bluuebunny/crossref_metadata_2025_split huggingface dataset:
The SIAH2-NRF1 axis spatially regulates tumor microenvironment remodeling for tumor progression
Authors: Ma Biao , Cheng Hongcheng , Mu Chenglong , Geng Guangfeng , Zhao Tian , Luo Qian , Ma Kaili , Chang Rui , Liu Qiangqiang , Gao Ruize , Nie Junli , Xie Jiaying , Han Jinxue , Chen Linbo , Ma Gui , Zhu Yushan , Chen Quan 
Published: March 2019

AbstractThe interactions between tumor cells with their microenvironments, including hypoxia, acidosis and immune cells, lead to the tumor heterogeneity which promotes tumor progression. Here, we show that SIAH2-NRF1 axis remodels tumor microenvironment through regulating tumor mitochondrial function, tumor-associated macrophages (TAMs) polarization and cell death for tumor maintenance and progression. Mechanistically, low mitochondrial gene expression in breast cancers is associated with a poor clinical outcome. The hypoxia-activated E3 ligase SIAH2 spatially downregulates nuclear-encoded mitochondrial gene expression including pyruvate dehydrogenase beta via degrading NRF1 (Nuclear Respiratory Factor 1) through ubiquitination on lysine 230, resulting in enhanced Warburg effect, metabolic reprogramming and pro-tumor immune response. Dampening NRF1 degradation under hypoxia not only impairs the polarization of TAMs, but also promotes tumor cells to become more susceptible to apoptosis in a FADD-dependent fashion, resulting in secondary necrosis due to the impairment of efferocytosis. These data represent that inhibition of NRF1 degradation is a potential therapeutic strategy against cancer.
ACVR1 R206H cooperates with H3.1K27M in promoting diffuse intrinsic pontine glioma pathogenesis
Authors: Hoeman Christine M. , Cordero Francisco J. , Hu Guo , Misuraca Katie , Romero Megan M. , Cardona Herminio J. , Nazarian Javad , Hashizume Rintaro , McLendon Roger , Yu Paul , Procissi Daniele , Gadd Samantha , Becher Oren J. 
Published: March 2019

AbstractDiffuse intrinsic pontine glioma (DIPG) is an incurable pediatric brain tumor, with approximately 25% of DIPGs harboring activating ACVR1 mutations that commonly co-associate with H3.1K27M mutations. Here we show that in vitro expression of ACVR1 R206H with and without H3.1K27M upregulates mesenchymal markers and activates Stat3 signaling. In vivo expression of ACVR1 R206H or G328V with H3.1K27M and p53 deletion induces glioma-like lesions but is not sufficient for full gliomagenesis. However, in combination with PDGFA signaling, ACVR1 R206H and H3.1K27M significantly decrease survival and increase tumor incidence. Treatment of ACVR1 R206H mutant DIPGs with exogenous Noggin or the ACVR1 inhibitor LDN212854 significantly prolongs survival, with human ACVR1 mutant DIPG cell lines also being sensitive to LDN212854 treatment. Together, our results demonstrate that ACVR1 R206H and H3.1K27M promote tumor initiation, accelerate gliomagenesis, promote a mesenchymal profile partly due to Stat3 activation, and identify LDN212854 as a promising compound to treat DIPG.
Helical antimicrobial peptides assemble into protofibril scaffolds that present ordered dsDNA to TLR9
Authors: Lee Ernest Y. , Zhang Changsheng , Di Domizio Jeremy , Jin Fan , Connell Will , Hung Mandy , Malkoff Nicolas , Veksler Veronica , Gilliet Michel , Ren Pengyu , Wong Gerard C. L. 
Published: March 2019

AbstractAmphiphilicity in ɑ-helical antimicrobial peptides (AMPs) is recognized as a signature of potential membrane activity. Some AMPs are also strongly immunomodulatory: LL37-DNA complexes potently amplify Toll-like receptor 9 (TLR9) activation in immune cells and exacerbate autoimmune diseases. The rules governing this proinflammatory activity of AMPs are unknown. Here we examine the supramolecular structures formed between DNA and three prototypical AMPs using small angle X-ray scattering and molecular modeling. We correlate these structures to their ability to activate TLR9 and show that a key criterion is the AMP’s ability to assemble into superhelical protofibril scaffolds. These structures enforce spatially-periodic DNA organization in nanocrystalline immunocomplexes that trigger strong recognition by TLR9, which is conventionally known to bind single DNA ligands. We demonstrate that we can “knock in” this ability for TLR9 amplification in membrane-active AMP mutants, which suggests the existence of tradeoffs between membrane permeating activity and immunomodulatory activity in AMP sequences.
Protein and RNA dynamical fingerprinting
Authors: Niessen Katherine A. , Xu Mengyang , George Deepu K. , Chen Michael C. , Ferré-D’Amaré Adrian R. , Snell Edward H. , Cody Vivian , Pace James , Schmidt Marius , Markelz Andrea G. 
Published: March 2019

AbstractProtein structural vibrations impact biology by steering the structure to functional intermediate states; enhancing tunneling events; and optimizing energy transfer. Strong water absorption and a broad continuous vibrational density of states have prevented optical identification of these vibrations. Recently spectroscopic signatures that change with functional state were measured using anisotropic terahertz microscopy. The technique however has complex sample positioning requirements and long measurement times, limiting access for the biomolecular community. Here we demonstrate that a simplified system increases spectroscopic structure to dynamically fingerprint biomacromolecules with a factor of 6 reduction in data acquisition time. Using this technique, polarization varying anisotropy terahertz microscopy, we show sensitivity to inhibitor binding and unique vibrational spectra for several proteins and an RNA G-quadruplex. The technique’s sensitivity to anisotropic absorbance and birefringence provides rapid assessment of macromolecular dynamics that impact biology.
Synthetic energy sensor AMPfret deciphers adenylate-dependent AMPK activation mechanism
Authors: Pelosse Martin , Cottet-Rousselle Cécile , Bidan Cécile M. , Dupont Aurélie , Gupta Kapil , Berger Imre , Schlattner Uwe 
Published: March 2019

AbstractAMP-activated protein kinase AMPK senses and regulates cellular energy state. AMPK activation by increasing AMP and ADP concentrations involves a conformational switch within the heterotrimeric complex. This is exploited here for the construction of a synthetic sensor of cellular energetics and allosteric AMPK activation, AMPfret. Based on engineered AMPK fused to fluorescent proteins, the sensor allows direct, real-time readout of the AMPK conformational state by fluorescence resonance energy transfer (FRET). AMPfret faithfully and dynamically reports the binding of AMP and ADP to AMPK γ-CBS sites, competed by Mg2+-free ATP. FRET signals correlate with activation of AMPK by allosteric mechanisms and protection from dephosphorylation, attributed here to specific CBS sites, but does not require activation loop phosphorylation. Moreover, AMPfret detects binding of pharmacological compounds to the AMPK α/β-ADaM site enabling activator screening. Cellular assays demonstrate that AMPfret is applicable in vivo for spatiotemporal analysis of energy state and allosteric AMPK activation.
Atypical functional connectome hierarchy in autism
Authors: Hong Seok-Jun , Vos de Wael Reinder , Bethlehem Richard A. I. , Lariviere Sara , Paquola Casey , Valk Sofie L. , Milham Michael P. , Di Martino Adriana , Margulies Daniel S. , Smallwood Jonathan , Bernhardt Boris C. 
Published: March 2019

AbstractOne paradox of autism is the co-occurrence of deficits in sensory and higher-order socio-cognitive processing. Here, we examined whether these phenotypical patterns may relate to an overarching system-level imbalance—specifically a disruption in macroscale hierarchy affecting integration and segregation of unimodal and transmodal networks. Combining connectome gradient and stepwise connectivity analysis based on task-free functional magnetic resonance imaging (fMRI), we demonstrated atypical connectivity transitions between sensory and higher-order default mode regions in a large cohort of individuals with autism relative to typically-developing controls. Further analyses indicated that reduced differentiation related to perturbed stepwise connectivity from sensory towards transmodal areas, as well as atypical long-range rich-club connectivity. Supervised pattern learning revealed that hierarchical features predicted deficits in social cognition and low-level behavioral symptoms, but not communication-related symptoms. Our findings provide new evidence for imbalances in network hierarchy in autism, which offers a parsimonious reference frame to consolidate its diverse features.
A small secreted protein triggers a TLR2/4-dependent inflammatory response during invasive Candida albicans infection
Authors: Wang Wenjuan , Deng Zihou , Wu Hongyu , Zhao Qun , Li Tiantian , Zhu Wencheng , Wang Xiongjun , Tang Longhai , Wang Chengshu , Cui Shu-Zhong , Xiao Hui , Chen Jiangye 
Published: March 2019

AbstractCandida albicans can switch from commensal to pathogenic mode, causing mucosal or disseminated candidiasis. The host relies on pattern-recognition receptors including Toll-like receptors (TLRs) and C-type lectin receptors (CLRs) to sense invading fungal pathogens and launch immune defense mechanisms. However, the complex interplay between fungus and host innate immunity remains incompletely understood. Here we report that C. albicans upregulates expression of a small secreted cysteine-rich protein Sel1 upon encountering limited nitrogen and abundant serum. Sel1 activates NF-κB and MAPK signaling pathways, leading to expression of proinflammatory cytokines and chemokines. Comprehensive genetic and biochemical analyses reveal both TLR2 and TLR4 are required for the recognition of Sel1. Further, SEL1-deficient C. albicans display an impaired immune response in vivo, causing increased morbidity and mortality in a bloodstream infection model. We identify a critical component in the Candida-host interaction that opens a new avenue to tackle Candida infection and inflammation.
Probing hydrogen bond strength in liquid water by resonant inelastic X-ray scattering
Authors: Vaz da Cruz Vinícius , Gel’mukhanov Faris , Eckert Sebastian , Iannuzzi Marcella , Ertan Emelie , Pietzsch Annette , Couto Rafael C. , Niskanen Johannes , Fondell Mattis , Dantz Marcus , Schmitt Thorsten , Lu Xingye , McNally Daniel , Jay Raphael M. , Kimberg Victor , Föhlisch Alexander , Odelius Michael 
Published: March 2019

AbstractLocal probes of the electronic ground state are essential for understanding hydrogen bonding in aqueous environments. When tuned to the dissociative core-excited state at the O1s pre-edge of water, resonant inelastic X-ray scattering back to the electronic ground state exhibits a long vibrational progression due to ultrafast nuclear dynamics. We show how the coherent evolution of the OH bonds around the core-excited oxygen provides access to high vibrational levels in liquid water. The OH bonds stretch into the long-range part of the potential energy curve, which makes the X-ray probe more sensitive than infra-red spectroscopy to the local environment. We exploit this property to effectively probe hydrogen bond strength via the distribution of intramolecular OH potentials derived from measurements. In contrast, the dynamical splitting in the spectral feature of the lowest valence-excited state arises from the short-range part of the OH potential curve and is rather insensitive to hydrogen bonding.
The Caspase-3 homolog DrICE regulates endocytic trafficking during Drosophila tracheal morphogenesis
Authors: McSharry Saoirse S. , Beitel Greg J. 
Published: March 2019

AbstractAlthough well known for its role in apoptosis, the executioner caspase DrICE has a non-apoptotic function that is required for elongation of the epithelial tubes of the Drosophila tracheal system. Here, we show that DrICE acts downstream of the Hippo Network to regulate endocytic trafficking of at least four cell polarity, cell junction and apical extracellular matrix proteins involved in tracheal tube size control: Crumbs, Uninflatable, Kune-Kune and Serpentine. We further show that tracheal cells are competent to undergo apoptosis, even though developmentally-regulated DrICE function rarely kills tracheal cells. Our results reveal a developmental role for caspases, a pool of DrICE that co-localizes with Clathrin, and a mechanism by which the Hippo Network controls endocytic trafficking. Given reports of in vitro regulation of endocytosis by mammalian caspases during apoptosis, we propose that caspase-mediated regulation of endocytic trafficking is an evolutionarily conserved function of caspases that can be deployed during morphogenesis.
Longitudinal tracking and quantification of individual Plasmodium falciparum clones in complex infections
Authors: Lerch Anita , Koepfli Cristian , Hofmann Natalie E. , Kattenberg Johanna H. , Rosanas-Urgell Anna , Betuela Inoni , Mueller Ivo , Felger Ingrid 
Published: March 2019

AbstractLongitudinal tracking of individual Plasmodium falciparum strains in multi-clonal infections is essential for investigating infection dynamics of malaria. The traditional genotyping techniques did not permit tracking changes in individual clone density during persistent natural infections. Amplicon deep sequencing (Amp-Seq) offers a tool to address this knowledge gap. The sensitivity of Amp-Seq for relative quantification of clones was investigated using three molecular markers, ama1-D2, ama1-D3, and cpmp. Amp-Seq and length-polymorphism based genotyping were compared for their performance in following minority clones in longitudinal samples from Papua New Guinea. Amp-Seq markers were superior to length-polymorphic marker msp2 in detecting minority clones (sensitivity Amp-Seq: 95%, msp2: 85%). Multiplicity of infection (MOI) by Amp-Seq was 2.32 versus 1.73 for msp2. The higher sensitivity had no effect on estimates of force of infection because missed minority clones were detected in preceding or succeeding bleeds. Individual clone densities were tracked longitudinally by Amp-Seq despite MOI > 1, thus providing an additional parameter for investigating malaria infection dynamics. Amp-Seq based genotyping of longitudinal samples improves detection of minority clones and estimates of MOI. Amp-Seq permits tracking of clone density over time to study clone competition or the dynamics of specific, i.e. resistance-associated genotypes.
Experimental investigation on True Triaxial Deformation and Progressive Damage Behaviour of Sandstone
Authors: Li Zhaolin , Wang Lianguo , Lu Yinlong , Li Wenshuai , Wang Kai , Fan Hao 
Published: March 2019

AbstractStudying the true triaxial deformation characteristics and progressive damage behavior of sandstone is of great significance for the stability control of roadways. Both the conventional triaxial test (CTT) and the true triaxial compression test (TTT) were conducted for sandstone to investigate its deformation characteristics and the variation laws of volume strain during the progressive damage process under different confining pressures. The conducted experiments showed that both the axial and lateral strains of the rock prior to failure under CTT conditions increased with increasing confining pressure. However, with increasing intermediate principal stress (σ2) under TTT conditions, both the axial strain, and the lateral strain (ε2) gradually decreased, and the lateral strain (ε3, expansion) first slow down and then accelerated. Moreover, the anisotropic characteristics first gradually weakened and then enhanced. The variation of the volume strain increment and the volume strain rate of rock combined with the acoustic emission activity and a three-dimensional rock theoretical model with microcrack defects were analyzed in detail. During the stable crack growth stage III, the volume strain increment and volume strain rate increased with increasing confining pressure under CTT conditions, while they decrease after the initial increase with increasing σ2 under TTT conditions. During the unstable crack growth stage IV, the volume strain increment increased sharply, while the volume strain rate gradually slowed down with increasing confining pressure under CTT conditions. The internal cracks of the rock were gradually suppressed and the lateral expansion was gradually constrained. The volume strain increment first increased followed by a decrease, and the volume strain rate gradually slowed down after a noticeable acceleration with increasing σ2 under TTT conditions. The internal micro-cracks gradually evolved from inhibition (in the planes parallel to plane 1–2 and plane 2–3) to accelerated expansion (the planes along the σ2 direction), and the lateral deformation first weakened and then strengthened.
Adherence to the Mediterranean diet is positively associated with sperm motility: A cross-sectional analysis
Authors: Salas-Huetos Albert , Babio Nancy , Carrell Douglas T. , Bulló Mònica , Salas-Salvadó Jordi 
Published: March 2019

AbstractThe aim of this cross-sectional analysis is to investigate the associations between the adherence to the Mediterranean Diet (MD) and semen quality parameters. To assess the adherence to the MD, the Trichopoulou score was used. Semen parameters were assessed as described in the 2010 WHO’s report and the results are showed across tertiles of MD adherence. A total of 106 participants were included. Compared to those in the lowest MD adherence tertile, participants in the top tertile had statistically significant higher BMI and waist circumference and consumed more energy, and also had statistically significant higher semen pH, and total sperm motility and progressive sperm motility percentages, and lower sperm immotility percentages. Moreover, percentage of total and progressive motility were significantly higher among those subjects in the higher adherence to MD in comparison with those in low-medium adherence category. The multivariable linear regression models evaluating the relationship between the sperm quality parameters and tertiles of MD adherence adjusted by age, energy and BMI showed that compared with the lowest tertile, men in the highest tertile had a higher percentage of total sperm motility [β non-standardized coefficient = 12.785]. These findings suggest that adherence to the MD was positively associated with sperm motility.
Intensive tropical land use massively shifts soil fungal communities
Authors: Brinkmann Nicole , Schneider Dominik , Sahner Josephine , Ballauff Johannes , Edy Nur , Barus Henry , Irawan Bambang , Budi Sri Wilarso , Qaim Matin , Daniel Rolf , Polle Andrea 
Published: March 2019

AbstractSoil fungi are key players in nutrient cycles as decomposers, mutualists and pathogens, but the impact of tropical rain forest transformation into rubber or oil palm plantations on fungal community structures and their ecological functions are unknown. We hypothesized that increasing land use intensity and habitat loss due to the replacement of the hyperdiverse forest flora by nonendemic cash crops drives a drastic loss of diversity of soil fungal taxa and impairs the ecological soil functions. Unexpectedly, rain forest conversion was not associated with strong diversity loss but with massive shifts in soil fungal community composition. Fungal communities clustered according to land use system and loss of plant species. Network analysis revealed characteristic fungal genera significantly associated with different land use systems. Shifts in soil fungal community structure were particularly distinct among different trophic groups, with substantial decreases in symbiotrophic fungi and increases in saprotrophic and pathotrophic fungi in oil palm and rubber plantations in comparison with rain forests. In conclusion, conversion of rain forests and current land use systems restructure soil fungal communities towards enhanced pathogen pressure and, thus, threaten ecosystem health functions.
A transcriptome-wide analysis deciphers distinct roles of G1 cyclins in temporal organization of the yeast cell cycle
Authors: Teufel Lotte , Tummler Katja , Flöttmann Max , Herrmann Andreas , Barkai Naama , Klipp Edda 
Published: March 2019

AbstractOscillating gene expression is crucial for correct timing and progression through cell cycle. In Saccharomyces cerevisiae, G1 cyclins Cln1–3 are essential drivers of the cell cycle and have an important role for temporal fine-tuning. We measured time-resolved transcriptome-wide gene expression for wild type and cyclin single and double knockouts over cell cycle with and without osmotic stress. Clustering of expression profiles, peak time detection of oscillating genes, integration with transcription factor network dynamics, and assignment to cell cycle phases allowed us to quantify the effect of genetic or stress perturbations on the duration of cell cycle phases. Cln1 and Cln2 showed functional differences, especially affecting later phases. Deletion of Cln3 led to a delay of START followed by normal progression through later phases. Our data and network analysis suggest mutual effects of cyclins with the transcriptional regulators SBF and MBF.
The complete mitochondrial genomes of two sibling species of camellia weevils (Coleoptera: Curculionidae) and patterns of Curculionini speciation
Authors: Zhang Shou-ke , Shu Jin-ping , Wang Yang-dong , Liu Ya-ning , Peng Han , Zhang Wei , Wang Hao-jie 
Published: March 2019

AbstractComplete mitochondrial genomes contain large and diverse datasets for species delineation. To better understand the divergence of the two morphologically indistinguishable weevil species in Curculionini, we first sequenced and compared their complete mitochondrial genomes. The complete mitochondrial genomes of Curculio chinensis and Curculio sp. were 19,713 bp with an A + T content of 76.61% and 19,216 bp with an A + T content of 76.85%, respectively. All 37 of the typical mitochondrial genes were determined in both species. The 13 protein sequences of the two species shared high homology (about 90%) except for ATP8 (73.08%). The differences in secondary structure of ATP8 were the number of possible proteins and nucleic acid binding sites. There were 22 and 15 mismatched base-pairs in the tRNA secondary structures from C. chinensis and Curculio sp., respectively. Maximum Likelihood and Bayesian analyses indicated that Curculio sp. is a novel species closely related to C. chinensis. The divergence time estimation suggests that Cryptorhynchinae and Curculionini lines diverged in the Cenozoic Period, while C. chinensis and Curculio sp. diverged at 6.7079 (95% CI 5–13) Mya. This study demonstrates the utility of using complete mitochondrial gene sets for phylogenetic analysis and enhances our understanding of the genetic basis for the evolution of the Curculionini.