bluuebunny/crossref_metadata_2025_split huggingface dataset:
Embryonic ethanol exposure alters expression of sox2 and other early transcripts in zebrafish, producing gastrulation defects
Authors: Sarmah Swapnalee , Srivastava Rajneesh , McClintick Jeanette N. , Janga Sarath C. , Edenberg Howard J. , Marrs James A. 
Published: March 2020

AbstractEthanol exposure during prenatal development causes fetal alcohol spectrum disorder (FASD), the most frequent preventable birth defect and neurodevelopmental disability syndrome. The molecular targets of ethanol toxicity during development are poorly understood. Developmental stages surrounding gastrulation are very sensitive to ethanol exposure. To understand the effects of ethanol on early transcripts during embryogenesis, we treated zebrafish embryos with ethanol during pre-gastrulation period and examined the transcripts by Affymetrix GeneChip microarray before gastrulation. We identified 521 significantly dysregulated genes, including 61 transcription factors in ethanol-exposed embryos. Sox2, the key regulator of pluripotency and early development was significantly reduced. Functional annotation analysis showed enrichment in transcription regulation, embryonic axes patterning, and signaling pathways, including Wnt, Notch and retinoic acid. We identified all potential genomic targets of 25 dysregulated transcription factors and compared their interactions with the ethanol-dysregulated genes. This analysis predicted that Sox2 targeted a large number of ethanol-dysregulated genes. A gene regulatory network analysis showed that many of the dysregulated genes are targeted by multiple transcription factors. Injection of sox2 mRNA partially rescued ethanol-induced gene expression, epiboly and gastrulation defects. Additional studies of this ethanol dysregulated network may identify therapeutic targets that coordinately regulate early development.
Dual dynamics of mitochondrial permeability transition pore opening
Authors: Wacquier Benjamin , Combettes Laurent , Dupont Geneviève 
Published: March 2020

AbstractMitochondria play an essential role in bioenergetics and cellular Ca$${}^{2+}$$2+ handling. The mitochondrial permeability transition pore (mPTP) is a non-specific channel located in the inner mitochondrial membrane. Long-lasting openings of the pore allow the rapid passage of ions and large molecules, which can result in cell death. The mPTP also exhibits transient, low conductance openings that contribute to Ca$${}^{2+}$$2+ homeostasis. Although many regulators of the pore have been identified, none of them uniquely governs the passage between the two operating modes, which thus probably relies on a still unidentified network of interactions. By developing a core computational model for mPTP opening under the control of mitochondrial voltage and Ca$${}^{2+}$$2+, we uncovered the existence of a positive feedback loop leading to bistability. The characteristics of the two stable steady-states correspond to those of the two opening states. When inserted in a full model of Ca$${}^{2+}$$2+ handling by mitochondria, our description of the pore reproduces observations in mitochondrial suspensions. Moreover, the model predicted the occurrence of hysteresis in the switching between the two modes, upon addition and removal of free Ca$${}^{2+}$$2+ in the extra-mitochondrial medium. Stochastic simulations then confirmed that the pore can undergo transient openings resembling those observed in intact cells.
Structure and mechanism of a redesigned multidrug transporter from the Major Facilitator Superfamily
Authors: Wu Hsin-Hui , Symersky Jindrich , Lu Min 
Published: March 2020

AbstractThe rapid increase of multidrug resistance poses urgent threats to human health. Multidrug transporters prompt multidrug resistance by exporting different therapeutics across cell membranes, often by utilizing the H+ electrochemical gradient. MdfA from Escherichia coli is a prototypical H+ -dependent multidrug transporter belonging to the Major Facilitator Superfamily. Prior studies revealed unusual flexibility in the coupling between multidrug binding and deprotonation in MdfA, but the mechanistic basis for this flexibility was obscure. Here we report the X-ray structures of a MdfA mutant E26T/D34M/A150E, wherein the multidrug-binding and protonation sites were revamped, separately bound to three different substrates at resolutions up to 2.0 Å. To validate the functional relevance of these structures, we conducted mutational and biochemical studies. Our data elucidated intermediate states during antibiotic recognition and suggested structural changes that accompany the substrate-evoked deprotonation of E26T/D34M/A150E. These findings help to explain the mechanistic flexibility in drug/H+ coupling observed in MdfA and may inspire therapeutic development to preempt efflux-mediated antimicrobial resistance.
Activation Complexity: A Cognitive Impairment Tool for Characterizing Neuro-isolation
Authors: Napoli Nicholas J. , Demas Matthew , Stephens Chad L. , Kennedy Kellie D. , Harrivel Angela R. , Barnes Laura E. , Pope Alan T. 
Published: March 2020

AbstractElectroencephalography (EEG) is a method for recording electrical activity, indicative of cortical brain activity from the scalp. EEG has been used to diagnose neurological diseases and to characterize impaired cognitive states. When the electrical activity of neurons are temporally synchronized, the likelihood to reach their threshold potential for the signal to propagate to the next neuron, increases. This phenomenon is typically analyzed as the spectral intensity increasing from the summation of these neurons firing. Non-linear analysis methods (e.g., entropy) have been explored to characterize neuronal firings, but only analyze temporal information and not the frequency spectrum. By examining temporal and spectral entropic relationships simultaneously, we can better characterize how neurons are isolated, (the signal’s inability to propagate to adjacent neurons), an indicator of impairment. A novel time-frequency entropic analysis method, referred to as Activation Complexity (AC), was designed to quantify these dynamics from key EEG frequency bands. The data was collected during a cognitive impairment study at NASA Langley Research Center, involving hypoxia induction in 49 human test subjects. AC demonstrated significant changes in EEG firing patterns characterize within explanatory (p < 0.05) and predictive models (10% increase in accuracy). The proposed work sets the methodological foundation for quantifying neuronal isolation and introduces new potential technique to understand human cognitive impairment for a range of neurological diseases and insults.
Visuocortical tuning to a threat-related feature persists after extinction and consolidation of conditioned fear
Authors: Antov Martin I. , Plog Elena , Bierwirth Philipp , Keil Andreas , Stockhorst Ursula 
Published: March 2020

AbstractNeurons in the visual cortex sharpen their orientation tuning as humans learn aversive contingencies. A stimulus orientation (CS+) that reliably predicts an aversive noise (unconditioned stimulus: US) is selectively enhanced in lower-tier visual cortex, while similar unpaired orientations (CS−) are inhibited. Here, we examine in male volunteers how sharpened visual processing is affected by fear extinction learning (where no US is presented), and how fear and extinction memory undergo consolidation one day after the original learning episode. Using steady-state visually evoked potentials from electroencephalography in a fear generalization task, we found that extinction learning prompted rapid changes in orientation tuning: Both conditioned visuocortical and skin conductance responses to the CS+ were strongly reduced. Next-day re-testing (delayed recall) revealed a brief but precise return-of-tuning to the CS+ in visual cortex accompanied by a brief, more generalized return-of-fear in skin conductance. Explorative analyses also showed persistent tuning to the threat cue in higher visual areas, 24 h after successful extinction, outlasting peripheral responding. Together, experience-based changes in the sensitivity of visual neurons show response patterns consistent with memory consolidation and spontaneous recovery, the hallmarks of long-term neural plasticity.
Genome-wide analysis of the HSP101/CLPB gene family for heat tolerance in hexaploid wheat
Authors: Erdayani Eva , Nagarajan Ragupathi , Grant Nathan P. , Gill Kulvinder S. 
Published: March 2020

AbstractHeat Shock Protein 101 (HSP101), the homolog ofCaseinolytic ProteaseB (CLPB) proteins, has functional conservation across species to play roles in heat acclimation and plant development. In wheat, severalTaHSP101/CLPBgenes were identified, but have not been comprehensively characterized. Given the complexity of a polyploid genome with its phenomena of homoeologous expression bias, detailed analysis on the wholeTaCLPBfamily members is important to understand the genetic basis of heat tolerance in hexaploid wheat. In this study, a genome-wide analysis revealed thirteen members ofTaCLPBgene family and their expression patterns in various tissues, developmental stages, and stress conditions. Detailed characterization ofTaCLPBgene and protein structures suggested potential variations of the sub-cellular localization and their functional regulations. We revealed homoeologous specific variations amongTaCLPBgene copies that have not been reported earlier. A study of the Chromosome 1TaCLPBin four wheat genotypes demonstrated unique patterns of the homoeologous gene expression under moderate and extreme heat treatments. The results give insight into the strategies to improve heat tolerance by targeting one or some of theTaCLPBgenes in wheat.
Micromonospora zhangzhouensis sp. nov., a Novel Actinobacterium Isolated from Mangrove Soil, Exerts a Cytotoxic Activity in vitro
Authors: Fu Geyi , Wang Ruijun , Ding Jinglin , Qi Huan , Zhao Zhe , Chen Can , Zhang Hui , Xue Zhenglian , Wang Jidong , Wu Min 
Published: March 2020

AbstractA new bacterial strain, designated HM134T, was isolated from a sample of soil collected from a Chinese mangrove Avicennia marina forest. Assessed by a polyphasic approach, the taxonomy of strain HM134T was found to be associated with a range of phylogenetic and chemotaxonomic properties consistent with the genus Micromonospora. Phylogenetic analysis based on the 16s rRNA gene sequence indicated that strain HM134T formed a distinct lineage with the most closely related species, including M. rifamycinica AM105T, M. wenchangensis CCTCC AA 2012002T and M. mangrovi 2803GPT1-18T. The ANI values between strain HM134T and the reference strains ranged from 82.6% to 95.2%, which was below the standard criteria for classifying strains as the same species (96.5%). Strain HM134T and related species shared in silico dDDH similarities values below the recommended 70% cut-off for the delineation of species (range from 25.7–62.6%). The DNA G+C content of strain HM134T was 73.2 mol%. Analysis of phylogenetic, genomic, phenotypic and chemotaxonomic characteristics revealed that strain HM134T is considered to represent a novel species of the genus Micromonospora, for which the name M. zhangzhouensis sp. nov. is proposed. The extract of strain HM134T was demonstrated to exhibit cytotoxic activity against the human cancer cell lines HepG2, HCT-116 and A549. Active substance presented in the fermentation broth of strain HM134T was isolated by bioassay-guided analysis and purified afterwards. A new derivative of diterpenoid was identified through electrospray ionizing mass spectrometry (MS) and nuclear magnetic resonance (NMR). The compound showed different cytotoxic activities against cancer cells, with the highest cytotoxicity against HCT-116, corresponding to IC50 value of 38.4 μg/mL.
Supplemental Anti Vegf A-Therapy Prevents Rebound Neovascularisation After Fine Needle Diathermy Treatment to Regress Pathological Corneal (LYMPH)Angiogenesis
Authors: Le Viet Nhat Hung , Hou Yanhong , Bock Felix , Cursiefen Claus 
Published: March 2020

AbstractFine needle diathermy (FND) is an effective method to destroy and regress pathologic corneal blood and lymphatic vessels. However, it is unknown whether FND itself causes a rebound corneal neovascularisation and whether that can be prevented by VEGF blockade. In female BALB/c mice, the suture-induced inflammatory corneal neovascularisation model was used to induce hem- and lymphangiogenesis. Thereafter, prevascularized mice were divided into 2 groups: the combination therapy group received FND cauterization and subsequent VEGF TrapR1R2 eye drops three times per day whereas the monotherapy group was treated only with FND. Three, 7 and 14 days after the treatment, corneas were collected and stained with FITC-conjugated CD31 and LYVE-1 followed by Cy3-conjugated secondary antibody to quantify corneal blood and lymphatic vessels. Relative mRNA expression of VEGF in the cornea was quantified by using qPCR. FND cauterization as monotherapy significantly obliterated (lymph)angiogenesis at early time points; however, this treatment led to secondary corneal hem- and lymphangiogenesis associated with significant upregulation of pro(lymph)angiogenic VEGF-A, VEGF-C, VEGF-D and infiltration of macrophages. Combining FND cauterization with VEGF TrapR1R2 treatment prevented the undesired effect of the FND procedure alone and significantly better regressed corneal blood and lymphatic vessels at 1 week after the treatment compared to monotherapy and control group (p < 0.01).
Implicit emotion regulation deficits in individuals with high schizotypal traits: an ERP study
Authors: Hoid Delhii , Pan Dong-ni , Wang Yi , Li Xuebing 
Published: March 2020

AbstractSchizotypy is associated with poor emotion regulation that is thought to contribute to the development of psychotic symptoms and to indicate a predisposition to schizophrenia. Having focused primarily on the relationship between schizotypy and explicit emotion regulation, existing studies have, until now, neglected to acknowledge the potentially important role of implicit emotion regulation. Our aim in the current study was to investigate implicit emotion regulation deficits in schizotypy. To this end, we used a newly developed Priming-Identification (PI) ERP paradigm, consisting of a priming phase and an emotion identification phase, to test 30 individuals with schizotypy and 30 healthy controls while also acquiring EEG data. During the priming phase, we aimed to manipulate emotion regulation goals (i.e., to bring about an intended emotional state) by presenting a category of words related to emotion regulation alongside a category of control words. Associated brain responses occurring during the subsequent stage were indexed according to three ERP components: N170, early posterior negativity (EPN) and late positive potential (LPP). Results showed that, in the control group, priming words associated with emotion regulation led to enhancements in the early N170 amplitude and the middle EPN during expression identification. The same pattern was not observed in the schizotypy group. In summary, our results suggest the presence of deficits in the early and middle stages of the implicit emotion regulation process among individuals with high schizotypal traits.
HDMAC: A Web-Based Interactive Program for High-Dimensional Analysis of Molecular Alterations in Cancer
Authors: Chang Chung , Sung Chan-Yu , Hsiao Han , Chen Jiabin , Chen I.-Hsuan , Kuo Wei-Ting , Cheng Lung-Feng , Korla Praveen Kumar , Chung Ming-Jhe , Wu Pei-Jhen , Yu Chia-Cheng , Sheu Jim Jinn-Chyuan 
Published: March 2020

AbstractRecent advances in high-throughput genomic technologies have nurtured a growing demand for statistical tools to facilitate identification of molecular changes as potential prognostic biomarkers or drugable targets for personalized precision medicine. In this study, we developed a web-based interactive and user-friendly platform for high-dimensional analysis of molecular alterations in cancer (HDMAC) (https://ripsung26.shinyapps.io/rshiny/). On HDMAC, several penalized regression models that are suitable for high-dimensional data analysis, Ridge, Lasso and adaptive Lasso, are offered, with Cox regression for survival and logistic regression for binary outcomes. Choice of a first-step screening is provided to address the multiple-comparison issue that often arises with large-volume genomic data. Hazard ratio or estimated coefficient is provided with each selected gene so that a multivariate regression model may be built based on the genes selected. Cross validation is provided as the method to estimate the prediction power of each regression model. In addition, R codes are also provided to facilitate download of whole sets of molecular variables from TCGA. In this study, illustration of the use of HDMAC was made through a set of data on gene mutations and a set on mRNA expression from ovarian cancer patients and a set on mRNA expression from bladder cancer patient. From the analysis of each set of data, a list of candidate genes was obtained that might be associated with mutations or abnormal expression of genes in ovarian and bladder cancers. HDMAC offers a solution for rigorous and validation analysis of high-dimensional genomic data.
Parental non-hereditary teratogenic exposure factors on the occurrence of congenital heart disease in the offspring in the northeastern Sichuan, China
Authors: Liang Yun , Hu Xingsheng , Li Xiaoqin , Wen Bing , Wang Liang , Wang Cheng 
Published: March 2020

AbstractNonhereditary factors play an important role in the occurrence of congenital heart disease (CHD). This study was to explore the possible parental nonhereditary exposure factors relevant to the occurrence of CHD in the northeastern Sichuan area. A total of 367 children with CHD and 367 children without congenital malformations aged 0 to 14 years old were recruited from the Affiliated Hospital of North Sichuan Medical College and Nanchong Central Hospital between March 2016 and November 2018. This study was designed as a case-control study with 1:1 frequency matching, in which the parents of cases and controls were interviewed with the same questionnaire according to the gestational age of the child, maternal age during pregnancy and the same maternal race/ethnicity. Then, 322 matched case-control pairs were analysed by SPSS 22. Thirty-one suspicious factors were entered into the binary logistic regression analysis after univariate regression analysis of 55 factors (alpha = 0.05). The analysis results showed that 7 factors were significantly associated with the occurrence of CHD. Thus, augmenting maternal mental healthcare, improving the quality of drinking water, obtaining adequate nutrition, maintaining a healthy physical condition during pregnancy, enhancing parents’ level of knowledge and maintaining a healthy lifestyle may lower the occurrence of CHD.
Expanded inverted repeat region with large scale inversion in the first complete plastid genome sequence of Plantago ovata
Authors: Asaf Sajjad , Khan Abdul Latif , Lubna  , khan Adil , Khan Arif , Khan Gulzar , Lee In-Jung , Al-Harrasi Ahmed 
Published: March 2020

AbstractPlantago ovata (Plantaginaceae) is an economically and medicinally important species, however, least is known about its genomics and evolution. Here, we report the first complete plastome genome of P. ovata and comparison with previously published genomes of related species from Plantaginaceae. The results revealed that P. ovata plastome size was 162,116 bp and that it had typical quadripartite structure containing a large single copy region of 82,084 bp and small single copy region of 5,272 bp. The genome has a markedly higher inverted repeat (IR) size of 37.4 kb, suggesting large-scale inversion of 13.8 kb within the expanded IR regions. In addition, the P. ovata plastome contains 149 different genes, including 43 tRNA, 8 rRNA, and 98 protein-coding genes. The analysis revealed 139 microsatellites, of which 71 were in the non-coding regions. Approximately 32 forward, 34 tandem, and 17 palindromic repeats were detected. The complete genome sequences, 72 shared genes, matK gene, and rbcL gene from related species generated the same phylogenetic signals, and phylogenetic analysis revealed that P. ovata formed a single clade with P. maritima and P. media. The divergence time estimation as employed in BEAST revealed that P. ovata diverged from P. maritima and P. media about 11.0 million years ago (Mya; 95% highest posterior density, 10.06–12.25 Mya). In conclusion, P. ovata had significant variation in the IR region, suggesting a more stable P. ovata plastome genome than that of other Plantaginaceae species.
Collective effects of long-range DNA methylations predict gene expressions and estimate phenotypes in cancer
Authors: Kim Soyeon , Park Hyun Jung , Cui Xiangqin , Zhi Degui 
Published: March 2020

AbstractDNA methylation of various genomic regions has been found to be associated with gene expression in diverse biological contexts. However, most genome-wide studies have focused on the effect of (1) methylation in cis, not in trans and (2) a single CpG, not the collective effects of multiple CpGs, on gene expression. In this study, we developed a statistical machine learning model, geneEXPLORE (geneexpression prediction by long-range epigenetics), that quantifies the collective effects of both cis- and trans- methylations on gene expression. By applying geneEXPLORE to The Cancer Genome Atlas (TCGA) breast and 10 other types of cancer data, we found that most genes are associated with methylations of as much as 10 Mb from the promoters or more, and the long-range methylation explains 50% of the variation in gene expression on average, far greater than cis-methylation. geneEXPLORE outperforms competing methods such as BioMethyl and MethylXcan. Further, the predicted gene expressions could predict clinical phenotypes such as breast tumor status and estrogen receptor status (AUC = 0.999, 0.94 respectively) as accurately as the measured gene expression levels. These results suggest that geneEXPLORE provides a means for accurate imputation of gene expression, which can be further used to predict clinical phenotypes.
Immunogenicity of rat-neu+ mouse mammary tumours determines the T cell-dependent therapeutic efficacy of anti-neu monoclonal antibody treatment
Authors: Sow Heng Sheng , Benonisson Hreinn , Brouwers Conny , Linssen Margot M. , Camps Marcel , Breukel Cor , Claassens Jill , van Hall Thorbald , Ossendorp Ferry , Fransen Marieke F. , Verbeek J. Sjef 
Published: March 2020

AbstractThe use of Trastuzumab (Herceptin), a monoclonal antibody (mAb) targeting HER2/neu, results in an increased median survival in Her2+breast cancer patients. The tumour mutational burden and the presence of tumour infiltrating lymphocytes (TILs) clearly correlate with response to trastuzumab. Here, we investigated if the immunogenicity of the transplantable rat-neu+tumour cell line (TUBO) derived from a BALB/c-NeuT primary tumour is associated with the response to anti-neu mAb therapy. We compared the TUBO tumour outgrowth and tumour infiltrating T cells in isogenic (BALB/c-NeuT) and non-isogenic (WT BALB/c) recipient mice. Furthermore, therapeutic efficacy of anti-neu mAb and the contribution of T cells were examined in both mouse strains. The outgrowth of untreated tumours was significantly better in BALB/c-NeuT than WT BALB/c mice. Moreover, tumour infiltrating T cells were more abundantly present in WT BALB/c than BALB/c-NeuT mice, showing that the TUBO tumour was more immunogenic in WT BALB/c mice. In TUBO tumour bearing WT BALB/c mice, anti-neu mAb therapy resulted in an increase of tumour infiltrating T cells and long-term survival. When T cells were depleted, this strong anti-tumour effect was reduced to an outgrowth delay. In contrast, in TUBO tumour bearing BALB/c-NeuT mice, treatment with anti-neu mAb resulted only in tumour outgrowth delay, both in the presence and absence of T cells. We concluded that in immunogenic tumours the response to anti-neu mAb therapy is enhanced by additional T cell involvement compared to the response to anti-neu mAb in non-immunogenic tumours.