bluuebunny/crossref_metadata_2025_split huggingface dataset:
CAMOIP: A Web Server for Comprehensive Analysis on Multi-Omics of Immunotherapy in Pan-cancer
Authors: Lin Anqi , Wei Ting , Liang Junyi , Qi Chang , Li Mengyao , Luo Peng , Zhang Jian 
Published: September 2021

ABSTRACTImmune checkpoint inhibitors (ICIs) have completely changed the therapeutic approach for tumor patients. Immunotherapy has also produced much needed data about mutation, expression, and prognosis, providing an unprecedented opportunity for discovering candidate drug targets and screening for immunotherapy-relevant biomarkers. Although existing web tools enable biologists to analyze the expression, mutation, and prognosis data on tumors, they are currently not able to carry out data mining and mechanism analyses related to immune checkpoint therapy. Thus, we developed our own web-based tool called Comprehensive Analysis on Multi-Omics of Immunotherapy in Pan-cancer (CAMOIP), in which we can screen prognostic markers and analyze the mechanisms involved with markers and immunotherapy (more than 4000 patients). The analyses include survival analysis, expression analysis, drug sensitivity analysis, mutational landscape, immune checkpoint analysis, immune related signature analysis, immune cell analysis, immune gene analysis, immunogenicity analysis and gene sets enrichment analysis (GSEA). This comprehensive analysis of biomarkers for immunotherapy can be carried out by a click of CAMOIP, and the software should greatly encourage the further development of immunotherapy. CAMOIP fills the gap between the big data of cancer genomics based on immunotherapy and providing comprehensive information to users, helping to release the value of current ICI-treated data resources. CAMOIP can be found inhttps://www.camoip.net.
Unique features of transcription termination and initiation at closely spaced tandem human genes
Authors: Nissani Noa , Ulitsky Igor 
Published: September 2021

AbstractThe synthesis of RNA Polymerase II (Pol2) products, which include messenger RNAs or long noncoding RNAs, culminates in transcription termination. How the transcriptional termination of a gene impacts the activity of promoters found immediately downstream of it, and which can be subject to potential transcriptional interference, remains largely unknown. We examined in an unbiased manner features of the intergenic region of pairs of tandem and closely spaced (<2kb) genes found on the same strand. Intergenic regions separating tandem genes are enriched with Guanines and are characterized by binding of several proteins, including AGO1 and AGO2 of the RNA interference pathway. Additionally, we found that Pol2 with a specific modification pattern is particularly enriched in this region, and it is lost upon perturbations affecting splicing or transcriptional elongation. Perturbations of genes involved in Pol2 pausing and R loop biology preferentially affect expression of downstream genes in tandem gene pairs. Overall, we find that features associated with potential Pol2 recycling rather than those associated with avoidance of transcriptional interference are the predominant driving force shaping these regions.
Deep Learning identifies new morphological patterns of Homologous Recombination Deficiency in luminal breast cancers from whole slide images
Authors: Lazard Tristan , Bataillon Guillaume , Naylor Peter , Popova Tatiana , Bidard François-Clément , Stoppa-Lyonnet Dominique , Stern Marc-Henri , Decencière Etienne , Walter Thomas , Salomon Anne Vincent 
Published: September 2021

AbstractHomologous Recombination DNA-repair deficiency (HRD) is a well-recognized marker of platinum-salt and PARP inhibitor chemotherapies in ovarian and breast cancers (BC). Causing high genomic instability, HRD is currently determined by BRCA1/2 sequencing or by genomic signatures, but its morphological manifestation is not well understood. Deep Learning (DL) is a powerful machine learning technique that has been recently shown to be capable of predicting genomic signatures from stained tissue slides. However, DL is known to be sensitive to dataset biases and lacks interpretability. Here, we present and evaluate a strategy to control for biases in retrospective cohorts. We train a deep-learning model to predict the HRD in a controlled cohort with unprecedented accuracy (AUC: 0.86) and we develop a new visualization technique that allows for automatic extraction of new morphological features related to HRD. We analyze in detail the extracted morphological patterns that open new hypotheses on the phenotypic impact of HRD.
Clinical grade ACE2 as a universal agent to block SARS-CoV-2 variants
Authors: Wirnsberger Gerald , Monteil Vanessa , Eaton Brett , Postnikova Elena , Murphy Michael , Braunsfeld Benedict , Crozier Ian , Kricek Franz , Niederhöfer Janine , Schwarzböck Alice , Breid Helene , Sanchez Jimenez Anna , Bugajska-Schretter Agnes , Dohnal Alexander , Ruf Christine , Gugenberger Romana , Hagelkruys Astrid , Montserrat Nuria , Holbrook Michael R. , Oostenbrink Chris , Shoemaker Robert H. , Mirazimi Ali , Penninger Josef M. 
Published: September 2021

AbstractThe recent emergence of multiple SARS-CoV-2 variants has caused considerable concern due to reduced vaccine efficacy and escape from neutralizing antibody therapeutics. It is therefore paramount to develop therapeutic strategies that inhibit all known and future SARS-CoV-2 variants. Here we report that all SARS-CoV-2 variants analyzed, including variants of concern (VOC) Alpha, Beta, Gamma, and Delta, exhibit enhanced binding affinity to clinical grade and phase 2 tested recombinant human soluble ACE2 (APN01). Importantly, soluble ACE2 neutralized infection of VeroE6 cells and human lung epithelial cells by multiple VOC strains with markedly enhanced potency when compared to reference SARS-CoV-2 isolates. Effective inhibition of infections with SARS-CoV-2 variants was validated and confirmed in two independent laboratories. These data show that SARS-CoV-2 variants that have emerged around the world, including current VOC and several variants of interest, can be inhibited by soluble ACE2, providing proof of principle of a pan-SARS-CoV-2 therapeutic.
Human-specific enrichment of schizophrenia risk-genes in callosal neurons of the developing neocortex
Authors: Zuccaro Emanuela , Murek Vanessa , Kim Kwanho , Chen Hsu-Hsin , Mancinelli Sara , Oyler-Castrillo Paul , Jiménez-Barrón Laura T. , Gerhardinger Chiara , Brown Juliana R. , Byrnes Andrea , Neale Benjamin M. , Levin Joshua Z. , Ziller Michael J. , Lodato Simona , Arlotta Paola 
Published: September 2021

SummaryHuman genetic studies have provided a wealth of information on genetic risk factors associated with neuropsychiatric diseases. However, whether different brain cell types are differentially affected in disease states and when in their development and maturation alterations occur is still poorly understood. Here we generated a longitudinal transcriptional map of excitatory projection neuron (PN) and inhibitory interneuron (IN) subtypes of the cerebral cortex, across a timeline of mouse embryonic and postnatal development, as well as fetal human cortex and human cortical organoids. We found that three types of gene signatures uniquely defined each cortical neuronal subtype: dynamic (developmental), adult (terminal), and constitutive (stable), with individual neuronal subtypes varying in the degree of similarity of their signatures between species. In particular, human callosal projection neurons (CPN) displayed the greatest species divergence, with molecular signatures highly enriched for non-coding, human-specific RNAs. Evaluating the association of neuronal class-specific signatures with neuropsychiatric disease risk genes using linkage disequilibrium score regression showed that schizophrenia risk genes were enriched in CPN identity signatures from human but not mouse cortex. Human cortical organoids confirmed the association with excitatory projection neurons. The data indicate that risk gene enrichment is both species- and cell type-specific. Our study reveals molecular determinants of cortical neuron diversification and identifies human callosal projection neurons as the most species-divergent population and a potentially vulnerable neuronal class in schizophrenia.
Intranasal administration of a VLP-based vaccine against COVID-19 induces neutralizing antibodies against SARS-CoV-2 and Variants of Concerns
Authors: Rothen Dominik A. , Krenger Pascal S. , Nonic Aleksandra , Balke Ina , Vogt Anne-Cathrine S. , Chang Xinyue , Manenti Alessandro , Vedovi Fabio , Resevica Gunta , Walton Senta M. , Zeltins Andris , Montomoli Emanuele , Vogel Monique , Bachmann Martin F. , Mohsen Mona O. 
Published: September 2021

AbstractBackgroundThe highly contagious SARS-CoV-2 is mainly transmitted by respiratory droplets and aerosols. Consequently, people are required to wear masks and maintain a social distance to avoid spreading of the virus. Despite the success of the commercially available vaccines, the virus is still uncontained globally. Given the tropism of SARS-CoV-2, a mucosal immune reaction would help to reduce viral shedding and transmission locally. Only seven out of hundreds of ongoing clinical trials are testing the intranasal delivery of COVID-19 vaccines.MethodsIn the current study, we tested in murine model the immunogenicity of a conventional vaccine platform based on virus-like particles (VLPs) displaying RBD of SARS-CoV-2 for intranasal vaccination. The candidate vaccine, CuMVTT-RBD, has been immunologically optimized to incorporate tetanus-toxin and is self-adjuvanted with TLR7/8 ligands.ResultsCuMVTT-RBD elicited strong RBD- and spike- specific systemic IgG and IgA antibody responses of high avidity. Local immune responses were assessed and results demonstrate strong mucosal antibody and plasma cell production in lung tissue. The induced systemic antibodies could efficiently recognize and neutralize different Variants of Concerns of mutated SARS-CoV-2 RBDs.ConclusionIn summary, intranasal vaccination with CuMVTT-RBD shows high immunogenicity and induces protective systemic and local specific antibody response against SARS-CoV-2 and its variants.One sentence summaryEvaluation of an intransal administrated conventional VLP-based vaccine against COVID-19 in a murine model.
Kv1.3 induced hyperpolarisation and Cav3.2-mediated calcium entry are required for efficient Kaposi’s sarcoma-associated herpesvirus lytic replication
Authors: Carden Holli , Dallas Mark L. , Hughes David J. , Lippiat Jonathan D. , Mankouri Jamel , Whitehouse Adrian 
Published: September 2021

AbstractUnderstanding the host factors critical for Kaposi’s sarcoma-associated herpesvirus (KSHV) lytic replication can identify new targets for therapeutic intervention. Using pharmacological and genetic silencing approaches, we reveal for the first time that KSHV requires a B cell expressed voltage-gated K+channel, Kv1.3, to enhance lytic replication. We show that the KSHV replication and transcription activator (RTA) protein upregulates Kv1.3 expression, leading to enhanced K+channel activity and hyperpolarisation of the B cell membrane. Enhanced Kv1.3 activity then promotes intracellular Ca2+influx through Cav3.2, a T-type Ca2+channel, leading to the Ca2+driven nuclear localisation of NFAT and the subsequent NFAT1-responsive gene expression. Importantly, KSHV lytic replication and infectious virion production could be inhibited by both Kv1.3 and Cav3.2 blockers or through Kv1.3 silencing. These findings provide new mechanistic insight into the essential role of host ion channels during KSHV infection and highlight Kv1.3 and Cav3.2 as new druggable host factors that are key to the successful completion of KSHV lytic replication.
SILAC phosphoproteomics reveals unique signaling circuits in CAR-T cells and the inhibition of B cell-activating phosphorylation in target cells
Authors: Griffith Alijah A. , Callahan Kenneth P. , King Nathan Gordo , Xiao Qian , Su Xiaolei , Salomon Arthur R. 
Published: September 2021

AbstractChimeric antigen receptor (CAR) is a single-pass transmembrane receptor designed to specifically target and eliminate cancers. While CARs prove highly efficacious against B cell malignancies, the intracellular signaling events which promote CAR T cell activity remain elusive. To gain further insight into both CAR T cell signaling and the potential signaling response of cells targeted by CAR, we analyzed phosphopeptides captured by two separate phopshoenrichment strategies from third generation CD19-CAR T cells cocultured with SILAC labeled Raji B cells by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Here, we report that CD19-CAR T cells upregulated several key phosphorylation events also observed in canonical T cell receptor (TCR) signaling while Raji B cells exhibited a significant decrease in B cell receptor-signaling related phosphorylation events in response to coculture. Our data suggest that CD19-CAR stimulation activates a mixture of unique CD19-CAR-specific signaling pathways and canonical TCR signaling while global phosphorylation in Raji B cells is reduced after association with the CD19-CAR T cells.
An inactivated multivalent influenza A virus vaccine is broadly protective in mice and ferrets
Authors: Park Jaekeun , Fong Sharon , Schwartzman Louis M. , Sheng Zhong-Mei , Freeman Ashley , Matthews Lex , Xiao Yongli , Ramuta Mitchell D. , Batchenkova Natalia A. , Qi Li , Rosas Luz Angela , Williams Stephanie , Scherler Kelsey , Gouzoulis Monica , Bellayr Ian , Morens David M. , Walters Kathie-Anne , Memoli Matthew J. , Kash John C. , Taubenberger Jeffery K. 
Published: September 2021

AbstractInfluenza A viruses (IAVs) present major public health threats from annual seasonal epidemics, from pandemics caused by novel virus subtypes, and from viruses adapted to a variety of animals including poultry, pigs and horses. Vaccines that broadly protect against all such IAVs, so-called “universal” influenza vaccines, do not currently exist, but are urgently needed. This study demonstrates that an inactivated, multivalent whole virus vaccine, delivered intramuscularly or intranasally, is broadly protective against challenges with multiple IAV HA/NA subtypes in both mice and ferrets, including challenges with IAV subtypes not contained in the vaccine. This vaccine approach indicates the feasibility of eliciting broad “universal” IAV protection, and identifies a promising candidate for influenza vaccine clinical development.One-Sentence SummaryAn inactivated, whole avian influenza virus vaccine delivered intramuscularly or intranasally provides extremely broad protection against antigenically divergent viral challenge and is a promising candidate for a “universal” influenza virus vaccine.
Essential functions of mosquito ecdysone importers in development and reproduction
Authors: Hun Lewis V. , Okamoto Naoki , Imura Eisuke , Maxson Roilea , Bittar Riyan , Yamanaka Naoki 
Published: September 2021

ABSTRACTThe primary insect steroid hormone ecdysone requires a membrane transporter to enter its target cells. Although an organic anion-transporting polypeptide (OATP) named Ecdysone Importer (EcI) serves this role in the fruit fly Drosophila melanogaster and most likely in other arthropod species, this highly conserved transporter is apparently missing in mosquitoes. Here we report three additional OATPs that facilitate cellular incorporation of ecdysone in Drosophila and the yellow fever mosquito Aedes aegypti. These additional ecdysone importers (EcI-2, 3, and 4) are dispensable for development and reproduction in Drosophila, consistent with the predominant role of EcI. In contrast, in Aedes, EcI-2 is indispensable for ecdysone-mediated development, whereas EcI-4 is critical for vitellogenesis induced by ecdysone in adult females. Altogether, our results indicate unique and essential functions of these additional ecdysone importers in mosquito development and reproduction, making them attractive molecular targets for species- and stage-specific control of ecdysone signaling in mosquitoes.
Another step towards understanding evolutionary changes inBruggmanniellaTavares, 1909 group (Diptera, Cecidomyiidae, Asphondyliini)
Authors: Garcia Carolina de Almeida , Lamas Carlos José Einicker , Urso-Guimarães Maria Virginia 
Published: September 2021

AbstractAn update of the delimitation of the genusBruggmanniellabased on phylogenetic analysis using morphological data is presented. We included the seven new species ofBruggmannielladescribed between 2019 and 2020, and discuss some aspects of the evolutionary changes among the closely related generaBruggmanniella, Pseudasphondylia, andIlliciomyia. Bruggmanniellais confirmed here as a monophyletic Neotropical lineage, divergent from the Asian species. The phylogenetic reconstruction hypothesized here reinforces the pertinence of the genusOdontokerosto house all species occurring in the Oriental/Palearctic region underBruggmanniella. The delimitation ofBruggmanniella, the geographical distribution, and niche occupation are discussed.
Applying Historical Data in a Nonlinear Mixed-Effects Model Can Reduce the Number of Control Rats Required for Calculation of The Relative Potency of Insulin Analogues
Authors: Nielsen Emilie Prang , Andersen Søren , Brand Christian Lehn , Ditlevsen Susanne 
Published: September 2021

AbstractThis paper examines how to reduce the number of control animals in preclinical hyperinsulemic glucose clamp studies if we make use of information on historical studies. A data set consisting of 59 studies in rats to investigate new insulin analogues for diabetics, collected in the years 2000 to 2015, is analysed. A simulation experiment is performed based on a carefully built nonlinear mixed-effects model including historical information, comparing results (for the relative log-potency) with the standard approach ignoring previous studies. We find that by including historical information in the form of the mixed-effects model proposed, we can to remove between 23% and 51% of the control rats in the two studies looked closely upon to get the same level of precision on the relative log-potency as in the standard analysis. How to incorporate the historical information in the form of the mixed-effects model is discussed, where both a meta approach as well as a Bayesian approach are suggested. The conclusions are similar for the two approaches, and therefore, we conclude that the inclusion of historical information is beneficial in regard to using fewer control rats.
LRP-1 Commands Two Parallel Signalling Mechanisms to Support Constitutive Tumour Cell Motility in the Absence of Blood Supply
Authors: Chang Cheng , Tang Xin , Mosallaei Daniel , Chen Mei , Woodley David T. , Schönthal Axel H. , Li Wei 
Published: September 2021

AbstractTumour cells often face the stress of ischemic (nutrient paucity and hypoxia) environment and must act self-sufficient to migrate toward the nearest blood supply or die. The mechanism that supports the constitutive motility of tumour cells under stress is poorly understood. We and others have previously shown that the low-density lipoprotein receptor-related protein 1 (LRP-1) plays a critical role in tumour cell migration and invasion in vitro and tumour formation in mice. Herein we show that depletion of LRP-1 completely abolishes the self-supported and serum-independent tumour cell motility. More intriguingly, we demonstrate that LRP-1 commands the full tumour cell motility by connecting with two independent cell surface signalling pathways. First, LRP-1 mediates secreted Hsp90α signalling via the “Hsp90α > LRP-1 receptor autocrine loop” for a half of tumour cell motility. Second, LRP1 stabilizes constitutively activated EGFR signalling that contributes the other half of tumour cell motility. Only combined inhibitions of the secreted Hsp90α autocrine and the EGFR signalling reproduces the effect of LRP1 down-regulation on constitutive tumour cell motility. This study reveals a novel mechanism of how tumour cells migrate in the absence of blood support.
Cysteine induces mitochondrial reductive stress in glioblastoma through hydrogen peroxide production
Authors: Noch Evan K , Palma Laura , Yim Isaiah , Barnett Daniel , Walsh Alexander , Bhinder Bhavneet , Benedetti Elisa , Krumsiek Jan , Gurvitch Justin , Khwaja Sumaiyah , Elemento Olivier , Cantley Lewis C. 
Published: September 2021

SummaryGlucose and amino acid metabolism are critical for glioblastoma (GBM) growth, but little is known about the specific metabolic alterations in GBM that are targetable with FDA-approved compounds. To investigate tumor metabolism signatures unique to GBM, we interrogated The Cancer Genome Atlas for alterations in glucose and amino acid signatures in GBM relative to other human cancers and found that GBM exhibits the highest levels of cysteine and methionine pathway gene expression of 32 human cancers. Treatment of patient-derived GBM cells with the FDA-approved cysteine compound N-acetylcysteine (NAC) reduce GBM cell growth and mitochondrial oxygen consumption, which was worsened by glucose starvation. Mechanistic experiments revealed that cysteine compounds induce rapid mitochondrial H2O2 production and reductive stress in GBM cells, an effect blocked by oxidized glutathione, thioredoxin, and redox enzyme overexpression. These findings indicate that GBM is uniquely susceptible to NAC-driven reductive stress and could synergize with glucose-lowering treatments for GBM.
Successful Application of Wastewater-Based Epidemiology in Prediction and Monitoring of the Second Wave of COVID-19 in India with Fragmented Sewerage Systems- A Case Study of Jaipur (India)
Authors: Arora Sudipti , Nag Aditi , Kalra Aakanksha , Sinha Vikky , Meena Ekta , Saxena Samvida , Sutaria Devanshi , Kaur Manpreet , Pamnani Tamanna , Sharma Komal , Saxena Sonika , Shrivastava Sandeep K , Gupta A. B. , Li Xuan , Jiang Guangming 
Published: September 2021

AbstractThe present study tracked the city-wide dynamics of severe acute respiratory syndrome-corona virus 2 (SARS-CoV-2) RNA in the wastewater from nine different wastewater treatment plants (WWTPs) in Jaipur during second wave of COVID-19 out-break in India. A total of 164 samples were collected weekly between February 19th and June 8th, 2021. SARS-CoV-2 was detected in 47.2% (52/110) influent samples and 37% (20/54) effluent samples. The increasing percentage of positive influent samples correlated with the city’s increasing active clinical cases during the second wave of COVID-19 in Jaipur. Furthermore, WBE based evidence clearly showed early detection of about 20 days (9/9 samples reported positive on April 20th, 2021) prior to the maximum cases & maximum deaths reported in the city on May 8th, 2021. The present study further observed the presence of SARS-CoV-2 RNA in treated effluents at the time window of maximum active cases in the city even after tertiary disinfection treatments of UV & Chlorine. The average genome concentration in the effluents and removal efficacy of six commonly used treatments; Activated Sludge Treatment + Chlorine disinfection (ASP + Cl2), Moving Bed Biofilm Reactor (MBBR) with Ultraviolet radiations disinfection (MBBR + UV), MBBR + Chlorine (Cl2), Sequencing Batch Reactor (SBR) and SBR + Cl2 were compared with removal efficacy of SBR + Cl2 (81.2%)> MBBR + UV (68.8%) > SBR (57.1%) > ASP (50%) > MBBR + Cl2(36.4%). The study observed the trends & prevalence of four genes (E, RdRp, N, and ORF1ab gene) based on two different kits and found that prevalence of N> ORF1ab >RdRp> E gene, suggested that the effective genome concentration should be calculated based on the presence/absence of multiple genes. Hence, it is imperative to say that using a combination of different detection genes (E, N, RdRp & ORF1ab genes) reduce false positives in WBE.Graphical AbstractHighlightsSuccessful application of WBE with prediction of 14-20 days for COVID-19 in JaipurA comparison of SARS-CoV-2 RNA removal efficacy of 9 WWTPs was investigatedSBR showed better performance than MBBR with SARS-CoV-2 RNA removal from wastewaterPresence of SARS-CoV-2 in effluents even after UV and Chlorine disinfectionUsing a combination of different detection genes reduce false positives in WBE