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Guiping Wang, Jeffrey R Moffitt, Xiaowei Zhuang
As an image-based single-cell transcriptomics approach, multiplexed error-robust fluorescence in situ hybridization (MERFISH) allows hundreds to thousands of RNA species to be identified, counted and localized in individual cells while preserving the native spatial context of RNAs. In MERFISH, RNAs are identified via a combinatorial labeling approach that encodes RNA species with error-robust barcodes followed by sequential rounds of single-molecule FISH (smFISH) to read out these barcodes. The accuracy of RNA identification relies on spatially separated signals from individual RNA molecules, which limits the density of RNAs that can be measured and makes the multiplexed imaging of a large number of high-abundance RNAs challenging...
March 19, 2018: Scientific Reports
Myeongsang Lee, Hyunsung Choi, Gwonchan Yoon, Sungsoo Na
Experimental force spectroscopy has been effectively utilized for measuring structural characterization of biomolecules and mechanical properties of biomaterials. Specifically, atomic force microscopy (AFM) has been widely used to portray biomolecular characterization in single-molecule experiment by observing the unfolding behavior of the proteins. Not only the experimental techniques enable us to characterize globular protein, but computational methods like molecular dynamics (MD) also gives insight into understanding biomolecular structures...
March 12, 2018: Journal of Molecular Graphics & Modelling
Qingyi Tong, Huijuan You, Xintao Chen, Kongchao Wang, Weiguang Sun, Yufeng Pei, Xiaodan Zhao, Ming Yuan, Hucheng Zhu, Zengwei Luo, Yonghui Zhang
Despite All-trans retinoic acid (ATRA) has transformed acute promyelocytic leukemia (APL) from the most fatal to the most curable hematological cancer, there remains a clinical challenge that many high-risk APL patients who fail to achieve a complete molecular remission or relapse and become resistant to ATRA. Herein, we report that 5-(4-methoxyphenethyl)-[1, 3] dioxolo [4, 5-j] phenanthridin-6(5H)-one (ZYH005) exhibits specific anticancer effects on APL and ATRA-resistant APL in vitro and vivo, while shows negligible cytotoxic effect on non-cancerous cell lines and peripheral blood mononuclear cells from healthy donors...
March 15, 2018: Nucleic Acids Research
Yair Fastman, Shany Assaraf, Miriam Rose, Elad Milrot, Katherine Basore, B Sivanandam Arasu, Sanjay A Desai, Michael Elbaum, Ron Dzikowski
Plasmodium falciparum, the causative agent of the deadliest form of human malaria, alternates expression of variable antigens, encoded by members of a multi-copy gene family named var. In var2csa, the var gene implicated in pregnancy-associated malaria, translational repression is regulated by a unique upstream open reading frame (uORF) found only in its 5' UTR. Here, we report that this translated uORF significantly alters both transcription and posttranslational protein trafficking. The parasite can alter a protein's destination without any modifications to the protein itself, but instead by an element within the 5' UTR of the transcript...
March 15, 2018: Nucleic Acids Research
Tomasz Krzywkowski, Malte Kühnemund, Di Wu, Mats Nilsson
Phi29 (Φ29) DNA polymerase is an enzyme commonly used in DNA amplification methods such as rolling circle amplification (RCA) and multiple strand displacement amplification (MDA), as well as in DNA sequencing methods such as single molecule real time (SMRT) sequencing. Here, we report the ability of phi29 DNA polymerase to amplify RNA-containing circular substrates during RCA. We found that circular substrates with single RNA substitutions are amplified at a similar amplification rate as non-chimeric DNA substrates, and that consecutive RNA pyrimidines were generally preferred over purines...
March 15, 2018: Nucleic Acids Research
Steven Quinn, Shwetha Srinivasan, Jesse Gordon, Wei He, Kermit L Carraway, Matthew A Coleman, Gabriela S Schlau-Cohen
The epidermal growth factor receptor (EGFR) is critical to normal cellular signaling pathways. Moreover, it has been implicated in a range of pathologies, including cancer. As a result, it is the primary target of many anti-cancer drugs. One limitation to the design and development of these drugs has been the lack of molecular-level information about the interactions and conformational dynamics of EGFR. To overcome this limitation, this work reports the development and characterization of functional fluorescently-labeled full-length EGFR in model membrane nanolipoprotein particles (NLPs) for in vitro fluorescence studies...
March 19, 2018: Biochemistry
Magdalena Nüesch-Inderbinen, Katrin Zurfluh, Marc J A Stevens, Roger Stephan
OBJECTIVES: Carbapenem-resistant Klebsiella pneumoniae (CRKP) have emerged worldwide and represent a major threat to human health. Here, we report the genome sequence of K. pneumoniae 002SK2, an NDM-9 and CTX-M-15 producing strain isolated from wastewater in Switzerland and belonging to the international high-risk clone ST147. METHODS: Whole genome sequencing of K. pneumoniae 002SK2 was performed using Pacific Biosciences (PacBio) single-molecule real-time (SMRT) technology RS2 reads (C4/P6 chemistry)...
March 15, 2018: Journal of Global Antimicrobial Resistance
Bernard Knoops, Sarah Becker, Mégane Anne Poncin, Julien Glibert, Sylvie Derclaye, André Clippe, David Alsteens
Inflammation is a pathophysiological response of innate immunity to infection or tissue damage. This response is among others triggered by factors released by damaged or dying cells, termed damage-associated molecular pattern (DAMP) molecules that act as danger signals. DAMPs interact with pattern recognition receptors (PRRs) to contribute to the induction of inflammation. However, how released peroxiredoxins (PRDXs) are able to activate PRRs, such as Toll-like receptors (TLRs), remains elusive. Here, we used force-distance curve-based atomic force microscopy to investigate the molecular mechanisms by which extracellular human PRDX5 can activate a proinflammatory response...
March 5, 2018: Cell Chemical Biology
Hemendra Yadav, Pulkit Sharma
Single molecule analysis can help us study genomics efficiently. It involves studying single DNA molecules for genomic studies. DNA combing is one of such techniques which allowed us to study single DNA molecules for multiple uses. DNA combing technology can be used to perform Fiber-FISH and optical mapping. Physical mapping of genomes can be studied by restriction digestion of combed DNA on glass slides. Restriction fragments can be arranged into optical maps by gathering fluorescent intensity data by CCD camera and image analysis by softwares...
March 14, 2018: Genomics
James L Januzzi, Sunil Suchindran, Adrian Coles, Maros Ferencik, Manesh R Patel, Udo Hoffmann, Geoffrey S Ginsburg, Pamela S Douglas
OBJECTIVES: The goal of this study was to examine associations between concentrations of high-sensitivity troponin I (hsTnI) (measured by using a single-molecule counting method) and obstructive coronary artery disease (CAD) in 1,844 stable, symptomatic outpatients with suspected CAD randomized to undergo coronary computed tomography angiography (CTA) in the PROMISE (Prospective Multicenter Imaging Study for Evaluation of Chest Pain) trial. BACKGROUND: Elevated concentrations of hsTnI are associated with CAD in patients with myocardial infarction...
March 9, 2018: JACC. Cardiovascular Imaging
David Wu, Adam Waalkes, Kelsi Penewit, Stephen J Salipante
BACKGROUND: Genomic chimerism, the co-occurrence of cells from different genetic origins, provides important diagnostic information in diverse clinical contexts, including graft injury detection and longitudinal surveillance of hematopoietic stem cell transplantation patients, but existing assays are limiting. Here we applied single-molecule molecular inversion probes (smMIPs), a high-throughput sequencing technology combining multiplexed target capture with read quantification mediated by unique molecular identifiers, to detect chimerism based on the presence or absence of polymorphic genomic loci...
March 16, 2018: Clinical Chemistry
Aykut Erbaş, Monica Olvera de la Cruz, John F Marko
We study unbinding of multivalent cationic ligands from oppositely charged polymeric binding sites sparsely grafted on a flat neutral substrate. Our molecular dynamics simulations are suggested by single-molecule studies of protein-DNA interactions. We consider univalent salt concentrations spanning roughly a 1000-fold range, together with various concentrations of excess ligands in solution. To reveal the ionic effects on unbinding kinetics of spontaneous and facilitated dissociation mechanisms, we treat electrostatic interactions both at a Debye-Hückel (DH) (or implicit ions, i...
February 2018: Physical Review. E
Seung Yub Han, Alesia Antoine, David Howard, Bryant Chang, Woo Sung Chang, Matthew Slein, Gintaras Deikus, Sofia Kossida, Patrice Duroux, Marie-Paule Lefranc, Robert P Sebra, Melissa L Smith, Ismael Ben F Fofana
The simian immunodeficiency virus (SIV)/macaque model of human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome pathogenesis is critical for furthering our understanding of the role of antibody responses in the prevention of HIV infection, and will only increase in importance as macaque immunoglobulin (IG) gene databases are expanded. We have previously reported the construction of a phage display library from a SIV-infected rhesus macaque ( Macaca mulatta ) using oligonucleotide primers based on human IG gene sequences...
2018: Frontiers in Immunology
Jeroen Frank, Sebastian Lücker, Rolf H A M Vossen, Mike S M Jetten, Richard J Hall, Huub J M Op den Camp, Seyed Yahya Anvar
Anaerobic ammonium-oxidizing (anammox) bacteria are a group of strictly anaerobic chemolithoautotrophic microorganisms. They are capable of oxidizing ammonium to nitrogen gas using nitrite as a terminal electron acceptor, thereby facilitating the release of fixed nitrogen into the atmosphere. The anammox process is thought to exert a profound impact on the global nitrogen cycle and has been harnessed as an environment-friendly method for nitrogen removal from wastewater. In this study, we present the first closed genome sequence of an anammox bacterium, Kuenenia stuttgartiensis MBR1...
March 15, 2018: Scientific Reports
Lianbin Yao, Sten Ohlson, Brian W Dymock
Inhibition of multiple signaling pathways in a cancer cell with a single molecule could result in better therapies that are simpler to administer. Efficacy may be achieved with reduced potency against individual targets if there is synergy through multiple pathway inhibition. To achieve this, it is necessary to be able to build multi-component ligands by joining together key pharmacophores in a way which maintains sufficient activity against the individual pathways. In this work, designed triple inhibiting ligands are explored aiming to block three completely different target types: a kinase (JAK2), an epigenetic target (HDAC) and a chaperone (HSP90)...
March 3, 2018: Bioorganic & Medicinal Chemistry Letters
Niels Vandenberk, Anders Barth, Doortje Borrenberghs, Johan Hofkens, Jelle Hendrix
Förster resonance energy transfer (FRET) is a powerful tool to probe molecular interactions, activity, analytes, forces and structure. Single-molecule (sm) FRET additionally allows real-time quantifications of conformation and conformational dynamics. SmFRET robustness critically depends on the employed dyes, yet a systematic comparison of different dye pairs is lacking. Here, we evaluated blue (Atto488 and Alexa488) and far-red (Atto647N, Alexa647, StarRed and Atto655) dyes using confocal smFRET spectroscopy on freely diffusing dsDNA molecules...
March 15, 2018: Journal of Physical Chemistry. B
Yan Zhang, Zhongyuan Huang, Letao Wang, Chunming Wang, Changde Zhang, Thomas E Wiese, Guangdi Wang, Kevin Eugene Riley, Zhe Wang
This work aims to face the challenge of monitoring small molecule drugs accurately and rapidly for point-of-care (POC) diagnosis in current clinical settings. Overdose of acetaminophen (AP), a commonly used OTC analgesic drug, has been determined to be a major cause of acute liver failure in the US and the UK. However, there is no rapid and accurate detection method available for this drug in the emergency room. The present study examined an AP sensing strategy that relies on a previously unexplored strong interaction between AP and the arginine (Arg) molecule...
March 15, 2018: Analytical Chemistry
Geng Li, Chenhui He, Peixuan Bu, Huimin Bi, Sichen Pan, Ronghua Sun, Xin Sheng Zhao
Skp and SurA are both periplasmic chaperones involved in the biogenesis of E. coli β-barrel outer membrane proteins (OMPs). It is commonly assumed that SurA plays a major role, whereas Skp is a minor factor. However, there is no molecular evidence for whether their roles are redundant or not. Here, by using different dilution methods, we obtained monodisperse and aggregated forms of OmpC and studied their interactions with Skp and SurA by single-molecule fluorescence resonance energy transfer (smFRET) and fluorescence correlation spectroscopy (FCS)...
March 15, 2018: ACS Chemical Biology
Akhil Kumar, Ashish Tiwari, Ashok Sharma
Alzheimer disease (AD) is now considered as a multifactorial neurodegenerative disorder and rapidly increasing to an alarming situation and causing higher death rate. One target one ligand hypothesis is not able to provide complete solution of AD due to multifactorial nature of disease and one target one drug seems to fail to provide better treatment against AD. Moreover, current available treatments are limited and most of the upcoming treatments under clinical trials are based on modulating single target...
March 15, 2018: Current Neuropharmacology
Nelly Siller, Jens Kuhle, Muthuraman Muthuraman, Christian Barro, Timo Uphaus, Sergiu Groppa, Ludwig Kappos, Frauke Zipp, Stefan Bittner
BACKGROUND: Monitoring neuronal injury remains one key challenge in early relapsing-remitting multiple sclerosis (RRMS) patients. Upon axonal damage, neurofilament - a major component of the neuro-axonal cytoskeleton - is released into the cerebrospinal fluid (CSF) and subsequently peripheral blood. OBJECTIVE: To investigate the relevance of serum neurofilament light chain (sNfL) for acute and chronic axonal damage in early RRMS. METHODS: sNfL levels were determined in 74 patients (63 therapy-naive) with recently diagnosed clinically isolated syndrome (CIS) or RRMS using Single Molecule Array technology...
March 1, 2018: Multiple Sclerosis: Clinical and Laboratory Research
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