bluuebunny/crossref_metadata_2025_split huggingface dataset:
Uncovering the cell type specificity of blood sample derived gene signatures using RNA expression data
Authors: Pomaznoy Mikhail , Ha Brendan , Peters Bjoern 
Published: June 2019

AbstractAnalysis of transcriptomic data derived from blood samples is complicated by the complex mixture of cell types such samples contain. Transcriptomic signatures derived from such samples are often driven by a particular cell lineage within the mixture. Identifying this most contributing lineage can help to provide a biological interpretation of the signature. We created a web application CellTypeScore which quantifies and visually represents the expression level of signature genes in common blood cell types. This is done by constructing an interactive stacked bar plot with the bars representing expression of genes across blood cell types. Summed scores serve as a measure of how highly the combined signature is expressed in different cell types. An online version of the application can be found at https://tools.dice-database.org/celltypescore/.
A quantitative framework for evaluating single-cell data structure preservation by dimensionality reduction techniques
Authors: Heiser Cody N. , Lau Ken S. 
Published: June 2019

SummaryHigh-dimensional data, such as those generated using single-cell RNA sequencing, present challenges in interpretation and visualization. Numerical and computational methods for dimensionality reduction allow for low-dimensional representation of genome-scale expression data for downstream clustering, trajectory reconstruction, and biological interpretation. However, a comprehensive and quantitative evaluation of the performance of these techniques has not been established. We present an unbiased framework that defines metrics of global and local structure preservation in dimensionality reduction transformations. Using discrete and continuous scRNA-seq datasets, we find that input cell distribution and method parameters are largely determinant of global, local, and organizational data structure preservation by eleven published dimensionality reduction methods. Code available atgithub.com/KenLauLab/DR-structure-preservationallows for rapid evaluation of further datasets and methods.
A geographical cline in craniofacial morphology across populations of Mesoamerican lake-dwelling fishes
Authors: Powers Amanda K. , Garita-Alvarado Carlos A. , Rodiles-Hernández Rocío , Berning Daniel J. , Gross Joshua B. , Ornelas-García Claudia Patricia 
Published: June 2019

AbstractThe complex geological history and tropical climate of Mesoamerica create a rich source of biodiversity from which we can study evolutionary processes. Here, we discuss highly divergent forms of lake-dwelling fishes distributed across southern Mexico and Central America, originally recognized as members of different genera (AstyanaxandBramocharax). Recent phylogenetic studies suggest these morphotypes group within the same genus and readily hybridize. Despite genetic similarities,Bramocharaxmorphs exhibit stark differences in cranial shape and dentition. We investigated the evolution of several cranial traits that vary across morphs collected from four lakes in Mexico and Nicaragua and discovered an ecomorphological cline from the northern to southern lakes. Northern populations of sympatric morphs exhibit similar cranial shape and tooth morphology. Southern populations ofBramocharax, however, have more maxillary teeth, larger unicuspid teeth, an elongated snout and a streamlined cranium compared toAstyanax. The divergence of craniofacial morphology in southern lakes likely evolved in response to environmental pressures. We discuss the ecological differences across the four lake systems in terms of geological history and trophic dynamics. In summary, our study suggests thatBramocharaxare likely locally-adapted members derived fromAstyanaxlineages, highlighting the complex evolutionary history of theAstyanaxgenus.
Elucidation of protein-protein interactions necessary for maintenance of the BCR-ABL signaling complex
Authors: Gregor Tomas , Bosakova Michaela Kunova , Nita Alexandru , Abraham Sara P. , Fafilek Bohumil , Cernohorsky Nicole H. , Rynes Jan , Foldynova-Trantirkova Silvie , Mayer Jiri , Trantirek Lukas , Krejci Pavel 
Published: June 2019

AbstractApproximately 50% of chronic myeloid leukemia (CML) patients in deep remission experience a return of clinical CML after withdrawal of tyrosine kinase inhibitors (TKIs). This suggests signaling of inactive BCR-ABL, which allows for survival of cancer cells, leading to relapse. Understanding the dynamics of BCR-ABL signaling complex holds a key to the mechanism of BCR-ABL signaling. Here, we demonstrate that TKIs inhibit catalytic activity of BCR-ABL, but do not dissolve the BCR-ABL core signaling complex consisting of CrkL, SHC1, Grb2, SOS1, cCbl, and SHIP2. We show that CrkL binds to proline-rich regions located in C-terminal, intrinsically disordered region of BCR-ABL, that deletion of pleckstrin homology domain of BCR-ABL diminishes interaction with SHC1, and that BCR-ABL sequence motif located in disordered region around phosphorylated tyrosine 177 mediates binding of at least three core complex members, the Grb2, SOS1 and cCbl. Introduction of Y177F substitution blocks association with Grb2, SOS1 and cCbl. Further, we identified SHIP2 binding sites within the src-homology and tyrosine kinase domains of BCR-ABL. We found that BCR-ABL is unable to phosphorylate SHC1 in cells lacking SHIP2. Reintroducing SHIP2 into Ship2 knock-out cells restored SHC1 phosphorylation, which depended on inositol phosphatase activity of SHIP2. Our findings provide characterization of protein-protein interactions in the BCR-ABL signaling complex, and support the concept of targeting BCR-ABL signaling in CML by inhibition of its interactions with the members of the core complex.
Estrogen controls mTOR signaling and mitochondrial function via WNT4 in lobular carcinoma cells
Authors: Shackleford Madeleine T. , Rao Deviyani M. , Bordeaux Evelyn K. , Hicks Hannah M. , Oesterreich Steffi , Sikora Matthew J. 
Published: June 2019

AbstractInvasive lobular carcinoma of the breast (ILC) is strongly estrogen-driven and represents a unique context for estrogen receptor (ER) signaling. In ILC, ER controls the expression of the Wnt ligand WNT4, which is critical for endocrine response and anti-estrogen resistance. However, signaling mediated by WNT4 is poorly understood. We utilized reverse phase protein array (RPPA) to characterize ER and WNT4-driven signaling in ILC cells and identified that WNT4 mediates downstream mTOR signaling via S6K. Additionally, independent of mTOR/S6K, ER and WNT4 control levels of MCL-1, which alters mitochondrial function. In this context, WNT4 knockdown caused decreased ATP production and increased mitochondrial fragmentation. WNT4 regulation of both mTOR signaling and MCL-1 were also observed in antiestrogen resistant models of ILC. Further, we identified that highWNT4expression is associated with similar mTOR pathway activation in serous ovarian cancer tumors, suggesting that WNT4 signaling is important in multiple tumor types. The identified downstream pathways offer insight in to WNT4 signaling and represent potential targets to overcome anti-estrogen resistance for patients with ILC.
Altered frequency of CD24highCD38high transitional B cells in patients with cardiac involvement of chronic Chagas disease
Authors: Girard Magalí C. , Acevedo Gonzalo R. , Ossowski Micaela S. , Alcaráz Paula B. , Fernández Marisa , Hernández Yolanda , Chadi Raul , Gómez Karina A. 
Published: June 2019

ABSTRACTThe cardiomyopathy developed by patients with chronic Chagas disease (CCD), one of the most severe consequences of T. cruzi infection, is mainly associated with an imbalance between an excessive inflammatory reaction and a defective immunomodulatory profile cause by host-parasite interaction. Despite the growing importance of the regulatory function of B-cells in many malignancies, few studies have addressed their immunosuppressive role in chronic Chagas disease. In this work, we tackled this issue by studying the proportion of different B cell subpopulations and their capacity to secrete IL-10 in individuals with distinct clinical forms of CCD. Seven-colour flow cytometry was performed to examine the peripheral blood B cell compartment in chronic Chagas disease (CCD) patients with and without cardiac manifestations (n=10 for each group) and non-infected donors (n=9). Peripheral blood mononuclear cells (PBMC) were incubated for 5h with PMA, ionomicyn and brefeldin A. According to the expression of markers CD19, CD24 and CD38, we showed an expansion of total B cell and transitional CD24highCD38high B cell subsets in CCD patients with cardiac involvement compared to non-infected donors. Furthermore, although no differences were observed in the frequency of total IL-10 producing B cells (B10) among the groups, CCD patients with cardiac involvement showed a statistically significant increased proportion of naïve B10 cells and a tendency to an increased frequency of transitional B10 cells compared to non-infected donors. These findings suggest that immature transitional CD24highCD38high B cells are greatly expanded in patients with the cardiac form of chronic Chagas disease and these cells retain their ability to secrete IL-10 compared to non-infected donors. Furthermore, the distribution of naïve, transitional and memory B cells inside the B10 cells followed the same pattern in chronic patients without cardiac involvement and non-infected individuals. Our work provides insight into the phenotypic distribution of regulatory B cell in CCD, an important step towards new strategies to prevent cardiomiopathy associated with T. cruzi infection.
Prenatal alcohol exposure programs offspring disease: Insulin resistance in adult males in a rat model of acute exposure
Authors: Nguyen Tam M T , Steane Sarah E , Moritz Karen M , Akison Lisa K 
Published: June 2019

AbstractAlcohol consumption is highly prevalent amongst women of reproductive age. Given that approximately 50% of pregnancies are unplanned, alcohol has the potential to affect fetal development and program chronic disease in offspring. We examined the effect of an acute but moderate prenatal alcohol exposure (PAE) on glucose metabolism, lipid levels and dietary preference in adolescent and/or adult rat offspring. Pregnant Sprague-Dawley rats received an oral gavage of ethanol (1g/kg maternal body weight, n=9 dams) or an equivalent volume of saline (control, n=8 dams) at embryonic days 13.5 and 14.5. PAE resulted in a blood alcohol concentration of 0.05-0.06% 1h post-gavage in dams. Fasting blood glucose concentration was not affected by PAE in offspring at any age, nor were blood glucose levels during a glucose tolerance test (GTT) in 6-month old offspring (P>0.5). However, there was evidence of insulin resistance in PAE male offspring at 6 months of age, with significantly elevated fasting plasma insulin (P= 0.001), a tendency for increased first phase insulin secretion during the GTT and impaired glucose clearance following an insulin challenge (P= 0.007). This was accompanied by modest alterations in protein kinase B (AKT) signalling in adipose tissue. PAE also resulted in reduced calorie consumption by offspring compared to controls (P= 0.04). These data suggest that a relatively low-level, acute PAE programs metabolic dysfunction in offspring in a sex-specific manner. These results highlight that alcohol consumption during pregnancy has the potential to affect the long-term health of offspring.Key points summaryPrenatal alcohol exposure has the potential to affect fetal development and program chronic disease in offspring.Previous preclinical models typically use high, chronic doses of alcohol throughout pregnancy to examine effects on offspring, particularly on the brain and behaviour.In this study we use a rat model of moderate, acute, prenatal alcohol exposure to determine if this can be detrimental to maintenance of glucose homeostasis in adolescent and adult offspring.Although female offspring were relatively unaffected, there was evidence of insulin resistance in 6-month old male offspring exposed to prenatal alcohol, suggestive of a pre-diabetic state.This result suggests that even a relatively low-dose, acute exposure to alcohol during pregnancy can still program metabolic dysfunction in a sex-specific manner.
Ran GTPase regulates non-centrosomal microtubule nucleation and is transported by actin waves towards the neurite tip
Authors: Huang Yung-An , Hsu Chih-Hsuan , Chiu Ho-Chieh , Ho Chris T. , Lo Wei-Lun , Hwang Eric 
Published: June 2019

AbstractMicrotubule (MT) is the most abundant cytoskeleton in neurons and controls multiple facets of their development. While the organizing center of MTs in mitotic cells is typically located at the centrosome, MT nucleation in post-mitotic neurons switches to non-centrosomal sites. A handful of proteins and organelle have been shown to promote non-centrosomal MT formation in neurons, yet the regulation mechanism remains unknown. Here we demonstrate that the small GTPase Ran is a key regulator of non-centrosomal MT nucleation in neurons. The GTP-bound Ran (RanGTP) localizes to the neurite tips and around the soma. Using the RanGTP- and RanGDP-mimic mutants, we show that RanGTP promotes MT nucleation at the tip of the neurite. To demonstrate that RanGTP can promote MT nucleation in regions other than the neurite tip, an optogenetic tool called RanTRAP was constructed to enable light-induced local production of RanGTP in the neuronal cytoplasm. An increase of non-centrosomal MT nucleation can be observed by elevating the RanGTP level along the neurite using RanTRAP, establishing a new role for Ran in regulating neuronal MTs. Additionally, the mechanism of RanGTP enrichment at the neurite tip was examined. We discovered that actin waves drive the anterograde transport of RanGTP towards the neurite tip. Pharmacological disruption of actin waves abolishes the enrichment of RanGTP and reduces the non-centrosomal MT nucleation at the neurite tip. These observations provide a novel regulation mechanism of MTs and an indirect connection between the actin and MT cytoskeletons in neurons.
Synergic Interaction between Permethrin and Bt toxins discovered using RNA-seq
Authors: Sakamoto Takuma , Kozaki Toshinori , Ogata Norichika 
Published: June 2019

AbstractActing against the development of resistance to antibiotics and insecticides, involving negatively correlated cross-resistance (NCR) is an alternative to use- and-discard approach. It is termed NCR that toxic chemicals interact with each other and resistance of target organisms to one chemical is sometimes associated with increased susceptibility to a second chemical when; an allele confers resistance to one toxic chemical and hyper-susceptibility to another, NCR occurs. However, only 11 toxin pairs have been revealed to cause NCR in insects. Finding novel NCRs is needed for integrated pest management. We analyzed permethrin, an insecticide, induced transcriptomes of cultured fat bodies of the silkworm Bombyx mori, a lepidopteran model insect. Differentially expressed gene analyses suggested Bacillus thuringiensis (Bt) toxin was an NCR toxin of permethrin. NCR to permethrin and Bt toxins in Thysanoplusia intermixta, the agricultural pest moth, was examined; the children of permethrin survivor T. intermixta had increased susceptibility to Bt toxin. A novel NCR toxin pair, permethrin and Bt toxin, was discovered. The screening and developmental method for negatively correlated cross-resistance toxins established in this study was effective, in vitro screening using model organisms and in vivo verification using agricultural pests.
Inhibition of IRF4 in dendritic cells by PRR-independent and -dependent signals inhibit Th2 and promote Th17 responses
Authors: Lee Jihyung , Zhang Junyan , Chung Young-Jun , Kim Jun Hwan , Kook Chae Min , González-Navajas José M. , Herdman David S. , Nürnberg Bernd , Insel Paul A. , Corr Maripat , Tao Ailin , Yasuda Kei , Rifkin Ian R. , Broide David , Sciammas Roger , Webster Nicholas J.G. , Raz Eyal 
Published: June 2019

AbstractCyclic AMP (cAMP) is involved in multiple biological processes. However, little is known about its role in shaping immunity. Here we show that cAMP-PKA-CREB signaling (a pattern recognition receptor [PRR]-independent) regulates conventional type-2 Dendritic Cells (cDC2s), but not cDC1s and reprograms their Th17-inducing properties via repression of IRF4 and KLF4, transcription factors (TFs) for Th2 induction. Genetic loss of IRF4 phenocopies the effects of cAMP signaling on Th17-induction, indicating that the cAMP effect is secondary to repression of IRF4. Moreover, signaling in cDC2s by a PRR-dependent microbial product, curdlan, represses IRF4 and KLF4, resulting in a pro-Th17 phenotype. These results define a novel signaling pathway by which cDC2s display plasticity and provide a new molecular basis for the novel cDC2 and cDC17 classification. In addition, the data reveal that cAMP signaling can alter DCs function and fate by repressing IRF4 and KLF4, a pathway that can be harnessed for immuno-regulation.
Computational design of anti-CRISPR proteins with improved inhibition potency and expanded specificity
Authors: Mathony Jan , Harteveld Zander , Schmelas Carolin , Upmeier zu Belzen Julius , Aschenbrenner Sabine , Hoffmann Mareike D. , Stengl Christina , Scheck Andreas , Rosset Stéphane , Grimm Dirk , Eils Roland , Correia Bruno E. , Niopek Dominik 
Published: June 2019

AbstractAnti-CRISPR (Acr) proteins are bacteriophage-derived antagonists of CRISPR-Cas systems. To date, Acrs were obtained either by mining sequence databanks or experimentally screening phage collections, both of which yield a limited repertoire of naturally occurring variants. Here, we applied structure-based engineering on AcrIIC1, a broad-spectrum inhibitor of type II-C CRISPR systems, to improve its efficacy and expand its specificity. We first show that fusing exogenous protein domains into AcrIIC1 dramatically enhances inhibition of the natural Neisseria meningitidis Cas9 target. Then, using structure-guided design, we converted AcrIIC1 into AcrX, a potent inhibitor of the type II-A CRISPR-Cas9 from Staphylococcus aureus widely applied for in vivo genome editing. Our work introduces designer Acrs as important biotechnological tools and provides an innovative strategy to safeguard the CRISPR technology.
Single-cell genomic atlas of great ape cerebral organoids uncovers human-specific features of brain development
Authors: Kanton Sabina , Boyle Michael James , He Zhisong , Santel Malgorzata , Weigert Anne , Calleja Fatima Sanchis , Sidow Leila , Fleck Jonas , Guijarro Patricia , Han Dingding , Qian Zhengzong , Heide Michael , Huttner Wieland , Khaitovich Philipp , Pääbo Svante , Treutlein Barbara , Camp J. Gray 
Published: June 2019

ABSTRACTThe human brain has changed dramatically since humans diverged from our closest living relatives, chimpanzees and the other great apes1–5. However, the genetic and developmental programs underlying this divergence are not fully understood6–8. Here, we have analyzed stem cell-derived cerebral organoids using single-cell transcriptomics (scRNA-seq) and accessible chromatin profiling (scATAC-seq) to explore gene regulatory changes that are specific to humans. We first analyze cell composition and reconstruct differentiation trajectories over the entire course of human cerebral organoid development from pluripotency, through neuroectoderm and neuroepithelial stages, followed by divergence into neuronal fates within the dorsal and ventral forebrain, midbrain and hindbrain regions. We find that brain region composition varies in organoids from different iPSC lines, yet regional gene expression patterns are largely reproducible across individuals. We then analyze chimpanzee and macaque cerebral organoids and find that human neuronal development proceeds at a delayed pace relative to the other two primates. Through pseudotemporal alignment of differentiation paths, we identify human-specific gene expression resolved to distinct cell states along progenitor to neuron lineages in the cortex. We find that chromatin accessibility is dynamic during cortex development, and identify instances of accessibility divergence between human and chimpanzee that correlate with human-specific gene expression and genetic change. Finally, we map human-specific expression in adult prefrontal cortex using single-nucleus RNA-seq and find developmental differences that persist into adulthood, as well as cell state-specific changes that occur exclusively in the adult brain. Our data provide a temporal cell atlas of great ape forebrain development, and illuminate dynamic gene regulatory features that are unique to humans.
Serotonin and early life stress interact to shape brain architecture and anxious avoidant behavior – a TPH2 imaging genetics approach
Authors: Liu Congcong , Xu Lei , Li Jialin , Zhou Feng , Yang Xi , Zheng Xiaoxiao , Fu Meina , Li Keshuang , Sindermann Cornelia , Montag Christian , Ma Yina , Scheele Dirk , Ebstein Richard P. , Yao Shuxia , Kendrick Keith M. , Becker Benjamin 
Published: June 2019

AbstractBackgroundEarly life stress has been associated with emotional dysregulations and altered architecture of limbic-prefrontal brain systems engaged in emotional processing. Serotonin regulates both, developmental and experience-dependent neuroplasticity in these circuits. Central serotonergic biosynthesis rates are regulated by Tryptophan hydroxylase 2 (TPH2), and transgenic animal models suggest that TPH2-gene associated differences in serotonergic signaling mediate the impact of aversive early life experiences on a phenotype characterized by anxious avoidance.MethodsThe present study employed an imaging genetics approach that capitalized on individual differences in a TPH2 polymorphism (703G/T; rs4570625) to determine whether differences in serotonergic signaling modulate the effects of early life stress on brain structure and function and punishment sensitivity in humans (n = 252).ResultsHigher maltreatment exposure before the age of 16 was associated with increased gray matter volumes in a circuitry spanning thalamic-limbic-prefrontal regions and decreased intrinsic communication in limbic-prefrontal circuits selectively in TT carriers. In an independent replication sample, associations between higher early life stress and increased frontal volumes in TT carriers were confirmed. On the phenotype level, the genotype moderated the association between higher early life stress exposure and higher punishment sensitivity. In TT carriers, the association between higher early life stress exposure and punishment sensitivity was critically mediated by increased thalamic-limbic-prefrontal volumes.ConclusionsThe present findings suggest that early life stress shapes the neural organization of the limbic-prefrontal circuits in interaction with individual variations in the TPH2 gene to promote a phenotype characterized by facilitated threat avoidance, thus promoting early adaptation to an adverse environment.