bluuebunny/crossref_metadata_2025_split huggingface dataset:
AstragalusSaponins, Astragaloside VII and Newly Synthesized Derivatives, Induce Dendritic Cell Maturation and T Cell Activation Through IL-1β Production
Authors: Yakubogullari Nilgun , Cagir Ali , Bedir Erdal , Sag Duygu 
Published: July 2021

AbstractAstragaloside VII (AST VII), a plant triterpenoid saponin isolated fromAstragalusspecies, shows promise as vaccine adjuvant, as it supports a balanced Th1/Th2 immune response. However, the underlying mechanisms of its adjuvant activity have not been defined. Here we investigated the impact of AST VII and its newly synthesized semi-synthetic analogs on human whole blood cells, as well as on mouse bone marrow-derived dendritic cells (BMDCs). Cells were stimulated with AST VII and its derivatives in the presence or absence of LPS or PMA/ionomycin and the secretion of cytokines and the expression of activation markers were analyzed by ELISA and flow cytometry, respectively. AST VII and its analogs increased the production of IL-1β in PMA/ionomycin stimulated human whole blood cells. In LPS-treated mouse BMDCs, AST VII increased the production of IL-1β and IL-12, and the expression of MHC II, CD86, and CD80. The strength of the IL-1β boost correlated directly with the hydrophobicity of the AST VII compounds. In mixed leukocyte reaction, AST VII and derivatives increased the expression of the activation marker CD44 on mouse CD4+and CD8+T cells. In conclusion, AST VII and its derivatives strengthen pro-inflammatory responses, support dendritic cell maturation, and T cell activationin vitro. Our results provide insights into the mechanisms of the adjuvant activities of AST VII and its analogs, which will be instrumental to improve their utility as vaccine adjuvant.
Extending the gap and loading RecA: the presynaptic phase plays a pivotal role in modulating lesion tolerance pathways
Authors: Laureti Luisa , Lee Lara , Philippin Gaëlle , Kahi Michel , Pagès Vincent 
Published: July 2021

ABSTRACTDuring replication, the presence of unrepaired lesions results in the formation of single stranded DNA (ssDNA) gaps that need to be repaired to preserve genome integrity and cell survival. All organisms have evolved two major lesion tolerance pathways to continue replication: Translesion Synthesis (TLS), potentially mutagenic, and Homology Directed Gap Repair (HDGR), that relies on homologous recombination. In Escherichia coli, the RecF pathway repairs such ssDNA gaps by processing them to produce a recombinogenic RecA nucleofilament during the presynaptic phase. In this study, we show that the presynaptic phase is crucial for modulating lesion tolerance pathways. Indeed, impairing either the extension of the ssDNA gap (mediated by the nuclease RecJ and the helicase RecQ) or the loading of RecA (mediated by the RecFOR complex) leads to a decrease in HDGR. We suggest a model where defects in the presynaptic phase delay the formation of the D-loop and increase the time window allowed for TLS. We indeed observe an increase in TLS independent of SOS induction. In addition, we revealed an unexpected synergistic interaction between recF and recJ genes, that results in a recA deficient-like phenotype in which HDGR is almost completely abolished.
Drivers of phylogenetic structure in Amazonian freshwater fish assemblages
Authors: Salgueiro Laís , Cassemiro Fernanda , Albert James S. , Frederico Renata G. , Hidalgo Max , Hugueny Bernard , Jézéquel Céline , Ortega Hernan , Tedesco Pablo A. , Torrente-Vilara Gislene , Zuanon Jansen , Oberdorff Thierry , Dias Murilo S. 
Published: July 2021

ABSTRACTAimCommunity phylogenetics provides important information about the evolutionary and ecological factors help structure regional species assemblages. Here, we analyze phylogenetic diversity (phylodiversity) patterns among fish species in 97 sub-drainages of the Amazon basin, to evaluate the roles of historical and contemporary processes in generating and maintaining the exceptional richness and endemism of Amazonian fish species assemblages.LocationAmazon River basinTaxonFreshwater fishesMethodsUsing a large comprehensive database of freshwater fish species distributions, and a well-sampled molecular phylogeny of ray-finned (actinopterygian) fishes, we develop of multivariate statistical model to correlate estimated historical and contemporary environmental parameters with sub-drainage phylodiversity patterns. The model employs three phylogenetic metrics: i.e.: phylogenetic diversity (PD) sensu stricto, mean pairwise phylogenetic distance (MPD) between species capturing phylodiversity variation at older evolutionary timescales), and mean nearest taxon distance (MNTD) capturing variation in phylodiversity at younger evolutionary timescales.ResultsThe model recovered significant effects of elevation gradients, contemporary climate, habitat fragmentation, water types, and past marine incursions on assemblage phylodiversity patterns. The model also found significantly negative relationships among the three phylogenetic metrics, and between these metrics and distance to mouth of the Amazon, representing a West-East longitudinal gradient.Main conclusionsOur study revealed a highly non-random spatial and environmental distribution of our three phylogenetic diversity metrics across the 97 sub-drainages of the Amazon basin. Beyond significant regional effects of several environmental and historical drivers, we also found a significant West-East gradient of increasing phylogenetic diversity and phylogenetic relatedness, both patterns suggesting deeper evolutionary divergences among taxa located to the east, and more diverse, more recent radiations in the western sub-drainages. We conclude that western Amazonia can be seen as an evolutionary “cradle” of biodiversity for freshwater fishes in the Amazon basin as a whole.Significance StatementThis manuscript reveals spatial patterns of freshwater fish phylogenetic diversity and relatedness and explains its major contemporary and historical drivers in the Amazon basin. Amazon basin contains the highest freshwater biodiversity on Earth, as so investigate phylogenetic dimension of diversity is extremally relevant from the perspective of understanding the information on the evolutionary processes that had shaped Amazonian contemporary fish assemblages.
Discovering molecular features of intrinsically disordered regions by using evolution for contrastive learning
Authors: Lu Alex X , Lu Amy X , Pritišanac Iva , Zarin Taraneh , Forman-Kay Julie D , Moses Alan M 
Published: July 2021

AbstractA major challenge to the characterization of intrinsically disordered regions (IDRs), which are widespread in the proteome, but relatively poorly understood, is the identification of molecular features that mediate functions of these regions, such as short motifs, amino acid repeats and physicochemical properties. Here, we introduce a proteome-scale feature discovery approach for IDRs. Our approach, which we call “reverse homology”, exploits the principle that important functional features are conserved over evolution. We use this as a contrastive learning signal for deep learning: given a set of homologous IDRs, the neural network has to correctly choose a held-out homologue from another set of IDRs sampled randomly from the proteome. We pair reverse homology with a simple architecture and standard interpretation techniques, and show that the network learns conserved features of IDRs that can be interpreted as motifs, repeats, or bulk features like charge or amino acid propensities. We also show that our model can be used to produce visualizations of what residues and regions are most important to IDR function, generating hypotheses for uncharacterized IDRs. Our results suggest that feature discovery using unsupervised neural networks is a promising avenue to gain systematic insight into poorly understood protein sequences.
A Kernel Method for Dissecting Genetic Signals in Tests of High-Dimensional Phenotypes
Authors: Solis-Lemus Claudia , Holleman Aaron M. , Todor Andrei , Bradley Bekh , Ressler Kerry J. , Ghosh Debashis , Epstein Michael P. 
Published: July 2021

AbstractGenomewide association studies increasingly employ multivariate tests of multiple correlated phenotypes to exploit likely pleiotropy to improve power. Typical multivariate methods produce a global p-value of association between a variant (or set of variants) and multiple phenotypes. When the global test is significant, subsequent interest then focuses on dissecting the signal and, in particular, delineating the set of phenotypes where the genetic variant(s) have a direct effect from the remaining phenotypes where the genetic variant(s) possess either indirect or no effect. While existing techniques like mediation models can be utilized for this purpose, they generally cannot handle high-dimensional phenotypic and genotypic data. To assist in filling this important gap, we propose a modification of a kernel distance-covariance framework for gene mapping of multiple variants with multiple phenotypes to test instead whether the association between the variants and a group of phenotypes is driven through a direct association with just a subset of the phenotypes. We use simulated data to show that our new method controls for type I error and is powerful to detect a variety of models demonstrating different patterns of direct and indirect effects. We further illustrate our method using GWAS data from the Grady Trauma Project and show that an existing signal between genetic variants in the ZHX2 gene and 21 items within the Beck Depression Inventory appears to be due to a direct effect of these variants on only 3 of these items. Our approach scales to genomewide analysis, and is applicable to high-dimensional correlated phenotypes.
Building integrated representations through interleaved learning
Authors: Zhou Zhenglong , Singh Dhairyya , Tandoc Marlie C. , Schapiro Anna C. 
Published: July 2021

AbstractInferring relationships that go beyond our direct experience is essential for understanding our environment. This capacity requires either building representations that directly reflect structure across experiences as we encounter them, or computing the indirect relationships across experiences as the need arises. Building structure directly into overlapping representations allows for powerful learning and generalization in neural network models, but building these so-calleddistributed representationsrequires inputs to be encountered in interleaved order. We test whether interleaving similarly facilitates the formation of representations that directly integrate related experiences in humans, and what advantages such integration may confer for behavior. In a series of behavioral experiments, we present evidence that interleaved learning indeed promotes the formation of representations that directly link across related experiences. As in neural network models, interleaved learning gives rise to fast and automatic recognition of item relatedness, affords efficient generalization, and is especially critical for inference when learning requires statistical integration of noisy information over time. We use the data to adjudicate between several existing computational models of human memory and inference. The results demonstrate the power of interleaved learning and implicate the formation of integrated, distributed representations that support generalization in humans.
Cryptic genetic structure and copy-number variation in the ubiquitous forest symbiotic fungus Cenococcum geophilum
Authors: Dauphin Benjamin , de Freitas Pereira Maíra , Kohler Annegret , Grigoriev Igor V. , Barry Kerrie , Na Hyunsoo , Amirebrahimi Mojgan , Lipzen Anna , Martin Francis , Peter Martina , Croll Daniel 
Published: July 2021

SummaryEctomycorrhizal (ECM) fungi associated with plants constitute one of the most successful symbiotic interactions in forest ecosystems. ECM support trophic exchanges with host plants and are important factors for the survival and stress resilience of trees. However, ECM clades often harbour morpho-species and cryptic lineages, with weak morphological differentiation. How this relates to intraspecific genome variability and ecological functioning is poorly known. Here, we analysed 16 European isolates of the ascomycete Cenococcum geophilum, an extremely ubiquitous forest symbiotic fungus with no known sexual or asexual spore forming structures but with a massively enlarged genome. We carried out whole-genome sequencing to identify single-nucleotide polymorphisms. We found no geographic structure at the European scale but divergent lineages within sampling sites. Evidence for recombination was restricted to specific cryptic lineages. Lineage differentiation was supported by extensive copy-number variation. Finally, we confirmed heterothallism with a single MAT1 idiomorph per genome. Synteny analyses of the MAT1 locus revealed substantial rearrangements and a pseudogene of the opposite MAT1 idiomorph. Our study provides the first evidence for substantial genome-wide structural variation, lineage-specific recombination and low continent-wide genetic differentiation in C. geophilum. Our study provides a foundation for targeted analyses of intra-specific functional variation in this major symbiosis.Originality-Significance StatementWe provide the first report on the genetic structure and copy-number variation of the globally ubiquitous and key forest symbiotic fungus Cenococcum geophilum using whole-genome sequencing data. We found divergent lineages within sampling sites, while closely related lineages appear over large geographic distances on a continental scale. Even though no sexual spore forming structures have been reported to date, we provide evidence of recombination in a specific lineage suggesting mating activity. Our findings help explain the high genetic diversity occurring within populations and their resilience to changing and adverse environmental conditions. Furthermore, we identify a single MAT1 idiomorph per genome, confirming heterothallism, and discover that major genomic rearrangements are found in their flanking regions based on chromosomal synteny analysis. Intriguingly, a pseudogene of the opposite functional idiomorph has been characterised in each genome, suggesting a common homothallic ancestor to the species. As Cenococcum geophilum is a pivotal mycorrhizal associate of a broad range of trees and shrubs providing nutrition and water supply to their hosts, we highlight and discuss the potential role of the large genome-wide structural variations in environmental selection.
A semisynthetic glycoconjugate provides expanded cross-serotype protection againstStreptococcus pneumoniae
Authors: Kaplonek Paulina , Yao Ling , Reppe Katrin , Voß Franziska , Kohler Thomas , Ebner Friederike , Schäfer Alexander , Blohm Ulrike , Priegue Patricia , Bräutigam Maria , Pereira Claney L. , Parameswarappa Sharavathi G. , Emmadi Madhu , Ménová Petra , Witzenrath Martin , Hammerschmidt Sven , Hartmann Susanne , Sander Leif E. , Seeberger Peter H. 
Published: July 2021

AbstractStreptococcus pneumoniaeinfections are the leading cause of child mortality globally. Current vaccines fail to induce a protective immune response towards a conserved part of the pathogen, resulting in new serotypes causing disease. Therefore, new vaccine strategies are urgently needed. Described is a two-pronged approach combiningS.pneumoniaeproteins, pneumolysin and PspA, with a precisely defined synthetic oligosaccharide, whereby the carrier protein acts as a serotype-independent antigen to provide additional protection. Proof of concept in mice and swine models revealed that the conjugates inhibit colonization of the nasopharynx, decrease the bacterial load and reduce disease severity in the bacteria challenged model. Immunization of piglets provided the first evidence for the immunogenicity and protective potential of synthetic glycoconjugate vaccine in a large animal model. A combination of synthetic oligosaccharides with proteins from the target pathogen opens the path to create broadly cross-protective (“universal“) pneumococcal vaccines.
Surface Electromyography for Identification of Pre-Phonatory Activity
Authors: Kothare Hardik , Courey Mark S. , Yung Katherine C. , Schneider Sarah L. , Nagarajan Srikantan , Houde John 
Published: July 2021

AbstractSurface electrode EMG is an established method for studying biomechanical activity. It has not been well studied in detecting laryngeal biomechanical activity of pre-phonatory onset. Our aims were to compare the sensitivity of surface EMG in identifying pre-phonatory laryngeal activity to needle electrode laryngeal EMG and to compare the pre-phonatory period in patients with adductor laryngeal dystonia (ADLD) with that in controls. ADLD patients (n = 10) undergoing needle LEMG prior to Botox® injection and participants with normal voices (n = 6) were recruited. Surface EMG electrodes were placed over the cricoid ring and thyrohyoid membrane. Needle EMG electrodes were inserted into the thyroarytenoid muscle. EMG and auditory output samples were collected during phonation onset. Tracings were de-identified and evaluated. Measurements of time from onset in change of the amplitude and motor unit frequency on the interference pattern to onset of phonation were calculated by two blinded raters. 42 of 71 patient and 40 of 50 control tracings were available for analysis. Correlation for pre-phonatory time between electrode configuration was 0.70 for patients, 0.64 for controls and 0.79 for all the data combined. Interrater correlation was 0.97 for needle and 0.96 for surface electrodes. ADLD patients had a longer pre-phonatory time than control subjects by 169.48ms with surface electrode and 140.23ms with needle electrode (p < 0.001). Surface EMG demonstrates equal reliability as Needle EMG in detecting pre-phonatory activity in controls and subjects. Patients with ADLD have a significantly prolonged pre-phonatory period when compared with controls.
Differential impact of a dyskeratosis congenita mutation in TPP1 on mouse hematopoiesis and germline
Authors: Graniel Jacqueline V. , Bisht Kamlesh , Friedman Ann , White James , Perkey Eric , Vanderbeck Ashley , Moroz Alina , Carrington Léolène J. , Brandstadter Joshua D. , Allen Frederick , Shami Adrienne Niederriter , Thomas Peedikayil , Crayton Aniela , Manzor Mariel , Mychalowych Anna , Chase Jennifer , Hammoud Saher S. , Keegan Catherine E. , Maillard Ivan , Nandakumar Jayakrishnan 
Published: July 2021

ABSTRACTTelomerase extends chromosome ends in somatic and germline stem cells to ensure continued proliferation. Mutations in genes critical for telomerase function result in telomeropathies such as dyskeratosis congenita (DC), frequently resulting in spontaneous bone marrow failure. While knockout of telomerase in mice has been instrumental in highlighting the importance of telomere length maintenance at an organismal level, it may not be representative of human telomeropathy mutations in vivo. A DC mutation in the shelterin protein TPP1 (K170Δ) that compromises telomerase recruitment to telomeres but leaves other functions of TPP1 and the integrity of the telomerase holoenzyme intact is a physiologically relevant tool to evaluate telomerase-dependent telomere length maintenance in mice. We used CRISPR-Cas9 to generate a mutant mouse knocked in for the equivalent of the TPP1 K170Δ mutation (TPP1 K82Δ) and investigated both its bone marrow and germline compartments in unprecedented detail. TPP1 K82Δ caused progressive telomere erosion with increasing generation number but did not induce steady-state hematopoietic defects. Strikingly, K82Δ caused mouse infertility, consistent with gross morphological defects in the testis and sperm, the appearance of either empty or severely disorganized seminiferous tubules, and a decrease in both spermatogonia and spermatocytes. It is intriguing that both TPP1 K82Δ mice and previously characterized telomerase knockout mice show no spontaneous bone marrow failure but rather succumb to a robust infertility phenotype at steady state. We speculate that telomere length maintenance contributes differently to the evolutionary fitness of humans and mice. Telomere length maintenance in the human bone marrow can ensure progression to reproductive age, while that in the mouse germline can help meet the elevated demand for sperm to produce multiple offspring.
The role of the atypical chemokine receptor CCRL2 in myelodysplastic syndrome and secondary acute myeloid leukemia
Authors: Karantanos Theodoros , Teodorescu Patric , Perkins Brandy , Christodoulou Ilias , Esteb Christopher , Varadhan Ravi , Helmenstine Eric , Rajkhowa Trivikram , Paun Bogdan C. , Bonifant Challice , Dalton W. Brian , Gondek Lukasz P. , Moliterno Alison R. , Levis Mark J. , Ghiaur Gabriel , Jones Richard J. 
Published: July 2021

ABSTRACTThe identification of new molecular pathways supporting the growth of myelodysplastic syndrome (MDS) stem and progenitor cells is needed to understand clinical variation and develop targeted therapies. Within myeloid malignancies, men have worse outcomes compared to women, suggesting male sex hormone driven effects in malignant hematopoiesis. The androgen receptor promotes the expression of five granulocyte-colony factor receptor regulated genes. Among them, CCRL2 encodes an atypical chemokine receptor that regulates cytokine signaling in differentiated granulocytes but its role in myeloid malignancies is unknown. Our study revealed that CCRL2 is upregulated in stem and progenitor cells from patients with MDS and secondary acute leukemia. CCRL2 knockdown suppressed the growth and clonogenicity of MDS92 and MDS-L cells in vitro and in vivo. Moreover, CCRL2 knockdown significantly suppressed the phosphorylation of JAK2, STAT3, and STAT5 in MDS cells. CCRL2 co-precipitated with JAK2 and its suppression decreased the interaction of JAK2 with STAT proteins. Cell lines expressing JAK2V617F showed less effect of CCRL2 knockdown on growth and clonogenicity compared to those expressing wild type. However, the selective JAK2 inhibitor fedratinib potentiated the effects of CCRL2 knockdown in MDS and leukemia cells expressing both wild type JAK2 and JAK2V617F. In conclusion, our results implicate CCRL2 as a mediator of MDS and secondary acute leukemia cell growth, in part through JAK2/STAT signaling.