bluuebunny/crossref_metadata_2025_split huggingface dataset:
A DNMT3A PWWP mutation leads to methylation of bivalent chromatin and growth retardation in mice
Authors: Sendžikaitė Gintarė , Hanna Courtney W. , Stewart-Morgan Kathleen R. , Ivanova Elena , Kelsey Gavin 
Published: April 2019

AbstractDNA methyltransferases (DNMTs) deposit DNA methylation, which regulates gene expression and is essential for mammalian development. Histone post-translational modifications modulate the recruitment and activity of DNMTs. The PWWP domains of DNMT3A and DNMT3B are posited to interact with histone 3 lysine 36 trimethylation (H3K36me3); however, the functionality of this interaction for DNMT3A remains untested in vivo. Here we present a mouse model carrying a D329A point mutation in the DNMT3A PWWP domain. The mutation causes dominant postnatal growth retardation. At the molecular level, it results in progressive DNA hypermethylation across domains marked by H3K27me3 and bivalent chromatin, and de-repression of developmental regulatory genes in adult hypothalamus. Evaluation of non-CpG methylation, a marker of de novo methylation, further demonstrates the altered recruitment and activity of DNMT3AD329A at bivalent domains. This work provides key molecular insights into the function of the DNMT3A-PWWP domain and role of DNMT3A in regulating postnatal growth.
Neural substrates, dynamics and thresholds of galvanic vestibular stimulation in the behaving primate
Authors: Kwan Annie , Forbes Patrick A. , Mitchell Diana E. , Blouin Jean-Sébastien , Cullen Kathleen E. 
Published: April 2019

AbstractGalvanic vestibular stimulation (GVS) uses the external application of electrical current to selectively target the vestibular system in humans. Despite its recent popularity for the assessment/treatment of clinical conditions, exactly how this non-invasive tool activates the vestibular system remains an open question. Here we directly investigate single vestibular afferent responses to GVS applied to the mastoid processes of awake-behaving monkeys. Transmastoid GVS produces robust and parallel activation of both canal and otolith afferents. Notably, afferent activation increases with intrinsic neuronal variability resulting in constant GVS-evoked neuronal detection thresholds across all afferents. Additionally, afferent tuning differs for GVS versus natural self-motion stimulation. Using a stochastic model of repetitive activity in afferents, we largely explain the main features of GVS-evoked vestibular afferent dynamics. Taken together, our results reveal the neural substrate underlying transmastoid GVS-evoked perceptual, ocular and postural responses—information that is essential to advance GVS applicability for biomedical uses in humans.
YAP-independent mechanotransduction drives breast cancer progression
Authors: Lee Joanna Y. , Chang Jessica K. , Dominguez Antonia A. , Lee Hong-pyo , Nam Sungmin , Chang Julie , Varma Sushama , Qi Lei S. , West Robert B. , Chaudhuri Ovijit 
Published: April 2019

AbstractIncreased tissue stiffness is a driver of breast cancer progression. The transcriptional regulator YAP is considered a universal mechanotransducer, based largely on 2D culture studies. However, the role of YAP during in vivo breast cancer remains unclear. Here, we find that mechanotransduction occurs independently of YAP in breast cancer patient samples and mechanically tunable 3D cultures. Mechanistically, the lack of YAP activity in 3D culture and in vivo is associated with the absence of stress fibers and an order of magnitude decrease in nuclear cross-sectional area relative to 2D culture. This work highlights the context-dependent role of YAP in mechanotransduction, and establishes that YAP does not mediate mechanotransduction in breast cancer.
Diverse synaptic and dendritic mechanisms of complex spike burst generation in hippocampal CA3 pyramidal cells
Authors: Raus Balind Snezana , Magó Ádám , Ahmadi Mahboobeh , Kis Noémi , Varga-Németh Zsófia , Lőrincz Andrea , Makara Judit K. 
Published: April 2019

AbstractComplex spike bursts (CSBs) represent a characteristic firing pattern of hippocampal pyramidal cells (PCs). In CA1PCs, CSBs are driven by regenerative dendritic plateau potentials, produced by correlated entorhinal cortical and CA3 inputs that simultaneously depolarize distal and proximal dendritic domains. However, in CA3PCs neither the generation mechanisms nor the computational role of CSBs are well elucidated. We show that CSBs are induced by dendritic Ca2+ spikes in CA3PCs. Surprisingly, the ability of CA3PCs to produce CSBs is heterogeneous, with non-uniform synaptic input-output transformation rules triggering CSBs. The heterogeneity is partly related to the topographic position of CA3PCs; we identify two ion channel types, HCN and Kv2 channels, whose proximodistal activity gradients contribute to subregion-specific modulation of CSB propensity. Our results suggest that heterogeneous dendritic integrative properties, along with previously reported synaptic connectivity gradients, define functional subpopulations of CA3PCs that may support CA3 network computations underlying associative memory processes.
Promotion of growth factor signaling as a critical function of β-catenin during HCC progression
Authors: Kim Eunsun , Lisby Amanda , Ma Connie , Lo Nathanael , Ehmer Ursula , Hayer Katharina E. , Furth Emma E. , Viatour Patrick 
Published: April 2019

AbstractHepatocellular carcinoma (HCC) is the second leading cause of cancer-related deaths worldwide. β-catenin is widely thought to be a major oncogene in HCC based on the frequency of mutations associated with aberrant Wnt signaling in HCC patients. Challenging this model, our data reveal that β-catenin nuclear accumulation is restricted to the late stage of the disease. Until then, β-catenin is primarily located at the plasma membrane in complex with multiple cadherin family members where it drives tumor cell survival by enhancing the signaling of growth factor receptors such as EGFR. Therefore, our study reveals the evolving nature of β-catenin in HCC to establish it as a compound tumor promoter during the progression of the disease.
Adenosine receptor agonism protects against NETosis and thrombosis in antiphospholipid syndrome
Authors: Ali Ramadan A. , Gandhi Alex A. , Meng He , Yalavarthi Srilakshmi , Vreede Andrew P. , Estes Shanea K. , Palmer Olivia R. , Bockenstedt Paula L. , Pinsky David J. , Greve Joan M. , Diaz Jose A. , Kanthi Yogendra , Knight Jason S. 
Published: April 2019

AbstractPotentiation of neutrophil extracellular trap (NET) release is one mechanism by which antiphospholipid antibodies (aPL Abs) effect thrombotic events in patients with antiphospholipid syndrome (APS). Surface adenosine receptors trigger cyclic AMP (cAMP) formation in neutrophils, and this mechanism has been proposed to regulate NETosis in some contexts. Here we report that selective agonism of the adenosine A2Areceptor (CGS21680) suppresses aPL Ab-mediated NETosis in protein kinase A-dependent fashion. CGS21680 also reduces thrombosis in the inferior vena cavae of both control mice and mice administered aPL Abs. The antithrombotic medication dipyridamole is known to potentiate adenosine signaling by increasing extracellular concentrations of adenosine and interfering with the breakdown of cAMP. Like CGS21680, dipyridamole suppresses aPL Ab-mediated NETosis via the adenosine A2Areceptor and mitigates venous thrombosis in mice. In summary, these data suggest an anti-inflammatory therapeutic paradigm in APS, which may extend to thrombotic disease in the general population.
Genetics and evidence for balancing selection of a sex-linked colour polymorphism in a songbird
Authors: Kim Kang-Wook , Jackson Benjamin C. , Zhang Hanyuan , Toews David P. L. , Taylor Scott A. , Greig Emma I. , Lovette Irby J. , Liu Mengning M. , Davison Angus , Griffith Simon C. , Zeng Kai , Burke Terry 
Published: April 2019

AbstractColour polymorphisms play a key role in sexual selection and speciation, yet the mechanisms that generate and maintain them are not fully understood. Here, we use genomic and transcriptomic tools to identify the precise genetic architecture and evolutionary history of a sex-linked colour polymorphism in the Gouldian finchErythrura gouldiaethat is also accompanied by remarkable differences in behaviour and physiology. We find that differences in colour are associated with an ~72-kbp region of the Z chromosome in a putative regulatory region forfollistatin, an antagonist of theTGF-βsuperfamily genes. The region is highly differentiated between morphs, unlike the rest of the genome, yet we find no evidence that an inversion is involved in maintaining the distinct haplotypes. Coalescent simulations confirm that there is elevated nucleotide diversity and an excess of intermediate frequency alleles at this locus. We conclude that this pleiotropic colour polymorphism is most probably maintained by balancing selection.
Critical role of bacterial dissemination in an infant rabbit model of bacillary dysentery
Authors: Yum Lauren K. , Byndloss Mariana X. , Feldman Sanford H. , Agaisse Hervé 
Published: April 2019

AbstractThe bacterial pathogen Shigella flexneri causes 270 million cases of bacillary dysentery (blood in stool) worldwide every year, resulting in more than 200,000 deaths. A major challenge in combating bacillary dysentery is the lack of a small-animal model that recapitulates the symptoms observed in infected individuals, including bloody diarrhea. Here, we show that similar to humans, infant rabbits infected with S. flexneri experience severe inflammation, massive ulceration of the colonic mucosa, and bloody diarrhea. T3SS-dependent invasion of epithelial cells is necessary and sufficient for mediating immune cell infiltration and vascular lesions. However, massive ulceration of the colonic mucosa, bloody diarrhea, and dramatic weight loss are strictly contingent on the ability of the bacteria to spread from cell to cell. The infant rabbit model features bacterial dissemination as a critical determinant of S. flexneri pathogenesis and provides a unique small-animal model for research and development of therapeutic interventions.
RUNX3 regulates cell cycle-dependent chromatin dynamics by functioning as a pioneer factor of the restriction-point
Authors: Lee Jung-Won , Kim Da-Mi , Jang Ju-Won , Park Tae-Geun , Song Soo-Hyun , Lee You-Soub , Chi Xin-Zi , Park Il Yeong , Hyun Jin-Won , Ito Yoshiaki , Bae Suk-Chul 
Published: April 2019

AbstractThe cellular decision regarding whether to undergo proliferation or death is made at the restriction (R)-point, which is disrupted in nearly all tumors. The identity of the molecular mechanisms that govern the R-point decision is one of the fundamental issues in cell biology. We found that early after mitogenic stimulation, RUNX3 binds to its target loci, where it opens chromatin structure by sequential recruitment of Trithorax group proteins and cell-cycle regulators to drive cells to the R-point. Soon after, RUNX3 closes these loci by recruiting Polycomb repressor complexes, causing the cell to pass through the R-point toward S phase. If the RAS signal is constitutively activated, RUNX3 inhibits cell cycle progression by maintaining R-point-associated genes in an open structure. Our results identify RUNX3 as a pioneer factor for the R-point and reveal the molecular mechanisms by which appropriate chromatin modifiers are selectively recruited to target loci for appropriate R-point decisions.
Spatial and temporal localization of immune transcripts defines hallmarks and diversity in the tuberculosis granuloma
Authors: Carow Berit , Hauling Thomas , Qian Xiaoyan , Kramnik Igor , Nilsson Mats , Rottenberg Martin E. 
Published: April 2019

AbstractGranulomas are the pathological hallmark of tuberculosis (TB) and the niche where bacilli can grow and disseminate or the immunological microenvironment in which host cells interact to prevent bacterial dissemination. Here we show 34 immune transcripts align to the morphology of lung sections from Mycobacterium tuberculosis-infected mice at cellular resolution. Colocalizing transcript networks at <10 μm in C57BL/6 mouse granulomas increase complexity with time after infection. B-cell clusters develop late after infection. Transcripts from activated macrophages are enriched at subcellular distances from M. tuberculosis. Encapsulated C3HeB/FeJ granulomas show necrotic centers with transcripts associated with immunosuppression (Foxp3, Il10), whereas those in the granuloma rims associate with activated T cells and macrophages. We see highly diverse networks with common interactors in similar lesions. Different immune landscapes of M. tuberculosis granulomas depending on the time after infection, the histopathological features of the lesion, and the proximity to bacteria are here defined.
Multi-metal electrohydrodynamic redox 3D printing at the submicron scale
Authors: Reiser Alain , Lindén Marcus , Rohner Patrik , Marchand Adrien , Galinski Henning , Sologubenko Alla S. , Wheeler Jeffrey M. , Zenobi Renato , Poulikakos Dimos , Spolenak Ralph 
Published: April 2019

AbstractAn extensive range of metals can be dissolved and re-deposited in liquid solvents using electrochemistry. We harness this concept for additive manufacturing, demonstrating the focused electrohydrodynamic ejection of metal ions dissolved from sacrificial anodes and their subsequent reduction to elemental metals on the substrate. This technique, termed electrohydrodynamic redox printing (EHD-RP), enables the direct, ink-free fabrication of polycrystalline multi-metal 3D structures without the need for post-print processing. On-the-fly switching and mixing of two metals printed from a single multichannel nozzle facilitates a chemical feature size of <400 nm with a spatial resolution of 250 nm at printing speeds of up to 10 voxels per second. As shown, the additive control of the chemical architecture of materials provided by EHD-RP unlocks the synthesis of 3D bi-metal structures with programmed local properties and opens new avenues for the direct fabrication of chemically architected materials and devices.
Palaeodemographic modelling supports a population bottleneck during the Pleistocene-Holocene transition in Iberia
Authors: Fernández-López de Pablo Javier , Gutiérrez-Roig Mario , Gómez-Puche Madalena , McLaughlin Rowan , Silva Fabio , Lozano Sergi 
Published: April 2019

AbstractDemographic change lies at the core of debates on genetic inheritance and resilience to climate change of prehistoric hunter-gatherers. Here we analyze the radiocarbon record of Iberia to reconstruct long-term changes in population levels and test different models of demographic growth during the Last Glacial-Interglacial transition. Our best fitting demographic model is composed of three phases. First, we document a regime of exponential population increase during the Late Glacial warming period (c.16.6-12.9 kya). Second, we identify a phase of sustained population contraction and stagnation, beginning with the cold episode of the Younger Dryas and continuing through the first half of the Early Holocene (12.9-10.2 kya). Finally, we report a third phase of density-dependent logistic growth (10.2-8 kya), with rapid population increase followed by stabilization. Our results support a population bottleneck hypothesis during the Last Glacial-Interglacial transition, providing a demographic context to interpret major shifts of prehistoric genetic groups in south-west Europe.
Molecular subtyping reveals immune alterations associated with progression of bronchial premalignant lesions
Authors: Beane Jennifer E. , Mazzilli Sarah A. , Campbell Joshua D. , Duclos Grant , Krysan Kostyantyn , Moy Christopher , Perdomo Catalina , Schaffer Michael , Liu Gang , Zhang Sherry , Liu Hanqiao , Vick Jessica , Dhillon Samjot S. , Platero Suso J. , Dubinett Steven M. , Stevenson Christopher , Reid Mary E. , Lenburg Marc E. , Spira Avrum E. 
Published: April 2019

AbstractBronchial premalignant lesions (PMLs) are precursors of lung squamous cell carcinoma, but have variable outcome, and we lack tools to identify and treat PMLs at risk for progression to cancer. Here we report the identification of four molecular subtypes of PMLs with distinct differences in epithelial and immune processes based on RNA-Seq profiling of endobronchial biopsies from high-risk smokers. The Proliferative subtype is enriched with bronchial dysplasia and exhibits up-regulation of metabolic and cell cycle pathways. A Proliferative subtype-associated gene signature identifies subjects with Proliferative PMLs from normal-appearing uninvolved large airway brushings with high specificity. In progressive/persistent Proliferative lesions expression of interferon signaling and antigen processing/presentation pathways decrease and immunofluorescence indicates a depletion of innate and adaptive immune cells compared with regressive lesions. Molecular biomarkers measured in PMLs or the uninvolved airway can enhance histopathological grading and suggest immunoprevention strategies for intercepting the progression of PMLs to lung cancer.
K27-linked ubiquitination of BRAF by ITCH engages cytokine response to maintain MEK-ERK signaling
Authors: Yin Qing , Han Tao , Fang Bin , Zhang Guolin , Zhang Chao , Roberts Evan R. , Izumi Victoria , Zheng Mengmeng , Jiang Shulong , Yin Xiu , Kim Minjung , Cai Jianfeng , Haura Eric B. , Koomen John M. , Smalley Keiran S. M. , Wan Lixin 
Published: April 2019

AbstractBRAF plays an indispensable role in activating the MEK/ERK pathway to drive tumorigenesis. Receptor tyrosine kinase and RAS-mediated BRAF activation have been extensively characterized, however, it remains undefined how BRAF function is fine-tuned by stimuli other than growth factors. Here, we report that in response to proinflammatory cytokines, BRAF is subjected to lysine 27-linked poly-ubiquitination in melanoma cells by the ITCH ubiquitin E3 ligase. Lysine 27-linked ubiquitination of BRAF recruits PP2A to antagonize the S365 phosphorylation and disrupts the inhibitory interaction with 14–3–3, leading to sustained BRAF activation and subsequent elevation of the MEK/ERK signaling. Physiologically, proinflammatory cytokines activate ITCH to maintain BRAF activity and to promote proliferation and invasion of melanoma cells, whereas the ubiquitination-deficient BRAF mutant displays compromised kinase activity and reduced tumorigenicity. Collectively, our study reveals a pivotal role for ITCH-mediated BRAF ubiquitination in coordinating the signals between cytokines and the MAPK pathway activation in melanoma cells.
A unified strategy toward total syntheses of lindenane sesquiterpenoid [4 + 2] dimers
Authors: Du Biao , Huang Zhengsong , Wang Xiao , Chen Ting , Shen Guo , Fu Shaomin , Liu Bo 
Published: April 2019

AbstractThe dimeric lindenane sesquiterpenoids are mainly isolated from the plants of Chloranthaceae family. Structurally, they have a crowded molecular scaffold decorated with more than 11 stereogenic centers. Here we report divergent syntheses of eight dimeric lindenane sesquiterpenoids, shizukaols A, C, D, I, chlorajaponilide C, multistalide B, sarcandrolide J and sarglabolide I. In particular, we present a unified dimerization strategy utilizing a base-mediated thermal [4 + 2] cycloaddition between a common furyl diene, generated in situ, and various types of dienophiles. Accordingly, all the three types of lindenane [4 + 2] dimers with versatile biological activities are accessible, which would stimulate future probing of their pharmaceutical potential.
Climate policy implications of nonlinear decline of Arctic land permafrost and other cryosphere elements
Authors: Yumashev Dmitry , Hope Chris , Schaefer Kevin , Riemann-Campe Kathrin , Iglesias-Suarez Fernando , Jafarov Elchin , Burke Eleanor J. , Young Paul J. , Elshorbany Yasin , Whiteman Gail 
Published: April 2019

AbstractArctic feedbacks accelerate climate change through carbon releases from thawing permafrost and higher solar absorption from reductions in the surface albedo, following loss of sea ice and land snow. Here, we include dynamic emulators of complex physical models in the integrated assessment model PAGE-ICE to explore nonlinear transitions in the Arctic feedbacks and their subsequent impacts on the global climate and economy under the Paris Agreement scenarios. The permafrost feedback is increasingly positive in warmer climates, while the albedo feedback weakens as the ice and snow melt. Combined, these two factors lead to significant increases in the mean discounted economic effect of climate change: +4.0% ($24.8 trillion) under the 1.5 °C scenario, +5.5% ($33.8 trillion) under the 2 °C scenario, and +4.8% ($66.9 trillion) under mitigation levels consistent with the current national pledges. Considering the nonlinear Arctic feedbacks makes the 1.5 °C target marginally more economically attractive than the 2 °C target, although both are statistically equivalent.
Ultrafast charge transfer coupled with lattice phonons in two-dimensional covalent organic frameworks
Authors: Kim Tae Wu , Jun Sunhong , Ha Yoonhoo , Yadav Rajesh K. , Kumar Abhishek , Yoo Chung-Yul , Oh Inhwan , Lim Hyung-Kyu , Shin Jae Won , Ryoo Ryong , Kim Hyungjun , Kim Jeongho , Baeg Jin-Ook , Ihee Hyotcherl 
Published: April 2019

AbstractCovalent organic frameworks (COFs) have emerged as a promising light-harvesting module for artificial photosynthesis and photovoltaics. For efficient generation of free charge carriers, the donor–acceptor (D-A) conjugation has been adopted for two-dimensional (2D) COFs recently. In the 2D D-A COFs, photoexcitation would generate a polaron pair, which is a precursor to free charge carriers and has lower binding energy than an exciton. Although the character of the primary excitation species is a key factor in determining optoelectronic properties of a material, excited-state dynamics leading to the creation of a polaron pair have not been investigated yet. Here, we investigate the dynamics of photogenerated charge carriers in 2D D-A COFs by combining femtosecond optical spectroscopy and non-adiabatic molecular dynamics simulation. From this investigation, we elucidate that the polaron pair is formed through ultrafast intra-layer hole transfer coupled with coherent vibrations of the 2D lattice, suggesting a mechanism of phonon-assisted charge transfer.
Phase-field modeling and machine learning of electric-thermal-mechanical breakdown of polymer-based dielectrics
Authors: Shen Zhong-Hui , Wang Jian-Jun , Jiang Jian-Yong , Huang Sharon X. , Lin Yuan-Hua , Nan Ce-Wen , Chen Long-Qing , Shen Yang 
Published: April 2019

AbstractUnderstanding the breakdown mechanisms of polymer-based dielectrics is critical to achieving high-density energy storage. Here a comprehensive phase-field model is developed to investigate the electric, thermal, and mechanical effects in the breakdown process of polymer-based dielectrics. High-throughput simulations are performed for the P(VDF-HFP)-based nanocomposites filled with nanoparticles of different properties. Machine learning is conducted on the database from the high-throughput simulations to produce an analytical expression for the breakdown strength, which is verified by targeted experimental measurements and can be used to semiquantitatively predict the breakdown strength of the P(VDF-HFP)-based nanocomposites. The present work provides fundamental insights to the breakdown mechanisms of polymer nanocomposite dielectrics and establishes a powerful theoretical framework of materials design for optimizing their breakdown strength and thus maximizing their energy storage by screening suitable nanofillers. It can potentially be extended to optimize the performances of other types of materials such as thermoelectrics and solid electrolytes.