bluuebunny/crossref_metadata_2025_split huggingface dataset:
CUB domain containing protein 1 (CDPC1) is a target for radioligand therapy in castration resistant prostate cancer
Authors: Zhao Ning , Trepka Kai , Wang Yung-hua , Chopra Shalini , Hooshdaran Nima , Kim Hyunjung , Zhuo Jie , Lim Shion A. , Yang Jianing , Leung Kevin K. , Egusa Emily , Zhang Li , Foye Adam , Chou Jonathon , Feng Felix Y. , Small Eric J. , Wells James A. , Aggarwal Rahul , Evans Michael J. 
Published: June 2021

AbstractPurposeRadioligand therapy (RLT) is relatively unexplored in metastatic castration resistant prostate cancer (mCRPC), with much of the focus having been on bone seeking radionuclides and PSMA-directed RLT. Herein, we evaluated if CUB domain containing protein 1 (CDCP1) can be exploited to treat mCRPC with RLT, particularly for subsets like small cell neuroendocrine prostate cancer (SCNC) that would not be expected to respond to current options.Experimental DesignCDCP1 mRNA levels were evaluated in the RNA-seq data from 119 recent mCRPC biopsies. Protein expression was assessed in twelve SCNC and adenocarcinoma patient derived xenografts. Saturation binding assays were performed with 4A06, a recombinant human antibody that targets the CDCP1 ectodomain. The feasibility of imaging and treating mCRPC in vivo was tested with 89Zr-4A06 and 177Lu-4A06.ResultsCDCP1 mRNA expression was observed in over 90% of mCRPC biopsies, including SCNC and in adenocarcinoma with low FOLH1 (PSMA) levels. A modest anticorrelation was observed between CDCP1 and PTEN. Overall survival was not significantly different based on CDCP1 mRNA levels, regardless of PTEN status. Full length and/or cleaved CDCP1 was expressed in ten of twelve PDX samples. Bmax values of ~22,000 and ~6,200 fmol/mg were calculated for two human prostate cancer cell lines. Five prostate cancer models were readily detected in vivo with 89Zr-4A06. 177Lu-4A06 significantly suppressed the growth of DU145 tumors compared to control.ConclusionsThe antitumor data and the overexpression of CDCP1 reported herein provide the first evidence promoting CDCP1 directed RLT as a treatment strategy for mCRPC.Statement of Translational RelevanceNew targets for RLT are needed to address the subset of mCRPC that cannot be treated with bone seeking radionuclides or PSMA directed RLT. We report herein the first data credentialing CDCP1 as a target for mCRPC, in both adenocarcinoma and neuroendocrine subtypes. Combined with low expression in normal human tissues, these data provide a compelling scientific rationale for testing CDCP1 directed RLT clinically in mCRPC patients alone or in combination with other systemic therapies.
mRNA- and factor-driven dynamic variability controls eIF4F-cap recognition for translation initiation
Authors: Çetin Burak , O’Leary Seán E. 
Published: June 2021

SUMMARYmRNA 5ʹ cap recognition by eIF4F is a key step in eukaryotic translational control. While different mRNAs respond differently to eIF4F-directed regulation, the molecular basis for this variability remains unclear. We developed single-molecule fluorescence assays to directly observe eIF4F– mRNA interactions. We uncovered a complex interplay of mRNA features with factor activities that differentiates cap recognition between mRNAs. eIF4E–cap association rates are anticorrelated with mRNA length. eIF4A leverages ATP binding to differentially accelerate eIF4E– mRNA association; the extent of this acceleration correlates with translation efficiencyin vivo. eIF4G lengthens eIF4E–cap binding to persist on the initiation timescale. The full eIF4F complex discriminates between mRNAs in an ATP-dependent manner. After eIF4F–mRNA binding, eIF4E is ejected from the cap by eIF4A ATP hydrolysis. Our results suggest features throughout mRNA coordinate in controlling cap recognition at the 5ʹ end, and suggest a model for how eIF4F–mRNA dynamics establish mRNA sensitivity to translational control processes.
Image quantification technique reveals novel lung cancer cytoskeletal phenotype with partial EMT signature
Authors: Basu Arkaprabha , Paul Manash K. , Alioscha-Perez Mitchel , Grosberg Anna , Sahli Hichem , Dubinett Steven M. , Weiss Shimon 
Published: June 2021

AbstractEpithelial-mesenchymal Transition (EMT) is a multi-step process that involves cytoskeletal rearrangement. Here, using novel image quantification tools, we have identified an intermediate EMT state with a specific cytoskeletal signature. We have been able to partition EMT into two steps: (1) initial formation of transverse arcs and dorsal stress fibers and (2) their subsequent conversion to ventral stress fibers with a concurrent alignment of fibers. Using the Orientational Order Parameter (OOP) as a figure of merit, we have been able to track EMT progression in live cells as well as characterize and quantify drug responses. Our technique has improved throughput and is non-destructive, making it a viable candidate for studying a broad range of biological processes. Further, owing to the increased stiffness (and hence invasiveness) of the intermediate phenotype compared to mesenchymal cells, our work can be instrumental in aiding the search for new treatment strategies that combat metastasis by specifically targeting the fiber alignment process.
Nanopore callers for epigenetics from limited supervised data
Authors: Yao Brian , Hsu Chloe , Goldner Gal , Michaeli Yael , Ebenstein Yuval , Listgarten Jennifer 
Published: June 2021

AbstractNanopore sequencing platforms combined with supervised machine learning (ML) have been effective at detecting base modifications in DNA such as 5mC and 6mA. These ML-based nanopore callers have typically been trained on data that span all modifications on all possible DNA k-mer backgrounds—a complete training dataset. However, as nanopore technology is pushed to more and more epigenetic modifications, such complete training data will not be feasible to obtain. Nanopore calling has historically been performed with Hidden Markov Models (HMMs) that cannot make successful calls for k-mer contexts not seen during training because of their independent emission distributions. However, deep neural networks (DNNs), which share parameters across contexts, are increasingly being used as callers, often outperforming their HMM cousins. It stands to reason that a DNN approach should be able to better generalize to unseen k-mer contexts. Indeed, herein we demonstrate that a common DNN approach (DeepSignal) outperforms a common HMM approach (Nanopolish) in the incomplete data setting. Furthermore, we propose a novel hybrid HMM-DNN approach, Amortized-HMM, that outperforms both the pure HMM and DNN approaches on 5mC calling when the training data are incomplete. Such an approach is expected to be useful for calling 5hmC and combinations of cytosine modifications, where complete training data are not likely to be available.
Cellular and molecular signatures of in vivo GABAergic neurotransmission in the human brain
Authors: Lukow PB , Martins D , Veronese M , Vernon AC , McGuire P , Turkheimer FE , Modinos G 
Published: June 2021

AbstractDiverse GABAergic interneuron microcircuits orchestrate information processing in the brain. Understanding the cellular and molecular composition of these microcircuits, and whether these can be imaged by available non-invasive in vivo methods is crucial for the study of GABAergic neurotransmission in health and disease. Here, we use human gene expression data and state-of-the-art imaging transcriptomics to uncover co-expression patterns between GABAA receptor subunits and interneuron subtype-specific markers, and to decode the cellular and molecular signatures of gold-standard GABA PET radiotracers, [11C]Ro15-4513 and [11C]flumazenil. We find that the interneuron marker somatostatin is co-expressed with GABAA receptor-subunit genes GABRA5 and GABRA2, and their distribution maps onto [11C]Ro15-4513 binding in vivo. In contrast, the interneuron marker parvalbumin co-expressed with more predominant GABAA receptor subunits (GABRA1, GABRB2 and GABRG2), and their distribution tracks [11C]flumazenil binding in vivo. These results have important implications for the non-invasive study of GABAergic microcircuit dysfunction in psychiatric conditions.
Multi-omics network-based functional annotation of unknown Arabidopsis genes
Authors: Depuydt Thomas , Vandepoele Klaas 
Published: June 2021

SummaryUnraveling gene functions is pivotal to understand the signaling cascades controlling plant development and stress responses. Given that experimental profiling is costly and labor intensive, the need for high-confidence computational annotations is evident. In contrast to detailed gene-specific functional information, transcriptomics data is widely available in both model and crop species. Here, we developed a novel automated function prediction (AFP) algorithm, leveraging complementary information present in multiple expression datasets through the analysis of study-specific gene co-expression networks. Benchmarking the prediction performance on recently characterizedArabidopsis thalianagenes, we showed that our method outperforms state-of-the-art expression-based approaches. Next, we predicted biological process annotations for known (n=15,790) and unknown (n=11,865) genes inA. thalianaand validated our predictions using experimental protein-DNA and protein-protein interaction data (covering >220 thousand interactions in total), obtaining a set of high-confidence functional annotations. 5,054 (42.6%) unknown genes were assigned at least one validated annotation, and 3,408 (53.0%) genes with only computational annotations gained at least one novel validated function. These omics-supported functional annotations shed light on a variety of developmental processes and molecular responses, such as flower and root development, defense responses to fungi and bacteria, and phytohormone signaling, and help alleviate the knowledge gap of biological process annotations in Arabidopsis. An in-depth analysis of two context-specific networks, modeling seed development and response to water deprivation, shows how previously uncharacterized genes function within the respective networks. Moreover, our AFP approach can be applied in future studies to facilitate gene discovery for crop improvement.Significance statementFor the majority of plant genes, it is unknown in which processes they are involved. Using a multi-omics approach, leveraging transcriptome, protein-DNA and protein-protein interaction data, we functionally annotated 42.6% of unknownArabidopsis thalianagenes, providing insight into a variety of developmental processes and molecular responses, as well as a resource of annotations which can be explored by the community to facilitate future research.
Autopolyploidization affects transcript patterns and gene targeting frequencies in Physcomitrella
Authors: Rempfer Christine , Wiedemann Gertrud , Schween Gabriele , Kerres Klaus L. , Lucht Jan M. , Horres Ralf , Decker Eva L. , Reski Ralf 
Published: June 2021

AbstractQualitative changes in gene expression after an autopolyploidization event, a pure duplication of the whole genome, might be relevant for a different regulation of molecular mechanisms between angiosperms growing in a life cycle with a dominant diploid sporophytic stage and the haploid-dominant bryophytes. Whereas angiosperms repair DNA double strand breaks (DSB) preferentially via non-homologous end joining (NHEJ), in bryophytes homologous recombination (HR) is the main DNA-DSB repair pathway facilitating the precise integration of foreign DNA into the genome via gene targeting (GT). Here, we studied the influence of ploidy on gene expression patterns and GT efficiency in the moss Physcomitrella using haploid plants and autodiploid plants, generated via an artificial duplication of the whole genome. Single cells (protoplasts) were transfected with a GT construct and material from different time-points after transfection was analysed by microarrays and SuperSAGE sequencing. In the SuperSAGE data, we detected 3.7% of the Physcomitrella genes as differentially expressed in response to the whole genome duplication event. Among the differentially expressed genes involved in DNA-DSB repair was an upregulated gene encoding the X-ray repair cross-complementing protein 4 (XRCC4), a key player in NHEJ. Analysing the GT efficiency, we observed that autodiploid plants were significantly GT suppressed (p<0.001) attaining only one third of the expected GT rates. Hence, an alteration of global transcript patterns, including genes related to DNA repair, in autodiploid Physcomitrella plants correlated with a drastic suppression of HR.
Strategic decision support for long-term conservation management planning
Authors: Abelson Eric S. , Reynolds Keith M. , Manley Patricia , Paplanus Steven 
Published: June 2021

ABSTRACTForward thinking conservation-planning can benefit from modeling future landscapes that result from multiple alternative management scenarios. However, long-term landscape modeling and downstream analyses of modeling results can lead to massive amounts of data that are difficult to assemble, analyze, and to report findings in a way that is easily accessible to decision makers. In this study, we developed a decision support process to evaluate modeled forest conditions resulting from five management scenarios, modeled across 100 years in California’s Lake Tahoe basin; to this end we drew upon a large and complex hierarchical dataset intended to evaluate landscape resilience. Trajectories of landscape characteristics used to inform an analysis of landscape resilience in the Lake Tahoe basin were modeled with the spatially explicit LANDIS-II vegetation simulator. Downstream modeling outputs of additional landscape characteristics were derived from the LANDIS-II outputs (e.g., wildlife conditions, water quality, effects of fire). The later modeling processes resulted in the generation of massive data sets with high dimensionality of landscape characteristics at both high spatial and temporal resolution. Ultimately, our analysis distilled hundreds of data inputs into trajectories of the performance of the five management scenarios over the 100-year time horizon of the modeling. We then evaluated each management scenario based on inter-year variability, and absolute and relative performance. We found that the management scenario that relied on prescribed fire, outperformed the other four management approaches. Both these results, and the process that led to them, provided decision makers with easy-to-understand results based on a rational, transparent, and repeatable decision support process.One sentence descriptionWe present a novel approach to employ decision support tools for conservation over long time horizons.
Oligomeric α-Synuclein induces skin degeneration in a reconstructed human epidermis model
Authors: Oliveira Júlia T. , De Vecchi Rodrigo , Dakic Vanja , Vitória Gabriela , Pedrosa Carolina , Mendes Mayara , Aragão Luiz Guilherme H.S. , Cardim-Pires Thyago R. , Furtado Daniel Rodrigues , Pinheiro Roberta O. , Foguel Débora , Breton Lionel , Bouez Charbel , Guimarães Marilia Zaluar P. , Rehen Stevens 
Published: June 2021

AbstractCell senescence may promote epidermal inflammation and degeneration, termed as inflammaging, which is accompanied by keratinocyte loss, resulting in fine lines of wrinkles. Recent findings showed that healthy elderly skin expresses age- and neuron-related amyloidogenic proteins, such as tau, β-Amyloid34, and α-synuclein (α-Syn), typically found in patients with neurodegenerative diseases. These proteins form toxic aggregates that trigger inflammatory signals. Herein, we investigated the impact of oligomeric α-Syn (Oα-Syn) on the neurosphere (NP) and the reconstructed human epidermis (RHE) 3D models. First, we found the expression of α-Syn, β-Amyloid, and amyloid precursor protein (APP) in the RHE. Second, we challenged the RHE and NP with Oα-Syn, which decreased RHE regeneration, measured by the percentage of cell proliferation and thickness of the stratum basale, but did not affect NP neurite outgrowth. Oα-Syn did not decrease the number of human neonatal epidermal keratinocytes (HEKn) but, as seen for the RHE, it also decreased the proliferation of HEKn. We confirmed that the oligomeric, and not the monomeric α-Syn species, accounted for the proliferation-decreasing effect. Oα-Syn also increased the NF-kB nuclear translocation in HEKn analyzed by nucleus/cytoplasm NF-κB fluorescence intensity. In addition, Oα-Syn triggered inflammation in the RHE, by increasing the mRNA levels of IL-1β and tumor necrosis factor-alpha (TNF-α), and the release of TNF-α in a time-dependent manner. These findings show that Oα-Syn does not affect neurite outgrowth but induces a decrease in keratinocyte proliferation along with epidermal inflammation. With our tridimensional models, we demonstrated that the neurodegenerative protein Oα-Syn also degenerates the epidermis, drawing attention to the need of target-based screening to prevent and treat the effects of skin aging.
Visual and Quantitative Analyses of Virus Genomic Sequences using a Metric-based Algorithm
Authors: Belinsky Alexandra , Kouzaev Guennadi A. 
Published: June 2021

AbstractThis work aims to study the virus RNAs using a novel algorithm for accelerated exploring any-length genomic fragments in sequences using Hamming distance between the binary-expressed characters of an RNA and query patterns. The found repetitive genomic sub-sequences of different lengths were placed on one plot as genomic trajectories (walks) to increase the effectiveness of geometrical multi-scale genomic studies. Primary attention was paid to the building and analysis of theatg-triplet walks composing the schemes or skeletons of the viral RNAs. The 1-D distributions of these codon-startingatg-triplets were built with the single-symbol walks for full-scale analyses. The visual examination was followed by calculating statistical parameters of genomic sequences, including the estimation of geometry deviation and fractal properties of inter-atgdistances. This approach was applied to the SARS CoV-2, MERS CoV, Dengue and Ebola viruses, whose complete genomic sequences are taken from GenBank and GISAID databases. The relative stability of these distributions for SARS CoV-2 and MERS CoV viruses was found, unlike the Dengue and Ebola distributions that showed an increased deviation of their geometrical and fractal characteristics ofatg-distributions. The results of this work can found in classification of the virus families and in the study of their mutation.
Progesterone receptor-A isoform interaction with RUNX transcription factors controls chromatin remodelling at promoters during ovulation
Authors: Dinh DT , Breen J , Nicol B , Smith KM , Nicholls M , Emery A , Wong YY , Barry SC , Yao HHC , Robker RL , Russell DL 
Published: June 2021

SummaryProgesterone receptor (PGR) plays diverse roles in reproductive tissues and thus coordinates mammalian fertility. In the ovary, acutely induced PGR is the key determinant of ovulation through transcriptional control of a unique set of genes that culminates in follicle rupture. However, the molecular mechanisms for PGR’s specialised function in ovulation is poorly understood. To address this, we assembled a detailed genomic profile of PGR action through combined ATAC-seq, RNA-seq and ChIP-seq analysis in wildtype and isoform-specific PGR null mice. We demonstrated the unique action of PGR-A isoform in the ovary through a transcriptional complex involving physical interaction with RUNX and JUN/FOS transcription factors. The assembly of this unique complex directs targeting of PGR binding to proximal promoter regions and enables chromatin accessibility, leading to ovulatory gene induction. This PGR signalling mechanism is specific to ovulation and provides potential targets for infertility treatments as well as new contraceptives that block ovulation.
Rotavirus NSP1 contributes to intestinal viral replication, pathogenesis, and transmission
Authors: Hou Gaopeng , Zeng Qiru , Matthijnssens Jelle , Greenberg Harry B. , Ding Siyuan 
Published: June 2021

ABSTRACTRotavirus (RV)-encoded non-structural protein 1 (NSP1), the product of gene segment 5, effectively antagonizes host interferon (IFN) signaling via multiple mechanisms. Recent studies with the newly established RV reverse genetics system indicate that NSP1 is not essential for the replication of simian RV SA11 strain in cell culture. However, the role of NSP1 in RV infection in vivo remains poorly characterized due to the limited replication of heterologous simian RVs in the suckling mouse model. Here, we used an optimized reverse genetics system and successfully recovered recombinant murine RVs with or without NSP1 expression. While the NSP1-null virus replicated comparably with the parental murine RV in IFN-deficient and IFN-competent cell lines in vitro, it was highly attenuated in 5-day-old wild-type suckling pups. In the absence of NSP1 expression, murine RV had significantly reduced replication in the ileum, systemic spread to mesenteric lymph nodes, fecal shedding, diarrhea occurrence, and transmission to uninoculated littermates. Of interest, the replication and pathogenesis defects of NSP1-null RV were only minimally rescued in Stat1 knockout pups, suggesting that NSP1 facilitates RV replication in an IFN-independent manner. Our findings highlight a pivotal function of NSP1 during homologous RV infections in vivo and identify NSP1 as an ideal viral protein for targeted attenuation for future vaccine development.IMPORTANCERotavirus remains one of the most important causes of severe diarrhea and dehydration in young children worldwide. Although NSP1 is dispensable for rotavirus replication in cell culture, its exact role in virus infection in vivo remains unclear. In this study, we demonstrate that in the context of a fully replication-competent, pathogenic, and transmissible murine rotavirus, loss of NSP1 expression substantially attenuated virus replication in the gastrointestinal tract, diarrheal disease, and virus transmission in suckling mice. Notably, the NSP1-deficient murine rotavirus also replicated poorly in mice lacking host interferon signaling. Our data provide the first piece of evidence that NSP1 is essential for murine rotavirus replication in vivo, making it an attractable target for developing improved next-generation rotavirus vaccines better suited for socioeconomically disadvantaged and immunocompromised individuals.