bluuebunny/crossref_metadata_2025_split huggingface dataset:
MRI-BASED DEEP LEARNING METHOD FOR DETERMINING METHYLATION STATUS OF THE O6-METHYLGUANINE–DNA METHYLTRANSFERASE PROMOTER OUTPERFORMS TISSUE BASED METHODS IN BRAIN GLIOMAS
Authors: Bangalore Yogananda Chandan Ganesh , Shah Bhavya R. , Nalawade Sahil S. , Murugesan Gowtham K. , Yu Frank F. , Pinho Marco C. , Wagner Benjamin C. , Mickey Bruce , Patel Toral R. , Fei Baowei , Madhuranthakam Ananth J. , Maldjian Joseph A. 
Published: May 2020

ABSTRACTPURPOSEMethylation of the O6-Methylguanine-DNA Methyltransferase (MGMT) promoter results in epigenetic silencing of the MGMT enzyme and confers an improved prognosis and treatment response in gliomas. The purpose of this study was to develop a deep-learning network for determining the methylation status of the MGMT Promoter in gliomas using T2-w magnetic resonance images only.METHODSBrain MRI and corresponding genomic information were obtained for 247 subjects from The Cancer Imaging Archive (TCIA) and The Cancer Genome Atlas (TCGA). 163 subjects had a methylated MGMT promoter. A T2-w image only network (MGMT-net) was developed to determine MGMT promoter methylation status and simultaneous single label tumor segmentation. The network was trained using 3D-Dense-UNets. Three-fold cross-validation was performed to generalize the networks’ performance. Dice-scores were computed to determine tumor segmentation accuracy.RESULTSMGMT-net demonstrated a mean cross validation accuracy of 94.73% across the 3 folds (95.12%, 93.98%, and 95.12%, standard dev=0.66) in predicting MGMT methylation status with a sensitivity and specificity of 96.31% ±0.04 and 91.66% ±2.06, respectively and a mean AUC of 0.93 ±0.01. The whole tumor segmentation mean Dice-score was 0.82 ± 0.008.CONCLUSIONWe demonstrate high classification accuracy in predicting the methylation status of the MGMT promoter using only T2-w MR images that surpasses the sensitivity, specificity, and accuracy of invasive histological methods such as pyrosequencing, methylation-specific PCR, and immunofluorescence methods. This represents an important milestone toward using MRI to predict glioma histology, prognosis, and response to treatment.
Phylogenetic analysis of migration, differentiation, and class switching in B cells
Authors: Hoehn Kenneth B. , Pybus Oliver G. , Kleinstein Steven H. 
Published: May 2020

AbstractB cells undergo rapid mutation and selection for antibody binding affinity when producing antibodies capable of neutralizing pathogens. This evolutionary process can be intermixed with migration between tissues, differentiation between cellular subsets, and switching between functional isotypes. B cell receptor (BCR) sequence data has the potential to elucidate important information about these processes. However, there is currently no robust, generalizable framework for making such inferences from BCR sequence data. To address this, we develop three parsimony-based summary statistics to characterize migration, differentiation, and isotype switching along B cell phylogenetic trees. We use simulations to demonstrate the effectiveness of this approach. We then use this framework to infer patterns of cellular differentiation and isotype switching from high throughput BCR sequence datasets obtained from patients in a study of HIV infection and a study of food allergy. These methods are implemented in the R packagedowser, available athttps://bitbucket.org/kleinstein/dowser.Author summaryB cells produce high affinity antibodies through an evolutionary process of mutation and selection during adaptive immune responses. Migration between tissues, differentiation to cellular subtypes, and switching between different antibody isotypes can be important factors in shaping the role B cells play in response to infection, autoimmune disease, and allergies. B cell receptor (BCR) sequence data has the potential to elucidate important information about these processes. However, there is currently no robust, generalizable framework for making such inferences from BCR sequence data. Here, we develop three parsimony-based summary statistics to characterize migration, differentiation, and isotype switching along B cell phylogenetic trees. Using simulations, we confirm the effectiveness of our approach, as well as identify some caveats. We further use these summary statistics to investigate patterns of cellular differentiation in three HIV patients, and patterns of isotype switching in an individual with food allergies. Our methods are released in the R packagedowser:https://bitbucket.org/kleinstein/dowser.
A high-quality genome assembly and annotation of the gray mangrove,Avicennia marina
Authors: Friis Guillermo , Vizueta Joel , Nelson David R. , Khraiwesh Basel , Qudeimat Enas , Salehi-Ashtiani Kourosh , Ortega Alejandra , Marshell Alyssa , Duarte Carlos M. , Burt John A. 
Published: May 2020

AbstractThe gray mangrove [Avicennia marina(Forsk.) Vierh.] is the most widely distributed mangrove species, ranging throughout the Indo-West Pacific. It presents remarkable levels of geographic variation both in phenotypic traits and habitat, often occupying extreme environments at the edges of its distribution. However, subspecific evolutionary relationships and adaptive mechanisms remain understudied, especially across populations of the West Indian Ocean. High-quality genomic resources accounting for such variability are also sparse. Here we report the first chromosome-level assembly of the genome ofA. marina. We used a previously release draft assembly and proximity ligation libraries Chicago and Dovetail HiC for scaffolding, producing a 456,526,188 bp long genome. The largest 32 scaffolds (22.4 Mb to 10.5 Mb) accounted for 98 % of the genome assembly, with the remaining 2% distributed among much shorter 3,759 scaffolds (62.4 Kb to 1 Kb). We annotated 23,331 protein-coding genes using tissue-specific RNA-seq data, from which 13,312 were associated to GO terms. Genome assembly and annotated set of genes yield a 96.7% and 92.3% completeness score, respectively, when compared with the eudicots BUSCO dataset. Furthermore, an FSTsurvey based on resequencing data successfully identified a set of candidate genes potentially involved in local adaptation, and revealed patterns of adaptive variability correlating with a temperature gradient in Arabian mangrove populations. OurA. marinagenomic assembly provides a highly valuable resource for genome evolution analysis, as well as for identifying functional genes involved in adaptive processes and speciation.
PP2ARts1antagonizes Rck2-mediated hyperosmotic stress signaling in yeast
Authors: Hollenstein D. , Veis J. , Romanov N. , Gérecová G. , Ogris E. , Hartl M. , Ammerer G. , Reiter W. 
Published: May 2020

AbstractInSaccharomyces cerevisiaeimpairment of protein phosphatase PP2ARts1leads to temperature and hyperosmotic stress sensitivity, yet the underlying mechanism and the scope of action of the phosphatase in the stress response remain elusive. Using quantitative mass spectrometry-based approaches we have identified a set of putative substrate proteins that show both, hyperosmotic stress- and PP2ARts1-dependent changes in their phosphorylation pattern. A comparative analysis with published MS-shotgun data revealed that the phosphorylation status of many of these sites is regulated by the MAPKAP kinase Rck2, suggesting a node of regulation. Detailed gel mobility shift assays and protein-protein interaction analysis strongly suggest that Rck2 activity is directly regulated by PP2ARts1via a SLiM B56-family interaction motif, uncovering a previously unknown mechanism of how PP2A influences the response to hyperosmotic stress in Yeast.
Herpes Simplex Virus type 1 neuronal infection triggers disassembly of key structural components of dendritic spines
Authors: Acuña-Hinrichsen Francisca , Covarrubias-Pinto Adriana , Ishizuka Yuta , Stolzenbach Maria Francisca , Martin Carolina , Salazar Paula , Castro Maite A. , Bramham Clive , Otth Carola 
Published: May 2020

ABSTRACTHerpes simplex virus type 1 (HSV-1) is a widespread neurotropic virus. The primary infection in facial epithelium leads to retrograde axonal transport to the central nervous system (CNS) where it establishes latency. Under stressful conditions, the virus reactivates, and new progeny is transported anterogradely to the primary site of infection. In late stages of neuronal infection, axonal damage is known to occur. However, the impact of HSV-1 infection on morphology and functional integrity at earlier stages of infection in neuronal dendrites is unknown. Previously, we demonstrated that acute HSV-1 infection in neuronal cell lines selectively enhances the expression of Arc protein - a major regulator of long-term synaptic plasticity and memory consolidation, known for being a protein-interaction hub in the postsynaptic dendritic compartment. Thus, HSV-1 induced Arc may alter the functionality of the infected neurons having an impact on dendritic spine dynamics. In this study we demonstrated that HSV-1 infection causes structural disassembly and functional deregulation in cultured cortical neurons, through protein homeostasis alteration with intracellular accumulation of Arc, and decreased expression of spine scaffolding-like proteins such as PSD-95, Drebrin and CaMKIIβ. Our findings reveal progressive deleterious effects of HSV-1 infection on excitatory neuronal synapse function and dendritic morphology, supporting the thesis of the infectious origin of neurodegenerative processes.
Dynamin-2 regulates synaptic podosome maturation to facilitate neuromuscular junction development
Authors: Lin Shan-Shan , Hsieh Tsung-Lin , Liou Gunn-Guang , Li Tsai-Ning , Lin Hsin-Chieh , Chang Chiung-Wen , Wu Hsiang-Yi , Yao Chi-Kuang , Liu Ya-Wen 
Published: May 2020

AbstractNeuromuscular junctions (NMJs) govern rapid and efficient neuronal communication with muscle cells, which relies on the proper architecture of specialized postsynaptic compartments. However, the intrinsic mechanism in muscle cells contributing to elaborate NMJ development has been unclear. In this study, we reveal that the GTPase dynamin-2 (Dyn2), best-known for catalyzing synaptic vesicle endocytosis at the presynaptic membrane, is also involved in postsynaptic morphogenesis. We demonstrate that Dyn2 is enriched in the postsynaptic membrane of muscle cells and is involved in the maturation of neurotransmitter receptor clusters via its actin bundling ability. Dyn2 functions as a molecular girdle to regulate synaptic podosome turnover and promote morphogenesis of the postsynaptic apparatus. InDrosophilaNMJs, Dyn2 is required to organize the postsynaptic actin cytoskeleton and to mediate its electrophysiological activities. Mechanistically, the actin binding, self-assembly, GTP hydrolysis ability, and Y597 phosphorylation of Dyn2 all regulate its actin bundling activity. Together, our study uncovers a role for Dyn2 in cytoskeleton remodeling and organization at the postsynaptic membrane of NMJs.
Large ribosomal subunit, eIF5B, Met-tRNAiMetand mRNA cooperate to complete accurate initiation
Authors: Wang Jinfan , Wang Jing , Shin Byung-Sik , Dever Thomas E. , Puglisi Joseph D. , Fernández Israel S. 
Published: May 2020

AbstractRecognition of a start codon by the first aminoacyl-tRNA (Met-tRNAiMet) determines the reading frame of messenger RNA (mRNA) translation by the ribosome. In eukaryotes, the GTPase eIF5B collaborates in the correct positioning of Met-tRNAiMeton the ribosome in the later stages of translation initiation, gating entrance into elongation. Leveraging the long residence time of eIF5B on the ribosome recently identified by single-molecule fluorescence measurements, we determined the cryoEM structure of the naturally long-lived ribosome complex with eIF5B and Met-tRNAiMetimmediately before transition into elongation. The structure uncovered an unexpected, eukaryotic specific and dynamic fidelity checkpoint implemented by eIF5B in concert with components of the large ribosomal subunit.One sentence summaryCryoEM structure of a naturally long-lived translation initiation intermediate with Met-tRNAiMetand eIF5B post GTP hydrolysis.
Stagewise identification of significantly mutated and dysregulated gene clusters in major molecular classes of breast invasive carcinoma
Authors: Agarwal Shivangi , Naik Sanoj , Kumari Pratima , Mishra Sandip K. , Adhya Amit K. , Kashaw Sushil K. , Dixit Anshuman 
Published: May 2020

AbstractBreast invasive carcinoma (BRCA) is most malignant and leading cause of death in women. The efforts are ongoing for improvement in early detection, prevention and treatment. Therefore, identification of biomarkers/candidate genes has become very important. The current work includes comprehensive analysis of RNA-sequencing data of 1097 BRCA samples and 114 normal adjacent tissues to identify dysregulated genes in major molecular classes of BRCA in various clinical stages. Huge number of dysregulated genes were found, some were stage-specific, and others were common. The pathways as interferon signaling, tryptophan degradation III, granulocyte adhesion & diapedesis and catecholamine biosynthesis were found in ER/PR+/HER-2- (p-value<0.010), pathways as RAR activation, adipogenesis, role of JAK1, JAK2 in interferon signaling, TGF-ß and STAT3 signaling (p-value<0.014) intricated in ER/PR-/HER-2+ and pathways as IL-1/IL-8 signaling, TNFR1/TNFR2 signaling, TWEAK and relaxin signaling (p-value<0.005) were found in triple negative breast cancer. The genes were clustered based on their mutation profile which revealed nine mutated clusters, some of which were known to be involved in well-known cancer signalling pathways while others were less characterized. Each cluster was analyzed in detail which led us to discover genes viz. NLGN3, MAML2, TTN, SYNE1, ANK2 as candidates in BRCA. The genes were found to be involved in important processes as chemotaxis, axon guidance, notch binding, cell-adhesion-molecule binding etc. They are central genes in the protein-protein-interaction network indicating they can have important regulatory roles. The qRT-PCR and western blot confirmed our findings in breast cancer cell-lines. Further, immunohistochemistry corroborated the results in ~100 tissue samples. The genes can be used as biomarker in BRCA.
Rrp1 translocase and ubiquitin ligase activities restrict the genome destabilising effects of Rad51 in fission yeast
Authors: Muraszko Jakub , Argunhan Bilge , Ito Kentaro , Baranowska Gabriela , Barg-Wojas Anna , Kramarz Karol , Kurokawa Yumiko , Iwasaki Hiroshi , Dziadkowiec Dorota 
Published: May 2020

AbstractRad51 is the key protein in homologous recombination DNA repair and has important roles during DNA replication. Auxiliary factors regulate Rad51 activity to facilitate productive, and prevent inappropriate, recombination that could lead to genome instability. Previous genetic analyses identified a function for Rrp1 (a member of the Rad5/16-like group of SWI2/SNF2 translocases) in counteracting Rad51 activity, shared with the Rad51 mediator Swi5-Sfr1 and the Srs2 anti-recombinase. Here, we show that Rrp1 overproduction alleviates the toxicity associated with excessive Rad51 activity in a manner dependent on Rrp1 ATPase domain. Purified Rrp1 binds to DNA and has a DNA-dependent ATPase activity. Importantly, Rrp1 directly interacts with Rad51 and removes it from double-stranded DNA, confirming that Rrp1 is a translocase capable of modulating Rad51 activity. Additionally, we demonstrate that Rrp1 possesses E3 ubiquitin ligase activity with Rad51 as a substrate, suggesting that Rrp1 regulates Rad51 in a multi-tiered fashion.
Stop codon readthrough of a POU transcription factor regulates steroidogenesis and developmental transitions
Authors: Zhao Yunpo , Lindberg Bo Gustav , Esfahani Shiva Seyedoleslami , Tang Xiongzhuo , Piazza Stefano , Engström Ylva 
Published: May 2020

AbstractTranslational stop codon readthrough generates C-terminally extended protein isoforms. While evidence mounts of readthrough as a global phenomenon, proofs of its functional consequences are scarce. We show that readthrough of the mRNA for theDrosophilaPOU/Oct transcription factor Drifter occurs at a high rate and in a spatiotemporal mannerin vivo, reaching above 50% in the prothoracic gland. Phylogenetic analyses suggested that readthrough ofdrifteris conserved among Dipterans, with C-terminal extensions harboring intrinsically disordered regions, and amino acids streches implied in transcriptional activation. The C-terminally extended Drifter isoform is required for maintaining normal levels of the growth hormone ecdysone through regulation of its biosynthetic genes, acting in synergy with the transcription factor Molting defective. A 14-bp deletion that abolished readthrough, caused prolonged larval development and delayed metamorphosis. This study provides a striking example of alternative genetic decoding that feeds into the progression from one life cycle stage to another.
UDP-Glucose 6-Dehydrogenase Knockout Impairs Migration and Decreasesin vivoMetastatic Ability of Breast Cancer Cells
Authors: Teoh Shao Thing , Ogrodzinski Martin P. , Lunt Sophia Y. 
Published: May 2020

ABSTRACTDysregulated metabolism is a hallmark of cancer that supports tumor growth and metastasis. One understudied aspect of cancer metabolism is altered nucleotide sugar biosynthesis, which drives aberrant cell surface glycosylation known to support various aspects of cancer cell behavior including migration and signaling. We examined clinical association of nucleotide sugar pathway gene expression and found thatUGDH, encoding UDP-glucose 6-dehydrogenase which catalyzes production of UDP-glucuronate, is associated with worse breast cancer patient survival. Knocking out the mouse homologUgdhin highly-metastatic 6DT1 breast cancer cells impaired migration ability without affectingin vitroproliferation. Further,Ugdh-KOresulted in significantly decreased metastatic capacityin vivowhen the cells were orthotopically injected in syngeneic mice. Our experiments show that UDP-glucuronate biosynthesis is critical for metastasis in a mouse model of breast cancer.
Interactions between the microbiome and mating influence the female’s transcriptional profile inDrosophila melanogaster
Authors: Delbare Sofie Y. N. , Ahmed-Braimah Yasir H. , Wolfner Mariana F. , Clark Andrew G. 
Published: May 2020

AbstractDrosophila melanogasterfemales undergo a variety of post-mating changes that influence their activity, feeding behavior, metabolism, egg production and gene expression. These changes are induced either by mating itself or by sperm or seminal fluid proteins. In addition, studies have shown that axenic females—those lacking a microbiome—have altered fecundity compared to females with a microbiome, and that the microbiome of the female’s mate can influence reproductive success. However, the extent to which post-mating changes in transcript abundance are affected by microbiome state is not well-characterized. Here we investigated fecundity and the post-mating transcript abundance profile of axenic or control females after mating with either axenic or control males. We observed interactions between the female’s microbiome and her mating status: transcripts of genes involved in reproduction and genes with neuronal functions were differentially abundant depending on the females’ microbiome status, but only in mated females. In addition, immunity genes showed varied responses to either the microbiome, mating, or a combination of those two factors. We further observed that the male’s microbiome status influences the fecundity of both control and axenic females, while only influencing the transcriptional profile of axenic females. Our results indicate that the microbiome plays a vital role in the post-mating switch of the female’s transcriptome.
Lmo7a Coordinates Neural Crest Migration and Lineage Specification by Regulating Cell Adhesion Dynamics
Authors: Tatarakis David , Tuttle Adam , Schilling Thomas F. 
Published: May 2020

ABSTRACTCell migration requires dynamic regulation of cell-cell signaling and cell adhesion. Neural crest (NC) cells are highly migratory cells, which undergo an epithelial-mesenchymal transition (EMT) to leave the neural epithelium and migrate throughout the body to give rise to many different derivatives. We have identified a Lim-domain only (Lmo) protein, Lmo7a, expressed in early NC cells that controls both actin cytoskeletal dynamics and Wnt signaling during NC migration. In embryos deficient in Lmo7a, many NC cells fail to migrate away from the dorsal midline, and form aggregates. Unlike the majority of NC cells that appear to migrate normally, cells that aggregate in Lmo7a-deficient embryos mislocalize paxillin (Pxn) and have reduced levels of phosphorylated focal adhesion kinase (pFAK). Lmo7a loss-of-function also disrupts canonical Wnt signaling such that after the onset of NC cell migration, Wnt responses and nuclear β-catenin levels increase in the cells that aggregate. However, this increase in Wnt signaling appears secondary to the defect in migration. Similar to mutants for other Wnt regulators in NC cells, the NC cells in Lmo7a-deficient aggregates exhibit gene expression signatures of pigment cell progenitors, but also express markers of Schwann cell progenitors, suggesting a role for Lmo7a in pigment-glial specification. We propose that Lmo7a modulates cell adhesion to facilitate both robust NC cell migration and a subset of lineage decisions.
How the brain negotiates divergent executive processing demands: Evidence of network reorganization during fleeting brain states
Authors: Liu Mengting , Backer Robert A. , Amey Rachel C. , Forbes Chad E. 
Published: May 2020

AbstractDuring performance in everyday contexts, multiple networks draw from shared executive resources to maintain attention, regulate arousal, and problem solve. At times, requirements for attention and self-regulation appear to be in competition for a “limited pool” of resources. How does the brain attempt to resolve conflicts arising from multiple processing demands? In the present study, participants were exposed to either a stress or control prime, after which electroencephalographic (EEG) activity was recorded as they solved math problems. Phase-locking was examined within four networks implicated in math-solving and evaluative stress: frontopareital (FP), default mode (DM), emotion generation (EG), and emotion regulation (ER) networks. Findings revealed differing strategies, depending on the presence of stress: states dominated by frontopareital and emotion regulation network dynamics supported optimum performance generally, while during stress, states dominated by emotion regulation and default mode networks are more important for performance. Implications for networks’ cooperative dynamics and DMN’s role in coping are considered.