bluuebunny/crossref_metadata_2025_split huggingface dataset:
Immunofluorescence can assess the efficacy of mTOR pathway therapeutic agent Everolimus in breast cancer models
Authors: Kuo Chun-Ting , Chen Chen-Lin , Li Chih-Chi , Huang Guan-Syuan , Ma Wei-Yuan , Hsu Wei-Fan , Lin Ching-Hung , Lu Yen-Shen , Wo Andrew M. 
Published: July 2019

AbstractWhen breast cancer patients start to exhibit resistance to hormonal therapy or chemotherapy, the mTOR inhibitor everolimus can be considered as an alternative therapeutic agent. Everolimus can deregulate the PI3K/AKT/mTOR pathway and affect a range of cellular functions. In some patients, the agent does not exhibit the desired efficacy and, even worse, not without the associated side effects. This study assessed the use of immunofluorescence (IF) as a modality to fill this unmet need of predicting the efficacy of everolimus prior to administration. Cell viability and MTT assays based on IF intensities of pho-4EBP1 Thr37/46 and pho-S6K1 Ser424 on breast cancer cells (Hs578T, MCF7, BT474, MDA-MB-231) and patient-derived cell culture from metastatic sites (ABC-82T and ABC-16TX1) were interrogated. Results show that independent pho-4EBP1 Thr37/46 and pho-S6K1 Ser424 IF expressions can classify data into different groups: everolimus sensitive and resistant. The combined IF baseline intensity of these proteins is predictive of the efficacy of everolimus, and their intensities change dynamically when cells are resistant to everolimus. Furthermore, mTOR resistance is not only consequence of the AKT/mTOR pathway but also through the LKB1 or MAPK/ERK pathway. The LKB1 and pho-GSK3β may also be potential predictive markers for everolimus.
Enterotype-based Analysis of Gut Microbiota along the Conventional Adenoma-Carcinoma Colorectal Cancer Pathway
Authors: Yang Tzu-Wei , Lee Wei-Hsiang , Tu Siang-Jyun , Huang Wei-Chih , Chen Hui-Mei , Sun Ting-Hsuan , Tsai Ming-Chang , Wang Chi-Chih , Chen Hsuan-Yi , Huang Chi-Chou , Shiu Bei-Hao , Yang Tzu-Ling , Huang Hsin-Tzu , Chou Yu-Pao , Chou Chih-Hung , Huang Ya-Rong , Sun Yi-Run , Liang Chao , Lin Feng-Mao , Ho Shinn-Ying , Chen Wen-Liang , Yang Shun-Fa , Ueng Kwo-Chang , Huang Hsien-Da , Huang Chien-Ning , Jong Yuh-Jyh , Lin Chun-Che 
Published: July 2019

AbstractThe dysbiosis of human gut microbiota is strongly associated with the development of colorectal cancer (CRC). The dysbiotic features of the transition from advanced polyp to early-stage CRC are largely unknown. We performed a 16S rRNA gene sequencing and enterotype-based gut microbiota analysis study. In addition to Bacteroides- and Prevotella-dominated enterotypes, we identified an Escherichia-dominated enterotype. We found that the dysbiotic features of CRC were dissimilar in overall samples and especially Escherichia-dominated enterotype. Besides a higher abundance of Fusobacterium, Enterococcus, and Aeromonas in all CRC faecal microbiota, we found that the most notable characteristic of CRC faecal microbiota was a decreased abundance of potential beneficial butyrate-producing bacteria. Notably, Oscillospira was depleted in the transition from advanced adenoma to stage 0 CRC, whereas Haemophilus was depleted in the transition from stage 0 to early-stage CRC. We further identified 7 different CAGs by analysing bacterial clusters. The abundance of microbiota in cluster 3 significantly increased in the CRC group, whereas that of cluster 5 decreased. The abundance of both cluster 5 and cluster 7 decreased in the Escherichia-dominated enterotype of the CRC group. We present the first enterotype-based faecal microbiota analysis. The gut microbiota of colorectal neoplasms can be influenced by its enterotype.
Heterozygous mutations in valosin-containing protein (VCP) and resistance to VCP inhibitors
Authors: Bastola Prabhakar , Bilkis Rabeya , De Souza Cristabelle , Minn Kay , Chien Jeremy 
Published: July 2019

AbstractIn recent years, multiple studies including ours have reported on the mechanism of resistance towards valosin-containing protein (VCP) inhibitors. While all these studies reported target alterations via mutations in VCP as the primary mechanism of resistance, discrepancies persist to date regarding the zygosity of these mutations responsible for the resistance. In addition, the extent to which resistant cells harbor additional mutations in other genes is not well described. In this study, we performed global transcript analysis of the parental and previously reported VCP inhibitor (CB-5083) resistant cells and found additional mutations in the resistant cells. However, our CRISPR-Cas9 gene editing studies indicate that specific mutations in VCP are sufficient to produce resistance to CB-5083 suggesting the importance of on-target mutations in VCP for resistance. Strikingly, our analysis indicates a preexisting heterozygous frameshift mutation at codon 616 (N616fs*) in one of the VCP alleles in HCT116 cells, and we showed that this mutant allele is subjected to the nonsense-mediated decay (NMD). Accordingly, we identified a heterozygous mutation at codon 526 (L526S) in genomic DNA sequencing but a homozygous L526S mutation in complementary DNA sequencing in our independently generated CB-5083 resistant HCT116 cells, implying that the L526S mutation occurs in the allele that does not harbor the frameshift N616fs* mutation. Our results suggest the NMD as a possible mechanism for achieving the homozygosity of VCP mutant responsible for the resistance to VCP inhibitors while resolving the discrepancies among previous studies. Our results also underscore the importance of performing simultaneous genomic and complementary DNA sequencing when attributing mutational effects on the functionality particularly for an oligomer protein like VCP.
Dual dose-dependent effects of fingolimod in a mouse model of Alzheimer’s disease
Authors: Carreras Isabel , Aytan Nurgul , Choi Ji-Kyung , Tognoni Christina M. , Kowall Neil W. , Jenkins Bruce G. , Dedeoglu Alpaslan 
Published: July 2019

AbstractLipid metabolism is abnormal in Alzheimer’s disease (AD) brain leading to ceramide and sphingosine accumulation and reduced levels of brain sphingosine-1-phosphate (S1P). We hypothesize that changes in S1P signaling are central to the inflammatory and immune-pathogenesis of AD and the therapeutic benefits of fingolimod, a structural analog of sphingosine that is FDA approved for the treatment of multiple sclerosis. We recently reported that the neuroprotective effects of fingolimod in 5xFAD transgenic AD mice treated from 1–3 months of age were greater at 1 mg/kg/day than at 5 mg/kg/day. Here we performed a dose-response study using fingolimod from 0.03 to 1 mg/kg/day in 5xFAD mice treated from 1–8 months of age. At 1 mg/kg/day, fingolimod decreased both peripheral blood lymphocyte counts and brain Aβ levels, but at the lowest dose tested (0.03 mg/kg/day), we detected improved memory, decreased activation of brain microglia and astrocytes, and restored hippocampal levels of GABA and glycerophosphocholine with no effect on circulating lymphocyte counts. These findings suggests that, unlike the case in multiple sclerosis, fingolimod may potentially have therapeutic benefits in AD at low doses that do not affect peripheral lymphocyte function.
Elucidating the functional role of Mycobacterium smegmatis recX in stress response
Authors: Prasad Deepika , Arora Divya , Nandicoori Vinay Kumar , Muniyappa K. 
Published: July 2019

AbstractThe RecX protein has attracted considerable interest because therecXmutants exhibit multiple phenotypes associated with RecA functions. To further our understanding of the functional relationship betweenrecAandrecX, the effect of different stress treatments on their expression profiles, cell yield and viability were investigated. A significant correlation was found between the expression ofMycobacterium smegmatis recAandrecXgenes at different stages of growth, and in response to different stress treatments albeitrecXexhibiting lower transcript and protein abundance at the mid-log and stationary phases of the bacterial growth cycle. To ascertain their rolesin vivo, a targeted deletion of therecXandrecArecXwas performed inM.smegmatis. The growth kinetics of these mutant strains and their sensitivity patterns to different stress treatments were assessed relative to the wild-type strain. The deletion ofrecAaffected normal cell growth and survival, whilerecXdeletion showed no significant effect. Interestingly, deletion of bothrecXandrecAgenes results in a phenotype that is intermediate between the phenotypes of theΔrecAmutant and the wild-type strain. Collectively, these results reveal a previously unrecognized role forM.smegmatis recXand support the notion that it may regulate a subset of the yet unknown genes involved in normal cell growth and DNA-damage repair.
ORCA-SPOT: An Automatic Killer Whale Sound Detection Toolkit Using Deep Learning
Authors: Bergler Christian , Schröter Hendrik , Cheng Rachael Xi , Barth Volker , Weber Michael , Nöth Elmar , Hofer Heribert , Maier Andreas 
Published: July 2019

AbstractLarge bioacoustic archives of wild animals are an important source to identify reappearing communication patterns, which can then be related to recurring behavioral patterns to advance the current understanding of intra-specific communication of non-human animals. A main challenge remains that most large-scale bioacoustic archives contain only a small percentage of animal vocalizations and a large amount of environmental noise, which makes it extremely difficult to manually retrieve sufficient vocalizations for further analysis – particularly important for species with advanced social systems and complex vocalizations. In this study deep neural networks were trained on 11,509 killer whale (Orcinus orca) signals and 34,848 noise segments. The resulting toolkit ORCA-SPOT was tested on a large-scale bioacoustic repository – the Orchive – comprising roughly 19,000 hours of killer whale underwater recordings. An automated segmentation of the entire Orchive recordings (about 2.2 years) took approximately 8 days. It achieved a time-based precision or positive-predictive-value (PPV) of 93.2% and an area-under-the-curve (AUC) of 0.9523. This approach enables an automated annotation procedure of large bioacoustics databases to extract killer whale sounds, which are essential for subsequent identification of significant communication patterns. The code will be publicly available in October 2019 to support the application of deep learning to bioaoucstic research. ORCA-SPOT can be adapted to other animal species.
Altered transcriptional regulatory proteins in glioblastoma and YBX1 as a potential regulator of tumor invasion
Authors: Gupta Manoj Kumar , Polisetty Ravindra Varma , Sharma Rakesh , Ganesh Raksha A. , Gowda Harsha , Purohit Aniruddh K. , Ankathi Praveen , Prasad Komal , Mariswamappa Kiran , Lakshmikantha Akhila , Uppin Megha S. , Sundaram Challa , Gautam Poonam , Sirdeshmukh Ravi 
Published: July 2019

AbstractWe have studied differentially regulated nuclear proteome of the clinical tissue specimens of glioblastoma (GBM, WHO Grade IV) and lower grades of gliomas (Grade II and III) using high resolution mass spectrometry- based quantitative proteomics approach. The results showed altered expression of many regulatory proteins from the nucleus such as DNA binding proteins, transcription and post transcriptional processing factors and also included enrichment of nuclear proteins that are targets of granzyme signaling – an immune surveillance pathway. Protein - protein interaction network analysis using integrated proteomics and transcriptomics data of transcription factors and proteins for cell invasion process (drawn from another GBM dataset) revealed YBX1, a ubiquitous RNA and DNA-binding protein and a transcription factor, as a key interactor of major cell invasion-associated proteins from GBM. To verify the regulatory link between them, the co-expression of YBX1 and six of the interacting proteins (EGFR, MAPK1, CD44, SOX2, TNC and MMP13) involved in cell invasion network was examined by immunohistochemistry on tissue micro arrays. Our analysis suggests YBX1 as a potential regulator of these key molecules involved in tumor invasion and thus as a promising target for development of new therapeutic strategies for GBM.
A neural perspective on when and why trait greed comes at the expense of others
Authors: Mussel Patrick , Hewig Johannes 
Published: July 2019

AbstractDepending on the point of view, conceptions of greed range from being a desirable and inevitable feature of a well-regulated, well-balanced economy to the root of all evil - radix omnium malorum avaritia (Tim 6.10). Regarding the latter, it has been proposed that greedy individuals strive for obtaining desired goods at all costs. Here, we show that trait greed predicts selfish economic decisions that come at the expense of others in a resource dilemma. This effect was amplified when individuals strived for obtaining real money, as compared to points, and when their revenue was at the expense of another person, as compared to a computer. On the neural level, we show that individuals high, compared to low in trait greed showed a characteristic signature in the EEG, a reduced P3 effect to positive, compared to negative feedback, indicating that they may have a lack of sensitivity to adjust behavior according to positive and negative stimuli from the environment. Brain-behavior relations further confirmed this lack of sensitivity to behavior adjustment as a potential underlying neuro-cognitive mechanism which explains selfish and reckless behavior that may come at the expense of others.
High-throughput identification of peptide agonists against GPCRs by co-culture of mammalian reporter cells and peptide-secreting yeast cells using droplet microfluidics
Authors: Yaginuma Kenshi , Aoki Wataru , Miura Natsuko , Ohtani Yuta , Aburaya Shunsuke , Kogawa Masato , Nishikawa Yohei , Hosokawa Masahito , Takeyama Haruko , Ueda Mitsuyoshi 
Published: July 2019

AbstractSince G-protein coupled receptors (GPCRs) are linked to various diseases, screening of functional ligands against GPCRs is vital for drug discovery. In the present study, we developed a high-throughput functional cell-based assay by combining human culture cells producing a GPCR, yeast cells secreting randomized peptide ligands, and a droplet microfluidic device. We constructed a reporter human cell line that emits fluorescence in response to the activation of human glucagon-like peptide-1 receptor (hGLP1R). We then constructed a yeast library secreting an agonist of hGLP1R or randomized peptide ligands. We demonstrated that high-throughput identification of functional ligands against hGLP1R could be performed by co-culturing the reporter cells and the yeast cells in droplets. We identified functional ligands, one of which had higher activity than that of an original sequence. The result suggests that our system could facilitate the discovery of functional peptide ligands of GPCRs.
The genome sequence of Streptomyces rochei 7434AN4, which carries a linear chromosome and three characteristic linear plasmids
Authors: Nindita Yosi , Cao Zhisheng , Fauzi Amirudin Akhmad , Teshima Aiko , Misaki Yuya , Muslimin Rukman , Yang Yingjie , Shiwa Yuh , Yoshikawa Hirofumi , Tagami Michihira , Lezhava Alexander , Ishikawa Jun , Kuroda Makoto , Sekizuka Tsuyoshi , Inada Kuninobu , Kinashi Haruyasu , Arakawa Kenji 
Published: July 2019

AbstractStreptomyces rochei 7434AN4 produces two structurally unrelated polyketide antibiotics, lankacidin and lankamycin, and carries three linear plasmids, pSLA2-L (211 kb), -M (113 kb), and -S (18 kb), whose nucleotide sequences were previously reported. The complete nucleotide sequence of the S. rochei chromosome has now been determined using the long-read PacBio RS-II sequencing together with short-read Illumina Genome Analyzer IIx sequencing and Roche 454 pyrosequencing techniques. The assembled sequence revealed an 8,364,802-bp linear chromosome with a high G + C content of 71.7% and 7,568 protein-coding ORFs. Thus, the gross genome size of S. rochei 7434AN4 was confirmed to be 8,706,406 bp including the three linear plasmids. Consistent with our previous study, a tap-tpg gene pair, which is essential for the maintenance of a linear topology of Streptomyces genomes, was not found on the chromosome. Remarkably, the S. rochei chromosome contains seven ribosomal RNA (rrn) operons (16S-23S-5S), although Streptomyces species generally contain six rrn operons. Based on 2ndFind and antiSMASH platforms, the S. rochei chromosome harbors at least 35 secondary metabolite biosynthetic gene clusters, including those for the 28-membered polyene macrolide pentamycin and the azoxyalkene compound KA57-A.
An actionable KCNH2 Long QT Syndrome variant detected by sequence and haplotype analysis in a population research cohort
Authors: Kerr Shona M. , Klaric Lucija , Halachev Mihail , Hayward Caroline , Boutin Thibaud S. , Meynert Alison M. , Semple Colin A. , Tuiskula Annukka M. , Swan Heikki , Santoyo-Lopez Javier , Vitart Veronique , Haley Chris , Dean John , Miedzybrodzka Zosia , Aitman Timothy J. , Wilson James F. 
Published: July 2019

AbstractThe Viking Health Study Shetland is a population-based research cohort of 2,122 volunteer participants with ancestry from the Shetland Isles in northern Scotland. The high kinship and detailed phenotype data support a range of approaches for associating rare genetic variants, enriched in this isolate population, with quantitative traits and diseases. As an exemplar, the c.1750G > A; p.Gly584Ser variant within the coding sequence of the KCNH2 gene implicated in Long QT Syndrome (LQTS), which occurred once in 500 whole genome sequences from this population, was investigated. Targeted sequencing of the KCNH2 gene in family members of the initial participant confirmed the presence of the sequence variant and identified two further members of the same family pedigree who shared the variant. Investigation of these three related participants for whom single nucleotide polymorphism (SNP) array genotypes were available allowed a unique shared haplotype of 1.22 Mb to be defined around this locus. Searching across the full cohort for this haplotype uncovered two additional apparently unrelated individuals with no known genealogical connection to the original kindred. All five participants with the defined haplotype were shown to share the rare variant by targeted Sanger sequencing. If this result were verified in a healthcare setting, it would be considered clinically actionable, and has been actioned in relatives ascertained independently through clinical presentation. The General Practitioners of four study participants with the rare variant were alerted to the research findings by letters outlining the phenotype (prolonged electrocardiographic QTc interval). A lack of detectable haplotype sharing between c.1750G > A; p.Gly584Ser chromosomes from previously reported individuals from Finland and those in this study from Shetland suggests that this mutation has arisen more than once in human history. This study showcases the potential value of isolate population-based research resources for genomic medicine. It also illustrates some challenges around communication of actionable findings in research participants in this context.
Previous contraceptive treatment relates to grey matter volumes in the hippocampus and basal ganglia
Authors: Pletzer Belinda , Harris TiAnni , Hidalgo-Lopez Esmeralda 
Published: July 2019

AbstractOral contraceptive (OC) effects on the brain have gained increasing interest, but are highly controversial. Previous studies suggest that OC users have larger hippocampi, parahippocampi, fusiform gyri and Cerebelli. Preliminary evidence from one of those studies even suggests an effect of previous contraceptive use on the hippocampi of women who are not current users of OCs. Furthermore, more recent studies postulate an involvement of previous OC treatment in later development of mood disorders. To address the question whether previous OC treatment affects women’s brain structure later in life, high resolution structural images were obtained from 131 naturally cycling women. Among them, 52 women had never used OC before, 52 had previously used one OC for a continuous time period and 27 had previously used multiple contraceptives. The groups did not differ in gray matter volumes. Since endogenous sex hormones modulate gray matter volumes of the hippocampus and basal ganglia along the menstrual cycle, we hypothesize effects of OC use on these areas. Specifically, we hypothesize that a longer duration of previous OC treatment is related to larger hippocampi and larger basal ganglia. Indeed we found the duration of previous OC use to be positively correlated to hippocampal and basal ganglia volumes bilaterally. For the hippocampus, but not for the basal ganglia, this association disappeared after controlling for the time since discontinuation. These results suggest that for the hippocampus, but not for the basal ganglia, effects of previous contraceptive treatment are reversed after a time period comparable to treatment duration. These data question the immediate reversibility of OC effects on brain structure. Accordingly, some changes in the brain due to long-term contraceptive use, while subtle, may be long-lasting.
Acute restraint stress reverses impaired LTP in the hippocampal CA1 region in mouse models of Alzheimer’s disease
Authors: Wang Ming , Ramasamy Vijay Sankar , Samidurai Manikandan , Jo Jihoon 
Published: July 2019

AbstractAcute stress facilitates long-term potentiation (LTP) in the mouse hippocampus by modulating glucocorticoid receptors and ion channels. Here, we analysed whether this occurs in mouse models of Alzheimer’s disease (AD) with impaired LTP induction. We found that a brief 30 min restraint stress protocol reversed the impaired LTP assessed with field excitatory postsynaptic potential recordings at cornu ammonis 3-1 (CA3-CA1) synapses in both Tg2576 and 5XFAD mice. This effect was accompanied by increased phosphorylation and surface expression of glutamate A1 (GluA1) -containing α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs). Moreover, enhanced LTP induction and GluA1 phosphorylation were sustained up to 4 h after the stress. Treatment with 200 nM dexamethasone produced similar effects in the hippocampi of these mice, which supports the glucocorticoid receptor-mediated mechanism in these models. Collectively, our results demonstrated an alleviation of impaired LTP and synaptic plasticity in the hippocampal CA1 region following acute stress in the AD mouse models.
Novel biotechnological glucosylation of high-impact aroma chemicals, 3(2H)- and 2(5H)-furanones
Authors: Effenberger Isabelle , Hoffmann Thomas , Jonczyk Rafal , Schwab Wilfried 
Published: July 2019

AbstractGlucosyltransferases are versatile biocatalysts to chemically modify small molecules and thus enhance their water solubility and structural stability. Although the genomes of all organisms harbor a multitude of glucosyltransferase genes, their functional characterization is hampered by the lack of high-throughput in-vivo systems to rapidly test the versatility of the encoded proteins. We have developed and applied a high-throughput whole cell biotransformation system to screen a plant glucosyltransferase library. As proof of principle, we identified 25, 24, 15, and 18 biocatalysts transferring D-glucose to sotolone, maple furanone, furaneol and homofuraneol, four highly appreciated flavor compounds, respectively. Although these 3(2H)- and 2(5H)-furanones have extremely low odor thresholds their glucosides were odorless. Upscaling of the biotechnological process yielded titers of 5.3 and 7.2 g/L for the new to nature β-D-glucopyranosides of sotolone and maple furanone, respectively. Consequently, plant glucosyltransferase show stunning catalytic activities, which enable the economical production of novel and unexplored chemicals with exciting new functionalities by whole-cell biotransformation.