bluuebunny/crossref_metadata_2025_split huggingface dataset:
KMT2D links TGF-β Signalling to Non-Canonical Activin Pathway and Regulates Pancreatic Cancer Cell Plasticity
Authors: Lu Shuang , Kim Hong Sun , Cao Yubo , Bedi Karan , Chain Krista , Zhao Lili , Narayanan Ishwarya Venkata , Yi Zhujun , Yang Jing , Gu Yumei , Paulsen Michelle T. , Ljungman Mats , Jeyarajan Sivakumar , Thomas Dafydd , Dou Yali , Crawford Howard , di Magliano Marina Pasca , Shi Jiaqi 
Published: April 2020

AbstractAlthough KMT2D, also known as MLL2, is known to play an essential role in development, differentiation, and tumor suppression, its role in pancreatic cancer development is not well understood. Here, we discovered a novel signaling axis mediated by KMT2D, which links TGF-β to the activin A pathway. We found that TGF-β upregulates a microRNA, miR-147b, which in turn leads to post-transcriptional silencing of KMT2D. Loss of KMT2D induces the expression and secretion of activin A, which activates a non-canonical p38 MAPK-mediated pathway to modulate cancer cell plasticity, promote a mesenchymal phenotype, and enhance tumor invasion and metastasis in mice. We observed a decreased KMT2D expression in human primary and metastatic pancreatic cancer. Furthermore, inhibition or knockdown of activin A reversed the pro-tumoral role of KMT2D. These findings reveal a tumor-suppressive role of KMT2D and identify miR-147b and activin A as novel therapeutic targets in pancreatic cancer.
Inhibition of PTEN activity promotes IB4-positive sensory neuronal axon growth
Authors: Zhou Li-Yu , Han Feng , Qi Shi-Bin , Ma Jin-Jin , Ma Yan-Xia , Zhang Hong-Cheng , Xie Ji-Le , Fu Xin-Ya , Chen Jian-Quan , Li Bin , Yang Hui-Lin , Zhou Feng , Saijilafu  
Published: April 2020

AbstractTraumatic nerve injuries have become a common clinical problem, and axon regeneration is a critical process in the successful functional recovery of the injured nervous system. In this study, we found that peripheral axotomy reduce total PTEN expression in adult sensory neurons, however, it did not alter the expression level of PTEN in IB4-positive sensory neurons. Additionally, our results indicate that the artificial inhibition of PTEN markedly promotes adult sensory axon regeneration, including IB4-positive neuronal axon growth. Thus, our results provide strong evidence that PTEN is a prominent repressor of adult sensory axon regeneration, especially in IB4-positive neurons.
Integrated analysis of cervical squamous cell carcinoma cohorts from three continents reveals conserved subtypes of prognostic significance
Authors: Chakravarthy Ankur , Reddin Ian , Henderson Stephen , Dong Cindy , Kirkwood Nerissa , Jeyakumar Maxmilan , Rodriguez Daniela Rothschild , Martinez Natalia Gonzalez , McDermott Jacqueline , Su Xiaoping , Egawa Nagayasau , Fjeldbo Christina S , Skingen Vilde Eide , Halle Mari Kyllesø , Krakstad Camilla , Soleiman Afschin , Sprung Susanne , Ellis Peter , Wass Mark , Michaelis Martin , Lyng Heidi , Fiegl Heidi , Salvesen Helga , Thomas Gareth , Doorbar John , Chester Kerry , Feber Andrew , Fenton Tim R 
Published: April 2020

AbstractHuman papillomavirus (HPV)-associated cervical cancer represents one of the leading causes of cancer death worldwide. Although low-middle income countries are disproportionately affected, our knowledge of the disease predominantly originates from populations in high-income countries. Using the largest multi-omic analysis of cervical squamous cell carcinoma (CSCC) to date, totalling 643 tumours and representing patient populations from the USA, Europe and Sub-Saharan Africa, we identify two CSCC subtypes (C1 and C2) with differing prognosis. C1 tumours are largely HPV16-driven, display increased cytotoxic T-lymphocyte infiltration and frequently harbourPIK3CAandEP300mutations. C2 tumours are associated with shorter overall survival, are frequently driven by HPVs from the HPV18-containing alpha-7 clade, harbour alterations in the Hippo signalling pathway and increased expression of immune checkpoint genes,B7-H3(also known asCD276) andNT5E(also known asCD73) andPD-L2(also known asPDCD1LG2). In conclusion, we identify two novel, therapy-relevant CSCC subtypes that share the same defining characteristics across three geographically diverse cohorts.
Monocyte-derived Prostaglandin E2 inhibits antigen-specific cutaneous immunity during ageing
Authors: Chambers Emma S , Vukmanovic-Stejic Milica , Shih Barbara B , Trahair Hugh , Subramanian Priya , Devine Oliver P , Glanville James , Gilroy Derek , Rustin Malcom , Freeman Tom C , Mabbot Neil A , Akbar Arne N 
Published: April 2020

AbstractAgeing results in a decline in immune function. We showed previously that healthy older humans (>65 years old) have reduced antigen-specific cutaneous immunity to varicella zoster virus (VZV) antigen challenge. This was associated with p38 MAP kinase driven inflammation that was induced by mild tissue injury caused by the injection of the antigen itself. Here we show that non-specific injury induced by injection of air or saline into the skin of older adults recruits CCR2+CD14+monocytes by CCL2 produced by senescent fibroblasts. These monocytes reduced TRMproliferation via secretion of prostaglandin E2 (PGE2). Pre-treatment with a p38-MAPK inhibitor (Losmapimod) in older adultsin vivosignificantly decreased CCL2 expression, recruitment of monocyte into the skin, COX2 expression and PGE2production. This enhanced the VZV response in the skin. Therefore, local inflammation arising from interaction between senescent cells and monocytes leads to immune decline in the skin during ageing, a process that can be reversed.SummaryInflammation resulting from tissue injury blocks antigen-specific cutaneous immunity during ageing. Monocytes recruited to the skin inhibit TRMfunction through COX2-derived prostaglandin E2production. Blocking inflammation and resulting prostaglandin E2production with a p38-MAP kinase inhibitor significantly enhances cutaneous antigen-specific responses.
Reactivation of atrium genes is a primer for heart infarction or regeneration
Authors: Zhen Yisong 
Published: April 2020

AbstractThe inability of the adult heart to repair or regenerate is manifested in prevalent morbidity and mortality related to myocardial infarction and heart failure. However, the cue to the reactivation of cardiomyocyte proliferation in the adult remains largely unknown. In the present study, three independent datasets were explored using bioinformatics analysis methods to solve the problem. Our results revealed that atrium genes were upregulated in response to the injury, which indicates the possible cell type withdraw and reinitiation of proliferation capability. Our findings might provide an alternative viewpoint on the cardiomyocyte regeneration or myocardial infarction.
AutoGenome V2: New Multimodal Approach Developed for Multi-Omics Research
Authors: Xu Chi , Liu Denghui , Zhang Lei , Xu Zhimeng , He Wenjun , Wang Deyong , Zheng Mingyue , Qiao Nan 
Published: April 2020

AbstractDeep learning is very promising in solving problems in omics research, such as genomics, epigenomics, proteomics, and metabolics. The design of neural network architecture is very important in modeling omics data against different scientific problems. Residual fully-connected neural network (RFCN) was proposed to provide better neural network architectures for modeling omics data. The next challenge for omics research is how to integrate informations from different omics data using deep learning, so that information from different molecular system levels could be combined to predict the target. In this paper, we present a novel multimodal approach that could efficiently integrate information from different omics data and achieve better accuracy than previous approaches. We evaluate our method in four different tasks: drug repositioning, target gene prediction, breast cancer subtyping and cancer type prediction, and all the four tasks achieved state of art performances. The multimodal approach is implemented in AutoGenome V2 and is also powered with all the previous AutoML convenience to facilitate biomedical researchers.
Attractiveness in the eyes: A possibility of positive loop between transient pupil constriction and facial attraction
Authors: Liao Hsin-I , Kashino Makio , Shimojo Shinsuke 
Published: April 2020

AbstractContrary to the long-held belief of a close linkage between pupil dilation and attractiveness, we found an early and transient pupil constriction response when participants viewed an attractive face (and the effect of luminance/contrast is controlled). While human participants were making an attractiveness judgment on faces, their pupil constricted more for the more attractive (as-to-be-rated) faces. Further experiments showed that the effect of pupil constriction to attractiveness judgment extended to intrinsically aesthetic visual objects such as natural scene images (as well as faces) but not to line-drawing geometric figures. When participants were asked to judge the roundness of faces, pupil constriction still correlated with their attractiveness but not the roundness rating score, indicating the automaticity of the pupil constriction to attractiveness. When pupillary responses were manipulated implicitly by relative background luminance changes (from the pre-stimulus screen), the facial attractiveness ratings were in accordance with the amount of pupil constriction, which could not be explained solely by simultaneous or sequential luminance contrast. The overall results suggest that pupil constriction not only reflects but, as a part of self-monitoring and attribution mechanisms, also possibly contributes facial attractiveness implicitly.
Systematic analysis of naturally occurring insertions and deletions that alter transcription factor spacing identifies tolerant and sensitive transcription factor pairs
Authors: Shen Zeyang , Li Rick Z. , Prohaska Thomas A. , Hoeksema Marten A. , Spann Nathan J. , Tao Jenhan , Fonseca Gregory J. , Le Thomas , Stolze Lindsey , Sakai Mashito , Romanoski Casey E. , Glass Christopher K. 
Published: April 2020

AbstractRegulation of gene expression requires the combinatorial binding of sequence-specific transcription factors (TFs) at promoters and enhancers. Prior studies showed that alterations in the spacing between TF binding sites can influence promoter and enhancer activity. However, the relative importance of TF spacing alterations resulting from naturally occurring insertions and deletions (InDels) has not been systematically analyzed. To address this question, we first characterized the genome-wide spacing relationships of 75 TFs in K562 cells as determined by ChIP-sequencing. We found a dominant pattern of a relaxed range of spacing between collaborative factors, including 46 TFs exclusively exhibiting relaxed spacing with their binding partners. Next, we exploited millions of InDels provided by genetically diverse mouse strains and human individuals to investigate the effects of altered spacing on TF binding and local histone acetylation. Spacing alterations resulting from naturally occurring InDels are generally tolerated in comparison to genetic variants directly affecting TF binding sites. A remarkable range of tolerance was further established for PU.1 and C/EBPβ, which exhibit relaxed spacing, by introducing synthetic spacing alterations ranging from 5-bp increase to >30-bp decrease using CRISPR/Cas9 mutagenesis. These findings provide implications for understanding mechanisms underlying enhancer selection and for the interpretation of non-coding genetic variation.
Diabetes induced decreases in PKA signaling in cardiomyocytes: the role of insulin
Authors: Eyster Craig A. , Matsuzaki Satoshi , Giorgione Jennifer R. , Humphries Kenneth M. 
Published: April 2020

AbstractThe cAMP-dependent protein kinase (PKA) signaling pathway is the primary means by which the heart regulates moment-to-moment changes in contractility and metabolism. We have previously found that PKA signaling is dysfunctional in the diabetic heart, yet the underlying mechanisms are not fully understood. The objective of this study was to determine if decreased insulin signaling contributes to a dysfunctional PKA response. To do so, we isolated adult cardiomyocytes (ACMs) from wild type and Akita type 1 diabetic mice. ACMs were cultured in the presence or absence of insulin and PKA signaling was visualized by immunofluorescence microscopy using an antibody that recognizes proteins specifically phosphorylated by PKA. We found significant decreases in proteins phosphorylated by PKA in wild type ACMs cultured in the absence of insulin. Akita ACMs also had decreased PKA signaling in the absence of insulin and this was not rescued by insulin. The decrease in PKA signaling was observed regardless of whether the kinase was stimulated with a beta-agonist, a cell-permeable cAMP analog, or with phosphodiesterase inhibitors. PKA content was unaffected, suggesting that the decrease in PKA signaling may be occurring by the loss of specific PKA substrates. Phospho-specific antibodies were therefore used to discern which potential substrates may be sensitive to the loss of insulin. Contractile proteins were phosphorylated similarly in wild type and Akita ACMs regardless of insulin. However, phosphorylation of the glycolytic regulator, PFK-2, was significantly decreased in an insulin-dependent manner in wild type ACMs and in an insulin-independent manner in Akita ACMs. These results demonstrate a defect in PKA activation in the diabetic heart, mediated in part by deficient insulin signaling, that results in an abnormal activation of a primary metabolic regulator.
Neuronal adenosine A2Areceptors signal ergogenic effects of caffeine
Authors: Aguiar Aderbal S , Speck Ana Elisa , Canas Paula M. , Cunha Rodrigo A. 
Published: April 2020

AbstractErgogenic aid is a substance or method used for enhancing exercise and sports performance. Caffeine is the most used ergogenic aid for athletes, but the mechanisms are still unknown. Forty-two adult female (19±0.6 g) and 40 male mice (24±0.4 g) from a global and forebrain A2AR knockout and colony (FMUC, University of Coimbra) underwent an open field and ergospirometry exercise test. Caffeine (15 mg/kg, i.p.) and SCH 58261 (1 mg/kg, i.p.) were administered 15 minutes before the animals ran to exhaustion. We also evaluate the estrous cycle and infrared temperature (rest and recovery). Caffeine was psychostimulant in wild type females and males, but we observed this expected effect of SCH-58261 only in males. Caffeine and SCH-58261 were also ergogenic for wild type animals, that is, they increased running power and maximal O2consumption (O2max). The psychostimulant and ergogenic effects of caffeine and SCH-58261 disappeared in A2AR knockout females (global) and males (forebrain). The estrous cycle did not influence any evaluated parameters, as well as exercise-induced hyperthermia was similar between savages and knockouts. Our results suggest that the neuronal A2AR receptors signal the ergogenic effects of caffeine in female and male mice.
Evaluating features of scientific conferences: A call for improvements
Authors: Sarabipour Sarvenaz , Khan Aziz , Seah Samantha , Mwakilili Aneth D. , Mumoki Fiona N. , Sáez Pablo J. , Schwessinger Benjamin , Debat Humberto J. , Mestrovic Tomislav 
Published: April 2020

AbstractScientific conferences provide valuable opportunities for researchers across career stages and disciplines to present their latest work, and to network with their peers. These meetings have largely been held in-person with rapid proliferation in the number of meetings and attendees. Yet the format and quality of their organization lag behind what is possible and as a result, the current experience of attending conferences in many disciplines remains unchanged in many respects. We created a database of 270 national and international academic conferences held in-person during 2018-2019 in various disciplines and examined them for their features, costs and impact on the community. We found that many meetings could still be improved significantly in terms of diversity, inclusivity, promoting early career researcher (ECR) networking and career development, venue accessibility, and importantly, reducing the meetings’ carbon footprint. It is important to accelerate and mandate efforts to improve conferences so that researchers in all disciplines, in particular ECRs, consistently benefit from scientific gatherings, for years to come. We discuss a combination of approaches and recommendations to make conferences more modern, effective, equitable and intellectually productive for the research community and environmentally sustainable for our planet.“They always say time changes things, but you actually have to change them yourself.”— Andy Warhol
Coordinated postnatal maturation of striatal cholinergic interneurons and dopamine release dynamics in mice
Authors: McGuirt Avery , Lieberman Ori , Post Michael , Pigulevskiy Irena , Sulzer David 
Published: April 2020

AbstractDynamic changes in motor abilities and motivated behaviors occur during the juvenile and adolescent periods. The striatum is a subcortical nucleus critical for action selection, motor learning and reward processing. Its tonically active cholinergic interneuron (ChI) is an integral regulator of the synaptic activity of other striatal neurons, as well as afferent axonal projections of midbrain dopamine neurons. Thalamic and dopaminergic inputs initiate pauses in ChI firing following salient sensory cues that are extended for several hundred milliseconds by intrinsic regenerative currents. Here, we characterize the electrophysiological and morphological features of ChIs during mouse postnatal development. We demonstrate that ChI spontaneous activity increases with age while the duration of the pause in firing induced by depolarizing inputs decreases during postnatal development. Maturation of ChI activity is driven by two distinct physiological changes: decreased amplitude of the afterhypolarization between P14 and P18 and and increased Ih conductance between the late postnatal period and adulthood. Finally, we uncover postnatal changes in dopamine release properties that are mediated by cholinergic signalling. At P10, striatal dopamine release is diminished compared to the adult, but our data show efficient summation of dopamine relase evoked by multiple grouped stimuli that subsides by P28. Blockade of nictonic acetylcholine receptors enhances release summation in mice older than P28 but has little effect at P10. These data demonstrate a physiological maturation of ChI activity and indicate a reciprocal interaction between the postnatal maturation of striatal ChI and dopamine neurotransmission.Significance StatementMotor skills and motivated behavior regimes develop rapidly during the postnatal period. The functional development of the striatal cholinergic interneuron (ChI), which contributes to these behaviors in adulthood, remains unexplored. In this study, we tracked the ontogeny of spontaneous ChI activity and cellular morphology, as well as the developmental trajectory of ion conductances characteristic to this population. We further report a developmental link between ChI activity and dopamine release, revealing a change in the frequency-dependence of dopamine release during the early postnatal period that is mediated by cholinergic signaling. This study provides evidence that striatal microcircuits are dynamic during the postnatal period and that they undergo coordinated maturation.
An influenza A hemagglutinin small-molecule fusion inhibitor identified by a new high-throughput fluorescence polarization screen
Authors: Yao Yao , Kadam Rameshwar U. , Lee Chang-Chun David , Woehl Jordan L. , Wu Nicholas C. , Zhu Xueyong , Kitamura Seiya , Wilson Ian A. , Wolan Dennis W. 
Published: April 2020

AbstractInfluenza hemagglutinin (HA) glycoprotein is the primary surface antigen targeted by the host immune response and a focus for development of novel vaccines, broadly neutralizing antibodies (bnAbs) and therapeutics. HA enables viral entry into host cells via receptor binding and membrane fusion and is a validated target for drug discovery. However, to date, only a very few bona fide small molecules have been reported against the HA. To identity new antiviral lead candidates against the highly conserved fusion machinery in the HA stem, we synthesized a fluorescence-polarization probe based on a recently described neutralizing cyclic peptide P7 derived from the complementarity-determining region loops of human bnAbs FI6v3 and CR9114 against the HA stem. We then designed a robust binding assay compatible with high-throughput screening to identify molecules with low μM to nM affinity to influenza A group 1 HAs. Our simple, low-cost, and efficient in vitro assay was used to screen H1/Puerto Rico/8/1934 HA trimer against approximately 72,000 compounds. The crystal structure of H1/Puerto Rico/8/1934 HA in complex with our best hit compound F0045(S) confirmed that it binds to pockets in the HA stem similar to bnAbs FI6v3 and CR9114, cyclic peptide P7, and small molecule inhibitor JNJ4796. F0045 is enantioselective against a panel of group 1 HAs and F0045(S) exhibits in vitro neutralization activity against multiple H1N1 and H5N1 strains. Our assay, compound characterization, and small-molecule candidate should further stimulate the discovery and development of new compounds with unique chemical scaffolds and enhanced influenza antiviral capabilities.SummaryInfluenza hemagglutinin (HA) glycoprotein enables viral entry into host cells and is the main target for antibodies in our immune system. While HA has now been established as a validated target for drug discovery, no FDA-approved small molecules are available that specifically prevent HA from binding host receptors or inhibit its membrane fusion activity and thus prevent infection. We therefore designed a fluorescence polarization probe to enable rapid identification of small molecules that bind to the stem fusion machinery of group 1 HAs. Application of our assay yielded a small molecule to the influenza A group 1 HA stem with antiviral efficacy.
A resource for exploring the understudied human kinome for research and therapeutic opportunities
Authors: Moret Nienke , Liu Changchang , Gyori Benjamin M. , Bachman John A. , Steppi Albert , Hug Clemens , Taujale Rahil , Huang Liang-Chin , Berginski Matthew E. , Gomez Shawn M. , Kannan Natarajan , Sorger Peter K. 
Published: April 2020

ABSTRACTThe functions of protein kinases have been widely studied and over 60 kinase inhibitors are FDA-approved drugs. Membership in the human kinome is nonetheless subject to multiple overlapping and inconsistent definitions and is unevenly studied, complicating functional genomics and chemical genetics. We describe objective criteria for refining the definition of the human kinome to comprise an extended set of 710 kinase domains and a more narrowly curated set of 557 protein kinase like (PKL) domains. An online tool (www.kinome.org)makes it possible to sort these sets on multiple structural and functional criteria. Focusing on the least studied one-third of the kinome we find that many proteins are differentially expressed, essential in multiple cell lines, and mutated in the Cancer Genome Atlas. We show that some understudied kinases are high affinity off-targets of clinical-grade compounds and approved drugs and we describe an optimized small molecule library making use of this information for selective kinome perturbation. We conclude that the understudied kinome contains physiologically important proteins, including possible targets for future drug discovery campaigns.