slowly around the roll axis – with a full-body ownership illusion paradigm – where the ownership of a stranger’s body seen from the first-person perspective in the center of the scene was manipulated by synchronous (illusion) or asynchronous (control) visual-tactile stimulation. Participants were asked to judge the appearance of shaded disk stimuli (a shape-from-shading test), which are perceived as three-dimensional (3D) spheres; this perception depends on perceived self-orientation. Illusory body ownership influenced self-orientation as reported subjectively in questionnaires and as evident from the objective shape-from-shading test data. Thus, body ownership determines self-orientation perception, presumably by boosting the weighting of visual cues over the gravitational forces detected by the vestibular system.
Regional diversity of complex dissolved organic matter across forested hemiboreal headwater streams
Authors: Hawkes Jeffrey A. , Radoman Nikola , Bergquist Jonas , Wallin Marcus B. , Tranvik Lars J. , Löfgren Stefan 
Published: October 2018

AbstractDissolved organic matter (DOM) from soils enters the aquatic environment via headwater streams. Thereafter, it is gradually transformed, removed by sedimentation, and mineralised. Due to the proximity to the terrestrial source and short water residence time, the extent of transformation is minimal in headwaters. DOM has variable composition across inland waters, but the amount of variability in the terrestrial end member is unknown. This gap in knowledge is crucial considering the potential impact large variability would have on modelling DOM degradation. Here, we used a novel liquid chromatography –mass spectrometry method to characterise DOM in 74 randomly selected, forested headwater streams in an 87,000 km2 region of southeast Sweden. We found a large degree of sample similarity across this region, with Bray-Curtis dissimilarity values averaging 8.4 ± 3.0% (mean ± SD). The identified variability could be reduced to two principle coordinates, correlating to varying groundwater flow-paths and regional mean temperature. Our results indicate that despite reproducible effects of groundwater geochemistry and climate, the composition of DOM is remarkably similar across catchments already as it leaves the terrestrial environment, rather than becoming homogeneous as different headwaters and sub-catchments mix.
Exogenous exosomes from mice with acetaminophen-induced liver injury promote toxicity in the recipient hepatocytes and mice
Authors: Cho Young-Eun , Seo Wonhyo , Kim Do-Kyun , Moon Pyong-Gon , Kim Sang-Hyun , Lee Byung-Heon , Song Byoung-Joon , Baek Moon-Chang 
Published: October 2018

AbstractExosomes are small extracellular membrane vesicles released from endosomes of various cells and could be found in most body fluids. The main functions of exosomes have been recognized as important mediators of intercellular communication and as potential biomarkers of various disease states. This study investigated whether exogenous exosomes from mice with acetaminophen (APAP)-induced liver injury can damage the recipient hepatic cells or promote hepatotoxicity in mice. We observed that exogenous exosomes derived from APAP-exposed mice were internalized into the primary mouse hepatocytes or HepG2 hepatoma cells and significantly decreased the viability of these recipient cells. They also elevated mRNA transcripts and proteins associated with the cell death signaling pathways in primary hepatocytes or HepG2 cells via exosomes-to-cell communications. In addition, confocal microscopy ofex vivoliver section showed that exogenously added exosomes were accumulated in recipient hepatocytes. Furthermore, plasma reactive oxygen species and hepatic TNF-α/IL-1β production were elevated in APAP-exosomes recipient mice compared to control-exosomes recipient mice. The levels of apoptosis-related proteins such as phospho-JNK/JNK, Bax, and cleaved caspase-3 were increased in mouse liver received APAP-exosomes. These results demonstrate that exogenous exosomes from APAP-exposed mice with acute liver injury are functional and stimulate cell death or toxicity of the recipient hepatocytes and mice.
Editing the duplicated insulin-like growth factor binding protein-2b gene in rainbow trout (Oncorhynchus mykiss)
Authors: Cleveland Beth M. , Yamaguchi Ginnosuke , Radler Lisa M. , Shimizu Munetaka 
Published: October 2018

AbstractIn salmonids, the majority of circulating insulin-like growth factor-I (IGF-I) is bound to IGF binding proteins (IGFBP), with IGFBP-2b being the most abundant in circulation. We used CRISPR/Cas9 methodology to disrupt expression of a functional IGFBP-2b protein by co-targeting for gene editing IGFBP-2b1 and IGFBP-2b2 subtypes, which represent salmonid-specific gene duplicates. Twenty-four rainbow trout were produced with mutations in the IGFBP-2b1 and IGFBP-2b2 genes. Mutant fish exhibited between 8–100% and 2–83% gene disruption for IGFBP-2b1 and IGFBP-2b2, respectively, with a positive correlation (P < 0.001) in gene mutation rate between individual fish. Analysis of IGFBP-2b protein indicated reductions in plasma IGFBP-2b abundance to between 0.04–0.96-fold of control levels. Plasma IGF-I, body weight, and fork length were reduced in mutants at 8 and 10 months post-hatch, which supports that IGFBP-2b is significant for carrying IGF-I. Despite reduced plasma IGF-I and IGFBP-2b in mutants, growth retardation in mutants was less severe between 10 and 12 months post-hatch (P < 0.05), suggesting a compensatory growth response occurred. These findings indicate that gene editing using CRISPR/Cas9 and ligand blotting is a feasible approach for characterizing protein-level functions of duplicated IGFBP genes in salmonids and is useful to unravel IGF-related endocrine mechanisms.
Mesenchymal stromal cells prevent progression of liver fibrosis in a novel zebrafish embryo model
Authors: van der Helm Danny , Groenewoud Arwin , de Jonge-Muller Eveline S. M. , Barnhoorn Marieke. C. , Schoonderwoerd Mark J. A. , Coenraad Minneke J. , Hawinkels Lukas J. A. C. , Snaar-Jagalska B. Ewa , van Hoek Bart , Verspaget Hein W. 
Published: October 2018

AbstractChronic liver damage leads to the onset of fibrogenesis. Rodent models for liver fibrosis have been widely used, but are less suitable for screening purposes. Therefore the aim of our study was to design a novel model for liver fibrosis in zebrafish embryos, suitable for high throughput screening. Furthermore, we evaluated the efficacy of mesenchymal stromal cells (MSCs) to inhibit the fibrotic process and thereby the applicability of this model to evaluate therapeutic responses. Zebrafish embryos were exposed to TAA or CCL4 and mRNA levels of fibrosis-related genes (Collagen-1α1, Hand-2, and Acta-2) and tissue damage-related genes (TGF-β and SDF-1a, SDF-1b) were determined, while Sirius-red staining was used to estimate collagen deposition. Three days after start of TAA exposure, MSCs were injected after which the fibrotic response was determined. In contrast to CCL4, TAA resulted in an upregulation of the fibrosis-related genes, increased extracellular matrix deposition and decreased liver sizes suggesting the onset of fibrosis. The applicability of this model to evaluate therapeutic responses was shown by local treatment with MSCs which resulted in decreased expression of the fibrosis-related RNA markers. In conclusion, TAA induces liver fibrosis in zebrafish embryos, thereby providing a promising model for future mechanistic and therapeutic studies.
Multi-species oral biofilm promotes reconstructed human gingiva epithelial barrier function
Authors: Shang Lin , Deng Dongmei , Buskermolen Jeroen Kees , Janus Marleen Marga , Krom Bastiaan Philip , Roffel Sanne , Waaijman Taco , van Loveren Cor , Crielaard Wim , Gibbs Susan 
Published: October 2018

AbstractSince the oral mucosa is continuously exposed to abundant microbes, one of its most important defense features is a highly proliferative, thick, stratified epithelium. The cellular mechanisms responsible for this are still unknown. The aim of this study was to determine whether multi-species oral biofilm contribute to the extensive stratification and primed antimicrobial defense in epithelium. Two in vitro models were used: 3D reconstructed human gingiva (RHG) and oral bacteria representative of multi-species commensal biofilm. The organotypic RHG consists of a reconstructed stratified gingiva epithelium on a gingiva fibroblast populated hydrogel (lamina propria). Biofilm was cultured from healthy human saliva, and consists of typical commensal genera Granulicatella and major oral microbiota genera Veillonella and Streptococcus. Biofilm was applied topically to RHG and host–microbiome interactions were studied over 7 days. Compared to unexposed RHG, biofilm exposed RHG showed increased epithelial thickness, more organized stratification and increased keratinocyte proliferation. Furthermore biofilm exposure increased production of RHG anti-microbial proteins Elafin, HBD2 and HBD3 but not HBD1, adrenomedullin or cathelicidin LL-37. Inflammatory and antimicrobial cytokine secretion (IL-6, CXCL8, CXCL1, CCL20) showed an immediate and sustained increase. In conclusion, exposure of RHG to commensal oral biofilm actively contributes to RHG epithelial barrier function.
Association between Neutrophil-to-Lymphocyte Ratio and Gut Microbiota in a Large Population: a Retrospective Cross-Sectional Study
Authors: Yoon Hee-Young , Kim Han-Na , Lee Su Hwan , Kim Soo Jung , Chang Yoosoo , Ryu Seungho , Shin Hocheol , Kim Hyung-Lae , Lee Jin Hwa 
Published: October 2018

AbstractGut microbiota and blood neutrophil-to-lymphocyte ratio (NLR) are associated with systemic inflammation; however, data on the association between gut microbiota and NLR are lacking. We investigated the association between gut microbiota and NLR. A total of 1,309 subjects who had available data on NLR and 16 S rRNA sequencing of gut microbiota were included in this study. They were grouped according to NLR quartile (Q) as follows: lower Q (n = 328, <25% of NLR range), middle 2Q (n = 653, ≥25% to <75%) and upper Q (n = 328, ≥75%). The diversity and composition of the human gut microbiota in the groups were calculated. The phylogenetic diversity of gut microbiota in the lower group was significantly higher than in the middle 2Q group (P = 0.040). The beta-diversity was significantly different among the three groups (P = 0.043), between the lower and middle 2Q groups (P = 0.029), and between the lower and upper groups (P = 0.026). Bacteroides eggerthii showed a positive correlation with NLR (q = 0.015). The diversity and composition of the gut microbiome were different between the NLR groups. Particularly, patients with a lower NLR had a greater diversity of gut microbiota.