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Jeffrey R Moffitt, Junjie Hao, Dhananjay Bambah-Mukku, Tian Lu, Catherine Dulac, Xiaowei Zhuang
Highly multiplexed single-molecule FISH has emerged as a promising approach to spatially resolved single-cell transcriptomics because of its ability to directly image and profile numerous RNA species in their native cellular context. However, background-from off-target binding of FISH probes and cellular autofluorescence-can become limiting in a number of important applications, such as increasing the degree of multiplexing, imaging shorter RNAs, and imaging tissue samples. Here, we developed a sample clearing approach for FISH measurements...
November 22, 2016: Proceedings of the National Academy of Sciences of the United States of America
Ana M Melo, Juliana Coraor, Garrett Alpha-Cobb, Shana Elbaum-Garfinkle, Abhinav Nath, Elizabeth Rhoades
Tau is an intrinsically disordered protein with an important role in maintaining the dynamic instability of neuronal microtubules. Despite intensive study, a detailed understanding of the functional mechanism of tau is lacking. Here, we address this deficiency by using intramolecular single-molecule Förster Resonance Energy Transfer (smFRET) to characterize the conformational ensemble of tau bound to soluble tubulin heterodimers. Tau adopts an open conformation on binding tubulin, in which the long-range contacts between both termini and the microtubule binding region that characterize its compact solution structure are diminished...
November 23, 2016: Proceedings of the National Academy of Sciences of the United States of America
Xinming Zhang, Aleksander A Rebane, Lu Ma, Feng Li, Junyi Jiao, Hong Qu, Frederic Pincet, James E Rothman, Yongli Zhang
Synaptic soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs) couple their stepwise folding to fusion of synaptic vesicles with plasma membranes. In this process, three SNAREs assemble into a stable four-helix bundle. Arguably, the first and rate-limiting step of SNARE assembly is the formation of an activated binary target (t)-SNARE complex on the target plasma membrane, which then zippers with the vesicle (v)-SNARE on the vesicle to drive membrane fusion. However, the t-SNARE complex readily misfolds, and its structure, stability, and dynamics are elusive...
November 28, 2016: Proceedings of the National Academy of Sciences of the United States of America
Kun Zhang, Chen Yuan, Fu-Sheng Guo, Yi-Quan Zhang, Yao-Yu Wang
In search of simple approaches to rationally enhance the energy barriers in polynuclear dysprosium single-molecule magnets, a new system containing two structurally closely related dinuclear dysprosium complexes, namely [Dy2(L)2(DBM)2(DMF)2] (1) and [Dy2(L)2(DBM)2(DMA)2]·2DMA (2) (HDBM = dibenzoylmethane, H2L = 2-hydroxy-N'-(2-hydroxy-3-methoxybenzylidene)benzohydrazide), is introduced and the structure-dependent magnetic properties are investigated. The two complexes display only slight variations in the coordination geometries of the Dy(iii) ion but display remarkably different magnetic behaviors...
December 2, 2016: Dalton Transactions: An International Journal of Inorganic Chemistry
Joran Deschamps, Andreas Rowald, Jonas Ries
Single-molecule localization microscopy (SMLM) relies on the switching of fluorescent molecules between a fluorescent and a dark state to achieve super resolution. This process is inherently dependent on the intensity distribution of the laser light used for both activation from the dark state and excitation of the bright state. Typically, laser light is coupled directly or via a single-mode fiber into the microscope, which leads to a Gaussian intensity profile in total internal reflection (TIR) or epi illumination...
November 28, 2016: Optics Express
Irina Sorokina, Arcady Mushegian
BACKGROUND: The set of forces and sequence of events that govern the transition from an unfolded polypeptide chain to a functional protein with correct spatial structure remain incompletely known, despite the importance of the problem and decades of theory development, computer simulations, and laboratory experiments. Information about the correctly folded state of most proteins is likely to be present in their sequences, and yet many proteins fail to attain native structure after overexpression in a non-native environment or upon experimental denaturation and refolding...
December 1, 2016: Biology Direct
Jean-Emmanuel Clément, Aymeric Leray, Alexandre Bouhelier, Eric Finot
In this contribution, we provide new insights on the temporal fluctuations of surface enhanced Raman spectra (SERS) of large single molecules such as proteins. Because they can only fit partly into small active volume, SERS analysis is referred to spectral pointillism where only protein subdomains are shined and the whole protein landscape is built from the dynamics of successive individual spectra. By applying our approach on bovine serum albumin, we show that single protein subdomains are mostly comprised of three distinct amino acids...
December 1, 2016: Physical Chemistry Chemical Physics: PCCP
Sagnik Basuray, Avinash Pathak, Sangho Bok, Biyan Chen, Steven C Hamm, Cherian J Mathai, Suchismita Guha, Keshab Gangopadhyay, Shubhra Gangopadhyay
Classical methods for enhancing the electromagnetic field from substrates for spectroscopic applications, such as surface-enhanced Raman spectroscopy (SERS), have involved the generation of hotspots through directed self-assembly of nanoparticles or by patterning nanoscale features using expensive nanolithography techniques. A novel large-area, cost-effective soft lithographic technique involving glancing angle deposition (GLAD) of silver on polymer gratings is reported here. This method produces hierarchical nanostructures with high enhancement factors capable of analyzing single-molecule SERS...
December 1, 2016: Nanotechnology
J-K Ou-Yang, N Saleh, G Fernandez Garcia, L Norel, F Pointillart, T Guizouarn, O Cador, F Totti, L Ouahab, J Crassous, B Le Guennic
Racemic and optically pure [Dy(hfac)3(L)] complexes with L = 3-(2-pyridyl)-4-aza[6]-helicene have been synthesized and characterized. Both the racemic and enantiopure forms behave as single molecule magnets in their crystalline phase, while electronic circular dichroism activity is evidenced. Ab initio calculations on isolated complexes followed by the determination of intermolecular dipolar couplings allowed the rationalization of the different low-temperature magnetic behaviours. The enantiopure SMM differs from the racemic one by the presence of a hysteresis loop in the former system...
December 1, 2016: Chemical Communications: Chem Comm
Hoon Je Seong, Hye-Jee Park, Eunji Hong, Sung Chul Lee, Woo Jun Sul, Sang-Wook Han
Single-molecule real-time (SMRT) sequencing allows identification of methylated DNA bases and methylation patterns/motifs at the genome level. Using SMRT sequencing, diverse bacterial methylomes including those of Helicobacter pylori, Lactobacillus spp., and Escherichia coli have been determined, and previously unreported DNA methylation motifs have been identified. However, the methylomes of Xanthomonas species, which belong to the most important plant pathogenic bacterial genus, have not been documented. Here, we report the methylomes of Xanthomonas axonopodis pv...
December 2016: Plant Pathology Journal
Chu Jian Ma, Bryan Gibb, YoungHo Kwon, Patrick Sung, Eric C Greene
Homologous recombination (HR) is a crucial pathway for double-stranded DNA break (DSB) repair. During the early stages of HR, the newly generated DSB ends are processed to yield long single-stranded DNA (ssDNA) overhangs, which are quickly bound by replication protein A (RPA). RPA is then replaced by the DNA recombinase Rad51, which forms extended helical filaments on the ssDNA. The resulting nucleoprotein filament, known as the presynaptic complex, is responsible for pairing the ssDNA with homologous double-stranded DNA (dsDNA), which serves as the template to guide DSB repair...
November 29, 2016: Nucleic Acids Research
Kevin D Whitley, Matthew J Comstock, Yann R Chemla
Despite its fundamental importance in cellular processes and abundant use in biotechnology, we lack a detailed understanding of the kinetics of nucleic acid hybridization. In particular, the identity of the transition state, which determines the kinetics of the two-state reaction, remains poorly characterized. Here, we used optical tweezers with single-molecule fluorescence to observe directly the binding and unbinding of short oligonucleotides (7-12 nt) to a complementary strand held under constant force. Binding and unbinding rate constants measured across a wide range of forces (1...
November 29, 2016: Nucleic Acids Research
Alexander Artyomenko, Nicholas C Wu, Serghei Mangul, Eleazar Eskin, Ren Sun, Alex Zelikovsky
As a result of a high rate of mutations and recombination events, an RNA-virus exists as a heterogeneous "swarm" of mutant variants. The long read length offered by single-molecule sequencing technologies allows each mutant variant to be sequenced in a single pass. However, high error rate limits the ability to reconstruct heterogeneous viral population composed of rare, related mutant variants. In this article, we present two single-nucleotide variants (2SNV), a method able to tolerate the high error rate of the single-molecule protocol and reconstruct mutant variants...
November 30, 2016: Journal of Computational Biology: a Journal of Computational Molecular Cell Biology
Parastoo Maleki, Yue Ma, Keisuke Iida, Kazuo Nagasawa, Hamza Balci
The potential use of G-quadruplex (GQ) stabilizing small molecules as anti-cancer drugs has created a flurry of activity on various aspects of these molecules. Telomestatin and oxazole telomestatin derivatives (OTD) are some of the most prominent of such molecules, yet the underlying dynamics of their interactions with GQ and the extent of heterogeneities in these interactions are not known. We performed single molecule measurements to study binding kinetics, rotational freedom, and dwell time distributions of a Cy5-labeled OTD (L1Cy5-7OTD) as it interacted with several different GQ structures...
November 29, 2016: Nucleic Acids Research
Xunshan Liu, Sara Sangtarash, David Reber, Dan Zhang, Hatef Sadeghi, Jia Shi, Zong-Yuan Xiao, Wenjing Hong, Colin J Lambert, Shi-Xia Liu
To guide the choice of future synthetic targets for single-molecule electronics, qualitative design rules are needed, which describe the effect of modifying chemical structure. Here the effect of heteroatom substitution on destructive quantum interference (QI) in single-molecule junctions is, for the first time experimentally addressed by investigating the conductance change when a "parent" meta-phenylene ethylene-type oligomer (m-OPE) is modified to yield a "daughter" by inserting one nitrogen atom into the m-OPE core...
November 29, 2016: Angewandte Chemie
Sören Bock, Oday Al-Owaedi, Samantha Eaves, David Milan, Mario Lemmer, Brian Skelton, Henrry Osorio, Richard Nichols, Simon Higgins, Pilar Cea, Nicholas Long, Tim Albrecht, Santiago Martín, Colin Lambert, Paul J Low
The compounds and complexes 1,4-C6H4(C≡C-cyclo-3-C4H3S)2 (2), trans-Pt(C≡C-cyclo-3-C4H3S)2(PEt3)2 (3), trans-Ru(C≡C-cyclo-3-C4H3S)2(dppe)2 (4) and trans-Ru(C≡C-cyclo-3-C4H3S)2{P(OEt)3}4 (5) featuring the 3-thienyl moiety as a surface contacting group for gold electrodes have been prepared, crystallographically characterised in the case of 3 - 5, and studied in metal|molecule|metal junctions using both STM-I(s) and STM-BJ methods. The compounds exhibit similar conductance profiles, with a low conductance feature being more readily identified by STM-I(s) methods, and a higher feature by the STM-BJ method...
November 29, 2016: Chemistry: a European Journal
John Huddleston, Mark Jp Chaisson, Karyn Meltz Steinberg, Wes Warren, Kendra Hoekzema, David S Gordon, Tina A Graves-Lindsay, Katherine M Munson, Zev N Kronenberg, Laura Vives, Paul Peluso, Matthew Boitano, Chen-Shin Chin, Jonas Korlach, Richard K Wilson, Evan E Eichler
In an effort to more fully understand the full spectrum of human genetic variation, we generated deep single-molecule, real-time (SMRT) sequencing data from two haploid human genomes. Using an assembly-based approach (SMRT-SV), we systematically assessed each genome independently for structural variants (SVs) and indels resolving the sequence structure of 461,553 genetic variants from 2 bp to 28 kbp in length. We find that >89% of these variants have been missed as part of analysis of the 1000 Genomes Project even after adjusting for more common variants (MAF >1%)...
November 28, 2016: Genome Research
Roheeth Kumar Pavana, Shruti Choudhary, Anja Bastian, Michael A Ihnat, Ruoli Bai, Ernest Hamel, Aleem Gangjee
The utility of cytostatic antiangiogenic agents (AA) in cancer chemotherapy lies in their combination with cytotoxic chemotherapeutic agents. Clinical combinations of AA with microtubule targeting agents (MTAs) have been particularly successful. The discovery, synthesis and biological evaluations of a series of 7-benzyl-N-substituted-pyrrolo[3,2-d]pyrimidin-4-amines are reported. Novel compounds which inhibit proangiogenic receptor tyrosine kinases (RTKs) including vascular endothelial growth factor receptor-2 (VEGFR-2), platelet-derived growth factor receptor-β (PDGFR-β) and epidermal growth factor receptor (EGFR), along with microtubule targeting in single molecules are described...
November 15, 2016: Bioorganic & Medicinal Chemistry
Maria Vera, Jeetayu Biswas, Adrien Senecal, Robert H Singer, Hye Yoon Park
Recent advancements in single-cell and single-molecule imaging technologies have resolved biological processes in time and space that are fundamental to understanding the regulation of gene expression. Observations of single-molecule events in their cellular context have revealed highly dynamic aspects of transcriptional and post-transcriptional control in eukaryotic cells. This approach can relate transcription with mRNA abundance and lifetimes. Another key aspect of single-cell analysis is the cell-to-cell variability among populations of cells...
November 23, 2016: Annual Review of Genetics
Antonio Abeyta, Maria Castella, Celine Jacquemont, Toshiyasu Taniguchi
Proteins essential for homologous recombination play a pivotal role in the repair of DNA double strand breaks, DNA inter-strand crosslinks and replication fork stability. Defects in homologous recombination also play a critical role in the development of cancer and the sensitivity of these cancers to chemotherapy. RAD51, an essential factor for homologous recombination and replication fork protection, accumulates and forms immunocytochemically detectable nuclear foci at sites of DNA damage. To identify kinases that may regulate RAD51 localization to sites of DNA damage, we performed a human kinome siRNA library screen, using DNA damage-induced RAD51 foci formation as readout...
November 28, 2016: Cell Cycle
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