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  • 1
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    American Association for the Advancement of Science (AAAS)
    Publication Date: 2018-09-06
    Description: We introduce here the concept of a transcranial brain atlas (TBA), a new kind of brain atlas specialized for transcranial techniques. A TBA is a probabilistic mapping from scalp space to atlas label space, relating scalp locations to anatomical, functional, network, genetic, or other labels. TBAs offer a new way to integrate and present structural and functional organization of the brain and allow previously subsurface and invisible atlas labels visible on the scalp surface to accurately guide the placement of transcranial devices directly on the scalp surface in a straightforward, visual manner. We present here a framework for building TBAs that includes (i) a new, continuous proportional coordinate system devised for the scalp surface to allow standardized specification of scalp positions; (ii) a high-resolution, large sample–based (114-participant) mapping from scalp space to brain space to accurately and reliably describe human cranio-cortical correspondence; and (iii) a two-step Markov chain to combine the probabilistic scalp-brain mapping with a traditional brain atlas, bringing atlas labels to the scalp surface. We assessed the reproducibility (consistency of TBAs generated from different groups) and predictiveness (prediction accuracy of labels for individuals without brain images) of the TBAs built via our framework. Moreover, we present an application of TBAs to a functional near-infrared spectroscopy finger-tapping experiment, illustrating the utility and benefits of TBAs in transcranial studies. Our results demonstrate that TBAs can support ongoing efforts to map the human brain using transcranial techniques, just as traditional brain atlases have supported magnetic resonance imaging and positron emission tomography studies.
    Electronic ISSN: 2375-2548
    Topics: Natural Sciences in General
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  • 2
    Publication Date: 2018-04-05
    Description: We describe a facile and low-cost approach for a flexibly integrated surface-enhanced Raman scattering (SERS) substrate in microfluidic chips. Briefly, a SERS substrate was fabricated by the electrostatic assembling of gold nanoparticles, and shaped into designed patterns by subsequent lift-up soft lithography. The SERS micro-pattern could be further integrated within microfluidic channels conveniently. The resulting microfluidic SERS chip allowed ultrasensitive in situ SERS monitoring from the transparent glass window. With its advantages in simplicity, functionality and cost-effectiveness, this method could be readily expanded into optical microfluidic fabrication for biochemical applications.
    Keywords: nanotechnology, analytical chemistry
    Electronic ISSN: 2054-5703
    Topics: Natural Sciences in General
    Published by Royal Society
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  • 3
    Publication Date: 2018-04-28
    Description: Background Hereditary sensorineural hearing loss is a genetically heterogeneous disorder. Objectives This study was designed to explore the genetic etiology of deafness in a large Chinese family with autosomal dominant, nonsyndromic, progressive sensorineural hearing loss (ADNSHL). Methods Whole exome sequencing and linkage analysis were performed to identify pathogenic mutation. Inner ear expression of Ifnlr1 was investigated by immunostaining in mice. ifnlr1 Morpholino knockdown Zebrafish were constructed to explore the deafness mechanism. Results We identified a cosegregating heterozygous missense mutation, c.296G〉A (p.Arg99His) in the gene encoding interferon lambda receptor 1 ( IFNLR1 ) – a protein that functions in the Jak/ STAT pathway– are associated with ADNSHL . Morpholino knockdown of ifnlr1 leads to a significant decrease in hair cells and non-inflation of the swim bladder in late-stage zebrafish, which can be reversed by injection with normal Zebrafish ifnlr1 mRNA. Knockdown of ifnlr1 in zebrafish causes significant upregulation of cytokine receptor family member b4 (interleukin-10r2), jak1, tyrosine kinase 2, stat3, and stat5b in the Jak1/STAT3 pathway at the mRNA level. Conclusion IFNLR1 function is required in the auditory system and that IFNLR1 mutations are associated with ADNSHL. To the best of our knowledge, this is the first study implicating an interferon lambda receptor in auditory function.
    Keywords: Open access
    Print ISSN: 0022-2593
    Electronic ISSN: 1468-6244
    Topics: Medicine
    Published by BMJ Publishing Group
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  • 4
    Publication Date: 2018-03-17
    Description: The ability to steer the flow of light toward desired propagation directions is critically important for the realization of key functionalities in optical communication and information processing. Although various schemes have been proposed for this purpose, the lack of capability to incorporate an external electric field to effectively tune the light propagation has severely limited the on-chip integration of photonics and electronics. Because of the noninteractive nature of photons, it is only possible to electrically control the flow of light by modifying the refractive index of materials through the electro-optic effect. However, the weak optical effects need to be strongly amplified for practical applications in high-density photonic integrations. We show a new strategy that takes advantage of the strong exciton-photon coupling in active waveguides to effectively manipulate photon transport by controlling the interaction between excitons and the external electric field. Single-crystal organic semiconductor nanowires were used to generate highly stable Frenkel exciton polaritons with strong binding and diffusion abilities. By making use of directional exciton diffusion in an external electric field, we have realized an electrically driven asymmetric photon transport and thus directional light propagation in a single nanowire. With this new concept, we constructed a dual-output single wire–based device to build an electrically controlled single-pole double-throw optical switch with fast temporal response and high switching frequency. Our findings may lead to the innovation of concepts and device architectures for optical information processing.
    Electronic ISSN: 2375-2548
    Topics: Natural Sciences in General
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  • 5
    Publication Date: 2018-06-30
    Description: Ye Zhang, Jian-Feng Chang, Jin Sun, Lu Chen, Xiao-Mei Yang, Huan-Yin Tang, Yuan-Ya Jing, Xuan Kang, Zhi-Min He, Jun-Yu Wu, Hui-Min Wei, Da-Liang Wang, Rong-Gang Xu, Rui-Bao Zhu, Ying Shen, Shi-Yang Zeng, Chen Wang, Kui-Nan Liu, Yong Zhang, Zhi-Yong Mao, Ci-Zhong Jiang, and Fang-Lin Sun Dysregulation of the homeostatic balance of histone H3 di- and tri-methyl lysine 27 (H3K27me2/3) levels caused by the mis-sense mutation of histone H3 (H3K27M) is reported to be associated with various types of cancers. In this study, we found that reduction in H3K27me2/3 caused by H3.1K27M, a mutation of H3 variants found in patients with diffuse intrinsic pontine glioma (DIPG), dramatically attenuated the presence of 53BP1 (also known as TP53BP1) foci and the capability of non-homologous end joining (NHEJ) in human dermal fibroblasts. H3.1K27M mutant cells showed increased rates of genomic insertions/deletions and copy number variations, as well as an increase in p53-dependent apoptosis. We further showed that both hypo-H3K27me2/3 and H3.1K27M interacted with FANCD2, a central player in the choice of DNA repair pathway. H3.1K27M triggered the accumulation of FANCD2 on chromatin, suggesting an interaction between H3.1K27M and FANCD2. Interestingly, knockdown of FANCD2 in H3.1K27M cells recovered the number of 53BP1-positive foci, NHEJ efficiency and apoptosis rate. Although these findings in HDF cells may differ from the endogenous regulation of the H3.1K27M mutant in the specific tumor context of DIPG, our results suggest a new model by which H3K27me2/3 facilitates NHEJ and the maintenance of genome stability. This article has an associated First Person interview with the first author of the paper .
    Keywords: Exploring the Nucleus
    Print ISSN: 0021-9533
    Electronic ISSN: 1477-9137
    Topics: Biology , Medicine
    Published by Company of Biologists
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  • 6
    Publication Date: 2018-07-03
    Description: Purpose: The third-generation EGFR tyrosine kinase inhibitor osimertinib is approved to treat patients with EGFR T790M-positive non–small cell lung cancer (NSCLC) who have developed resistance to earlier-generation drugs. Acquired EGFR C797S mutation has been reported to mediate osimertinib resistance in some patients. However, the remaining resistance mechanisms are largely unknown. Experimental Design: We performed mutation profiling using targeted next-generation sequencing (NGS) for 416 cancer-relevant genes on 93 osimertinib-resistant lung cancer patients' samples, mainly cell-free DNAs (cfDNAs), and matched pretreatment samples of 12 patients. In vitro experiments were conducted to functionally study the secondary EGFR mutations identified. Results: EGFR G796/C797, L792, and L718/G719 mutations were identified in 24.7%, 10.8%, and 9.7% of the cases, respectively, with certain mutations coexisting in one patient with different prevalence. L792 and L718 mutants markedly increased the half inhibitory concentration (IC 50 ) of osimertinib in vitro , among which the L718Q mutation conferred the greatest resistance to osimertinib, as well as gefitinib resistance when not coexisting with T790M. Further analysis of the 12 matched pretreatment samples confirmed that these EGFR mutations were acquired during osimertinib treatment. Alterations in parallel or downstream oncogenes such as MET, KRAS , and PIK3CA were also discovered, potentially contributing to the osimertinib-resistance in patients without EGFR secondary mutations. Conclusions: We present comprehensive mutation profiles of a large cohort of osimertinib-resistance lung cancer patients using mainly cfDNA. Besides C797 mutations, novel secondary mutations of EGFR L718 and L792 residues confer osimertinib resistance, both in vitro and in vivo , and are of great clinical and pharmaceutical relevance. Clin Cancer Res; 24(13); 3097–107. ©2018 AACR .
    Print ISSN: 1078-0432
    Electronic ISSN: 1557-3265
    Topics: Medicine
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  • 7
    Publication Date: 2018-06-16
    Description: Rong Fu, Yi Zhu, Xiaowan Jiang, Yuanbao Li, Ming Zhu, Mengqiu Dong, Zhaohui Huang, Chunxia Wang, Michel Labouesse, and Huimin Zhang Hemidesmosomes are epithelial-specific attachment structures that maintain tissue integrity and resist tension. Despite their importance, how hemidesmosomes are regulated at the post-transcriptional level is poorly understood. Caenorhabditis elegans hemidesmosomes (CeHDs) have a similar structure and composition to their mammalian counterparts, making C. elegans an ideal model for studying hemidesmosomes. Here, we focus on the transcription regulator CCAR-1, identified in a previous genetic screen searching for enhancers of mutations in the conserved hemidesmosome component VAB-10A (known as plectin in mammals). Loss of CCAR-1 function in a vab-10(e698) background results in CeHD disruption and muscle detachment from the epidermis. CCAR-1 regulates CeHD biogenesis, not by controlling the transcription of CeHD-related genes, but by affecting the alternative splicing of unc-52 (known as perlecan or HSPG2 in mammals), the predicted basement extracellular matrix (ECM) ligand of CeHDs. CCAR-1 physically interacts with HRP-2 (hnRNPR in mammals), a splicing factor known to mediate unc-52 alternative splicing to control the proportions of different UNC-52 isoforms and stabilize CeHDs. Our discovery underlines the importance of post-transcriptional regulation in hemidesmosome reorganization. It also uncovers previously unappreciated roles of CCAR-1 in alternative splicing and hemidesmosome biogenesis, shedding new light on the mechanisms through which mammalian CCAR1 functions in tumorigenesis.
    Print ISSN: 0021-9533
    Electronic ISSN: 1477-9137
    Topics: Biology , Medicine
    Published by Company of Biologists
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  • 8
    Publication Date: 2018-06-27
    Description: Long noncoding RNAs (lncRNAs) regulate gene expression. We investigated the role of lncRNAs in the inflammatory response to bacterial infection in the lungs. We identified the lncRNA MEG3 as a tissue-specific modulator of inflammatory responses during bacterial infection. Among the 10 transcript isoforms of MEG3, transcript 4 (referred to as MEG3-4) encodes the isoform with the lowest abundance in mouse lungs. Nonetheless, we found that MEG3-4 bound to the microRNA miR-138 in a competitive manner with mRNA encoding the proinflammatory cytokine interleukin-1β (IL-1β), thereby increasing IL-1β abundance and intensifying inflammatory responses to bacterial infection in alveolar macrophages and lung epithelial cells in culture and in lung tissue in mice. MEG3-4–mediated sponging of miR-138 in the cytoplasm increased the autocrine activity of IL-1β that subsequently induced a negative feedback mechanism mediated by nuclear factor B that decreased MEG3-4 abundance and inflammatory cytokine production. This timely reduction in MEG3-4 abundance tempered proinflammatory responses in mice with pulmonary bacterial infection, preventing the progression to sepsis. Together, these findings reveal that MEG3-4 dynamically modulates pulmonary inflammatory responses through transcriptional regulation of immune response genes, extending the decoy and sponge mechanism associated with lncRNAs to antibacterial immunity, which affects both response and disease progression.
    Print ISSN: 1945-0877
    Topics: Medicine
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  • 9
    Publication Date: 2011-02-15
    Description: The TrkH/TrkG/KtrB proteins mediate K(+) uptake in bacteria and probably evolved from simple K(+) channels by multiple gene duplications or fusions. Here we present the crystal structure of a TrkH from Vibrio parahaemolyticus. TrkH is a homodimer, and each protomer contains an ion permeation pathway. A selectivity filter, similar in architecture to those of K(+) channels but significantly shorter, is lined by backbone and side-chain oxygen atoms. Functional studies showed that TrkH is selective for permeation of K(+) and Rb(+) over smaller ions such as Na(+) or Li(+). Immediately intracellular to the selectivity filter are an intramembrane loop and an arginine residue, both highly conserved, which constrict the permeation pathway. Substituting the arginine with an alanine significantly increases the rate of K(+) flux. These results reveal the molecular basis of K(+) selectivity and suggest a novel gating mechanism for this large and important family of membrane transport proteins.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3077569/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3077569/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Cao, Yu -- Jin, Xiangshu -- Huang, Hua -- Derebe, Mehabaw Getahun -- Levin, Elena J -- Kabaleeswaran, Venkataraman -- Pan, Yaping -- Punta, Marco -- Love, James -- Weng, Jun -- Quick, Matthias -- Ye, Sheng -- Kloss, Brian -- Bruni, Renato -- Martinez-Hackert, Erik -- Hendrickson, Wayne A -- Rost, Burkhard -- Javitch, Jonathan A -- Rajashankar, Kanagalaghatta R -- Jiang, Youxing -- Zhou, Ming -- DK088057/DK/NIDDK NIH HHS/ -- GM05026/GM/NIGMS NIH HHS/ -- GM05026-SUB0007/GM/NIGMS NIH HHS/ -- HL086392/HL/NHLBI NIH HHS/ -- K05 DA022413/DA/NIDA NIH HHS/ -- P30 EB009998/EB/NIBIB NIH HHS/ -- R01 DK088057/DK/NIDDK NIH HHS/ -- R01 DK088057-01/DK/NIDDK NIH HHS/ -- R01 HL086392/HL/NHLBI NIH HHS/ -- R01 HL086392-05/HL/NHLBI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2011 Mar 17;471(7338):336-40. doi: 10.1038/nature09731. Epub 2011 Feb 13.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Physiology & Cellular Biophysics, College of Physicians and Surgeons, Columbia University, 630 West 168th Street, New York, New York 10032, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21317882" target="_blank"〉PubMed〈/a〉
    Keywords: ATP-Binding Cassette Transporters/chemistry ; Amino Acid Sequence ; Crystallography, X-Ray ; Escherichia coli Proteins/chemistry ; Ion Channel Gating ; Ion Transport ; Models, Molecular ; Molecular Sequence Data ; Potassium/metabolism ; Potassium Channels/*chemistry/*metabolism ; Structure-Activity Relationship ; Substrate Specificity ; Vibrio parahaemolyticus/*chemistry
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 10
    Publication Date: 2013-07-31
    Description: Mammalian pre-implantation development is a complex process involving dramatic changes in the transcriptional architecture. We report here a comprehensive analysis of transcriptome dynamics from oocyte to morula in both human and mouse embryos, using single-cell RNA sequencing. Based on single-nucleotide variants in human blastomere messenger RNAs and paternal-specific single-nucleotide polymorphisms, we identify novel stage-specific monoallelic expression patterns for a significant portion of polymorphic gene transcripts (25 to 53%). By weighted gene co-expression network analysis, we find that each developmental stage can be delineated concisely by a small number of functional modules of co-expressed genes. This result indicates a sequential order of transcriptional changes in pathways of cell cycle, gene regulation, translation and metabolism, acting in a step-wise fashion from cleavage to morula. Cross-species comparisons with mouse pre-implantation embryos reveal that the majority of human stage-specific modules (7 out of 9) are notably preserved, but developmental specificity and timing differ between human and mouse. Furthermore, we identify conserved key members (or hub genes) of the human and mouse networks. These genes represent novel candidates that are likely to be key in driving mammalian pre-implantation development. Together, the results provide a valuable resource to dissect gene regulatory mechanisms underlying progressive development of early mammalian embryos.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Xue, Zhigang -- Huang, Kevin -- Cai, Chaochao -- Cai, Lingbo -- Jiang, Chun-yan -- Feng, Yun -- Liu, Zhenshan -- Zeng, Qiao -- Cheng, Liming -- Sun, Yi E -- Liu, Jia-yin -- Horvath, Steve -- Fan, Guoping -- P01 HD006576/HD/NICHD NIH HHS/ -- P30 HD004612/HD/NICHD NIH HHS/ -- P50 DA005010/DA/NIDA NIH HHS/ -- England -- Nature. 2013 Aug 29;500(7464):593-7. doi: 10.1038/nature12364. Epub 2013 Jul 28.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Translational Center for Stem Cell Research, Tongji Hospital, Department of Regenerative Medicine, Tongji University School of Medicine, Shanghai 200065, China. xuezhigang75@gmail.com〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23892778" target="_blank"〉PubMed〈/a〉
    Keywords: Alleles ; Animals ; Blastocyst/cytology/metabolism ; Cell Cycle/genetics ; Embryo, Mammalian/cytology/*embryology/*metabolism ; Embryonic Development/*genetics ; Gene Expression Profiling ; *Gene Expression Regulation, Developmental ; Humans ; Mice ; Morula/cytology/metabolism ; Oocytes/cytology/metabolism ; *Sequence Analysis, RNA ; *Single-Cell Analysis
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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