bluuebunny/crossref_metadata_2025_split huggingface dataset:
Male differentiation in the marine copepodOithona nanareveals the development of a new nervous ganglion linked to Lin12-Notch-Repeat protein-associated proteolysis
Authors: Sugier Kevin , Laso-Jadart Romuald , Vacherie Benoit , Käfer Jos , Bertrand Laurie , Labadie Karine , Martins Nathalie , Orvain Céline , Petit Emmanuelle , Poulain Julie , Wincker Patrick , Jamet Jean-Louis , Alberti Adriana , Madoui Mohammed-Amin 
Published: May 2021

AbstractBackgroundCopepods are among the most numerous animals, and play an essential role in the marine trophic web and biogeochemical cycles. The genusOithonais described as having the highest density of copepods, and as being the most cosmopolite copepods. TheOithonamale paradox describes the activity states of males, which are obliged to alternate between immobile and mobile phases for ambush feeding and mate searching, respectively, while the female is typically less mobile and often feeding. To characterize the molecular basis of this sexual dimorphism, we combined immunofluorescence, genomics, transcriptomics, and protein-protein interaction approaches.ResultsImmunofluorescence of β3- and α-tubulin revealed two male-specific nervous ganglia in the lateral first segment of theOithona nanamale’s prosome. In parallel, transcriptomic analysis showed male-specific enrichment for nervous system development-related transcripts. Twenty-seven Lin12-Notch Repeat domain-containing protein coding genes (LDPGs) of the 75 LDPGs identified in the genome were specifically expressed only in males. Furthermore, most of the LDPGs (27%) coded for proteins having predicted proteolytic activity, and non-LDPG proteolysis-associated transcripts showed a male-specific enrichment. Using yeast double–hybrid assays, we constructed a protein-protein interaction network involving two LDPs with proteases, extracellular matrix proteins, and neurogenesis-related proteins.ConclusionsFor the first time, our study describes the lateral nervous ganglia ofO. nanamales, unique to copepods. We also demonstrated a role of LDPGs and their associated proteolysis in male-specific physiology, and we hypothesize a role of the LDPGs in the development of the lateral ganglia through directed lysis of the extracellular matrix for the growth of neurites and genesis of synapses.
PKC-ε Regulates Vesicle Delivery and Focal Exocytosis for Efficient IgG-mediated Phagocytosis
Authors: D’Amico Anna E. , Wong Alexander C. , Zajd Cheryl M. , Murali Ananya , Lennartz Michelle R. 
Published: May 2021

AbstractPKC-ε is required for membrane addition during IgG-mediated phagocytosis; its role in this process is ill-defined. High resolution imaging revealed that PKC-ε exits the Golgi and enters phagosomes on vesicles that then fuse. TNF-α and PKC-α colocalize at the Golgi and on vesicles that enter the phagosome. Loss of PKC-ε and TNF-α delivery upon nocodazole treatment confirmed vesicular transport on microtubules. That TNF-α+vesicles are not delivered in macrophages from PKC-ε null mice, or upon dissociation of the Golgi-associated pool of PKC-ε, implicates Golgi-tethered PKC-ε as a driver of Golgi-to-phagosome trafficking. Finally, we established that PKC-ε’s regulatory domain is sufficient for delivery of TNF-α+vesicles to the phagosome. These studies reveal a novel role for PKC-ε in focal exocytosis: its regulatory domain drives Golgi-derived vesicles to the phagosome while catalytic activity is required for their fusion. This is one of the first examples of a PKC requirement for vesicular trafficking and describes a novel function for a PKC regulatory domain.SummaryGolgi-tethered PKC-ε regulates vesicle trafficking along phagosomally-directed microtubules and vesicle fusion into forming phagosomes. Unexpectedly, the regulatory domain is sufficient for vesicle delivery.Graphical AbstractPKC-ε is required for Golgi-to-phagosome trafficking. Golgi-tethered PKC-ε+vesicles carry TNF-α to IgG phagosomes. Dissociation of PKC-ε from the Golgi with PIK93 or expression of hSac1-K2A prevents vesicle delivery. The regulatory domain of PKC-ε (εRD) is sufficient for vesicle delivery, but not fusion. Created withBioRender.com
Evaluation ofin vitroandin vivotoxicity of pristine molybdenum disulphide nanosheets in Swiss albino mice
Authors: Yadav Umakant , Singh Vimal , Mishra Himanshu , Saxena Preeti S. , Srivastava Anchal 
Published: May 2021

AbstractThe Molybdenum disulfide nanosheets (MoS2-NSs) thin films has received increasing attention recently due to their versatile multi functionality including catalytic properties, photoluminescence and flexibility, which suggests their future, uses for biomedical applications. However, there are no studies in detail related with biocompatibility of MoS2thin sheets. Here, weevaluated the dose-dependent effects of MoS2-NSs on cell viability (MTT assay) and release of lactate dehydrogenase (LDH) into culture media using MG-63 cells, as well as haemolysis, hematological, serum biochemical, antioxidants and histopathological parameters inSwiss albinomice. The MoS2-NSs was synthesizedviafacile hydrothermal method and characterized using XRD, Raman, SEM, TEM and HRTEM. Thein vitrostudy results suggest that at lower concentration MoS2-NSs does not causes any toxicity. The lethal dose (LD50) was evaluated by intraperitoneal administration with different concentrations and estimated as ~1.0 mg kg-1. The higher dose (1.5 mg kg-1) of MoS2-NSs showed significant alteration in hematological markers and serum biochemical enzymes, as compared to control. Lipid peroxidation also shows significant alteration with respect to the control. Histopathological, hematological and biochemical examination, revealed no remarkable changes at lower concentration (less than 1.0 mg kg-1), however, higher concentration (1.5 mg kg-1) causes significant histopathological, antioxidants and biochemical alterations in tissues and serum, respectively. The results suggest that the lower concentration of MoS2-NSs can be used in future biomedical applications.
Heterogeneity in viral infections increases the rate of deleterious mutation accumulation
Authors: Allman Brent , Koelle Katia , Weissman Daniel 
Published: May 2021

1AbstractRNA viruses have high mutation rates, with the majority of mutations being deleterious. We examine patterns of deleterious mutation accumulation over multiple rounds of viral replication, with a focus on how cellular coinfection and heterogeneity in viral output affect these patterns. Specifically, using agentbased intercellular simulations we find, in agreement with previous studies, that coinfection of cells by viruses relaxes the strength of purifying selection, and thereby increases the rate of deleterious mutation accumulation. We further find that cellular heterogeneity in viral output exacerbates the rate of deleterious mutation accumulation, regardless of whether this heterogeneity in viral output is stochastic or is due to variation in cellular multiplicity of infection. These results highlight the need to consider the unique life histories of viruses and their population structure to better understand observed patterns of viral evolution.
Tree Based Co-Clustering Identifies Variation in Chromatin Accessibility Across Hematopoietic Cell Types
Authors: George Thomas B. , Strawn Nathaniel K. , Leviyang Sivan 
Published: May 2021

AbstractChromatin accessibility, as measured by ATACseq, varies between hematopoietic cell types in different branches of the hematopoietic differentiation tree, e.g. T cells vs B cells, but methods that relate variation in chromatin accessibility to the placement of a cell type on the differentiation tree are lacking. Using an ATACseq dataset recently published by the ImmGen consortium, we construct associations between chromatin accessibility and hematopoietic cell types using a novel co-clustering approach that accounts for the structure of the hematopoietic, differentiation tree. Under a model in which all loci and cell types within a co-cluster have a shared accessibility state, we show that roughly 80% of cell type associated accessibility variation can be captured through 12 cell type clusters and 20 genomic locus clusters. Using publicly available ChIPseq datasets, we show that our clustering reflects transcription factor binding patterns with implications for regulation across cell types. Our results provide a framework for analysis of chromatin state variation across cell types related by a tree or network.
Molecular basis of selective cytokine signaling inhibition by antibodies targeting a shared receptor
Authors: Fields James K. , Kihn Kyle , Birkedal Gabriel S. , Klontz Erik H. , Sjöström Kjell , Günther Sebastian , Beadenkopf Robert , Forsberg Göran , Liberg David , Snyder Greg A. , Deredge Daniel , Sundberg Eric J. 
Published: May 2021

AbstractInterleukin-1 (IL-1) family cytokines are potent mediators of inflammation, acting to coordinate local and systemic immune responses to a wide range of stimuli. Aberrant signaling by IL-1 family cytokine members, however, is linked to myriad inflammatory syndromes, autoimmune conditions and cancers. As such, blocking the inflammatory signals inherent to IL-1 family signaling is an established and expanding therapeutic strategy. While several FDA-approved IL-1 inhibitors exists, including an Fc fusion protein, a neutralizing antibody, and an antagonist cytokine, none specifically targets the co-receptor IL-1 receptor accessory protein (IL-1RAcP). Most IL-1 family cytokines form productive signaling complexes by binding first to their cognate receptors – IL-1RI for IL-1α and IL-1β; ST2 for IL-33; and IL-36R for IL-36α, IL-36β and IL-36γ – after which they recruit the shared secondary receptor IL-1RAcP to form a ternary cytokine/receptor/co-receptor complex. Recently, IL-1RAcP was identified as a biomarker for both AML and CML. IL-1RAcP has also been implicated in tumor progression in solid tumors and an anti-IL1RAP antibody (nadunolimab, CAN04) is in phase II clinical studies in pancreatic cancer and non-small cell lung cancer (NCT03267316). As IL-1RAcP is common to all of the abovementioned IL-1 family cytokines, targeting this co-receptor raises the possibility of selective signaling inhibition for different IL-1 family cytokines. Indeed, previous studies of IL-1β and IL-33 signaling complexes have revealed that these cytokines employ distinct mechanisms of IL-1RAcP recruitment even though their overall cytokine/receptor/co-receptor complexes are structurally similar. Here, using functional, biophysical, and structural analyses, we show that antibodies specific for IL-1RAcP can differentially block signaling by IL-1 family cytokines depending on the distinct IL-1RAcP epitopes that they engage. Our results indicate that targeting a shared cytokine receptor is a viable therapeutic strategy for selective cytokine signaling inhibition.
Harnessing genetic diversity in the USDA pea (Pisum sativumL.) germplasm collection through genomic prediction
Authors: Al Bari Md. Abdullah , Zheng Ping , Viera Indalecio , Worral Hannah , Szwiec Stephen , Ma Yu , Main Dorrie , Coyne Clarice J. , McGee Rebecca , Bandillo Nonoy 
Published: May 2021

AbstractPhenotypic evaluation and efficient utilization of germplasm collections can be time-intensive, laborious, and expensive. However, with the plummeting costs of next-generation sequencing and the addition of genomic selection to the plant breeder’s toolbox, we now can more efficiently tap the genetic diversity within large germplasm collections. In this study, we applied and evaluated genomic selection’s potential to a set of 482 pea accessions – genotyped with 30,600 single nucleotide polymorphic (SNP) markers and phenotyped for seed yield and yield-related components – for enhancing selection of accessions from the USDA Pea Germplasm Collection. Genomic prediction models and several factors affecting predictive ability were evaluated in a series of cross-validation schemes across complex traits. Different genomic prediction models gave similar results, with predictive ability across traits ranging from 0.23 to 0.60, with no model working best across all traits. Increasing the training population size improved the predictive ability of most traits, including seed yield. Predictive abilities increased and reached a plateau with increasing number of markers presumably due to extensive linkage disequilibrium in the pea genome. Accounting for population structure effects did not significantly boost predictive ability, but we observed a slight improvement in seed yield. By applying the best genomic prediction model (e.g., RR-BLUP), we then examined the distribution of genotyped but nonphenotyped accessions and the reliability of genomic estimated breeding values (GEBV). The distribution of GEBV suggested that none of the nonphenotyped accessions were expected to perform outside the range of the phenotyped accessions. Desirable breeding values with higher reliability can be used to identify and screen favorable germplasm accessions. Expanding the training set and incorporating additional orthogonal information (e.g., transcriptomics, proteomics, metabolomics, physiological traits, etc.) into the genomic prediction framework could enhance prediction accuracy.
Mutation-specific reporter for the optimization and enrichment of prime editing
Authors: Schene I.F. , Joore I.P. , Baijens J.H.L. , Shehata S. , Ilcken E.F. , Bolhuis D.P. , van Rees R.C.M. , Spelier S.A. , van der Doef P.J. , Beekman J.M. , Nieuwenhuis E.E.S. , Fuchs S.A. 
Published: May 2021

AbstractWe present a fluorescent prime editing and enrichment reporter (fluoPEER), which can be tailored to any genomic target site. This system rapidly and faithfully ranks the efficiency of prime edit guide RNAs (pegRNAs) and any prime editor protein, including novel variants with flexible PAM recognition. Successful reporter editing enriches for genomic editing. FluoPEER can be employed for efficient correction of patient cells and to elucidate cellular mechanisms needed for successful prime editing.
Foldamers Reveal and Validate Novel Therapeutic Targets Associated with Toxic α-Synuclein Self-Assembly
Authors: Ahmed Jemil , Fitch Tessa C. , Donnelly Courtney M. , Joseph Johnson A. , Bassil Mikaela M. , Son Ahyun , Zhang Chen , Ledreux Aurélie , Horowitz Scott , Qin Yan , Paredes Daniel , Kumar Sunil 
Published: May 2021

ABSTRACTParkinson’s disease (PD) is a progressive neurodegenerative disorder for which there is no successful prevention or intervention. The pathological hallmark for PD involves the self-assembly of functional Alpha-Synuclein (αS) into non-functional amyloid structures. One of the potential therapeutic interventions against PD is the effective inhibition of αS aggregation. However, the bottleneck towards achieving this goal is the identification of αS domains/sequences that are essential for aggregation. Using a protein mimetic approach, we have identified αS sequences-based novel targets that are essential for aggregation and will have significant therapeutic implications. An extensive array ofin vitro, ex vivo, andin vivoassays was utilized to validate αS sequences and their structural characteristics that are essential for aggregation and propagation of PD phenotypes. The study aids in developing significant mechanistic and therapeutic insights into various facets of αS aggregation, which will pave the way for novel and effective treatments for PD.
Metabolic Complementation between Glucose and Amino Acid Drives HepaticDe NovoLipogenesis and Steatosis
Authors: Liao Yilie , Liu Lei , Li Honghao , Bai Xiaojie , Sun Fangfang , Xiao Xia , Fu Suneng 
Published: May 2021

AbstractIncreasedde novolipogenesis (DNL) is a hallmark of nonalcoholic fatty liver disease (NAFLD) in obesity, but the macronutrient source for >80% carbon backbone for fatty acid synthesis has not been determined. Here we take an integrated approach to dissect nutrient metabolism, bothex vivoandin vivo. We discover a castling effect of glucose and glutamine metabolism throughex vivoisotope tracing studies that limits the entrance of glucose carbon into the glutamine-dominated tricarboxylic acid cycle (TCA) and DNL pathways.In vivotracing studies with a high carbohydrate drink (glucose/amino acid, 3:1,w/w) confirm dietary amino acids are twice more efficient than glucose in labeling the hepatic acetyl-CoA and fatty acid pool, and together they account for over 70% of hepatic DNL substrate. Both glucose and glutamine carbon flux into DNL pathways are increased in obese hepatocytes, and metabolic rerouting of substrate carbon toward glycogen synthesis and energy production through GYS2 and GLUD1 overexpression improves hepatic steatosis. Together, these data reveal the quantitative contribution of glucose and amino acid carbon toward hepatic DNL and the development of hepatic steatosis in obesity.
An Enhanced Sampling Approach to the Induced Fit Docking Problem in Protein-Ligand Binding: the case of mono-ADP-ribosylation hydrolases inhibitors
Authors: Zhao Qianqian , Capelli Riccardo , Carloni Paolo , Lüscher Bernhard , Li Jinyu , Rossetti Giulia 
Published: May 2021

AbstractA variety of enhanced sampling methods can predict free energy landscapes associated with protein/ligand binding events, characterizing in a precise way the intermolecular interactions involved. Unfortunately, these approaches are challenged by not uncommon induced fit mecchanisms. Here, we present a variant of the recently reported volume-based metadynamics (MetaD) method which describes ligand binding even when it affects protein structure. The validity of the approach is established by applying it to a substrate/enzyme complexes of pharmacological relevance: this is the mono-ADP-ribose (ADPr) in complex with mono-ADP-ribosylation hydrolases (MacroD1 and MacroD2), where induced-fit phenomena are known to be operative. The calculated binding free energies are consistent with experiments, with an absolute error less than 0.5 kcal/mol. Our simulations reveal that in all circumstances the active loops, delimiting the boundaries of the binding site, rearrange from an open to a closed conformation upon ligand binding. The calculations further provide, for the first time, the molecular basis of the experimentally observed affinity changes in ADPr binding on passing from MacroD1 to MacroD2 and all its mutants. Our study paves the way to investigate in a completely general manner ligand binding to proteins and receptors.
Design, immunogenicity and efficacy of a Pan-SARS-CoV-2 synthetic DNA vaccine
Authors: Reed Charles C. , Schultheis Katherine , Andrade Viviane M. , Kalia Richa , Tur Jared , Schouest Blake , Elwood Dustin , Walters Jewell N. , Maricic Igor , Doan Arthur , Vazquez Miguel , Eblimit Zeena , Pezzoli Patrick , Amante Dinah , Porto Maciel , Narvaez Brandon , Lok Megan , Spence Brittany , Bradette Heath , Horn Heather , Yang Maria , Fader Joseph , Ferrer Roi , Weiner David B. , Kar Swagata , Kim J. Joseph , Humeau Laurent M. , Ramos Stephanie J. , Smith Trevor R.F. , Broderick Kate E. 
Published: May 2021

AbstractHere we have employed SynCon® design technology to construct a DNA vaccine expressing a pan-Spike immunogen (INO-4802) to induce broad immunity across SARS-CoV-2 variants of concern (VOC). Compared to WT and VOC-matched vaccines which showed reduced cross-neutralizing activity, INO-4802 induced potent neutralizing antibodies and T cell responses against WT as well as B.1.1.7, P.1, and B.1.351 VOCs in a murine model. In addition, a hamster challenge model demonstrated that INO-4802 conferred superior protection following intranasal B.1.351 challenge. Protection against weight loss associated with WT, B.1.1.7, P.1 and B.1.617.2 challenge was also demonstrated. Vaccinated hamsters showed enhanced humoral responses against VOC in a heterologous WT vaccine prime and INO-4802 boost setting. These results demonstrate the potential of the pan-SARS-CoV-2 vaccine, INO-4802 to induce cross-reactive immune responses against emerging VOC as either a standalone vaccine, or as a potential boost for individuals previously immunized with WT-matched vaccines.
Risk categorization in Portuguese organizations in times of the COVID-19 pandemic – an exploratory statistical analysis
Authors: Tavares Fernando , Santos Eulália , Tavares Vasco 
Published: May 2021

PurposeThis work aims to characterize the risks companies deal with in the context of a pandemic, and to ascertain which risk type is most present in Portuguese organizations. It is also intended to verify whether there are differences in the various risk types between companies that had or did not have a plan or strategy to act in a pandemic, such as the one caused by COVID-19.Design/methodology/approachA quantitative methodology was used, based on the application of a questionnaire survey targeting the Portuguese companies. The sample is composed of 1,647 Portuguese companies, which were queried through a questionnaire survey that analyses different risk types. Then, the software R was used to treat the results.FindingsThe results show that companies are exposed and vulnerable to uncertain events, and five risk types were formed: legal, image, financial, strategic and operational. There is a bigger concern about the management of financial risks.Practical implicationsAcademics and companies can become more aware and master the concept of risk and its different branches, which consequently favours the adoption of strategies to better manage and plan risk.Originality/valueThe literature on international businesses and their risks assumes that all crises are the same. However, the COVID-19 pandemic, besides causing a recession, obliges people and companies to adapt to a new scenario. Risks become more important to companies, in a way that had not been academically studied.
“I had a big bias”: disrupting children's biases, stereotypes through studying cultures
Authors: Torres Heidi J. 
Published: May 2021

PurposeThis article describes a study examining the influence of a curricular intervention on 25 third-graders' stereotypes and biases related to world cultures and the people who embody them.Design/methodology/approachThe qualitative study focused on privileging student voice through an inductive analytical approach. Triangulated data sources include focus group and paired interviews, recorded lessons, student and teacher curricular documents, as well as field notes.FindingsResults—primarily reported through the children's own thoughts and voices—describe students' initial ideas about world cultures and people prior to experiencing the curriculum, and afterward, documenting shifts in stereotypical beliefs and biased attitudes. Findings indicate many students made positive changes, altering incorrect assumptions about other cultures and people. In addition, some children became able to recognize stereotypes and biases, generalize what they learned to other situations beyond those addressed in the curriculum and identify their own bias.Originality/valueThis study provides insight into an understudied topic and population in social studies education. It presents evidence that young children are capable of successfully engaging with the complex topics of bias and stereotypes in meaningful ways, thus providing a rationale for addressing stereotypes and bias concerning world cultures in elementary classrooms.