bluuebunny/crossref_metadata_2025_split huggingface dataset:
Methylation determines the extracellular calcium sensitivity of the leak channel NALCN in hippocampal dentate granule cells
Authors: Lee Seul-Yi , Vuong Tuan Anh , Wen Xianlan , Jeong Hyeon-Ju , So Hyun-Kyung , Kwon Ilmin , Kang Jong-Sun , Cho Hana 
Published: October 2019

AbstractThe sodium leak channel NALCN is a key player in establishing the resting membrane potential (RMP) in neurons and transduces changes in extracellular Ca2+concentration ([Ca2+]e) into increased neuronal excitability as the downstream effector of calcium-sensing receptor (CaSR). Gain-of-function mutations in the human NALCN gene cause encephalopathy and severe intellectual disability. Thus, understanding the regulatory mechanisms of NALCN is important for both basic and translational research. This study reveals a novel mechanism for NALCN regulation by arginine methylation. Hippocampal dentate granule cells in protein arginine methyltransferase 7 (PRMT7)-deficient mice display a depolarization of the RMP, decreased threshold currents, and increased excitability compared to wild-type neurons. Electrophysiological studies combined with molecular analysis indicate that enhanced NALCN activities contribute to hyperexcitability in PRMT7−/− neurons. PRMT7 depletion in HEK293T cells increases NALCN activity by shifting the dose-response curve of NALCN inhibition by [Ca2+]ewithout affecting NALCN protein levels. In vitro methylation studies show that PRMT7 methylates a highly conserved Arg1653 of the NALCN gene located in the carboxy-terminal region that is implicated in CaSR-mediated regulation. A kinase-specific phosphorylation site prediction program shows that the adjacent Ser1652 is a potential phosphorylation site. Consistently, our data from site-specific mutants and PKC inhibitors suggest that Arg1653 methylation might modulate Ser1652 phosphorylation mediated by CaSR/PKC-delta, leading to [Ca2+]e-mediated NALCN suppression. Collectively, these data suggest that PRMT7 deficiency decreases NALCN methylation at Arg1653, which, in turn, decreases CaSR/PKC-mediated Ser1652 phosphorylation, lifting NALCN inhibition, thereby enhancing neuronal excitability. Thus, PRMT7-mediated NALCN inhibition provides a potential target for the development of therapeutic tools for neurological diseases.
Global profiling of O-GlcNAcylated and/or phosphorylated proteins in hepatoblastoma
Authors: Song Hang , Ma Ji , Bian Zhixuan , Chen Shuhua , Zhu Jiabei , Wang Jing , Huang Nan , Yin Minzhi , Sun Fenyong , Xu Min , Pan Qiuhui 
Published: October 2019

AbstractO-linked-β-N-acetylglucosamine (O-GlcNAc) glycosylation (O-GlcNAcylation) and phosphorylation are critical posttranslational modifications that are involved in regulating the functions of proteins involved in tumorigenesis and the development of various solid tumors. However, a detailed characterization of the patterns of these modifications at the peptide or protein level in hepatoblastoma (HB), a highly malignant primary hepatic tumor with an extremely low incidence in children, has not been performed. Here, we examined O-GlcNAc-modified or phospho-modified peptides and proteins in HB through quantitative proteomic analysis of HB tissues and paired normal liver tissues. Our results identified 114 O-GlcNAcylated peptides belonging to 78 proteins and 3494 phosphorylated peptides in 2088 proteins. Interestingly, 41 proteins were modified by both O-GlcNAcylation and phosphorylation. These proteins are involved in multiple molecular and cellular processes, including chromatin remodeling, transcription, translation, transportation, and organelle organization. In addition, we verified the accuracy of the proteomics results and found a competitive inhibitory effect between O-GlcNAcylation and phosphorylation of HSPB1. Further, O-GlcNAcylation modification of HSPB1 promoted proliferation and enhanced the chemotherapeutic resistance of HB cell lines in vitro. Collectively, our research suggests that O-GlcNAc-modified and/or phospho-modified proteins may play a crucial role in the pathogenesis of HB.
YAP integrates the regulatory Snail/HNF4α circuitry controlling epithelial/hepatocyte differentiation
Authors: Noce Valeria , Battistelli Cecilia , Cozzolino Angela Maria , Consalvi Veronica , Cicchini Carla , Strippoli Raffaele , Tripodi Marco , Marchetti Alessandra , Amicone Laura 
Published: October 2019

AbstractYes-associated protein (YAP) is a transcriptional co-factor involved in many cell processes, including development, proliferation, stemness, differentiation, and tumorigenesis. It has been described as a sensor of mechanical and biochemical stimuli that enables cells to integrate environmental signals. Although in the liver the correlation between extracellular matrix elasticity (greatly increased in the most of chronic hepatic diseases), differentiation/functional state of parenchymal cells and subcellular localization/activation of YAP has been previously reported, its role as regulator of the hepatocyte differentiation remains to be clarified. The aim of this study was to evaluate the role of YAP in the regulation of epithelial/hepatocyte differentiation and to clarify how a transducer of general stimuli can integrate tissue-specific molecular mechanisms determining specific cell outcomes. By means of YAP silencing and overexpression we demonstrated that YAP has a functional role in the repression of epithelial/hepatocyte differentiation by inversely modulating the expression of Snail (master regulator of the epithelial-to-mesenchymal transition and liver stemness) and HNF4α (master regulator of hepatocyte differentiation) at transcriptional level, through the direct occupancy of their promoters. Furthermore, we found that Snail, in turn, is able to positively control YAP expression influencing protein level and subcellular localization and that HNF4α stably represses YAP transcription in differentiated hepatocytes both in cell culture and in adult liver. Overall, our data indicate YAP as a new member of the HNF4/Snail epistatic molecular circuitry previously demonstrated to control liver cell state. In this model, the dynamic balance between three main transcriptional regulators, that are able to control reciprocally their expression/activity, is responsible for the induction/maintenance of different liver cell differentiation states and its modulation could be the aim of therapeutic protocols for several chronic liver diseases.
The crosstalk between autophagy and apoptosis was mediated by phosphorylation of Bcl-2 and beclin1 in benzene-induced hematotoxicity
Authors: Chen Yujiao , Zhang Wei , Guo Xiaoli , Ren Jing , Gao Ai 
Published: October 2019

AbstractIncreasing evidence suggested that benzene exposure resulted in different types of hematological cancer. Both autophagy and apoptosis were reported to play vital roles in benzene toxicity, but the relationship between autophagy and apoptosis remain unclear in benzene-induced hematotoxicity. In this study, the toxic effect of benzene on autophagy and apoptosis in benzene-exposed workers and in vitro were verified. Results showed that benzene metabolite (1, 4-benzoquinone, 1, 4-BQ) dose-dependently induced autophagy and apoptosis via enhancing phosphorylation of Bcl-2 and beclin1. Finally, we also found that the elevated ROS was in line with enhancing the phosphorylation of Bcl-2 and beclin1 which contributed to 1, 4-BQ-induced autophagy and apoptosis. Taken together, this study for the first time found that the effect of 1, 4-BQ on the crosstalk between autophagy and apoptosis were modulated by the ROS generation via enhancing phosphorylation of Bcl-2(Ser70) and phosphorylation of beclin1(Thr119), which offered a novel insight into underlying molecular mechanisms of benzene-induced hematotoxicity, and specifically how the crosstalk between autophagy and apoptosis was involved in benzene toxicity. This work provided novel evidence for the toxic effects and risk assessment of benzene.
A new family with a homozygous nonsense variant in NTHL1 further delineated the clinical phenotype of NTHL1-associated polyposis
Authors: Altaraihi Mays , Gerdes Anne-Marie , Wadt Karin 
Published: October 2019

AbstractA new family with NTHL1-associated polyposis (NAP) is described, involving a 58-year-old male affected with >100 colorectal polyps and a 55-year-old female sibling with nine colorectal polyps. The female was also diagnosed with a thyroid adenoma at age 40. Significantly, no malignant neoplasms have been detected in this family, which is important to further delineate the clinical phenotype related to NAP. A review of previously reported obligate heterozygous carriers of NTHL1 variants showed two patients affected with neoplasms at <55 years of age, generating a study to outline the phenotypic spectrum in patients with heterozygous pathogenic NTHL1 variants relevant.
N6-methyladenosine mRNA marking promotes selective translation of regulons required for human erythropoiesis
Authors: Kuppers Daniel A. , Arora Sonali , Lim Yiting , Lim Andrea R. , Carter Lucas M. , Corrin Philip D. , Plaisier Christopher L. , Basom Ryan , Delrow Jeffrey J. , Wang Shiyan , Hansen He Housheng , Torok-Storb Beverly , Hsieh Andrew C. , Paddison Patrick J. 
Published: October 2019

AbstractMany of the regulatory features governing erythrocyte specification, maturation, and associated disorders remain enigmatic. To identify new regulators of erythropoiesis, we utilize a functional genomic screen for genes affecting expression of the erythroid marker CD235a/GYPA. Among validating hits are genes coding for the N6-methyladenosine (m6A) mRNA methyltransferase (MTase) complex, including, METTL14, METTL3, and WTAP. We demonstrate that m6A MTase activity promotes erythroid gene expression programs through selective translation of ~300 m6A marked mRNAs, including those coding for SETD histone methyltransferases, ribosomal components, and polyA RNA binding proteins. Remarkably, loss of m6A marks results in dramatic loss of H3K4me3 marks across key erythroid-specific KLF1 transcriptional targets (e.g., Heme biosynthesis genes). Further, each m6A MTase subunit and a subset of their mRNAs targets are required for human erythroid specification in primary bone-marrow derived progenitors. Thus, m6A mRNA marks promote the translation of a network of genes required for human erythropoiesis.
Spontaneous ssDNA stretching on graphene and hexagonal boron nitride in plane heterostructures
Authors: Luan Binquan , Zhou Ruhong 
Published: October 2019

AbstractSingle-stranded DNA (ssDNA) molecules in solution typically form coiled structures, therefore stretching ssDNA is extremely crucial before applying any nanotechnology for ssDNA analysis. Recent advances in material fabrication enable the deployment of nanochannels to manipulate, stretch, sort and map double-stranded DNA (dsDNA) molecules, however nanochannels fail to stretch ssDNA molecules due to the ultra-short persistence length and the potential nonspecific-interaction-induced clogging. Given the significance of ssDNA stretching in genome analysis, here we report an ssDNA stretching platform: two dimensional in-plane heterostructure comprising graphene and hexagonal boron nitride (h-BN), and show that ssDNA can be stretched on a h-BN nanostripe sandwiched between two adjacent graphene domains (“nanochannel”). We further show that with a biasing voltage the stretched ssDNA can be electrophoretically transported along the “nanochannel”, allowing easy controls/manipulations. When being conveniently integrated with existing atomic resolution sensors, the heterostructure platform paves the way for sequencing DNA on a planar surface.
Allosteric activation of an ion channel triggered by modification of mechanosensitive nano-pockets
Authors: Kapsalis Charalampos , Wang Bolin , El Mkami Hassane , Pitt Samantha J. , Schnell Jason R. , Smith Terry K. , Lippiat Jonathan D. , Bode Bela E. , Pliotas Christos 
Published: October 2019

AbstractLipid availability within transmembrane nano-pockets of ion channels is linked with mechanosensation. However, the effect of hindering lipid-chain penetration into nano-pockets on channel structure has not been demonstrated. Here we identify nano-pockets on the large conductance mechanosensitive channel MscL, the high-pressure threshold channel. We restrict lipid-chain access to the nano-pockets by mutagenesis and sulfhydryl modification, and monitor channel conformation by PELDOR/DEER spectroscopy. For a single site located at the entrance of the nano-pockets and distal to the channel pore we generate an allosteric response in the absence of tension. Single-channel recordings reveal a significant decrease in the pressure activation threshold of the modified channel and a sub-conducting state in the absence of applied tension. Threshold is restored to wild-type levels upon reduction of the sulfhydryl modification. The modification associated with the conformational change restricts lipid access to the nano-pocket, interrupting the contact between the membrane and the channel that mediates mechanosensitivity.
Meiotic crossovers characterized by haplotype-specific chromosome painting in maize
Authors: do Vale Martins Lívia , Yu Fan , Zhao Hainan , Dennison Tesia , Lauter Nick , Wang Haiyan , Deng Zuhu , Thompson Addie , Semrau Kassandra , Rouillard Jean-Marie , Birchler James A. , Jiang Jiming 
Published: October 2019

AbstractMeiotic crossovers (COs) play a critical role in generating genetic variation and maintaining faithful segregation of homologous chromosomes during meiosis. We develop a haplotype-specific fluorescence in situ hybridization (FISH) technique that allows visualization of COs directly on metaphase chromosomes. Oligonucleotides (oligos) specific to chromosome 10 of maize inbreds B73 and Mo17, respectively, are synthesized and labeled as FISH probes. The parental and recombinant chromosome 10 in B73 x Mo17 F1 hybrids and F2 progenies can be unambiguously identified by haplotype-specific FISH. Analysis of 58 F2 plants reveals lack of COs in the entire proximal half of chromosome 10. However, we detect COs located in regions very close to the centromere in recombinant inbred lines from an intermated B73 x Mo17 population, suggesting effective accumulation of COs in recombination-suppressed chromosomal regions through intermating and the potential to generate favorable allelic combinations of genes residing in these regions.
Oligomeric state of the ZIKV E protein defines protective immune responses
Authors: Metz Stefan W. , Thomas Ashlie , Brackbill Alex , Forsberg John , Miley Michael J. , Lopez Cesar A. , Lazear Helen M. , Tian Shaomin , de Silva Aravinda M. 
Published: October 2019

AbstractThe current leading Zika vaccine candidates in clinical testing are based on live or killed virus platforms, which have safety issues, especially in pregnant women. Zika subunit vaccines, however, have shown poor performance in preclinical studies, most likely because the antigens tested do not display critical quaternary structure epitopes present on Zika E protein homodimers that cover the surface of the virus. Here, we produce stable recombinant E protein homodimers that are recognized by strongly neutralizing Zika specific monoclonal antibodies. In mice, the dimeric antigen stimulate strongly neutralizing antibodies that target epitopes that are similar to epitopes recognized by human antibodies following natural Zika virus infection. The monomer antigen stimulates low levels of E-domain III targeting neutralizing antibodies. In a Zika challenge model, only E dimer antigen stimulates protective antibodies, not the monomer. These results highlight the importance of mimicking the highly structured flavivirus surface when designing subunit vaccines.
Upper limb activity of twenty myoelectric prosthesis users and twenty healthy anatomically intact adults
Authors: Chadwell Alix , Kenney Laurence , Granat Malcolm , Thies Sibylle , Galpin Adam , Head John 
Published: October 2019

AbstractThe upper limb activity of twenty unilateral upper limb myoelectric prosthesis users and twenty anatomically intact adults were recorded over a 7-day period using two wrist worn accelerometers (Actigraph, LLC). This dataset reflects the real-world activities of the participants during their normal day-to-day routines. Participants included students, working adults, and retirees recruited from across the United Kingdom. This dataset offers a potential wealth of knowledge into a poorly understood cohort. The raw unprocessed data files and the activity count data exported from the Actilife software are provided. We also provide a non-wear algorithm developed for the removal of prosthesis non-wear periods and resulting activity count data corresponding to prothesis wear periods. Finally, we have included the transposed activity diaries provided by the participants. Analysis to date has primarily involved assessment of the symmetry of upper limb activity, however, there is potential to undertake additional analysis such as understanding the differences in the way a prosthesis is used compared to an anatomical arm.
Characterization of coral-associated microbial aggregates (CAMAs) within tissues of the coral Acropora hyacinthus
Authors: Wada Naohisa , Ishimochi Mizuki , Matsui Taeko , Pollock F. Joseph , Tang Sen-Lin , Ainsworth Tracy D. , Willis Bette L. , Mano Nobuhiro , Bourne David G. 
Published: October 2019

AbstractBacterial diversity associated with corals has been studied extensively, however, localization of bacterial associations within the holobiont is still poorly resolved. Here we provide novel insight into the localization of coral-associated microbial aggregates (CAMAs) within tissues of the coralAcropora hyacinthus.In total, 318 and 308 CAMAs were characterized via histological and fluorescentin situhybridization (FISH) approaches respectively, and shown to be distributed extensively throughout coral tissues collected from five sites in Japan and Australia. The densities of CAMAs within the tissues were negatively correlated with the distance from the coastline (i.e. lowest densities at offshore sites). CAMAs were randomly distributed across the six coral tissue regions investigated. Within each CAMA, bacterial cells had similar morphological characteristics, but bacterial morphologies varied among CAMAs, with at least five distinct types identified. Identifying the location of microorganisms associated with the coral host is a prerequisite for understanding their contributions to fitness. Localization of tissue-specific communities housed within CAMAs is particularly important, as these communities are potentially important contributors to vital metabolic functions of the holobiont.
Induced pluripotent stem cells-derived neurons from patients with Friedreich ataxia exhibit differential sensitivity to resveratrol and nicotinamide
Authors: Georges Pauline , Boza-Moran Maria-Gabriela , Gide Jacqueline , Pêche Georges Arielle , Forêt Benjamin , Bayot Aurélien , Rustin Pierre , Peschanski Marc , Martinat Cécile , Aubry Laetitia 
Published: October 2019

AbstractTranslation of pharmacological results from in vitro cell testing to clinical trials is challenging. One of the causes that may underlie these discrepant results is the lack of the phenotypic or species-specific relevance of the tested cells; today, this lack of relevance may be reduced by relying on cells differentiated from human pluripotent stem cells. To analyse the benefits provided by this approach, we chose to focus on Friedreich ataxia, a neurodegenerative condition for which the recent clinical testing of two compounds was not successful. These compounds, namely, resveratrol and nicotinamide, were selected because they had been shown to stimulate the expression of frataxin in fibroblasts and lymphoblastoid cells. Our results indicated that these compounds failed to do so in iPSC-derived neurons generated from two patients with Friedreich ataxia. By comparing the effects of both molecules on different cell types that may be considered to be non-relevant for the disease, such as fibroblasts, or more relevant to the disease, such as neurons differentiated from iPSCs, a differential response was observed; this response suggests the importance of developing more predictive in vitro systems for drug discovery. Our results demonstrate the value of utilizing human iPSCs early in drug discovery to improve translational predictability.
Quantitative biparametric analysis of hybrid 18F-FET PET/MR-neuroimaging for differentiation between treatment response and recurrent glioma
Authors: Lohmeier Johannes , Bohner Georg , Siebert Eberhard , Brenner Winfried , Hamm Bernd , Makowski Marcus R. 
Published: October 2019

AbstractWe investigated the diagnostic potential of simultaneous 18F-FET PET/MR-imaging for differentiation between recurrent glioma and post-treatment related effects (PTRE) using quantitative volumetric (3D-VOI) lesion analysis. In this retrospective study, a total of 42 patients including 32 patients with histologically proven glioma relapse and 10 patients with PTRE (histopathologic follow-up, n = 4, serial imaging follow-up, n = 6) were evaluated regarding recurrence. PET/MR-imaging was semi-automatically analysed based on FET tracer uptake using conservative SUV thresholding (isocontour 80%) with emphasis on the metabolically most active regions. Mean (relative) apparent diffusion coefficient (ADCmean, rADCmean), standardised-uptake-value (SUV) including target-to-background (TBR) ratio were determined. Glioma relapse presented higher ADCmean (MD ± SE, 284 ± 91, p = 0.003) and TBRmax (MD ± SE, 1.10 ± 0.45, p = 0.02) values than treatment-related changes. Both ADCmean (AUC ± SE = 0.82 ± 0.07, p-value < 0.001) and TBRmax (AUC ± SE = 0.81 ± 0.08, p-value < 0.001) achieved reliable diagnostic performance in differentiating glioma recurrence from PTRE. Bivariate analysis based on a combination of ADCmean and TBRmax demonstrated highest diagnostic accuracy (AUC ± SE = 0.90 ± 0.05, p-value < 0.001), improving clinical (false negative and false positive) classification. In conclusion, biparametric analysis using DWI and FET PET, both providing distinct information regarding the underlying pathophysiology, presented best diagnostic accuracy and clinical benefit in differentiating recurrent glioma from treatment-related changes.
Skew informations from an operational view via resource theory of asymmetry
Authors: Takagi Ryuji 
Published: October 2019

AbstractThe Wigner-Yanase skew information was proposed to quantify the information contained in quantum states with respect to a conserved additive quantity, and it was later extended to the Wigner-Yanase-Dyson skew informations. Recently, the Wigner-Yanase-Dyson skew informations have been recognized as valid resource measures for the resource theory of asymmetry, and their properties have been investigated from a resource-theoretic perspective. The Wigner-Yanse-Dyson skew informations have been further generalized to a class called metric-adjusted skew informations, and this general family of skew informations have also been found to be valid asymmetry monotones. Here, we analyze this general family of the skew informations from an operational point of view by utilizing the fact that they are valid asymmetry resource monotones. We show that such an approach allows for clear physical meanings as well as simple proofs of some of the basic properties of the skew informations. Notably, we constructively prove that any type of skew information cannot be superadditive, where the violation of the superadditivity had been only known for a specific class of skew informations with numerical counterexamples. We further show a weaker version of superadditivity relation applicable to the general class of the skew informations, which proves a conjecture made for the Wigner-Yanase skew information as a special case. We finally discuss an application of our results for a situation where quantum clocks are distributed to multiple parties.