bluuebunny/crossref_metadata_2025_split huggingface dataset:
Development of a Triazolobenzodiazepine-Based PET Probe for Subtype-Selective Vasopressin 1A Receptor Imaging
Authors: Haider Ahmed , Xiao Zhiwei , Xia Xiaotian , Chen Jiahui , Van Richard S. , Kuang Shi , Zhao Chunyu , Rong Jian , Shao Tuo , Ramesh Perla , Aravind Appu , Shao Yihan , Ran Chongzhao , Young Larry J. , Liang Steven H. 
Published: February 2021

AbstractObjectivesTo enable non-invasive real-time quantification of vasopressin 1A (V1A) receptors in peripheral organs, we sought to develop a suitable PET probe that would allow specific and selective V1A receptor imagingin vitroandin vivo.MethodsWe synthesized a high-affinity and -selectivity ligand, designated compound17. The target structure was labeled with carbon-11 and tested for its utility as a V1A-targeted PET tracer by cell uptake studies, autoradiography, in vivo PET imaging and ex vivo biodistribution experiments.ResultsCompound17(PF-184563) and the respective precursor for radiolabeling were synthesized in an overall yield of 49% (over 7 steps) and 40% (over 8 steps), respectively. An inhibitory constant of 0.9 nM towards the V1A receptor was measured, while excellent selectivity over the related V1B, V2 and OT receptor (IC50>10,000 nM) were obtained. Cell uptake studies revealed considerable V1A binding, which was significantly reduced in the presence of V1A antagonists. Conversely, there was no significant blockade in the presence of V1B and V2 antagonists.In vitroautoradiography and PET imaging studies in rodents indicated specific tracer binding mainly in the liver. Further, the pancreas, spleen and the heart exhibited specific binding of [11C]17([11C]PF-184563) byex vivobiodistribution experiments.ConclusionWe have developed the first V1A-targeted PET ligand that is suitable for subtype-selective receptor imaging in peripheral organs including the liver, heart, pancreas and spleen. Our findings suggest that [11C]PF-184563 can be a valuable tool to study the role of V1A receptors in liver diseases, as well as in cardiovascular pathologies.
N-glycosylation onOryza SativaRoot Germin-like Protein 1 is conserved but not required for stability or activity
Authors: Rubbab Tehseen , Pegg Cassandra L. , Phung Toan K. , Nouwens Amanda S. , Yeo K. Y. Benjamin , Zacchi Lucia F. , Muhammad Amna , Naqvi S. M. S Saqlan , Schulz Benjamin L. 
Published: February 2021

AbstractGermin and germin-like proteins (GLPs) are a broad family of extracellular glycoproteins ubiquitously distributed in plants. Overexpression ofOryza sativaroot germin like protein 1 (OsRGLP1) enhances superoxide dismutase (SOD) activity in transgenic plants. Here, we report bioinformatic analysis and heterologous expression ofOsRGLP1 to study the role of glycosylation onOsRGLP1 protein stability and activity. Sequence analysis ofOsRGLP1 homologs identified diverseN-glycosylation sequons, one of which was highly conserved. We therefore expressedOsRGLP1 in glycosylation-competentSaccharomyces cerevisiaeas a Maltose Binding Protein (MBP) fusion. Mass spectrometry analysis of purifiedOsRGLP1 showed it was expressed byS. cerevisiaein bothN-glycosylated and unmodified forms. Glycoprotein thermal profiling showed little difference in the thermal stability of the glycosylated and unmodified protein forms. Circular Dichroism spectroscopy of MBP-OsRGLP1 and a N-Q glycosylation-deficient variant showed that both glycosylated and unmodified MBP-OsRGLP1 had similar secondary structure, and both forms had equivalent SOD activity. Together, we concluded that glycosylation was not critical forOsRGLP1 protein stability or activity, and it could therefore likely be produced inEscherichia coliwithout glycosylation. Indeed, we found thatOsRGLP1 could be efficiently expressed and purified from K12 shuffleE. coliwith a specific activity of 1251±70 Units/mg. In conclusion, we find that some highly conservedN-glycosylation sites are not necessarily required for protein stability or activity, and describe a suitable method for production ofOsRGLP1 which paves the way for further characterization and use of this protein.
Prediction of occult tumor progression via platelet RNAs in a mouse melanoma model: a potential new platform of cancer screening for early detection of cancer
Authors: Yin Yue , Jiang Ruilan , Shen Mingwang , Li Zhaofang , Yan Ni , Feng Junqiao , Jiang Hong , Lv Jiaxin , Shi Lijuan , Wang Lina , Liu Xi , Zhang Kaiyun , Chen Di 
Published: February 2021

AbstractCancer screening provides the opportunity to detect cancer early, ideally before symptom onset and metastasis, and offers an increased opportunity for a better prognosis. The ideal biomarkers for cancer screening should discriminate individuals who have not developed invasive cancer yet but are destined to do so from healthy subjects1,2. However, most cancers lack effective screening recommendations. Therefore, further studies on novel screening strategies are urgently required. Here, our proof-of-concept study shows blood platelets could be a platform for liquid biopsy-based early cancer detection. By using a simple suboptimal inoculation melanoma mouse model, we identified differentially expressed RNAs in platelet signatures of mice injected with a suboptimal number of cancer cells (eDEGs) compared with mice with macroscopic melanomas and negative controls. These RNAs were strongly enriched in pathways related to immune response and regulation. Moreover, 36 genes selected from the eDEGs via bioinformatics analyses were verified in a mouse validation cohort via quantitative real-time PCR. LASSO regression was employed to generate the prediction models with gene expression signatures as the best predictors for occult tumor progression in mice. The prediction models showed great diagnostic efficacy and predictive value in our murine validation cohort, and could discriminate mice with occult tumors from control group (area under curve (AUC) of 0.935 (training data) and 0.912 (testing data)) (gene signature including Cd19, Cdkn1a, S100a9, Tap1, and Tnfrsf1b) and also from macroscopic tumor group (AUC of 0.920 (training data) and 0.936 (testing data)) (gene signature including Ccr7, Cd4, Kmt2d, and Ly6e). Our study provides evidence for potential clinical relevance of blood platelets as a platform for liquid biopsy-based early detection of cancer. Furthermore, the eDEGs are mostly immune-related, not tumor-specific. Hence it is possible platelets-based liquid biopsy could enable simultaneous early detection of cancers from multiple organs of origin3. It is also feasible to determine the origin of cancer since platelet profiles are influenced by tumor type3.
scPNMF: sparse gene encoding of single cells to facilitate gene selection for targeted gene profiling
Authors: Song Dongyuan , Li Kexin Aileen , Hemminger Zachary , Wollman Roy , Li Jingyi Jessica 
Published: February 2021

AbstractSingle-cell RNA sequencing (scRNA-seq) captures whole transcriptome information of individual cells. While scRNA-seq measures thousands of genes, researchers are often interested in only dozens to hundreds of genes for a closer study. Then a question is how to select those informative genes from scRNA-seq data. Moreover, single-cell targeted gene profiling technologies are gaining popularity for their low costs, high sensitivity, and extra (e.g., spatial) information; however, they typically can only measure up to a few hundred genes. Then another challenging question is how to select genes for targeted gene profiling based on existing scRNA-seq data. Here we develop the single-cell Projective Non-negative Matrix Factorization (scPNMF) method to select informative genes from scRNA-seq data in an unsupervised way. Compared with existing gene selection methods, scPNMF has two advantages. First, its selected informative genes can better distinguish cell types. Second, it enables the alignment of new targeted gene profiling data with reference data in a low-dimensional space to facilitate the prediction of cell types in the new data. Technically, scPNMF modifies the PNMF algorithm for gene selection by changing the initialization and adding a basis selection step, which selects informative bases to distinguish cell types. We demonstrate that scPNMF outperforms the state-of-the-art gene selection methods on diverse scRNA-seq datasets. Moreover, we show that scPNMF can guide the design of targeted gene profiling experiments and cell-type annotation on targeted gene profiling data.
Sub-diffraction error mapping for localization microscopy images
Authors: Marsh Richard J. , Costello Ishan , Gorey Mark-Alexander , Ma Donghan , Huang Fang , Gautel Mathias , Parsons Maddy , Cox Susan 
Published: February 2021

AbstractAssessing the quality of localization microscopy images is highly challenging due to difficulty in reliably detecting errors in experimental data, with artificial sharpening being a particularly common failure mode of the technique. Here we use Haar wavelet kernel analysis (HAWK), a localization microscopy data analysis method which is known to give results without artificial sharpening, to generate a reference image. This enables the mapping and quantification of this common artefact. By suppressing intensity information, we are able to map sharpening errors in a way which is not influenced by nonlinearity in the localisation imaging process. The HAWK Method for the Assessment of Nanoscopy (HAWKMAN) is a general approach which allows the reliability of localization information to be assessed.
Single paternal Dexamethasone challenge programs offspring metabolism and reveals circRNAs as novel candidates in RNA-mediated inheritance
Authors: Gapp Katharina , Parada Guillermo , Gross Fridolin , Corcoba Alberto , Grau Evelyn , Hemberg Martin , Bohacek Johannes , Miska Eric A. 
Published: February 2021

SummarySingle traumatic events that elicit an exaggerated stress response can lead to the development of neuropsychiatric conditions. Studies in mice suggests germline RNA as a mediator of effects of chronic environmental exposures to the progeny. The effects of an acute paternal stress exposure on the germline and their potential consequences on offspring remain unknown. We find that acute administration of an agonist for the stress- sensitive Glucocorticoid receptor, using the common corticosteroid Dexamethasone, affects the RNA payload of post-meiotic transcriptionally silent, mature sperm as soon as 3 hours post exposure. It further impacts early embryonic transcriptional trajectories, as determined by single embryo sequencing, and metabolism in the offspring. Importantly, we show persistent regulation of tRNA fragments in sperm and the descendant 2-cell- embryos, suggesting actual transmission from sperm to embryo. Lastly, we unravel environmentally induced alterations in the previously underconsidered class of sperm circRNAs, and their targets in the early embryo, highlighting this class as a novel candidate in RNA-mediated inheritance.
Identification and mechanistic analysis of an inhibitor of the CorC Mg2+transporter
Authors: Huang Yichen , Mu Kaijie , Teng Xinyu , Zhao Yimeng , Funato Yosuke , Miki Hiroaki , Zhu Weiliang , Xu Zhijian , Hattori Motoyuki 
Published: February 2021

AbstractThe CorC/CNNM family of Na+-dependent Mg2+transporters is ubiquitously conserved from bacteria to humans. CorC, the bacterial member of the CorC/CNNM family of proteins, is involved in resistance to antibiotic exposure and in the survival of pathogenic microorganisms in their host environment. The CorC/CNNM family proteins possess a cytoplasmic region containing the regulatory ATP-binding site. While CorC and CNNM have attracted interest as therapeutic targets, inhibitors targeting the ir regulatory ATP-binding site have not yet been identified.Here, we performed a virtual screening of CorC by targeting its regulatory ATP-binding site, identified a chemical compound named IGN95a with inhibitory effects on both ATP binding and Mg2+export, and determined the cytoplasmic domain structure in complex with IGN95a. Furthermore, a chemical cross-linking experiment indicated that with ATP bound to the cytoplasmic domain, the conformational equilibrium of CorC was shifted more towards the inward-facing state of the transmembrane domain. In contrast, IGN95a did not induce such a shift. Our results provide a structural basis for the further design and optimization of chemical compounds targeting the regulatory ATP-binding site of CorC as well as mechanistic insights into how ATP and chemical compounds modulate the transport activity of CorC.
Characterisation of immune cell subsets of tumour infiltrating lymphocytes in brain metastases
Authors: Croft Priyakshi Kalita-de , Chittoory Haarika , Nguyen Tam , Saunus Jodi M , Kim Woo Gyeong , Reed Amy McCart , Lim Malcolm , De Luca Xavier M , Ferguson Kaltin , Niland Colleen , Mazzieri Roberta , Dolcetti Riccardo , Simpson Peter T , Lakhani Sunil R 
Published: February 2021

AbstractThe heterogeneity of tumor infiltrating lymphocytes is not well characterized in brain metastasis. To address this, we performed a targeted analysis of immune cell subsets in brain metastasis tissues to test which immunosuppressive routes are involved in brain metastasis. We performed multiplex immunofluorescence (mIF), using commercially available validated antibodies on twenty formalin-fixed paraffin embedded whole sections. We quantitated the subsets of immune cells utilizing a targeted panel of proteins including PanCK, CD8, CD4, VISTA and Iba1, and analyzed an average of 15000 cells per sample. We classified tumours as either high (>30%) or low (<30%) tumour infiltrating lymphocytes (TILs) and found that increased TILs density correlated with survival. We next sought out to phenotype these TILs using mIF. The tumours with low TILs (n=9) had significantly higher expression of the immune-checkpoint molecule VISTA in tumor cells (p<0.01) as well as in their microenvironment (p<0.001). Contrastingly, the brain metastatic tumours with high TILs (n=8) displayed higher levels of activated microglia, as measured by Iba1 expression. Low TILs-tumours displayed CD8+ T-cells that co-express VISTA (p<0.01) significantly more compared to high TILs group, where CD8+ T-cells significantly co-express Iba1 (p<0.05). Interestingly, no definite phenotypes of CD4+ subsets were observed. These results were supported by RNA analysis of a publicly available, independent cohort. In conclusion, our work contributes to a growing understanding of the immune surveillance escape routes active in brain metastasis.Graphical AbstractGraphical abstract:Brain metastasis patients with low TILs have high VISTA expression and patients with high TILs have significantly more activated microglia
Fasting reverses drug-resistance in hepatocellular carcinoma through p53-dependent metabolic synergism
Authors: Krstic Jelena , Reinisch Isabel , Schindlmaier Katharina , Galhuber Markus , Berger Natascha , Kupper Nadja , Moyschewitz Elisabeth , Auer Martina , Michenthaler Helene , Nössing Christoph , Depaoli Maria R. , Ramadani-Muja Jeta , Stryeck Sarah , Pichler Martin , Rinner Beate , Deutsch Alexander J.A. , Reinisch Andreas , Madl Tobias , Chiozzi Riccardo Zenezini , Heck Albert J.R. , Huch Meritxell , Malli Roland , Prokesch Andreas 
Published: February 2021

ABSTRACTCancer cells voraciously consume nutrients to support their growth, exposing a metabolic vulnerability that can be therapeutically exploited. Here we show in hepatocellular carcinoma (HCC) cells, xenografts, and in patient-derived HCC organoids that fasting can synergistically sensitize resistant HCC to sorafenib. Mechanistically, sorafenib acts non-canonically as an inhibitor of mitochondrial respiration, causing resistant cells to depend on glycolysis for survival. Fasting, through reduction in glucose and impeded AKT/mTOR-signaling, prevents this Warburg shift. Regulating glucose transporter and pro-apoptotic protein expression, p53 is necessary and sufficient for the sorafenib-sensitizing effect of fasting. p53 is also crucial for fasting-mediated improvement of sorafenib efficacy in an orthotopic HCC mouse model. Together, our data suggest intermittent fasting and sorafenib as rational combination therapy for HCC with intact p53 signaling. As HCC therapy is currently severely limited by resistance, these results should instigate clinical studies aimed at improving therapy response in advanced-stage, and possibly even early-stage, HCC.HIGHLIGHTSFasting sensitizes resistant HCC xenografts and patient-derived organoids to sorafenibSorafenib-mediated Warburg shift is prevented by glucose limitation upon fastingFasting synergistically improves sorafenib efficacy in non-resistant modelsp53 is required for synergism by regulating glucose uptake and apoptosisGRAPHICAL ABSTRACT
Evidence of stock connectivity, hybridization and misidentification in white anglerfish support the need of a genetics-informed fisheries management framework
Authors: Aguirre-Sarabia Imanol , Díaz-Arce Natalia , Pereda-Agirre Iker , Mendibil Iñaki , Urtizberea Agurtzane , Gerritsen Hans D. , Burns Finlay , Holmes Ian , Landa Jorge , Coscia Ilaria , Quinconces Iñaki , Santurtún Marina , Zanzi Antonella , Martinsohn Jann T. , Rodríguez-Ezpeleta Naiara 
Published: February 2021

AbstractUnderstanding population connectivity within a species as well as potential interactions with its close relatives is crucial to define management units and to derive efficient management actions. However, although genetics can reveal mismatches between biological and management units and other relevant but hidden information such as species misidentification or hybridization, the uptake of genetic methods by the fisheries management process is far from having been consolidated. Here, we have assessed the power of genetics to better understand the population connectivity of white angelfish (Lophius piscatorius) and its interaction with its sister species, the black anglerfish (L. budegassa). Our analyses, based on thousands of genome-wide single nucleotide polymorphisms, show three findings that are crucial for white anglerfish management. We found i) that white anglerfish is likely composed of a single panmictic population throughout the Northeast Atlantic, challenging the three-stock based management, ii) that a fraction of specimens classified as white anglerfish using morphological characteristics are genetically identified as black anglerfish (L. budegassa) and iii) that the twoLophiusspecies naturally hybridize leading to a population of hybrids of up to 20% in certain areas. Our results set the basics for a genetics-informed white anglerfish assessment framework that accounts for stock connectivity, revises and establishes new diagnostic characters forLophiusspecies identification and evaluates the effect of hybrids in the current and future assessments of the white anglerfish. Furthermore, our study contributes to provide additional evidence of the potentially negative consequences of ignoring genetic data for assessing fisheries resources.
A pilot study on the home range and movement patterns of the Andean FoxLycalopex culpaeus(Molina, 1782) in Cotopaxi National Park, Ecuador
Authors: Castellanos Armando , Castellanos Francisco X. , Kays Roland , Brito Jorge 
Published: February 2021

AbstractThis study reports movement patterns and home range estimates of an Andean fox (Lycalopex culpaeus) in Cotopaxi National Park in Ecuador, representing the first GPS-tagging of the species. The GPS functioned well during the 197-day tracking period. Home range sizes ranged between 4.9 - 8.1 km2, depending on the estimation method. Movement speeds averaged 0.17 km/hr at day vs. 0.87 km/hr. at night, and distance traveled averaged 0.23 km at day vs. 0.89 km at night. These preliminary results highlight the importance of collecting unbiased, high-quality data which enables an enhanced understanding on mammal behavior and human/animal interaction.
The integration of continuous audio and visual speech in a cocktail-party environment depends on attention
Authors: Ahmed Farhin , Nidiffer Aaron R. , O’Sullivan Aisling E. , Zuk Nathaniel J. , Lalor Edmund C. 
Published: February 2021

AbstractIn noisy, complex environments, our ability to understand audio speech benefits greatly from seeing the speaker’s face. This is attributed to the brain’s ability to integrate audio and visual information, a process known as multisensory integration. In addition, selective attention to speech in complex environments plays an enormous role in what we understand, the so-called cocktail-party phenomenon. But how attention and multisensory integration interact remains incompletely understood. While considerable progress has been made on this issue using simple, and often illusory (e.g., McGurk) stimuli, relatively little is known about how attention and multisensory integration interact in the case of natural, continuous speech. Here, we addressed this issue by analyzing EEG data recorded from subjects who undertook a multisensory cocktail-party attention task using natural speech. To assess multisensory integration, we modeled the EEG responses to the speech in two ways. The first assumed that audiovisual speech processing is simply a linear combination of audio speech processing and visual speech processing (i.e., an A+V model), while the second allows for the possibility of audiovisual interactions (i.e., an AV model). Applying these models to the data revealed that EEG responses to attended audiovisual speech were better explained by an AV model than an A+V model, providing evidence for multisensory integration. In contrast, unattended audiovisual speech responses were best captured using an A+V model, suggesting that multisensory integration is suppressed for unattended speech. Follow up analyses revealed some limited evidence for early multisensory integration of unattended AV speech, with no integration occurring at later levels of processing. We take these findings as evidence that the integration of natural audio and visual speech occurs at multiple levels of processing in the brain, each of which can be differentially affected by attention.
Evaluating Wayfinding Designs in Healthcare Settings through EEG Data and Virtual Response Testing
Authors: Kalantari Saleh , Tripathi Vidushi , Rounds James D. , Mostafavi Armin , Snell Robin , Cruz-Garza Jesus G. 
Published: February 2021

ABSTRACTWayfinding difficulties in healthcare facilities have been shown to increase anxiety among patients and visitors and reduce staff operational efficiency. Wayfinding-oriented interior design features have proven beneficial, but the evaluation of their performance is hindered by the unique nature healthcare facilities and the expense of testing different navigational aids. This study implemented a virtual-reality testing platform to evaluate the effects of different signage and interior hospital design conditions during navigational tasks; evaluated through behavioral responses and mobile EEG. The results indicated that using color to highlight destinations and increase the contrast of wayfinding information yielded significant benefits when combined with wayfinding-oriented environmental affordances. Neural dynamics from the occipital cortex showed beta-band desynchronization with enhanced color condition and additional theta-band desynchronization with enhanced environmental affordance. This multimodal testing platform has the potential to establish a robust body of evidence for future wayfinding design strategies.