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Mario Prsa, Karin Morandell, Géraldine Cuenu, Daniel Huber
The spectral content of skin vibrations, produced by either displacing the finger across a surface texture1 or passively sensing external movements through the solid substrate2,3 , provides fundamental information about our environment. Low-frequency flutter (below 50 Hz) applied locally to the primate fingertip evokes cyclically entrained spiking in neurons of the primary somatosensory cortex (S1), and thus spike rates in these neurons increase linearly with frequency4,5 . However, the same local vibrations at high frequencies (over 100 Hz) cannot be discriminated on the basis of differences in discharge rates of S1 neurons4,6 , because spiking is only partially entrained at these frequencies6 ...
March 13, 2019: Nature
Meijing Li, Xian Xia, Yuanyuan Tian, Qi Jia, Xiaoyu Liu, Ying Lu, Ming Li, Xueming Li, Zhucheng Chen
Chromatin remodellers include diverse enzymes with distinct biological functions, but nucleosome-sliding activity appears to be a common theme1,2 . Among the remodelling enzymes, Snf2 serves as the prototype to study the action of this protein family. Snf2 and related enzymes share two conserved RecA-like lobes3 , which by themselves are able to couple ATP hydrolysis to chromatin remodelling. The mechanism by which these enzymes couple ATP hydrolysis to translocate the nucleosome along the DNA remains unclear2,4-8 ...
March 13, 2019: Nature
Katrina A Muraglia, Rajeev S Chorghade, Bo Ram Kim, Xiao Xiao Tang, Viral S Shah, Anthony S Grillo, Page N Daniels, Alexander G Cioffi, Philip H Karp, Lingyang Zhu, Michael J Welsh, Martin D Burke
Loss-of-function mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) compromise epithelial HCO3 - and Cl- secretion, reduce airway surface liquid pH, and impair respiratory host defences in people with cystic fibrosis1-3 . Here we report that apical addition of amphotericin B, a small molecule that forms unselective ion channels, restored HCO3 - secretion and increased airway surface liquid pH in cultured airway epithelia from people with cystic fibrosis. These effects required the basolateral Na+ , K+ -ATPase, indicating that apical amphotericin B channels functionally interfaced with this driver of anion secretion...
March 13, 2019: Nature
Milan M S Obradović, Baptiste Hamelin, Nenad Manevski, Joana Pinto Couto, Atul Sethi, Marie-May Coissieux, Simone Münst, Ryoko Okamoto, Hubertus Kohler, Alexander Schmidt, Mohamed Bentires-Alj
Diversity within or between tumours and metastases (known as intra-patient tumour heterogeneity) that develops during disease progression is a serious hurdle for therapy1-3 . Metastasis is the fatal hallmark of cancer and the mechanisms of colonization, the most complex step in the metastatic cascade4 , remain poorly defined. A clearer understanding of the cellular and molecular processes that underlie both intra-patient tumour heterogeneity and metastasis is crucial for the success of personalized cancer therapy...
March 13, 2019: Nature
J A Marchand, M E Neugebauer, M C Ing, C-I Lin, J G Pelton, M C Y Chang
Living systems can generate an enormous range of cellular functions, from mechanical infrastructure and signalling networks to enzymatic catalysis and information storage, using a notably limited set of chemical functional groups. This observation is especially notable when compared to the breadth of functional groups used as the basis for similar functions in synthetically derived small molecules and materials. The relatively small cross-section between biological and synthetic reactivity space forms the foundation for the development of bioorthogonal chemistry, in which the absence of a pair of reactive functional groups within the cell allows for a selective in situ reaction1-4 ...
March 13, 2019: Nature
Bo Zhang, Kai Biao Wang, Wen Wang, Xin Wang, Fang Liu, Jiapeng Zhu, Jing Shi, Ling Yu Li, Hao Han, Kuang Xu, Hong Yun Qiao, Xiao Zhang, Rui Hua Jiao, Kendall N Houk, Yong Liang, Ren Xiang Tan, Hui Ming Ge
Pericyclic reactions are powerful transformations for the construction of carbon-carbon and carbon-heteroatom bonds in organic synthesis. Their role in biosynthesis is increasingly apparent, and mechanisms by which pericyclases can catalyse reactions are of major interest1 . [4+2] cycloadditions (Diels-Alder reactions) have been widely used in organic synthesis2 for the formation of six-membered rings and are now well-established in biosynthesis3-6 . [6+4] and other 'higher-order' cycloadditions were predicted7 in 1965, and are now increasingly common in the laboratory despite challenges arising from the generation of a highly strained ten-membered ring system8,9 ...
March 13, 2019: Nature
Lorna A Farrelly, Robert E Thompson, Shuai Zhao, Ashley E Lepack, Yang Lyu, Natarajan V Bhanu, Baichao Zhang, Yong-Hwee E Loh, Aarthi Ramakrishnan, Krishna C Vadodaria, Kelly J Heard, Galina Erikson, Tomoyoshi Nakadai, Ryan M Bastle, Bradley J Lukasak, Henry Zebroski, Natalia Alenina, Michael Bader, Olivier Berton, Robert G Roeder, Henrik Molina, Fred H Gage, Li Shen, Benjamin A Garcia, Haitao Li, Tom W Muir, Ian Maze
Chemical modifications of histones can mediate diverse DNA-templated processes, including gene transcription1-3 . Here we provide evidence for a class of histone post-translational modification, serotonylation of glutamine, which occurs at position 5 (Q5ser) on histone H3 in organisms that produce serotonin (also known as 5-hydroxytryptamine (5-HT)). We demonstrate that tissue transglutaminase 2 can serotonylate histone H3 tri-methylated lysine 4 (H3K4me3)-marked nucleosomes, resulting in the presence of combinatorial H3K4me3Q5ser in vivo...
March 13, 2019: Nature
Huilin Huang, Hengyou Weng, Keren Zhou, Tong Wu, Boxuan Simen Zhao, Mingli Sun, Zhenhua Chen, Xiaolan Deng, Gang Xiao, Franziska Auer, Lars Klemm, Huizhe Wu, Zhixiang Zuo, Xi Qin, Yunzhu Dong, Yile Zhou, Hanjun Qin, Shu Tao, Juan Du, Jun Liu, Zhike Lu, Hang Yin, Ana Mesquita, Celvie L Yuan, Yueh-Chiang Hu, Wenju Sun, Rui Su, Lei Dong, Chao Shen, Chenying Li, Ying Qing, Xi Jiang, Xiwei Wu, Miao Sun, Jun-Lin Guan, Lianghu Qu, Minjie Wei, Markus Müschen, Gang Huang, Chuan He, Jianhua Yang, Jianjun Chen
DNA and histone modifications have notable effects on gene expression1 . Being the most prevalent internal modification in mRNA, the N6 -methyladenosine (m6 A) mRNA modification is as an important post-transcriptional mechanism of gene regulation2-4 and has crucial roles in various normal and pathological processes5-12 . However, it is unclear how m6 A is specifically and dynamically deposited in the transcriptome. Here we report that histone H3 trimethylation at Lys36 (H3K36me3), a marker for transcription elongation, guides m6 A deposition globally...
March 13, 2019: Nature
Eli L Diamond, Benjamin H Durham, Gary A Ulaner, Esther Drill, Justin Buthorn, Michelle Ki, Lillian Bitner, Hana Cho, Robert J Young, Jasmine H Francis, Raajit Rampal, Mario Lacouture, Lynn A Brody, Neval Ozkaya, Ahmet Dogan, Neal Rosen, Alexia Iasonos, Omar Abdel-Wahab, David M Hyman
Histiocytic neoplasms are a heterogeneous group of clonal haematopoietic disorders that are marked by diverse mutations in the mitogen-activated protein kinase (MAPK) pathway1,2 . For the 50% of patients with histiocytosis who have BRAFV600 mutations3-5 , RAF inhibition is highly efficacious and has markedly altered the natural history of the disease6,7 . However, no standard therapy exists for the remaining 50% of patients who lack BRAFV600 mutations. Although ERK dependence has been hypothesized to be a consistent feature across histiocytic neoplasms, this remains clinically unproven and many of the kinase mutations that are found in patients who lack BRAFV600 mutations have not previously been biologically characterized...
March 13, 2019: Nature
Renhong Yan, Xin Zhao, Jianlin Lei, Qiang Zhou
The L-type amino acid transporter 1 (LAT1; also known as SLC7A5) catalyses the cross-membrane flux of large neutral amino acids in a sodium- and pH-independent manner1-3 . LAT1, an antiporter of the amino acid-polyamine-organocation superfamily, also catalyses the permeation of thyroid hormones, pharmaceutical drugs, and hormone precursors such as L-3,4-dihydroxyphenylalanine across membranes2-6 . Overexpression of LAT1 has been observed in a wide range of tumour cells, and it is thus a potential target for anti-cancer drugs7-11 ...
March 13, 2019: Nature
Oscar M Rueda, Stephen-John Sammut, Jose A Seoane, Suet-Feung Chin, Jennifer L Caswell-Jin, Maurizio Callari, Rajbir Batra, Bernard Pereira, Alejandra Bruna, H Raza Ali, Elena Provenzano, Bin Liu, Michelle Parisien, Cheryl Gillett, Steven McKinney, Andrew R Green, Leigh Murphy, Arnie Purushotham, Ian O Ellis, Paul D Pharoah, Cristina Rueda, Samuel Aparicio, Carlos Caldas, Christina Curtis
The rates and routes of lethal systemic spread in breast cancer are poorly understood owing to a lack of molecularly characterized patient cohorts with long-term, detailed follow-up data. Long-term follow-up is especially important for those with oestrogen-receptor (ER)-positive breast cancers, which can recur up to two decades after initial diagnosis1-6 . It is therefore essential to identify patients who have a high risk of late relapse7-9 . Here we present a statistical framework that models distinct disease stages (locoregional recurrence, distant recurrence, breast-cancer-related death and death from other causes) and competing risks of mortality from breast cancer, while yielding individual risk-of-recurrence predictions...
March 13, 2019: Nature
Dmitri Lodygin, Moritz Hermann, Nils Schweingruber, Cassandra Flügel-Koch, Takashi Watanabe, Corinna Schlosser, Arianna Merlini, Henrike Körner, Hsin-Fang Chang, Henrike J Fischer, Holger M Reichardt, Marta Zagrebelsky, Brit Mollenhauer, Sebastian Kügler, Dirk Fitzner, Jens Frahm, Christine Stadelmann, Michael Haberl, Francesca Odoardi, Alexander Flügel
In this Article, owing to an error during the production process, the y-axis label of Fig. 2c should read "Number of Tβ-syn cells" rather than "Number of T1β-syn cells" and the left and right panels of Fig. 4 should be labelled 'a' and 'b', respectively. These errors have been corrected online.
March 13, 2019: Nature
Stephen Nayfach, Zhou Jason Shi, Rekha Seshadri, Katherine S Pollard, Nikos Kyrpides
Largely due to challenges cultivating microbes under laboratory conditions, the genome sequence of many species in the human gut microbiome remains unknown. To address this problem, we reconstructed 60,664 prokaryotic draft genomes from 3,810 faecal metagenomes from geographically and phenotypically diverse human subjects. These genomes provide reference points for 2,058 previously unknown species-level operational taxonomic units (OTUs), representing a 50% increase in the phylogenetic diversity of sequenced gut bacteria...
March 13, 2019: Nature
Mian Zhang, Brandon Buscaino, Cheng Wang, Amirhassan Shams-Ansari, Christian Reimer, Rongrong Zhu, Joseph M Kahn, Marko Lončar
Optical frequency combs consist of equally spaced discrete optical frequency components and are essential tools for optical communication, precision metrology, timing and spectroscopy1-9 . At present, combs with wide spectra are usually generated by mode-locked lasers10 or dispersion-engineered resonators with third-order Kerr nonlinearity11 . An alternative method of comb production uses electro-optic (EO) phase modulation in a resonator with strong second-order nonlinearity, resulting in combs with excellent stability and controllability12-14 ...
March 11, 2019: Nature
Xiang Gui, Hui Yang, Tuo Li, Xiaojun Tan, Peiqing Shi, Minghao Li, Fenghe Du, Zhijian J Chen
Cyclic GMP-AMP (cGAMP) synthase (cGAS) detects infections or tissue damage by binding to microbial or self DNA in the cytoplasm1 . Upon binding DNA, cGAS produces cGAMP that binds to and activates the adaptor protein STING, which then activates the kinases IKK and TBK1 to induce interferons and other cytokines2-6 . Here we report that STING also activates autophagy through a mechanism that is independent of TBK1 activation and interferon induction. Upon binding cGAMP, STING translocates to the endoplasmic reticulum-Golgi intermediate compartment (ERGIC) and the Golgi in a process that is dependent on the COP-II complex and ARF GTPases...
March 6, 2019: Nature
Jiyoung Lee, Ali E Yesilkanal, Joseph P Wynne, Casey Frankenberger, Juan Liu, Jielin Yan, Mohamad Elbaz, Daniel C Rabe, Felicia D Rustandy, Payal Tiwari, Elizabeth A Grossman, Peter C Hart, Christie Kang, Sydney M Sanderson, Jorge Andrade, Daniel K Nomura, Marcelo G Bonini, Jason W Locasale, Marsha Rich Rosner
Mitochondrial metabolism is an attractive target for cancer therapy1,2 . Reprogramming metabolic pathways could improve the ability of metabolic inhibitors to suppress cancers with limited treatment options, such as triple-negative breast cancer (TNBC)1,3 . Here we show that BTB and CNC homology1 (BACH1)4 , a haem-binding transcription factor that is increased in expression in tumours from patients with TNBC, targets mitochondrial metabolism. BACH1 decreases glucose utilization in the tricarboxylic acid cycle and negatively regulates transcription of electron transport chain (ETC) genes...
March 6, 2019: Nature
Selmaan N Chettih, Christopher D Harvey
The computations performed by local neural populations, such as a cortical layer, are typically inferred from anatomical connectivity and observations of neural activity. Here we describe a method-influence mapping-that uses single-neuron perturbations to directly measure how cortical neurons reshape sensory representations. In layer 2/3 of the primary visual cortex (V1), we use two-photon optogenetics to trigger action potentials in a targeted neuron and calcium imaging to measure the effect on spiking in neighbouring neurons in awake mice viewing visual stimuli...
March 6, 2019: Nature
Guijun Shang, Conggang Zhang, Zhijian J Chen, Xiao-Chen Bai, Xuewu Zhang
Infections by pathogens that contain DNA trigger the production of type-I interferons and inflammatory cytokines through cyclic GMP-AMP synthase, which produces 2'3'-cyclic GMP-AMP (cGAMP) that binds to and activates stimulator of interferon genes (STING; also known as TMEM173, MITA, ERIS and MPYS)1-8 . STING is an endoplasmic-reticulum membrane protein that contains four transmembrane helices followed by a cytoplasmic ligand-binding and signalling domain9-13 . The cytoplasmic domain of STING forms a dimer, which undergoes a conformational change upon binding to cGAMP9,14 ...
March 6, 2019: Nature
Jae W Lee, Meredith L Stone, Paige M Porrett, Stacy K Thomas, Chad A Komar, Joey H Li, Devora Delman, Kathleen Graham, Whitney L Gladney, Xia Hua, Taylor A Black, Austin L Chien, Krishna S Majmundar, Jeffrey C Thompson, Stephanie S Yee, Mark H O'Hara, Charu Aggarwal, Dong Xin, Abraham Shaked, Mingming Gao, Dexi Liu, Mitesh J Borad, Ramesh K Ramanathan, Erica L Carpenter, Ailing Ji, Maria C de Beer, Frederick C de Beer, Nancy R Webb, Gregory L Beatty
The liver is the most common site of metastatic disease1 . Although this metastatic tropism may reflect the mechanical trapping of circulating tumour cells, liver metastasis is also dependent, at least in part, on the formation of a 'pro-metastatic' niche that supports the spread of tumour cells to the liver2,3 . The mechanisms that direct the formation of this niche are poorly understood. Here we show that hepatocytes coordinate myeloid cell accumulation and fibrosis within the liver and, in doing so, increase the susceptibility of the liver to metastatic seeding and outgrowth...
March 6, 2019: Nature
R Alex Wu, Daniel R Semlow, Ashley N Kamimae-Lanning, Olga V Kochenova, Gheorghe Chistol, Michael R Hodskinson, Ravindra Amunugama, Justin L Sparks, Meng Wang, Lin Deng, Claudia A Mimoso, Emily Low, Ketan J Patel, Johannes C Walter
Cells often use multiple pathways to repair the same DNA lesion, and the choice of pathway has substantial implications for the fidelity of genome maintenance. DNA interstrand crosslinks covalently link the two strands of DNA, and thereby block replication and transcription; the cytotoxicity of these crosslinks is exploited for chemotherapy. In Xenopus egg extracts, the collision of replication forks with interstrand crosslinks initiates two distinct repair pathways. NEIL3 glycosylase can cleave the crosslink1 ; however, if this fails, Fanconi anaemia proteins incise the phosphodiester backbone that surrounds the interstrand crosslink, generating a double-strand-break intermediate that is repaired by homologous recombination2 ...
March 6, 2019: Nature
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