bluuebunny/crossref_metadata_2025_split huggingface dataset:
Chemotherapy induced immunogenic cell death alters response to exogenous activation of STING pathway and PD-L1 immune checkpoint blockade in a syngeneic murine model of ovarian cancer
Authors: Nersesian Sarah , Shakfa Noor , Peterson Nichole , Vidotto Thiago , AfriyieAsante Afrakoma , Lightbody Elizabeth , Koti Madhuri 
Published: October 2019

AbstractPoor response to platinum/taxane-based chemotherapy has remained a major hurdle in the management of high grade serous carcinoma of the ovary (HGSC). Recurrent HGSC is often treated with liposomal doxorubicin as a second line chemotherapy. Unfortunately, HGSC patients have not benefited from immunotherapies targeting the PD-1/PD-L1 immune checkpoint axis. In a pre-clinical study evaluating the efficacy of a “Stimulator of Interferon Genes” (STING) agonist, we demonstrated the synergistic potential of STING pathway activation in enhancing response to carboplatin chemotherapy and sensitization to PD-1 immune checkpoint blockade (ICB). Since carboplatin and doxorubicin exhibit distinct immunogenic cell death (ICD) inducing potential, we investigated the chemotherapy specific effect in the magnitude of response to exogenous STING pathway activation. Immunocompetent C57/BL6 mice were implanted with ID8-Trp53−/−cells followed by treatment with carboplatin or doxorubicin. Towards rationalized addition of STING agonist with or without PD-L1 blockade, we first determined the expression of 60 known ICD associated genes at an early time point following the initial treatment with carboplatin or doxorubicin with or without STING agonist. Doxorubicin treated tumours showed significantly higher expression of ICD genes,Cxcl10, Cd274, Isg15, Psmb9andCalr. Expression changes were further amplified following the addition of STING agonist. Significantly higher expression ofCxcl10andIsg15were observed in the doxorubicin + STING agonist treated mice compared to carboplatin + STING agonist combination. Interestingly,Ccl5gene expression was higher in the tumours from carboplatin or carboplatin and STING agonist combination treated mice compared to those treated with doxorubicin. Plasma cytokine analysis showed distinct profiles of CXCL10, CCL5, MCP-1 and IL6 post treatment with each chemotherapy type. Doxorubicin monotherapy treated mice showed significantly longer overall survival compared to their carboplatin counterparts with further increases following addition of either STING agonist or PD-L1 ICB. However, despite the stronger ICD inducing ability of doxorubicin, overall survival of mice treated with carboplatin + STING agonist + PD-L1 ICB was the longest. Findings from our pre-clinical study provide novel insights for rationalized combinations of immune sensitizing agents such as STING pathway activators to improve response of HGSC patients to chemotherapy and ICB in the primary and recurrent settings.
DG-CA3 circuitry mediates hippocampal representations of latent information
Authors: Keinath Alexandra T. , Nieto-posadas Andres , Robinson Jennifer C. , Brandon Mark P. 
Published: October 2019

AbstractSurvival in complex environments necessitates a flexible navigation system that incorporates memory of recent behavior and associations. Yet, how the hippocampal spatial circuit represents latent information independent of sensory inputs and future goals has not been determined. To address this, we imaged the activity of large ensembles in subregion CA1 via wide-field fluorescent microscopy during a novel behavioral paradigm. Our results demonstrated that latent information is represented through reliable firing rate changes during unconstrained navigation. We then hypothesized that the representation of latent information in CA1 is mediated by pattern separation/completion processes instantiated upstream within the dentate gyrus (DG) and CA3 subregions. Indeed, CA3 ensemble recordings revealed an analogous code for latent information. Moreover, selective chemogenetic inactivation of DG-CA3 circuitry completely and reversibly abolished the CA1 representation of latent information. These results reveal a causal and specific role of DG-CA3 circuitry in the maintenance of latent information within the hippocampus.
scATAC-pro: a comprehensive workbench for single-cell chromatin accessibility sequencing data
Authors: Yu Wenbao , Uzun Yasin , Zhu Qin , Chen Changya , Tan Kai 
Published: October 2019

AbstractSingle cell chromatin accessibility sequencing (scCAS) has become a powerful technology for understanding epigenetic heterogeneity of complex tissues. The development of several experimental protocols has led to a rapid accumulation of scCAS data. In contrast, there is a lack of open-source software tools for comprehensive processing, analysis and visualization of scCAS data generated using all existing experimental protocols. Here we present scATAC-pro for quality assessment, analysis and visualization of scCAS data. scATAC-pro provides flexible choice of methods for different data processing and analytical tasks, with carefully curated default parameters. A range of quality control metrics are computed for several key steps of the experimental protocol. scATAC-pro generates summary reports for both quality assessment and downstream analysis. It also provides additional utility functions for generating input files for various types of downstream analyses and data visualization. With the rapid accumulation of scCAS data, scATAC-pro will facilitate studies of epigenomic heterogeneity in healthy and diseased tissues.
Evolution in novel environments: do restored prairie populations experience strong selection?
Authors: Magnoli Susan M. , Lau Jennifer A. 
Published: October 2019

AbstractWhen populations colonize new habitats, they are likely to experience novel environmental conditions, and as a consequence may experience strong selection. While selection and the resulting evolutionary responses may have important implications for establishment success in colonizing populations, few studies have estimated selection in such scenarios. Here we examined evidence of selection in recently established plant populations in two prairie restorations in close proximity (< 15 km apart) using two approaches: 1) we tested for evidence of past selection on a suite of traits in twoChamaecrista fasciculatapopulations by comparing the restored populations to each other and their shared source population in common gardens to quantify evolutionary responses and 2) we measured selection in the field. We found evidence of past selection on flowering time, specific leaf area, and root nodule production in one of the populations, but detected contemporary selection on only one trait (plant height). This demonstrates that while selection can occur in colonizing populations, resulting in significant evolutionary responses in less than 6 generations, rapid evolutionary responses may be weak in even nearby populations sown with the same source population. Because contemporary measures of selection rarely predicted observed evolutionary responses, it also suggests that selection likely differs over the early stages of succession that characterize young prairies.
Mapping the Immune Landscape of Clear Cell Renal Cell Carcinoma by Single-Cell RNA-seq
Authors: Vishwakarma Ajaykumar , Bocherding Nicholas , Chimenti Michael S. , Vishwakarma Purshottam , Nepple Kenneth , Salem Aliasger , Jenkins Russell W. , Zhang Weizhou , Zakharia Yousef 
Published: October 2019

AbstractThe immune cells within the tumor microenvironment are considered key determinants of response to cancer immunotherapy. Immune checkpoint blockade (ICB) has transformed the treatment of clear cell renal cell carcinoma (ccRCC), although the role of specific immune cell states remains unclear. To characterize the tumor microenvironment (TME) of ccRCC, we applied single-cell RNA sequencing (scRNA-seq) along with paired T cell receptor sequencing to map the transcriptomic heterogeneity of 24,904 individual CD45+lymphoid and myeloid cells in matched tumor and blood from patients with ccRCC. We identified multiple distinct immune cell phenotypes for B and T (CD4 and CD8) lymphocytes, natural kill (NK) cells, and myeloid cells. Evaluation of T cell receptor (TCR) sequences revealed limited shared clonotypes between patients, whereas tumor-infiltrating T cell clonotypes were frequently found in peripheral blood, albeit in lower abundance. We further show that the circulating CD4+T cell clonality is far less diverse than peripheral CD8+. Evaluation of myeloid subsets revealed unique gene programs defining monocytes, dendritic cells and tumor-associated macrophages. In summary, here we have leveraged scRNA-seq to refine our understanding of the relative abundance, diversity and complexity of the immune landscape of ccRCC. This report represents the first characterization of ccRCC immune landscape using scRNA-seq. With further characterization and functional validation, these findings may identify novel sub-populations of immune cells amenable to therapeutic intervention.One Sentence SummarySingle-cell RNA-sequencing reveals unique lymphoid and myeloid gene programs with putative functions in clear cell renal cancer patients
Genome sequence and analysis of the eggplant (Solanum melongenaL.)
Authors: Li Dandan , Qian Jun , Li Wenjia , Jiang Yaqin , Gan Guiyun , Li Weiliu , Chen Riyuan , Yu Ning , Li Yan , Wu Yongguan , Kang Dexian , Lian Jinmin , Niu Yongchao , Wang Yikui 
Published: October 2019

SummaryThe eggplant (Solanum melongenaL.) is one of the most important Solanaceae crops, ranking third in the total production and economic value in the genusSolanum. Here, we report a high-quality, chromosome-scale eggplant reference genome sequence of 1,155.8 Mb, with N50 of 93.9 Mb, which was assembled by combining PacBio long reads and Hi-C sequencing data. Repetitive sequences occupied 70.1% of the assembly length, and 35,018 high-confidence protein-coding genes were annotated based on multiple evidence. Comparative analysis revealed 646 species-specific families and 364 positive selection genes, conferring distinguishing traits to the eggplant. We performed genome-wide identification of disease resistance genes and discovered an expanded gene family of bacterial spot resistance in the eggplant and pepper but not in tomato and potato. The genes involved in chlorogenic acid synthesis were comprehensively characterized. Highly similar chromosomal distribution patterns of polyphenol oxidase genes were observed in the eggplant, tomato, and potato genomes. The eggplant reference genome sequence will not only facilitate evolutionary studies in the Solanaceae but also facilitate their breeding and improvement.
The table-top visual search ability test for children and young people: normative response time data from typically developing children
Authors: Waddington Jonathan , Pickering Jade , Hodgson Timothy 
Published: October 2019

AbstractFive table-top tasks were developed to test the visual search ability of children and young people in a real-world context, and to assess the transfer of training related improvements in visual search on computerised tasks to real-world activities. Each task involved searching for a set of target objects among distracting objects on a table-top. Performance on the Table-top Visual Search Ability Test for Children (TVSAT-C) was measured as the time spent searching for targets divided by the number of targets found. 108 typically developing children (3-11 years old) and 8 children with vision impairment (7-12 years old) participated in the study. A significant correlation was found between log-transformed age and log-transformed performance (R2 = 0.65, p = 4 × 10−26) in our normative sample, indicating a monomial power law relationship between age and performance with an exponent of −1.67, 95% CI [−1.90, −1.43]. We calculated age-dependent percentiles and receiver operating characteristic curve analysis indicated the 3rd percentile as the optimal cut-off for detecting a visual search deficit, giving a specificity of 97.2%, 95% CI [92.2%, 99.1%] and sensitivity of 87.5%, 95% CI [52.9%, 97.8%] for the test. Further studies are required to calculate measures of reliability and external validity, to confirm sensitivity for visual search deficits, and to investigate the most appropriate response modes for participants with conditions that affect manual dexterity. Additionally, more work is needed to assess construct validity where semantic knowledge is required that younger children may not have experience with. We have made the protocol and age-dependent normative data available for those interested in using the test in research or practice, and to illustrate the smooth developmental trajectory of visual search ability during childhood.
Increasing vitrification temperature improves the cryo-electron microscopy reconstruction
Authors: Shi Huigang , Ling Wuchun , Zhu Dongjie , Zhang Xinzheng 
Published: October 2019

AbstractAt the initial stage of the cryo-electron microcopy (cryo-EM) samples irradiated by electrons, the cryo-EM samples suffer from a rapid “burst” phase (first 3~4 e−/Å2) of beam induced motion (BIM) which is too fast to be corrected by existing motion correction software, and lowers the quality of the initial frames. Therefore, these least radiation damaged, but ruined frames are commonly excluded or down-weighted during data processing, which reduces the undamaged signals in the reconstruction and decreases the reconstruction resolution by weakening the averaging power. Here, we show that increasing the freezing temperature of cryo-EM samples suppresses the BIM in this phase. The quality of initial frames is partially recovered after BIM correction and is better than that of subsequent frames in certain frames. Incorporating these initial frames into the reconstruction increases the resolution, at an equivalent of ~60% extra data. Moreover, these frames are least radiation damaged, thus preserves the high quality cryo-EM density of radiation sensitive residues. Such density is usually damaged or very weak in the canonical 3D reconstruction. In addition, we found that a different kind of radiation damage neglected previously occurs in the per-frame reconstruction after the exposure of 2.5 e−/Å2. Such radiation damage distorts the density of atoms. The deformation can be avoided by only including the frames from the first 2.5 e−/Å2into the reconstruction. Overall, the high temperature freezing not only provides extra undamaged signal to the reconstruction, but also increases the resolution of the reconstruction.
Chromatin structure changes inDaphniapopulations upon exposure to environmental cues – or – The discovery of Wolterecks “Matrix”
Authors: de Carvalho Augusto Ronaldo , Minoda Aki , Rey Oliver , Cosseau Céline , Chaparro Cristian , Vidal-Dupiol Jérémie , Allienne Jean-François , Duval David , Pinaud Silvain , Tönges Sina , Andriantsoa Ranja , Luquet Emilien , Aubret Fabien , Dia Sow Mamadou , David Patrice , Thomson Vicki , Federico Déborah , Joly Dominique , Lima Mariana Gomes , Danchin Etienne , Grunau Christoph 
Published: October 2019

AbstractPhenotypic plasticity is an important feature of biological systems that is likely to play a major role in the future adaptation of organisms to the ongoing global changes. It may allow an organism to produce alternative phenotypes in responses to environmental cues. Modifications in the phenotype can be reversible but are sometimes enduring and can even span over generations. The notion of phenotypic plasticity was conceptualized in the early 20thcentury by Richard Woltereck. He introduced the idea that the combined relations of a phenotypic character and all environmental gradients that influence on it can be defined as “norm of reaction”. Norms of reaction are specific to species and to lineages within species, and they are heritable. He postulated that reaction norms can progressively be shifted over generations depending on the environmental conditions. One of his biological models was the water-fleedaphnia. Woltereck proposed that enduring phenotypic modifications and gene mutations could have similar adaptive effects, and he postulated that their molecular bases would be different. Mutations occurred in genes, while enduring modifications were based on something he called theMatrix. He suggested that this matrix (i) was associated with the chromosomes, (ii) that it was heritable, (iii) it changed during development of the organisms, and (iv) that changes of the matrix could be simple chemical substitutions of an unknown, but probably polymeric molecule. We reasoned that the chromatin has all postulated features of this matrix and revisited Woltereck’s classical experiments withdaphnia. We developed a robust and rapid ATAC-seq technique that allows for analyzing chromatin of individual daphnia and show here (i) that this technique can be used with minimal expertise in molecular biology, and (ii) we used it to identify open chromatin structure in daphnia exposed to different environmental cues. Our result indicates that chromatin structure changes consistently in daphnia upon this exposure confirming Woltereck’s classical postulate.
A rationally designed oral vaccine induces Immunoglobulin A in the murine gut that directs the evolution of attenuatedSalmonellavariants
Authors: Diard Médéric , Bakkeren Erik , Lentsch Verena , Rocker Andrea , Bekele Nahimi Amare , Hoces Daniel , Aslani Selma , Arnoldini Markus , Böhi Flurina , Schumann-Moor Kathrin , Adamcik Jozef , Piccoli Luca , Lanzavecchia Antonio , Stadtmueller Beth M. , Donohue Nicholas , van der Woude Marjan W. , Hockenberry Alyson , Viollier Patrick H. , Falquet Laurent , Wüthrich Daniel , Bonfiglio Ferdinando , Loverdo Claude , Egli Adrian , Zandomeneghi Giorgia , Mezzenga Raffaele , Holst Otto , Meier Beat H. , Hardt Wolf-Dietrich , Slack Emma 
Published: October 2019

Introductory paragraphThe ability of gut bacterial pathogens to escape immunity by antigenic variation, particularly via changes to surface-exposed antigens, is a major barrier to immune clearance1. However, not all variants are equally fit in all environments2, 3. It should therefore be possible to exploit such immune escape mechanisms to direct an evolutionary trade-off. Here we demonstrated this phenomenon usingSalmonella entericasubspeciesentericaserovar Typhimurium (S.Tm). A dominant surface antigen ofS.Tm is its O-antigen: A long, repetitive glycan that can be rapidly varied by mutations in biosynthetic pathways or by phase-variation4, 5. We quantified the selective advantage of O-antigen variants in the presence and absence of O-antigen specific IgA and identified a set of evolutionary trajectories allowing immune escape without an associated fitness cost in naïve mice. Through the use of oral vaccines, we rationally induced IgA responses blocking all of these trajectories, which selected forSalmonellamutants carrying deletions of the O-antigen polymerasewzyB.Due to their short O-antigen, these evolved mutants were more susceptible to environmental stressors (detergents, complement), predation (bacteriophages), and were impaired in gut colonization and virulence in mice. Therefore, a rationally induced cocktail of intestinal antibodies can direct an evolutionary trade-off inS.Tm. This lays the foundations for the exploration of mucosal vaccines capable of setting evolutionary traps as a prophylactic strategy.
Shared neural representations of cognitive conflict and negative affect in the medial frontal cortex
Authors: Vermeylen Luc , Wisniewski David , González-García Carlos , Hoofs Vincent , Notebaert Wim , Braem Senne 
Published: October 2019

AbstractInfluential theories of medial frontal cortex (MFC) function suggest that the MFC registers cognitive conflict as an aversive signal, but no study directly tested this idea. Instead, recent studies suggested that non-overlapping regions in the MFC process conflict and affect. In this pre-registered human fMRI study, we used multivariate pattern analyses to identify which regions respond similarly to conflict and aversive signals. The results reveal that, of all conflict- and value-related regions, the ventral pre-supplementary motor area (or dorsal anterior cingulate cortex) showed a shared neural pattern response to different conflict and affect tasks. These findings challenge recent conclusions that conflict and affect are processed independently, and provide support for integrative views of MFC function.
Structure of the space of taboo-free sequences
Authors: Manuel Cassius , von Haeseler Arndt 
Published: October 2019

AbstractModels of sequence evolution typically assume that all sequences are possible. However, restriction enzymes that cut DNA at specific recognition sites provide an example where carrying a recognition sequence can be lethal. Motivated by this observation, we studied the set of strings over a finite alphabet withtaboos, that is, with prohibited substrings. The taboo-set is referred to asand any allowed string as a taboo-free string. We consider the graphwhose vertices are taboo-free strings of lengthnand whose edges connect two taboo-free strings if their Hamming distance equals 1. Any (random) walk on this graph describes the evolution of a DNA sequence that avoids deleterious taboos. We describe the construction of the vertex set of. Then we state conditions under whichand its suffix subgraphs are connected. Moreover, we provide a simple algorithm that can determine, for an arbitrary, if all these graphs are connected. We concluded that bacterial taboo-free Hamming graphs are nearly always connected, although 4 properly chosen taboos are enough to disconnect one of its suffix subgraphs.
SLAMF6 deficiency augments tumor killing and skews towards an effector phenotype revealing it as a novel T cell checkpoint
Authors: Hajaj Emma , Eisenberg Galit , Klein Shiri , Frankenburg Shoshana , Merims Sharon , Ben-David Inna , Eisenhaure Thomas , Henrickson Sarah E. , Villani Alexandra-Chloé , Hacohen Nir , Abudi Nathalie , Abramovich Rinat , Cohen Jonathan , Peretz Tamar , Veillette André , Lotem Michal 
Published: October 2019

AbstractSLAMF6 is a homotypic receptor of the Ig-superfamily whose exact role in immune modulation has remained elusive. Its constitutive expression on resting and activated T cells precludes it from being abona fideexhaustion marker. By breeding Pmel-1 mice with SLAMF6 KO mice, we generated donors for T cells lacking SLAMF6 and expressing a transgenic TCR for gp100-melanoma antigen. Activated Pmel-1xSLAMF6 KO CD8 T cells displayed improved polyfunctionality and strong tumor cytolysis. T-bet was the dominant transcription factor in Pmel-1xSLAMF6 KO cells, and upon activation, they acquired an effector-memory phenotype. Blocking LAG-3 improved the function of SLAMF6 deficient T cells even further. Finally, adoptive transfer of Pmel-1xSLAMF6 KO T cells into melanoma-bearing mice resulted in lasting tumor regression in contrast to temporary responses achieved with Pmel-1 T cells. These results support the notion that SLAMF6 is an inhibitory immune receptor whose absence enables powerful CD8 T cells to eradicate tumors.