bluuebunny/crossref_metadata_2025_split huggingface dataset:
ABC-transporter upregulation mediates resistance to the CDK7 inhibitors THZ1 and ICEC0942
Authors: Sava Georgina P. , Fan Hailing , Fisher Rosemary A. , Lusvarghi Sabrina , Pancholi Sunil , Ambudkar Suresh V. , Martin Lesley-Ann , Charles Coombes R. , Buluwela Lakjaya , Ali Simak 
Published: September 2019

AbstractThe CDK7 inhibitors (CDK7i) ICEC0942 and THZ1, are promising new cancer therapeutics. Resistance to targeted drugs frequently compromises cancer treatment. We sought to identify mechanisms by which cancer cells may become resistant to CDK7i. Resistant lines were established through continuous drug selection. ABC-transporter copy number, expression and activity were examined using real-time PCR, immunoblotting and flow cytometry. Drug responses were measured using growth assays. ABCB1 was upregulated in ICEC0942-resistant cells and there was cross-resistance to THZ1. THZ1-resistant cells upregulated ABCG2 but remained sensitive to ICEC0942. Drug resistance in both cell lines was reversible upon inhibition of ABC-transporters. CDK7i response was altered in adriamycin- and mitoxantrone-resistant cell lines demonstrating ABC-transporter upregulation. ABCB1 expression correlated with ICEC0942 and THZ1 response, and ABCG2 expression with THZ2 response, in a panel of cancer cell lines. We have identified ABCB1 upregulation as a common mechanism of resistance to ICEC0942 and THZ1, and confirmed that ABCG2 upregulation is a mechanism of resistance to THZ1. The identification of potential mechanisms of CDK7i resistance and differences in susceptibility of ICEC0942 and THZ1 to ABC-transporters, may help guide their future clinical use.
NRXN1 is associated with enlargement of the temporal horns of the lateral ventricles in psychosis
Authors: Alliey-Rodriguez Ney , Grey Tamar A. , Shafee Rebecca , Asif Huma , Lutz Olivia , Bolo Nicolas R. , Padmanabhan Jaya , Tandon Neeraj , Klinger Madeline , Reis Katherine , Spring Jonathan , Coppes Lucas , Zeng Victor , Hegde Rachal R. , Hoang Dung T. , Bannai Deepthi , Nawaz Uzma , Henson Philip , Liu Siyuan , Gage Diane , McCarroll Steven , Bishop Jeffrey R. , Hill Scot , Reilly James L. , Lencer Rebekka , Clementz Brett A. , Buckley Peter , Glahn David C. , Meda Shashwath A. , Narayanan Balaji , Pearlson Godfrey , Keshavan Matcheri S. , Ivleva Elena I. , Tamminga Carol , Sweeney John A. , Curtis David , Badner Judith A. , Keedy Sarah , Rapoport Judith , Liu Chunyu , Gershon Elliot S. 
Published: September 2019

AbstractSchizophrenia, Schizoaffective, and Bipolar disorders share behavioral and phenomenological traits, intermediate phenotypes, and some associated genetic loci with pleiotropic effects. Volumetric abnormalities in brain structures are among the intermediate phenotypes consistently reported associated with these disorders. In order to examine the genetic underpinnings of these structural brain modifications, we performed genome-wide association analyses (GWAS) on 60 quantitative structural brain MRI phenotypes in a sample of 777 subjects (483 cases and 294 controls pooled together). Genotyping was performed with the Illumina PsychChip microarray, followed by imputation to the 1000 genomes multiethnic reference panel. Enlargement of the Temporal Horns of Lateral Ventricles (THLV) is associated with an intronic SNP of the gene NRXN1 (rs12467877,P = 6.76E–10), which accounts for 4.5% of the variance in size. Enlarged THLV is associated with psychosis in this sample, and with reduction of the hippocampus and enlargement of the choroid plexus and caudate. Eight other suggestively significant associations (P < 5.5E–8) were identified with THLV and 5 other brain structures. Although rare deletions of NRXN1 have been previously associated with psychosis, this is the first report of a common SNP variant of NRXN1 associated with enlargement of the THLV in psychosis.
The lytic activity of VSV-GP treatment dominates the therapeutic effects in a syngeneic model of lung cancer
Authors: Schreiber Liesa-Marie , Urbiola Carles , Das Krishna , Spiesschaert Bart , Kimpel Janine , Heinemann Fabian , Stierstorfer Birgit , Müller Philipp , Petersson Monika , Erlmann Patrik , von Laer Dorothee , Wollmann Guido 
Published: September 2019

AbstractBackgroundOncolytic virotherapy is thought to result in direct virus-induced lytic tumour killing and simultaneous activation of innate and tumour-specific adaptive immune responses. Using a chimeric vesicular stomatitis virus variant VSV-GP, we addressed the direct oncolytic effects and the role of anti-tumour immune induction in the syngeneic mouse lung cancer model LLC1.MethodsTo study a tumour system with limited antiviral effects, we generated interferon receptor-deficient cells (LLC1-IFNAR1−/−). Therapeutic efficacy of VSV-GP was assessed in vivo in syngeneic C57BL/6 and athymic nude mice bearing subcutaneous tumours. VSV-GP treatment effects were analysed using bioluminescent imaging (BLI), immunohistochemistry, ELISpot, flow cytometry, multiplex ELISA and Nanostring® assays.ResultsInterferon insensitivity correlated with VSV-GP replication and therapeutic outcome. BLI revealed tumour-to-tumour spread of viral progeny in bilateral tumours. Histological and gene expression analysis confirmed widespread and rapid infection and cell killing within the tumour with activation of innate and adaptive immune-response markers. However, treatment outcome was increased in the absence of CD8+T cells and surviving mice showed little protection from tumour re-challenge, indicating limited therapeutic contribution by the activated immune system.ConclusionThese studies present a case for a predominantly lytic treatment effect of VSV-GP in a syngeneic mouse lung cancer model.
Identification of significant chromatin contacts from HiChIP data by FitHiChIP
Authors: Bhattacharyya Sourya , Chandra Vivek , Vijayanand Pandurangan , Ay Ferhat 
Published: September 2019

AbstractHiChIP/PLAC-seq is increasingly becoming popular for profiling 3D chromatin contacts among regulatory elements and for annotating functions of genetic variants. Here we describe FitHiChIP, a computational method for loop calling from HiChIP/PLAC-seq data, which jointly models the non-uniform coverage and genomic distance scaling of contact counts to compute statistical significance estimates. We also develop a technique to filter putative bystander loops that can be explained by stronger adjacent loops. Compared to existing methods, FitHiChIP performs better in recovering contacts reported by Hi-C, promoter capture Hi-C and ChIA-PET experiments and in capturing previously validated promoter-enhancer interactions. FitHiChIP loop calls are reproducible among replicates and are consistent across different experimental settings. Our work also provides a framework for differential HiChIP analysis with an option to utilize ChIP-seq data for further characterizing differential loops. Even though designed for HiChIP, FitHiChIP is also applicable to other conformation capture assays.
Neural JNK3 regulates blood flow recovery after hindlimb ischemia in mice via an Egr1/Creb1 axis
Authors: Kant Shashi , Craige Siobhan M. , Chen Kai , Reif Michaella M. , Learnard Heather , Kelly Mark , Caliz Amada D. , Tran Khanh-Van , Ramo Kasmir , Peters Owen M. , Freeman Marc , Davis Roger J. , Keaney John F. 
Published: September 2019

AbstractDiseases related to impaired blood flow such as peripheral artery disease (PAD) impact nearly 10 million people in the United States alone, yet patients with clinical manifestations of PAD (e.g., claudication and limb ischemia) have limited treatment options. In ischemic tissues, stress kinases such as c-Jun N-terminal kinases (JNKs), are activated. Here, we show that inhibition of the JNK3 (Mapk10) in the neural compartment strikingly potentiates blood flow recovery from mouse hindlimb ischemia. JNK3 deficiency leads to upregulation of growth factors such asVegfa,Pdgfb,Pgf,HbegfandTgfb3in ischemic muscle by activation of the transcription factors Egr1/Creb1. JNK3 acts through Forkhead box O3 (Foxo3a) to suppress the activity of Egr1/Creb1 transcription regulators in vitro. In JNK3-deficient cells, Foxo3a is suppressed which leads to Egr1/Creb1 activation and upregulation of downstream growth factors. Collectively, these data suggest that the JNK3-Foxo3a-Egr1/Creb1 axis coordinates the vascular remodeling response in peripheral ischemia.
Evolution of acoustic communication in blind cavefish
Authors: Hyacinthe Carole , Attia Joël , Rétaux Sylvie 
Published: September 2019

AbstractAcoustic communication allows the exchange of information within specific contexts and during specific behaviors. The blind, cave-adapted and the sighted, river-dwelling morphs of the species Astyanax mexicanus have evolved in markedly different environments. During their evolution in darkness, cavefish underwent a series of morphological, physiological and behavioral changes, allowing the study of adaptation to drastic environmental change. Here we discover that Astyanax is a sonic species, in the laboratory and in the wild, with sound production depending on the social contexts and the type of morph. We characterize one sound, the “Sharp Click”, as a visually-triggered sound produced by dominant surface fish during agonistic behaviors and as a chemosensory-, food odor-triggered sound produced by cavefish during foraging. Sharp Clicks also elicit different reactions in the two morphs in play-back experiments. Our results demonstrate that acoustic communication does exist and has evolved in cavefish, accompanying the evolution of its behaviors.
Visualization of supercritical water pseudo-boiling at Widom line crossover
Authors: Maxim Florentina , Contescu Cristian , Boillat Pierre , Niceno Bojan , Karalis Konstantinos , Testino Andrea , Ludwig Christian 
Published: September 2019

AbstractSupercritical water is a green solvent used in many technological applications including materials synthesis, nuclear engineering, bioenergy, or waste treatment and it occurs in nature. Despite its relevance in natural systems and technical applications, the supercritical state of water is still not well understood. Recent theories predict that liquid-like (LL) and gas-like (GL) supercritical water are metastable phases, and that the so-called Widom line zone is marking the crossover between LL and GL behavior of water. With neutron imaging techniques, we succeed to monitor density fluctuations of supercritical water while the system evolves rapidly from LL to GL as the Widom line is crossed during isobaric heating. Our observations show that the Widom line of water can be identified experimentally and they are in agreement with the current theory of supercritical fluid pseudo-boiling. This fundamental understanding allows optimizing and developing new technologies using supercritical water as a solvent.
Enhancing and controlling valley magnetic response in MoS2/WS2 heterostructures by all-optical route
Authors: Zhang Jing , Du Luojun , Feng Shun , Zhang Run-Wu , Cao Bingchen , Zou Chenji , Chen Yu , Liao Mengzhou , Zhang Baile , Yang Shengyuan A. , Zhang Guangyu , Yu Ting 
Published: September 2019

AbstractVan der Waals heterostructures of transition metal dichalcogenides with interlayer coupling offer an exotic platform to realize fascinating phenomena. Due to the type II band alignment of these heterostructures, electrons and holes are separated into different layers. The localized electrons induced doping in one layer, in principle, would lift the Fermi level to cross the spin-polarized upper conduction band and lead to strong manipulation of valley magnetic response. Here, we report the significantly enhanced valley Zeeman splitting and magnetic tuning of polarization for the direct optical transition of MoS2 in MoS2/WS2 heterostructures. Such strong enhancement of valley magnetic response in MoS2 stems from the change of the spin-valley degeneracy from 2 to 4 and strong many-body Coulomb interactions induced by ultrafast charge transfer. Moreover, the magnetic splitting can be tuned monotonically by laser power, providing an effective all-optical route towards engineering and manipulating of valleytronic devices and quantum-computation.
A shared core microbiome in soda lakes separated by large distances
Authors: Zorz Jackie K. , Sharp Christine , Kleiner Manuel , Gordon Paul M. K. , Pon Richard T. , Dong Xiaoli , Strous Marc 
Published: September 2019

AbstractIn alkaline soda lakes, concentrated dissolved carbonates establish productive phototrophic microbial mats. Here we show how microbial phototrophs and autotrophs contribute to this exceptional productivity. Amplicon and shotgun DNA sequencing data of microbial mats from four Canadian soda lakes indicate the presence of > 2,000 species of Bacteria and Eukaryotes. We recover metagenome-assembled-genomes for a core microbiome of < 100 abundant bacteria, present in all four lakes. Most of these are related to microbes previously detected in sediments of Asian alkaline lakes, showing that common selection principles drive community assembly from a globally distributed reservoir of alkaliphile biodiversity. Detection of > 7,000 proteins show how phototrophic populations allocate resources to specific processes and occupy complementary niches. Carbon fixation proceeds by the Calvin-Benson-Bassham cycle, in Cyanobacteria, Gammaproteobacteria, and, surprisingly, Gemmatimonadetes. Our study provides insight into soda lake ecology, as well as a template to guide efforts to engineer biotechnology for carbon dioxide conversion.
Quantitative expression of MMPs 2, 9, 14, and collagen IV in LCIS and paired normal breast tissue
Authors: Nyante Sarah J. , Wang Tengteng , Tan Xianming , Ozdowski Emily F. , Lawton Thomas J. 
Published: September 2019

AbstractCertain matrix metalloproteinases (MMPs) have the ability to degrade collagen IV, a main component of the breast lobular basement membrane. In this cross-sectional study, we evaluated expression of MMPs 2, 9, and 14 and collagen IV in LCIS and adjacent normal breast tissue among LCIS patients without invasive breast cancer to determine whether expression differed between benign and preinvasive breast epithelial tissue. A total of 64 LCIS patients, diagnosed 2004–2014, were included; 44 had sufficient paired normal tissue for analysis. Marker epithelial expression was measured using immunofluorescence and quantified using the H score (MMPs) or pixel intensity (collagen IV). Associations were evaluated using the Spearman correlation or the Wilcoxon signed-rank test. In LCIS and normal tissue, there was a strong correlation between MMP2 and MMP14 expression (LCIS r = 0.69, normal r = 0.81, both P < 0.01). Other pairwise correlations were moderate to weak (range: LCIS r = 0.32–0.47, normal r = 0.19–0.32). For all markers, expression was lower in LCIS vs. normal tissue (all P ≤ 0.05). In sum, collagenase MMPs were expressed in normal breast and LCIS lesions of LCIS patients. However, expression was not higher in LCIS compared with normal tissue, suggesting collagenase MMP expression does not increase as breast tissue gains a more proliferative phenotype.
Estimating the Frequency of Single Point Driver Mutations across Common Solid Tumours
Authors: Darbyshire Madeleine , du Toit Zachary , Rogers Mark F. , Gaunt Tom R. , Campbell Colin 
Published: September 2019

AbstractFor cancers, such as common solid tumours, variants in the genome give a selective growth advantage to certain cells. It has recently been argued that the mean count of coding single nucleotide variants acting as disease-drivers in common solid tumours is frequently small in size, but significantly variable by cancer type (hypermutation is excluded from this study). In this paper we investigate this proposal through the use of integrative machine-learning-based classifiers we have proposed recently for predicting the disease-driver status of single nucleotide variants (SNVs) in the human cancer genome. We find that predicted driver counts are compatible with this proposal, have similar variabilities by cancer type and, to a certain extent, the drivers are identifiable by these machine learning methods. We further discuss predicted driver counts stratified by stage of disease and driver counts in non-coding regions of the cancer genome, in addition to driver-genes.
Cohesion-driven mixing and segregation of dry granular media
Authors: Jarray Ahmed , Shi Hao , Scheper Bert J. , Habibi Mehdi , Luding Stefan 
Published: September 2019

AbstractGranular segregation is a common, yet still puzzling, phenomenon encountered in many natural and engineering processes. Here, we experimentally investigate the effect of particles cohesion on segregation in dry monodisperse and bidisperse systems using a rotating drum mixer. Chemical silanization, glass surface functionalization via a Silane coupling agent, is used to produce cohesive dry glass particles. The cohesive force between the particles is controlled by varying the reaction duration of the silanization process, and is measured using an in-house device specifically designed for this study. The effects of the cohesive force on flow and segregation are then explored and discussed. For monosized particulate systems, while cohesionless particles perfectly mix when tumbled, highly cohesive particles segregate. For bidisperse mixtures of particles, an adequate cohesion-tuning reduces segregation and enhances mixing. Based on these results, a simple scheme is proposed to describe the system’s mixing behaviour with important implications for the control of segregation or mixing in particulate industrial processes.
Simple 3D culture of dissociated kidney mesenchyme mimics nephron progenitor niche and facilitates nephrogenesis Wnt-independently
Authors: Dapkunas Arvydas , Rantanen Ville , Gui Yujuan , Lalowski Maciej , Sainio Kirsi , Kuure Satu , Sariola Hannu 
Published: September 2019

AbstractKidney mesenchyme (KM) and nephron progenitors (NPs) depend on WNT activity, and their culture in vitro requires extensive repertoire of recombinant proteins and chemicals. Here we established a robust, simple culture of mouse KM using a combination of 3D Matrigel and growth media supplemented with Fibroblast Growth Factor 2 (FGF2) and Src inhibitor PP2. This allows dissociated KM to spontaneously self-organize into spheres. To reassess the requirement of WNT activity in KM self-organization and NPs maintenance, cells were cultured with short pulse of high-dose GSK3β inhibitor BIO, on a constant low-dose or without BIO. Robust proliferation at 48 hours and differentiation at 1 week were observed in cultures with high BIO pulse. Importantly, dissociated KM cultured without BIO, similarly to that exposed to constant low dose of BIO, maintained NPs up to one week and spontaneously differentiated into nephron tubules at 3 weeks of culture. Our results show that KM is maintained and induced to differentiate in a simple culture system. They also imply that GSK3β/WNT-independent pathways contribute to the maintenance and induction of mouse KM. The robust and easy 3D culture enables further characterization of NPs, and may facilitate disease modeling when applied to human cells.
Comparative transcriptome analysis of the human endocervix and ectocervix during the proliferative and secretory phases of the menstrual cycle
Authors: Mukhopadhyay S. , Liang Y. , Hur H. , Villegas G. , Calenda G. , Reis A. , Millen L. , Barnable P. , Mamkina L. , Kumar N. , Kalir T. , Sperling R. , Teleshova N. 
Published: September 2019

AbstractDespite extensive studies suggesting increased susceptibility to HIV during the secretory phase of the menstrual cycle, the molecular mechanisms involved remain unclear. Our goal was to analyze transcriptomes of the endocervix and ectocervix during the proliferative and secretory phases using RNA sequencing to explore potential molecular signatures of susceptibility to HIV. We identified 202 differentially expressed genes (DEGs) between the proliferative and secretory phases of the cycle in the endocervix (adjusted p < 0.05). The biofunctions and pathways analysis of DEGs revealed that cellular assembly and epithelial barrier function in the proliferative phase and inflammatory response/cellular movement in the secretory phase were among the top biofunctions and pathways. The gene set enrichment analysis of ranked DEGs (score = log fold change/p value) in the endocervix and ectocervix revealed that (i) unstimulated/not activated immune cells gene sets positively correlated with the proliferative phase and negatively correlated with the secretory phase in both tissues, (ii) IFNγ and IFNα response gene sets positively correlated with the proliferative phase in the ectocervix, (iii) HIV restrictive Wnt/β-catenin signaling pathway negatively correlated with the secretory phase in the endocervix. Our data show menstrual cycle phase-associated changes in both endocervix and ectocervix, which may modulate susceptibility to HIV.
Bullfrog farms release virulent zoospores of the frog-killing fungus into the natural environment
Authors: Ribeiro Luisa P. , Carvalho Tamilie , Becker C. Guilherme , Jenkinson Thomas S. , Leite Domingos da Silva , James Timothy Y. , Greenspan Sasha E. , Toledo Luís Felipe 
Published: September 2019

AbstractBullfrog farming and trade practices are well-established, globally distributed, and economically valuable, but pose risks for biodiversity conservation. Besides their negative impacts on native amphibian populations as an invasive species, bullfrogs play a key role in spreading the frog-killing fungusBatrachochytrium dendrobatidis(Bd) in the natural environment. Bullfrogs are tolerant to Bd, meaning that they can carry high infection loads without developing chytridiomycosis. To test the potential of bullfrog farms as reservoirs for diverse and virulent chytrid genotypes, we quantified Bd presence, prevalence and infection loads across approximately 1,500 farmed bullfrogs and in the water that is released from farms into the environment. We also described Bd genotypic diversity within frog farms by isolating Bd from dozens of infected tadpoles. We observed individuals infected with Bd in all sampled farms, with high prevalence (reaching 100%) and high infection loads (average 71,029 zoospore genomic equivalents). Average outflow water volume from farms was high (60,000 L/day), with Bd zoospore concentration reaching approximately 50 million zoospores/L. Because virulent pathogen strains are often selected when growing in tolerant hosts, we experimentally tested whether Bd genotypes isolated from bullfrogs are more virulent in native anuran hosts compared to genotypes isolated from native host species. We genotyped 36 Bd isolates from two genetic lineages and found that Bd genotypes cultured from bullfrogs showed similar virulence in native toads when compared to genotypes isolated from native hosts. Our results indicate that bullfrog farms can harbor high Bd genotypic diversity and virulence and may be contributing to the spread of virulent genotypes in the natural environment. We highlight the urgent need to implement Bd monitoring and mitigation strategies in bullfrog farms to aid in the conservation of native amphibians.