bluuebunny/crossref_metadata_2025 huggingface dataset:
Glutamate spillover in C. elegans triggers repetitive behavior through presynaptic activation of MGL-2/mGluR5
Authors: Katz Menachem , Corson Francis , Keil Wolfgang , Singhal Anupriya , Bae Andrea , Lu Yun , Liang Yupu , Shaham Shai
Published: April 2019

Glutamate is a major excitatory neurotransmitter, and impaired glutamate clearance following synaptic release promotes spillover, inducing extra-synaptic signaling. The effects of glutamate spillover on animal behavior and its neural correlates are poorly understood. We developed a glutamate spillover model in Caenorhabditis elegans by inactivating the conserved glial glutamate transporter GLT-1. GLT-1 loss drives aberrant repetitive locomotory reversal behavior through uncontrolled oscillatory release of glutamate onto AVA, a major interneuron governing reversals. Repetitive glutamate release and reversal behavior require the glutamate receptor MGL-2/mGluR5, expressed in RIM and other interneurons presynaptic to AVA. mgl-2 loss blocks oscillations and repetitive behavior; while RIM activation is sufficient to induce repetitive reversals in glt-1 mutants. Repetitive AVA firing and reversals require EGL-30/Gαq, an mGluR5 effector. Our studies reveal that cyclic autocrine presynaptic activation drives repetitive reversals following glutamate spillover. That mammalian GLT1 and mGluR5 are implicated in pathological motor repetition suggests a common mechanism controlling repetitive behaviors.
Sequencing of human genomes with nanopore technology
Authors: Bowden Rory , Davies Robert W. , Heger Andreas , Pagnamenta Alistair T. , de Cesare Mariateresa , Oikkonen Laura E. , Parkes Duncan , Freeman Colin , Dhalla Fatima , Patel Smita Y. , Popitsch Niko , Ip Camilla L. C. , Roberts Hannah E. , Salatino Silvia , Lockstone Helen , Lunter Gerton , Taylor Jenny C. , Buck David , Simpson Michael A. , Donnelly Peter
Published: April 2019

Whole-genome sequencing (WGS) is becoming widely used in clinical medicine in diagnostic contexts and to inform treatment choice. Here we evaluate the potential of the Oxford Nanopore Technologies (ONT) MinION long-read sequencer for routine WGS by sequencing the reference sample NA12878 and the genome of an individual with ataxia-pancytopenia syndrome and severe immune dysregulation. We develop and apply a novel reference panel-free analytical method to infer and then exploit phase information which improves single-nucleotide variant (SNV) calling performance from otherwise modest levels. In the clinical sample, we identify and directly phase two non-synonymous de novo variants in SAMD9L, (OMIM #159550) inferring that they lie on the same paternal haplotype. Whilst consensus SNV-calling error rates from ONT data remain substantially higher than those from short-read methods, we demonstrate the substantial benefits of analytical innovation. Ongoing improvements to base-calling and SNV-calling methodology must continue for nanopore sequencing to establish itself as a primary method for clinical WGS.
Electrochemically primed functional redox mediator generator from the decomposition of solid state electrolyte
Authors: Li Matthew , Bai Zhengyu , Li Yejing , Ma Lu , Dai Alvin , Wang Xuefeng , Luo Dan , Wu Tianpin , Liu Ping , Yang Lin , Amine Khalil , Chen Zhongwei , Lu Jun
Published: April 2019

Recent works into sulfide-type solid electrolyte materials have attracted much attention among the battery community. Specifically, the oxidative decomposition of phosphorus and sulfur based solid state electrolyte has been considered one of the main hurdles towards practical application. Here we demonstrate that this phenomenon can be leveraged when lithium thiophosphate is applied as an electrochemically “switched-on” functional redox mediator-generator for the activation of commercial bulk lithium sulfide at up to 70 wt.% lithium sulfide electrode content. X-ray adsorption near-edge spectroscopy coupled with electrochemical impedance spectroscopy and Raman indicate a catalytic effect of generated redox mediators on the first charge of lithium sulfide. In contrast to pre-solvated redox mediator species, this design decouples the lithium sulfide activation process from the constraints of low electrolyte content cell operation stemming from pre-solvated redox mediators. Reasonable performance is demonstrated at strict testing conditions.
The future of Southeast Asia’s forests
Authors: Estoque Ronald C. , Ooba Makoto , Avitabile Valerio , Hijioka Yasuaki , DasGupta Rajarshi , Togawa Takuya , Murayama Yuji
Published: April 2019

While Southeast Asia’s forests play important roles in biodiversity conservation and global carbon (C) balance, the region is also a deforestation hotspot. Here, we consider the five shared socioeconomic pathways (SSPs) to portray a range of plausible futures for the region’s forests, employing a state-of-the-art land change modelling procedure and remotely sensed data. We find that by 2050 under the worst-case scenario, SSP 3 (regional rivalry/a rocky road), the region’s forests would shrink by 5.2 million ha. The region’s aboveground forest carbon stock (AFCS) would decrease by 790 Tg C, 21% of which would be due to old-growth forest loss. Conversely, under the best-case scenario, SSP 1 (sustainability/taking the green road), the region is projected to gain 19.6 million ha of forests and 1651 Tg C of AFCS. The choice of the pathway is thus critical for the future of the region’s forests and their ecosystem functions and services.
Cascaded collimator for atomic beams traveling in planar silicon devices
Authors: Li Chao , Chai Xiao , Wei Bochao , Yang Jeremy , Daruwalla Anosh , Ayazi Farrokh , Raman C.
Published: April 2019

Micro- and increasingly, nano-fabrication have enabled the miniaturization of atomic devices, from vapor cells to atom chips for Bose-Einstein condensation. Here we present microfabricated planar devices for thermal atomic beams. Etched microchannels were used to create highly collimated, continuous rubidium atom beams traveling parallel to a silicon wafer surface. Precise, lithographic definition of the guiding channels allowed for shaping and tailoring the velocity distributions in ways not possible using conventional machining. Multiple miniature beams with individually prescribed geometries were created, including collimated, focusing and diverging outputs. A “cascaded” collimator was realized with 40 times greater purity than conventional collimators. These localized, miniature atom beam sources can be a valuable resource for a number of quantum technologies, including atom interferometers, clocks, Rydberg atoms, and hybrid atom-nanophotonic systems, as well as enabling controlled studies of atom-surface interactions at the nanometer scale.
The neural dynamics of hierarchical Bayesian causal inference in multisensory perception
Authors: Rohe Tim , Ehlis Ann-Christine , Noppeney Uta
Published: April 2019

Transforming the barrage of sensory signals into a coherent multisensory percept relies on solving the binding problem – deciding whether signals come from a common cause and should be integrated or, instead, segregated. Human observers typically arbitrate between integration and segregation consistent with Bayesian Causal Inference, but the neural mechanisms remain poorly understood. Here, we presented people with audiovisual sequences that varied in the number of flashes and beeps, then combined Bayesian modelling and EEG representational similarity analyses. Our data suggest that the brain initially represents the number of flashes and beeps independently. Later, it computes their numbers by averaging the forced-fusion and segregation estimates weighted by the probabilities of common and independent cause models (i.e. model averaging). Crucially, prestimulus oscillatory alpha power and phase correlate with observers’ prior beliefs about the world’s causal structure that guide their arbitration between sensory integration and segregation.
Physical and functional interaction between A20 and ATG16L1-WD40 domain in the control of intestinal homeostasis
Authors: Slowicka Karolina , Serramito-Gómez Inmaculada , Boada-Romero Emilio , Martens Arne , Sze Mozes , Petta Ioanna , Vikkula Hanna K. , De Rycke Riet , Parthoens Eef , Lippens Saskia , Savvides Savvas N. , Wullaert Andy , Vereecke Lars , Pimentel-Muiños Felipe X. , van Loo Geert
Published: April 2019

Prevention of inflammatory bowel disease (IBD) relies on tight control of inflammatory, cell death and autophagic mechanisms, but how these pathways are integrated at the molecular level is still unclear. Here we show that the anti-inflammatory protein A20 and the critical autophagic mediator Atg16l1 physically interact and synergize to regulate the stability of the intestinal epithelial barrier. A proteomic screen using the WD40 domain of ATG16L1 (WDD) identified A20 as a WDD-interacting protein. Loss of A20 and Atg16l1 in mouse intestinal epithelium induces spontaneous IBD-like pathology, as characterized by severe inflammation and increased intestinal epithelial cell death in both small and large intestine. Mechanistically, absence of A20 promotes Atg16l1 accumulation, while elimination of Atg16l1 or expression of WDD-deficient Atg16l1 stabilizes A20. Collectively our data show that A20 and Atg16l1 cooperatively control intestinal homeostasis by acting at the intersection of inflammatory, autophagy and cell death pathways.
Single-cell trajectories reconstruction, exploration and mapping of omics data with STREAM
Authors: Chen Huidong , Albergante Luca , Hsu Jonathan Y. , Lareau Caleb A. , Lo Bosco Giosuè , Guan Jihong , Zhou Shuigeng , Gorban Alexander N. , Bauer Daniel E. , Aryee Martin J. , Langenau David M. , Zinovyev Andrei , Buenrostro Jason D. , Yuan Guo-Cheng , Pinello Luca
Published: April 2019

Single-cell transcriptomic assays have enabled the de novo reconstruction of lineage differentiation trajectories, along with the characterization of cellular heterogeneity and state transitions. Several methods have been developed for reconstructing developmental trajectories from single-cell transcriptomic data, but efforts on analyzing single-cell epigenomic data and on trajectory visualization remain limited. Here we present STREAM, an interactive pipeline capable of disentangling and visualizing complex branching trajectories from both single-cell transcriptomic and epigenomic data. We have tested STREAM on several synthetic and real datasets generated with different single-cell technologies. We further demonstrate its utility for understanding myoblast differentiation and disentangling known heterogeneity in hematopoiesis for different organisms. STREAM is an open-source software package.
Multifunctional CRISPR-Cas9 with engineered immunosilenced human T cell epitopes
Authors: Ferdosi Shayesteh R. , Ewaisha Radwa , Moghadam Farzaneh , Krishna Sri , Park Jin G. , Ebrahimkhani Mo R. , Kiani Samira , Anderson Karen S.
Published: April 2019

The CRISPR-Cas9 system has raised hopes for developing personalized gene therapies for complex diseases. Its application for genetic and epigenetic therapies in humans raises concerns over immunogenicity of the bacterially derived Cas9 protein. Here we detect antibodies to Streptococcus pyogenes Cas9 (SpCas9) in at least 5% of 143 healthy individuals. We also report pre-existing human CD8+T cell immunity in the majority of healthy individuals screened. We identify two immunodominant SpCas9 T cell epitopes for HLA-A*02:01 using an enhanced prediction algorithm that incorporates T cell receptor contact residue hydrophobicity and HLA binding and evaluated them by T cell assays using healthy donor PBMCs. In a proof-of-principle study, we demonstrate that Cas9 protein can be modified to eliminate immunodominant epitopes through targeted mutation while preserving its function and specificity. Our study highlights the problem of pre-existing immunity against CRISPR-associated nucleases and offers a potential solution to mitigate the T cell immune response.
Metabolic profiling of cancer cells reveals genome-wide crosstalk between transcriptional regulators and metabolism
Authors: Ortmayr Karin , Dubuis Sébastien , Zampieri Mattia
Published: April 2019

Transcriptional reprogramming of cellular metabolism is a hallmark of cancer. However, systematic approaches to study the role of transcriptional regulators (TRs) in mediating cancer metabolic rewiring are missing. Here, we chart a genome-scale map of TR-metabolite associations in human cells using a combined computational-experimental framework for large-scale metabolic profiling of adherent cell lines. By integrating intracellular metabolic profiles of 54 cancer cell lines with transcriptomic and proteomic data, we unraveled a large space of associations between TRs and metabolic pathways. We found a global regulatory signature coordinating glucose- and one-carbon metabolism, suggesting that regulation of carbon metabolism in cancer may be more diverse and flexible than previously appreciated. Here, we demonstrate how this TR-metabolite map can serve as a resource to predict TRs potentially responsible for metabolic transformation in patient-derived tumor samples, opening new opportunities in understanding disease etiology, selecting therapeutic treatments and in designing modulators of cancer-related TRs.
Dynamic fibroblast contractions attract remote macrophages in fibrillar collagen matrix
Authors: Pakshir Pardis , Alizadehgiashi Moien , Wong Boaz , Coelho Nuno Miranda , Chen Xingyu , Gong Ze , Shenoy Vivek B. , McCulloch Christopher A. , Hinz Boris
Published: April 2019

Macrophage (Mϕ)-fibroblast interactions coordinate tissue repair after injury whereas miscommunications can result in pathological healing and fibrosis. We show that contracting fibroblasts generate deformation fields in fibrillar collagen matrix that provide far-reaching physical cues for Mϕ. Within collagen deformation fields created by fibroblasts or actuated microneedles, Mϕ migrate towards the force source from several hundreds of micrometers away. The presence of a dynamic force source in the matrix is critical to initiate and direct Mϕ migration. In contrast, collagen condensation and fiber alignment resulting from fibroblast remodelling activities or chemotactic signals are neither required nor sufficient to guide Mϕ migration. Binding of α2β1 integrin and stretch-activated channels mediate Mϕ migration and mechanosensing in fibrillar collagen ECM. We propose that Mϕ mechanosense the velocity of local displacements of their substrate, allowing contractile fibroblasts to attract Mϕ over distances that exceed the range of chemotactic gradients.
Excessive miR-25-3p maturation via N6-methyladenosine stimulated by cigarette smoke promotes pancreatic cancer progression
Authors: Zhang Jialiang , Bai Ruihong , Li Mei , Ye Huilin , Wu Chen , Wang Chengfeng , Li Shengping , Tan Liping , Mai Dongmei , Li Guolin , Pan Ling , Zheng Yanfen , Su Jiachun , Ye Ying , Fu Zhiqiang , Zheng Shangyou , Zuo Zhixiang , Liu Zexian , Zhao Qi , Che Xu , Xie Dan , Jia Weihua , Zeng Mu-Sheng , Tan Wen , Chen Rufu , Xu Rui-Hua , Zheng Jian , Lin Dongxin
Published: April 2019

N6-methyladenosine (m6A) modification is an important mechanism in miRNA processing and maturation, but the role of its aberrant regulation in human diseases remained unclear. Here, we demonstrate that oncogenic primary microRNA-25 (miR-25) in pancreatic duct epithelial cells can be excessively maturated by cigarette smoke condensate (CSC) via enhanced m6A modification that is mediated by NF-κB associated protein (NKAP). This modification is catalyzed by overexpressed methyltransferase-like 3 (METTL3) due to hypomethylation of theMETTL3promoter also caused by CSC. Mature miR-25, miR-25-3p, suppresses PH domain leucine-rich repeat protein phosphatase 2 (PHLPP2), resulting in the activation of oncogenic AKT-p70S6K signaling, which provokes malignant phenotypes of pancreatic cancer cells. High levels of miR-25-3p are detected in smokers and in pancreatic cancers tissues that are correlated with poor prognosis of pancreatic cancer patients. These results collectively indicate that cigarette smoke-induced miR-25-3p excessive maturation via m6A modification promotes the development and progression of pancreatic cancer.
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

DNA 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

Galvanic 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

Increased 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

Complex 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

Hepatocellular 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

Potentiation 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

Colour 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

The 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

The 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

Granulomas 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

An 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

Demographic 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

Bronchial 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

BRAF 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

The 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

Arctic 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

Covalent 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

Understanding 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.
A suite of phenotypic assays to ensure pipeline diversity when prioritizing drug-like Cryptosporidium growth inhibitors
Authors: Jumani Rajiv S. , Hasan Muhammad M. , Stebbins Erin E. , Donnelly Liam , Miller Peter , Klopfer Connor , Bessoff Kovi , Teixeira Jose E. , Love Melissa S. , McNamara Case W. , Huston Christopher D.
Published: April 2019

Cryptosporidiosis is a leading cause of life-threatening diarrhea in children, and the only currently approved drug is ineffective in malnourished children and immunocompromised people. Large-scale phenotypic screens are ongoing to identify anticryptosporidial compounds, but optimal approaches to prioritize inhibitors and establish a mechanistically diverse drug development pipeline are unknown. Here, we present a panel of medium-throughput mode of action assays that enable testing of compounds in several stages of theCryptosporidiumlife cycle. Phenotypic profiles are given for thirty-nine anticryptosporidials. Using a clustering algorithm, the compounds sort by phenotypic profile into distinct groups of inhibitors that are either chemical analogs (i.e. same molecular mechanism of action (MMOA)) or known to have similar MMOA. Furthermore, compounds belonging to multiple phenotypic clusters are efficacious in a chronic mouse model of cryptosporidiosis. This suite of phenotypic assays should ensure a drug development pipeline with diverse MMOA without the need to identify underlying mechanisms.
Optimizing reaction paths for methanol synthesis from CO2 hydrogenation via metal-ligand cooperativity
Authors: Chen Yizhen , Li Hongliang , Zhao Wanghui , Zhang Wenbo , Li Jiawei , Li Wei , Zheng Xusheng , Yan Wensheng , Zhang Wenhua , Zhu Junfa , Si Rui , Zeng Jie
Published: April 2019

As diversified reaction paths exist over practical catalysts towards CO2 hydrogenation, it is highly desiderated to precisely control the reaction path for developing efficient catalysts. Herein, we report that the ensemble of Pt single atoms coordinated with oxygen atoms in MIL-101 (Pt1@MIL) induces distinct reaction path to improve selective hydrogenation of CO2 into methanol. Pt1@MIL achieves the turnover frequency number of 117 h−1 in DMF under 32 bar at 150 °C, which is 5.6 times that of Ptn@MIL. Moreover, the selectivity for methanol is 90.3% over Pt1@MIL, much higher than that (13.3%) over Ptn@MIL with CO as the major product. According to mechanistic studies, CO2 is hydrogenated into HCOO* as the intermediate for Pt1@MIL, whereas COOH* serves as the intermediate for Ptn@MIL. The unique reaction path over Pt1@MIL not only lowers the activation energy for the enhanced catalytic activity, but also contributes to the high selectivity for methanol.
Synthesizing a ν=2/3 fractional quantum Hall effect edge state from counter-propagating ν=1 and ν=1/3 states
Authors: Cohen Yonatan , Ronen Yuval , Yang Wenmin , Banitt Daniel , Park Jinhong , Heiblum Moty , Mirlin Alexander D. , Gefen Yuval , Umansky Vladimir
Published: April 2019

Topological edge-reconstruction occurs in hole-conjugate states of the fractional quantum Hall effect. The frequently studied filling factor, ν = 2/3, was originally proposed to harbor two counter-propagating modes: a downstream v = 1 and an upstream v = 1/3. However, charge equilibration between these two modes always led to an observed downstream v = 2/3 charge mode accompanied by an upstream neutral mode. Here, we present an approach to synthetize a v = 2/3 edge mode from its basic counter-propagating charged constituents, allowing a controlled equilibration between the two counter-propagating charge modes. This platform is based on a carefully designed double-quantum-well, which hosts two populated electronic sub-bands (lower and upper), with corresponding filling factors, vl and vu. By separating the 2D plane to two gated intersecting halves, each with different fillings, counter-propagating chiral modes can be formed along the intersection line. Equilibration between these modes can be controlled with the top gates’ voltage and the magnetic field.
Current forest carbon fixation fuels stream CO2 emissions
Authors: Campeau A. , Bishop K. , Amvrosiadi N. , Billett M. F. , Garnett M. H. , Laudon H. , Öquist M. G. , Wallin M. B.
Published: April 2019

Stream CO2 emissions contribute significantly to atmospheric climate forcing. While there are strong indications that groundwater inputs sustain these emissions, the specific biogeochemical pathways and timescales involved in this lateral CO2 export are still obscure. Here, via an extensive radiocarbon (14C) characterisation of CO2 and DOC in stream water and its groundwater sources in an old-growth boreal forest, we demonstrate that the 14C-CO2 is consistently in tune with the current atmospheric 14C-CO2 level and shows little association with the 14C-DOC in the same waters. Our findings thus indicate that stream CO2 emissions act as a shortcut that returns CO2 recently fixed by the forest vegetation to the atmosphere. Our results expose a positive feedback mechanism within the C budget of forested catchments, where stream CO2 emissions will be highly sensitive to changes in forest C allocation patterns associated with climate and land-use changes.
The neural development of empathy is sensitive to caregiving and early trauma
Authors: Levy Jonathan , Goldstein Abraham , Feldman Ruth
Published: April 2019

Empathy is a core human social ability shaped by biological dispositions and caregiving experiences; yet the mechanisms sustaining maturation of the neural basis of empathy are unknown. Here, we followed eighty-four children, including 42 exposed to chronic war-related adversity, across the first decade of life, and assessed parenting, child temperament, and anxiety disorders as contributors to the neural development of empathy. At preadolescence, participants underwent magenetoencephalography while observing others’ distress. Preadolescents show a widely-distributed response in structures implicating the overlap of affective (automatic) and cognitive (higher-order) empathy, which is predicted by mother-child synchrony across childhood. Only temperamentally reactive young children growing in chronic adversity, particularly those who later develop anxiety disorders, display additional engagement of neural nodes possibly reflecting hyper-mentalizing and ruminations over the distressing stimuli. These findings demonstrate how caregiving patterns fostering interpersonal resonance, reactive temperament, and chronic adversity combine across early development to shape the human empathic brain.
Conductivity and lithiophilicity gradients guide lithium deposition to mitigate short circuits
Authors: Pu Jun , Li Jiachen , Zhang Kai , Zhang Tao , Li Chaowei , Ma Haixia , Zhu Jia , Braun Paul V. , Lu Jun , Zhang Huigang
Published: April 2019

Lithium metal anodes hold great promise to enable high-energy battery systems. However, lithium dendrites at the interface between anode and separator pose risks of short circuits and fire, impeding the safe application. In contrast to conventional approaches of suppressing dendrites, here we show a deposition-regulating strategy by electrically passivating the top of a porous nickel scaffold and chemically activating the bottom of the scaffold to form conductivity/lithiophilicity gradients, whereby lithium is guided to deposit preferentially at the bottom of the anode, safely away from the separator. The resulting lithium anodes significantly reduce the probability of dendrite-induced short circuits. Crucially, excellent properties are also demonstrated at extremely high capacity (up to 40 mAh cm−2), high current density, and/or low temperatures (down to −15 °C), which readily induce dendrite shorts in particular. This facile and viable deposition-regulating strategy provides an approach to preferentially deposit lithium in safer positions, enabling a promising anode for next-generation lithium batteries.