1,750 Matching Annotations
  1. Aug 2015
    1. We removed the MSD dataset articles from the sample and searched the remaining articles for those with full-text available in PubMed Central (PMC) using the [sb] search tag.

      Again, it is disgraceful that even NIH does not have access to the full text of all articles for text mining purposes. I do believe that this is one of the central issues facing biomedicine moving forward and one that needs to be solved.

    2. While little is known about the full extent of non-publication in biomedical research, recent work indicates that as long as four years after study completion, the results from approximately one-third of clinical trials registered in ClinicalTrials.gov remains unpublished

      That number is lower than I would expect based on some estimates from Chalmers and others.

    3. Biomedical research is becoming increasingly data-centric

      Actually, it was never non-data centric. We just had no opportunity to share and preserve the data for reuse.

    4. Approximately 87% of the invisible datasets consist of data newly collected for the research reported; 13% reflect reuse of existing data. More than 50% of the datasets were derived from live human or non-human animal subjects.

      Another good statistic to have

    5. Among articles with invisible datasets, we found an average of 2.9 to 3.4 datasets, suggesting there were approximately 200,000 to 235,000 invisible datasets generated from NIH-funded research published in 2011.

      This is a good statistic to have handy.

    1. Kahn Jr, C. E., Langlotz, C. P., Channin, D. S., & Rubin, D. L. (2011). Informatics in Radiology: An Information Model of the DICOM Standard 1.Radiographics, 31(1), 295-304

      Need to tell Karl and others of the task force about this.

    2. ly. The provenance of annotations is modeled with Provenance, Authoring and Versioning (PAV) ontology [12] e.g. predicates such as createdBy, cre-atedOndescribe the annotation creator and date of creatio

      But not Prov?

    3. Each annotation has some has-Topic, context predicates and object class. Objects can be a particular entity such as protein or chemical name,a disease, or reified fact, while the context refers to a certain text seg-ment inside the sentence (see Fig.3).

      But do not address the anchoring of the annotation to the object.

    Annotators

    1. FDA is investigating the risk of brain deposits following repeated use of gadolinium-based contrast agents (GBCAs) for magnetic resonance imaging (MRI). Recent publications in the medical literature have reported that deposits of GBCAs remain in the brains of some patients who undergo four or more contrast MRI scans, long after the last administration. It is unknown whether these gadolinium deposits are harmful or can lead to adverse health effects.

      Did you know about Russ Poldrack's My Connectome? I'm hoping he didn't use a contrast agent. I'm assuming not.

    1. A needle biopsy revealed that the tumor was a ductal carcinoma, which was estrogen receptor(ER)positive,

      This is the same as Mom's tumor, I believe, although I don't know the PgR or HER2 status.

    2. Three years later, the existing lesions have not increased in size and no new lesion has appeared. Endocrine therapy may be effective for the treatment of advanced hormone-sensitive cancers in elderly patients.

      Even though we can't read the full article, this statement is encouraging.

    1. Fewer patients treated with hypofractionation had absence of skin induration during follow up (81.2% versus 84.5%, P=0.02)

      "Induration: Localized hardening of soft tissue of the body. The area becomes firm, but not as hard as bone."

      But very confusing the way this is phrased: so hypo fractionation is associated with slightly more skin induration. Don't care if it's significant, it's a very small effect.

    2. patients with ductal carcinoma in situ and those receiving regional nodal irradiation

      Probably could use some explanation; does this mean localized vs spread?

    3. At 6 months, patients treated with hypofractionated radiotherapy had less fatigue and were less likely to report lack of energy and difficulty meeting family needs.

      Six months? The length of recovery needs to be considered when treating the elderly.

    1. J. A. Masseyet al., Self-assembly of organometallic block copolymers: The role of crystallinity of the core-forming polyferrocene block in the micellar morphologies formed by poly(ferrocenylsilane- b -dimethylsiloxane) in n -alkane solvents. J. Am. Chem. Soc. 122, 11577 (2000). Y. Ni, R. Rulkens, I. Manners, Transition metal-based polymers with controlled architectures: Well-defined poly(ferrocenylsilane) homopolymers and multiblock copolymers via the living anionic ring-opening polymerization of silicon-bridged [1]ferrocenophanes. J. Am. Chem. Soc. 118, 4102 (1996). S. F. Mohd Yusoff, J. B. Gilroy, G. Cambridge, M. A. Winnik, I. Manners, End-to-end coupling and network formation behavior of cylindrical block copolymer micelles with a crystalline polyferrocenylsilane core. J. Am. Chem. Soc. 133, 11220 (2011).

      These references are not in the pdf

    2. H. Wang, M. A. Winnik, I. Manners, Synthesis and self-assembly of poly(ferrocenyldimethylsilane- b -2-vinylpyridine) diblock copolymers. Macromolecules 40, 3784 (2007).

      In this paper, the authors developed a new class of diblock copolymers that have a metal-containing hydrophobic block (PFS) and an organic hydrophilic block (P2VP): PFS = poly(ferrocenyldimethylsilane) and P2VP = poly(2-vinylpyridine). The authors of this publication discovered the ability to obtain spherical and cylindrical morphologies simply by using different alcohols. Having established the ability to obtain cylindrical micelles using the PFS-b-P2VP block copolymer system in isopropyl alcohol, the authors modified their approach in the current study to obtain supermicelles.

    3. P. A. Rupar, G. Cambridge, M. A. Winnik, I. Manners, Reversible cross-linking of polyisoprene coronas in micelles, block comicelles, and hierarchical micelle architectures using Pt(0)–olefin coordination. J. Am. Chem. Soc. 133, 16947 (2011).

      This paper established that Karstedt's catalysts ability to cross-link the double bonds in polyisoprene in the absences of silicon-containing molecules. Besides acquiring a variety of morphologies, the authors also investigated their ability to use Karstedt's catalyst to synthesize reversible polymer gel networks.

    4. X. S. Wanget al., Shell-cross-linked cylindrical polyisoprene- b -polyferrocenylsilane (PI- b -PFS) block copolymer micelles: One-dimensional (1D) organometallic nanocylinders. J. Am. Chem. Soc. 129, 5630 (2007).

      This reference investigates the development of 1D nano-structures through the use of cross-linked cylindrical micelles. This paper highlights possible applications for these 1D nanomaterials such as microfluidics.

    5. R. K. O’Reilly, C. J. Hawker, K. L. Wooley, Cross-linked block copolymer micelles: functional nanostructures of great potential and versatility. Chem. Soc. Rev. 35, 1068 (2006).

      This review paper describes the uses and progress made in the field of cross-linked micelles. Concepts covered include stabilization as well chemical modification and functionalization.

    6. W. Zhanget al., Supramolecular linear heterojunction composed of graphite-like semiconducting nanotubular segments. Science 334, 340 (2011).

      References: This paper describes the synthesis of semiconducting nanotubes through a process similar to CDSA by connecting dissimilar junctions, referred to as heterojuntions, to study the behaviors of photocarriers.

    7. Z.-X. Du, J.-T. Xu, Z.-Q. Fan, Micellar morphologies of poly(ε-caprolactone)- b -poly(ethylene oxide) block copolymers in water with a crystalline core. Macromolecules 40, 7633 (2007).

      This paper describes the use of a biodegradable polymer in order to obtain a variety of micelle morphologies. A concept referred to as tethering density is used in this paper to explain unexpected morphologies.

    8. Schmelz, M. Karg, T. Hellweg, H. Schmalz, General pathway toward crystalline-core micelles with tunable morphology and corona segregation. ACS Nano 5, 9523 (2011).

      This paper uses triblock copolymers to synthesize cylindrical and spherical micelles. By carefully controlling crystallization, the authors were able to control the micellar morphology in a highly selective fashion.

    9. T. Gädt, N. S. Ieong, G. Cambridge, M. A. Winnik, I. Manners, Complex and hierarchical micelle architectures from diblock copolymers using living, crystallization-driven polymerizations. Nat. Mater. 8, 144 (2009).

      This paper utilizes CDSA to synthesize noncylindrical block co-micelles. The authors utilized plateletlike micelle and cylindrical micelles in order to form scarflike architectures using platelet-cylindrical and cylindrical-cylindrical connections.

    10. X. S. Wanget al., Cylindrical block copolymer micelles and co-micelles of controlled length and architecture. Science 317, 644 (2007)

      This paper describes the discovery of CDSA. The authors draw a comparison to living polymerization and explain the phenomenon of epitaxial crystallization-induced co-micellization

    11. Y. Xia, B. D. Olsen, J. A. Kornfield, R. H. Grubbs, Efficient synthesis of narrowly dispersed brush copolymers and study of their assemblies: The importance of side chain arrangement. J. Am. Chem. Soc. 131, 18525 (2009).

      This reference describes the synthesis of brush block and random copolymers. The polymers are referred to as a "brush" because pendant groups are dangling off the main chain. The brush polymers synthesized were amphiphilic and demonstrated self-assembly.

    12. Walther, M. Drechsler, A. H. E. Müller, Structures of amphiphilic Janus discs in aqueous media. Soft Matter 5, 385 (2009).

      This paper describes the synthesis of amphiphilic Janus discs using a block terpolymer (three distinct blocks comprised of three distinct monomers). Two different size discs were made where, depending on size, the manner in which the hydrophobic side is "protected" from water can vary. The smaller discs are stabilized by the long hydrophilic polymer chains, protruding out of one side and shielding the hydrophobic side against water. The larger discs undergo aggregation as well as bending to again shield the hydrophobic side from the water by flipping over one part of the structure.

    13. J. Dupont, G. Liu, ABC triblock copolymer hamburger-like micelles, segmented cylinders, and Janus particles. Soft Matter 6, 3654 (2010).

      This reference is an example where triblock copolymers were photo-crosslinked to create Janus particles which were classified as "hamburger-like" micelles.

    14. Walther, A. H. E. Müller, Janus particles. Soft Matter 4, 663 (2008)

      This review paper discusses a class of noncentrosymmetric nanoparticles referred to as the Janus particle. These particles are rather challenging to synthesize because two different chemistries are present on the surface of the particle.

    15. H. Cui, Z. Chen, S. Zhong, K. L. Wooley, D. J. Pochan, Block copolymer assembly via kinetic control. Science 317, 647 (2007).

      This paper utilized charged polymers as well as metal cations and a variety of solvents to kinetically trap unique micelle morphologies. The self-assembly systems were forced down a specific pathway in order to form morphologies that would not have typically occurred without assistance.

    16. L. Zhang, A. Eisenberg, Multiple morphologies of “crew-cut” aggregates of polystyrene-b-poly(acrylic acid) block copolymers. Science 268, 1728 (1995).

      This paper was one of the first papers to establish the ability to form micelles of different morphologies (beyond just spherical) for systems using amphiphilic block copolymers

    17. optical microscope micrographs of the solution

      This optical microscope, commonly referred to as a light microscope, uses light to magnify images.

      The resolution power of an optical microscope is smaller than that of a TEM.

      Optical microscope images were taken to confirm/support the starlike supermicelles seen in the TEM (which were several micrometers in diameter). The authors stated since the supermicelles were approximately 3 micrometers in diameter, the optical microscope could resolve the starlike strucutres. However, if the supermicelles were much smaller than 3 micrometers then resolution using an optical microscope would not be possible.

    18. corona

      The outside of a micelle.

    19. core

      The center of a micelle.

    20. This will allow access to a wide variety of well-defined non-centrosymmetric architectures with control of segment length and segment composition.

      Because the authors have demonstrated the ability to synthesize noncentrosymmetric structures through coronal cross-linking, they have set a foundation to expand the field of non-centrosymmetric nanostrctures when coupled with CDSA.

    21. As expected on the basis of the behavior of other amphiphilic systems of different sizes, the A-B-C amphiphilic block co-micelles assembled into star-shaped supermicelles.

      Upon synthesis of a triblock co-micelle comprised of three different types of unimers (all of which have a crystalline PFS core), the amphiphilic block co-micelle demonstrated the ability to self-assemble into a star-shaped "supermicelle".

    22. Transmission electron microscopy (TEM) micrographs of a drop-cast sample of the solution showed the formation of large starlike structures

      TEM is a microscopy technique where a beam of electrons passes through a thin-film sample. As the electrons interact with the sample, an image is produced. Samples that have atoms with high atomic numbers can produce darker images/provide better contrast.

      The TEM samples were prepared on a carbon-coated grid. A drop of the micelle suspension was placed on the grid and then the excess solvent was removed using filter paper.

      Using TEM the authors can verify they have achieved unidirectional growth. Additionally, they were able to see larger starlike micellar aggregates formed from the target noncentrosymmetric micelles.

    23. turbid

      This term is used to describe solutions that have limited to no transparency; cloudy, opaque.

    24. The non-centrosymmetric A-B block co-micelles were also found to be active in further CDSA

      The authors showed they were able to definitively deactivate the micelle ends from CDSA by employing coronal cross-linking. Figs. 3D, E, and F demonstrate the ability for elongation to occur from only the non-crosslinked end.

    25. We found that dispersions of the triblock co-micelles in a decane:toluene (3:5 by volume) solution resulted in the selective dissolution of the central M(PFS60-b-PDMS660) micelle block, leaving short XLM(PI1424-b-PFS63) daughter micelles

      Connects to AP Chemistry Learning Standard 6: Any bond or intermolecular attraction that can be formed can be broken. These two processes are in dynamic competition, sensitive to initial conditions and external perturbations.

      Found on page 71 of the AP Chemistry Course and Exam Description:

      http://media.collegeboard.com/digitalServices/pdf/ap/ap-chemistry-course-and-exam-description.pdf

    26. to remove the central M(PFS60-b-PDMS660) micelle block from the XLM(PI1424-b-PFS63)-b-M(PFS60-b-PDMS660)-b-XLM(PI1424-b-PFS63) triblock co-micelles to release the XLM(PI1424-b-PFS63) daughter micelles

      Figure 1B depicts the synthetic strategy used to make micelles seeds capable of unidirectional growth:

      After the cross-linking step, a solvent is chosen to dissolve the middle block (PFS-b-PDMS) of the triblock co-micelle. By doing this, the remaining PI-B-PFS micelle blocks can be used as seeds for elongation from the non-crosslinked end.

    27. co-micelles did not elongate, thus verifying that CDSA was inhibited after cross-linking

      In order to test if the authors had successfully blocked the active micelle ends, the authors took TEM images before and after unimers were added to the cross-linked micelle solution. As the TEM figure shows, Fig. 2D, upon unimer addition the average micelle length did not increase.

    28. creation of a sample of triblock co-micelles with two cross-linkable corona domains located on the end blocks and a non–cross-linkable corona domain as the central block.

      Figure 1A depicts the synthetic strategy used to make triblock co-micelles:

      1) The first step was to make micelles with crystalline cores. They did this by making a suspension of poly (ferrocenyl dimethylsilane)-b-poly(dimethylsiloxane) in hexane at 60C°. The solution was allowed to age at room temperature. They then sonicated the suspension in order to break up the micelles into smaller micelle seeds.

      2) The next step was to add a second block copolymer to give bidirectional growth to form a triblock co-micelle. This was performed using a solution of unimers in THF which was added to the micelle suspension and allowed to age in order to form a longer micelle.

      3) Finally, the polyisoprene end of the block co-micelle is cross-linked to prevent further growth using Karstedt's catalyst.

    29. We therefore concluded that the corona cross-linking strategy provides an efficient method of blocking micelle termini toward further participation in CDSA.

      The authors have previously presented the ability to cross-link micelles for increased micellar stability as well as for the synthesis of polymer gel networks (see references).

      In this paper, they used this prior knowledge to cross-link the micelle corona to prevent CDSA and limit elongation by deactivating the ends of the micelles.

    30. Karstedt’s catalyst–promoted hydrosilylation with tetramethyldisiloxane was then used to cross-link the PI corona of the micelles to generate XLM(PI1424-b-PFS63) cylinders

      Karstedt's catalyst is a platinum compound capable of forming bonds between carbon and silicon atoms.

      In a separate publication, ref. 31 (DOI: 10.1021/ja206370k), the authors discovered the catalyst's ability to cross-link the double bonds in polyisoprene in the absences of silicon-containing molecules.

      In this paper, Karstedt's catalyst was used to prevent block elongation from one end of the exposed cylindrical core to achieve unidirectional growth.

    31. We previously established coronal cross-linking of PI in such BCP micelles as a means to achieve permanent micelle stability in good solvents for both blocks

      Winnik and Manners et. al. used Karstedt's catalysts to cross-link polyisoprene in order to create micelles of varying morphologies. They were able to apply this technique for the development of noncentrosymmetric micelles.

    32. epitaxial

      The growth of one crystalline material on the surface of another crystalline.

      In this case, the crystalline surface upon which epitaxial growth occurs is the exposed crystalline core of the cylindrical micelle. The exposed core can continue to elongate as more block copolymers are added to the solution.

    33. this method has been limited to the creation of centrosymmetric nanostructures

      Prior to this article, despite the usefulness of CDSA, many of the structures synthesized were centrosymmetric since growth can happen from both ends of the micelle core. This article presents the development of a method to overcome this limitation.

    34. semiconducting nanotubes
    35. In recent years, CDSA processes have been used to access elongated structures for a range of crystalline-coil BCPs

      After the discovery of CDSA, the synthetic strategy has been used with a range polymers including conducting, biocompatible, metal-containing, etc.

    36. colloidal dispersions

      A solution that has evenly dispersed particles that are 1 nm to 1000 nm. The particles are in solution and do not settle out. An example of a colloidal dispersion is milk.

    37. contour length

      Maximum end-to-end distance of a linear polymer chain.

    38. In several cases, CDSA has been demonstrated to be a living process because the ends or edges of the micelles remain active to the addition of further unimer

      Previous Work: During CDSA, the crystalline core of the micelle is partially "exposed" to the solvent. When unimers are added to the micelle solution, they are able to grow on existing micelle. However, if the chemical structure of the core prevents crystallization/is not a lattice match, then micelle growth will not happen. This technique has been widely used with a variety of materials such as diblock polymers and nanotubes to create unique self-assemblies.

    39. coil block

      In a block copolymer, a block which lacks crystallinity and has great freedom of rotation due to its flexible nature.

    40. crystallization-driven self-assembly (CDSA)

      This technique was first introduced in 2007 by Winnik and Manners et. al. where they discovered a "living" form of micellization. The term "living" in this scenario is derived from the phase "living polymerization" where monomers form long chains by continuous addition to the reactive chain ends, without termination. In the same way, certain micelles specifically those that had crystalline cores exhibited the ability to elongate when additional block copolymers are added to the micelle solution.

    41. ring-opening metathesis polymerization

      A type of polymerization mechanism that uses strained cyclic olefins (alkene) as the monomer source to produce polymer chains.

    42. amphiphilic

      A chemical compound that has a hydrophilic (water-loving) component and lipophilic (fat-loving) component.

    43. cross-linking

      A cross-link bonds together different polymer chains together at a specific site (i.e., double bonds, sulfur atoms) to form a larger polymer network.

    44. non-centrosymmetric

      Glossary: Molecules have different degrees of molecular symmetry. A molecule that is noncentrosymmetric will not contain an inversion center or a center of symmetry. An example of a molecule that is centrosymmetric is a benzene ring (C6H6) where the inversion center is the center of the ring.

    45. shape anisotropy

      Anisotropy is defined as having a directional dependence. In the case of shape, anisotropy it is referring to an object that is not spherical.

    46. BCPs assemble into a variety of different morphologies that are influenced by polymer molecular weights and block ratios, with further control possible through the manipulation of environmental conditions such as temperature, solvent, and concentration

      Connects to AP Chemistry Learning Standard:2.B

      Forces of attraction between particles (including the noble gases and also different parts of some large molecules) are important in determining many macroscopic properties of a substance, including how the observable physical state changes with temperature

      Found on page 27 of the AP Chemistry Course and Exam Description:

      http://media.collegeboard.com/digitalServices/pdf/ap/ap-chemistry-course-and-exam-description.pdf

    47. nanoparticles

      Particles of any shape that have at least one dimension less than 100 nm or less in size.

    48. solution

      Connects to AP Chemistry Learning Standard:2.A.3: Solutions are homogeneous mixtures in which the physical properties are dependent on the concentration of the solute and the strengths of all interactions among the particles of the solutes and solvent:

      Found on page 25 of the AP Chemistry Course and Exam Description:

      http://media.collegeboard.com/digitalServices/pdf/ap/ap-chemistry-course-and-exam-description.pdf

    49. hierarchical assemblies

      The formation of complex structures from a bottom-up approach.

    50. nanotechnology

      To read general information on nanotechnology click on the following link:

      http://www.nano.gov/nanotech-101/what/definition

      The following article is an interestng example of using nanotechnology to create jewelery:

      http://www.nytimes.com/2014/11/18/style/international/jewelry-nanotechnology.html

    51. unidirectionally

      From one direction or side.

    52. micelle corona

      A micelle is an aggregate comprised of amphiphilic molecules. A micelle will have a core (inside-lipophilic) and a corona (outside-hydrophilic).

      The individual components that make up this aggregate are referred to as unimers.

      Although most micelles are have hydrophobic cores and hydrophilic corona, these micelles don't fit this classification. The corona is PI (hydrophobic) and the core is PFS (also hydrophobic). Self-assembly is induced because hexane/decane are poor solvents for PFS but good for PI .

    53. self-assembly

      Molecular self-assembly is the process in which a disordered group of molecules occupy some organized arrangement without direction from an outside source.

    54. block copolymers

      A block copolymer is a polymer chain comprised of homopolymer subunits linked by a covalent bond.

      For example:

      Homopolymer (where A is the monomer unit) : A-A-A-A-A-A-A-A

      Block copolymer (where A and B are monomer units): A-A-A-A-B-B-B-B

    55. Non-Centrosymmetric Cylindrical Micelles by Unidirectional Growth

      Unidirectional Growth ... the Road to Designer Micelles

    56. Abstract

      As the field of nanotechnology continues to grow, the ability to carefully control nanoparticle size, shape, and composition still remains a challenge. Most nanoparticles exhibit a great deal of symmetry. The authors of this paper focused on developing a method to create block copolymer micelles that had very little symmetry (i.e., noncentrosymmetric). They were able to achieve their goal through unidirectional micelle growth. The authors later used this same strategy to synthesize a "supermicelle."

    1. and assistant-level Project Scientists

      Assistant project scientists are specifically mentioned. See next annotation.

    2. The Committee does not support individuals such as associate and full project scientists, post-docs, clinical instructors and non-salaried faculty.

      This implies that associate project scientists are not eligible, but I don't know why they don't just come out and say so.

    1. It is explaining the news in a way most accessible and actionable to Facebook users, who see these headlines next to trending topics and breaking news stories and oblique mentions from their friends, Actually, and who want not just to be given explanation but who may want, In One Tweet, within this strange engineered context, and through 11 Maps, to perform their understanding as well (Explained).

      Very clever. And, as the author implies, everything need not be seen through the lens of a Facebook user. There are still some of us out there who don't use Facebook (gasp!) and who prefer more in depth considerations of topics. But we now have more choices in how and where we wish to consume information.

    2. The first thing you notice when you spam your content across platforms is that it’s rare, in 2015, for one thing to do extraordinarily well in more than one or two venues without significant modification. The next thing you learn is that the best way to succeed on a given platform is to write/film/record/aggregate with that platform explicitly in mind.

      This is a point that I usually make when discussing the scholarly communications ecosystem. There are many platforms available and they are not interchangeable; rather, each does well with a relatively small piece of the pie. For a scholar, the goal should be to present content in the platform that is best for the content. Pieces of it can be disseminated through other venues, but we have to move beyond our current 1-2 sizes fits all system.

    3. They saw at least 50 percent of at least one ad for at least one second, and so they existed.

      A very limited definition of existence: "I view ads therefore I am"

    4. Reporters will write their articles, and their content management system will smoothly hand them to Facebook, Snapchat, or Apple News.

      This is the way I would like scholarly publishing to work as well.

  2. Jul 2015
    1. J. F. Soderholm, S. L. Bird, P. Kalab, Y. Sampathkumar, K. Hasegawa, M. Uehara-Bingen, K. Weis, R. Heald, Importazole, a small molecule inhibitor of the transport receptor importin-β. ACS Chem. Biol. 6, 700–708 (2011).

      Importazole is a small molecule inhibitor of the transport receptor importin-β. This inhibitor was identified by a screening assay developed by the authors of this paper.

    2. A. J. Firestone, J. S. Weinger, M. Maldonado, K. Barlan, L. D. Langston, M. O’Donnell, V. I. Gelfand, T. M. Kapoor, J. K. Chen, Small-molecule inhibitors of the AAA+ ATPase motor cytoplasmic dynein. Nature 484, 125–129 (2012). doi:10.1038/nature10936 pmid:22425997

      This work reported the discovery of ciliobrevins, the first specific small-molecule antagonists of cytoplasmic dynein.

    3. K. V. Butler, J. Kalin, C. Brochier, G. Vistoli, B. Langley, A. P. Kozikowski, Rational design and simple chemistry yield a superior, neuroprotective HDAC6 inhibitor, tubastatin A. J. Am. Chem. Soc. 132, 10842–10846 (2010). doi:10.1021/ja102758v pmid:20614936

      This paper reported the development of Tubastatin A, a potent and selective HDAC6 inhibitor.

    4. H. Ouyang, Y. O. Ali, M. Ravichandran, A. Dong, W. Qiu, F. MacKenzie, S. Dhe-Paganon, C. H. Arrowsmith, R. G. Zhai, Protein aggregates are recruited to aggresome by histone deacetylase 6 via unanchored ubiquitin C termini. J. Biol. Chem. 287, 2317–2327 (2012).

      This work suggested a novel ubiquitin-mediated signaling pathway, where the exposure of ubiquitin C termini within protein aggregates enables HDAC6 recognition and transport to the aggresome. The authors found that the ubiquitin-binding domain (ZnF-UBP) of HDAC6, instead of recognizing protein aggregates by binding directly to polyubiquitinated proteins, binds exclusively to the unanchored C-terminal diglycine motif of ubiquitin.

    5. Y. Zhang, B. Gilquin, S. Khochbin, P. Matthias, Two catalytic domains are required for protein deacetylation. J. Biol. Chem. 281, 2401–2404 (2006).

      In this report, the authors showed that both HDAC domains are required for the intact deacetylase activity of HDAC-6.

    6. Y. Zhang, S. Kwon, T. Yamaguchi, F. Cubizolles, S. Rousseaux, M. Kneissel, C. Cao, N. Li, H. L. Cheng, K. Chua, D. Lombard, A. Mizeracki, G. Matthias, F. W. Alt, S. Khochbin, P. Matthias, Mice lacking histone deacetylase 6 have hyperacetylated tubulin but are viable and develop normally. Mol. Cell. Biol. 28, 1688–1701 (2008). doi:10.1128/MCB.01154-06 pmid:18180281

      In this study, the author generated HDAC6 knock out mice and investigated the in vivo functions of HDAC6 and the relevance of tubulin acetylation/deacetylation. they observed that HDAC6-deficient mice are viable and fertile and show hyperacetylated tubulin in most tissues.They concluded that mice survive well without HDAC6 and that tubulin hyperacetylation is not detrimental to normal mammalian development.

    7. I. Kemler, G. Whittaker, A. Helenius, Nuclear import of microinjected influenza virus ribonucleoproteins. Virology 202, 1028–1033 (1994).

      
This work showed that when influenza virus ribonucleoproteins (vRNPs), devoid of M1, were introduced into the cytoplasm of cells by microinjection, they were found to be imported into the nucleus, and the RNA was transcribed. Their uptake into the nucleus was ATP-dependent, inhibited by antibodies to the nuclear pore complex, unaffected by the prior acidification of the vRNPs, and not inhibited by an anti-virurs, called amantadine. These experiments demonstrated that for productive infection, all the early stages of the viral entry pathway can be bypassed.

    8. anerjee, Y. Yamauchi, A. Helenius, P. Horvath, High-content analysis of sequential events during the early phase of influenza A virus infection. PLOS ONE 8, e68450 (2013).

      This study provides a powerful high-throughput platform to understand the host cell processes. The authors developed quantitative, imaging-based assays to dissect seven consecutive steps in the early phases of IAV infection in tissue culture cells.

    9. K. S. Matlin, H. Reggio, A. Helenius, K. Simons, Infectious entry pathway of influenza virus in a canine kidney cell line. J. Cell Biol. 91, 601–613 (1981).

      This work investigated the cell fusion process of representatives of 3 families of enveloped viruses. it was discovered that hemagglutinin plays a role for the influenza in the low-pH-dependent membrane fusion activity. Low-pH-induced fusion is a widespread property of enveloped animal viruses and that it may play a role in the infective process.

    10. L. H. Pinto, L. J. Holsinger, R. A. Lamb, Influenza virus M2 protein has ion channel activity. Cell 69, 517–528 (1992).

      The authors of this paper identified the ion channel activity of M2.

    11. J. White, K. Matlin, A. Helenius, Cell fusion by Semliki Forest, influenza, and vesicular stomatitis viruses. J. Cell Biol. 89, 674–679 (1981).

      This work investigated the cell fusion process of representatives of 3 families of enveloped viruses. it was discovered that hemagglutinin plays a role for the influenza in the low-pH-dependent membrane fusion activity. Low-pH-induced fusion is a widespread property of enveloped animal viruses and that it may play a role in the infective process.

    12. K. Martin, A. Helenius, Nuclear transport of influenza virus ribonucleoproteins: The viral matrix protein (M1) promotes export and inhibits import. Cell 67, 117–130 (1991). doi:10.1016/0092-8674(91)90576-K pmid:1913813

      This work described the nuclear transport of influenza virus ribonucleoproteins (vRNPs). Viral matrix protein (M1) associates with newly assembled vRNPs in the nucleus and escorts them to the cytoplasm through the nuclear pores. In contrast, during entry of the virus into a new host cell, M1 protein dissociates from the RNPs, allowing them to enter the nucleus.

    13. new antiviral strategies

      Possible Therapy? Find out what the author Dr. Yamauchi says in this regard.

      http://www.futurity.org/flu-virus-capsid-789992/

    14. cytoskeleton

      Cytoskeleton is a network of fibers composed of proteins (microfilaments made of actin and microtubules made of tubulin) contained within a cell's cytoplasm.

    15. HDAC6 is recruited

      HDAC6 binds to the free ubiqiuitin associated with the capsid and, in turn, activates cytoskeletal molecules. The involvement of HDAC6 is crucial for the virus to undergo the uncoating and release the vRNPs into the cytosol.

    16. our results demonstrated that key components of the aggresome formation and disassembly machinery promote IAV uncoating

      By studying the correlation between HDAC6 and dynein/dynactin, the authors discovered that proteins belonging to the aggresome formation and disassembly machinery participate to the IAV uncoating step during the virus host cell entry.

    17. The results showed that inhibitors of dynein, myosin II, actin, and MT assembly all reduced uncoating significantly

      
While before authors explore the role of dynein, myosin II, microtubules and actin on IAV uncoating after plasma membrane fusion, another set of experiments were performed in order to study the effect of these proteins on IAV uncoating when the virus enters by endocytosis. Inhibition of dynein, myosin II, actin and microtubules resulted in reduction of uncoating.

    18. Finally, we established that dynein, myosin II, MTs, and actin were also involved in uncoating when IAV entered by endocytosis.

      Because the host cell entry comprises multiple steps, the authors investigated which one was affected by the depletion of HDAC6. They noticed that HDAC6 has a function specifically during the uncoating and the vRNPs import.

    19. Using RNAi, we found that uncoating after PM fusion was decreased in myosin 10–depleted but not in myosin 9–depleted A549 cells (to 42% of control) (Fig. 3C). Inhibition of type II myosins with ML-9 and blebbistatin reduced uncoating to 38 and 48%, respectively

      Authors investigated the role of myosin 10 and 9, which belong to type II myosin, in IAV uncoating after plasma membrane fusion. They blocked separately the gene expression for both Myosin 9 and 10 and observed that uncoating was reduced only in myosin 10-depleted cells. Additionally, two different inhibitors of type II myosins inhibited the uncoating.

      Often, when more than one technique is available for exploring an hypothesis (i.e. involvement of myosin in IAV uncoating), scientists use them all to confirm their observations. By getting rid of myosins, authors can understand how important it is in the uncoating. Two ways were used to do so: blockage of the expression of the corresponding genes and inhibition of myosins by using drugs.

    20. Because dynein inhibition alone did not inhibit IAV uncoating completely, we investigated a possible additional role for the actomyosin system

      CCSS.ELA-LITERACY.RST.11-12.8

      http://www.corestandards.org/ELA-Literacy/RST/11-12/

      Whenever an observation is not fully understood, scientists try to analyze the issue from different angles. Here, the authors observed that the inhibition of dynein wasn't sufficient for inhibiting the viral uncoating completely. Therefore, they deduced that other factors were implicated with uncoating and decided to explore this possibility.

    21. Thus, HDAC6 binding to dynein and dynactin promoted IAV uncoating

      Authors concluded that both dynactin 2 and dynein are essential for the viral uncoating step.

    22. we found that

      
By depleting dynactin 2 via RNAi and inhibiting dynein via treatment with CilioD (dynein inhibitor), the authors found out that viral uncoating was reduced in A549 cells. Also, uncoating is decreased in MEFs expressing HDAC6 that lacks the dynein-binding domain.

    23. Via its interaction with dynein and dynactin, HDAC6 acts as an adaptor that mediates retrograde transport of misfolded protein aggregates along microtubules (MTs) to aggresomes (14).

      
Previous study demonstrated that HDAC6 has the capacity to bind both polyubiquitinated misfolded proteins and dynein motors, thereby acting to recruit misfolded protein cargo to dynein motors for transport to aggresomes.

      Cells deficient in HDAC6 fail to clear misfolded protein aggregates from the cytoplasm, cannot form aggresomes properly, and are hypersensitive to the accumulation of misfolded proteins.

    24. it was observed using indirect immunofluorescence that after ammonium chloride (NH4Cl) washout to allow penetration of capsids from LAMP1-positive endosomes, the distribution of HDAC6 changed (Fig. 2E). Instead of a diffuse cytosolic staining, HDAC6 now associated with M1-containing vacuoles, where it gave a distinct rim-staining

      This experiment confirmed that HDAC6 associates with M1. Authors highlighted HDAC6 associated to M1-containing vacuoles by using indirect immunofluorescence, in which one antibody binds to the target protein (HDAC6 in this experiment) and a second antibody, bearing a fluorophore, binds to the first antibody.

    25. coimmunoprecipitated

      Coimmunoprecipitation (Co-IP) is the immunoprecipitation of intact protein complexes. Co-IP works by selecting an antibody that targets a known protein that is believed to be a member of a larger complex of proteins. By targeting this known member with an antibody it may become possible to pull the entire protein complex out of solution and thereby identify unknown members of the complex.

      Immunoprecipitation (IP) is the technique of precipitating a protein antigen out of solution using an antibody that specifically binds to that particular protein. This process can be used to isolate and concentrate a particular protein from a sample containing many thousands of different proteins.

    26. Western blot

      Western blot is an analytical technique used to detect specific proteins in a sample of tissue homogenate or extract.

    27. Super-resolution microscopy of purified IAV using the same antibody showed free Ub staining in more than half of virus particles

      The authors verified that what observed by immunoblotting was ubiquitin by using the super-resolution microscopy technique.

    28. n vitro pull-down assay

      The pull-down assay is an in vitro method used to determine a physical interaction between two or more proteins.

    29. Triton X-100

      Triton X-100 is a detergent widely used to lyse cells to extract protein or organelles, or to permeabilize the membranes of living cells.

    30. Thus, the ZnF-UBP domain of HDAC6 was critical for IAV uncoating and infection, whereas the deacetylase activity was not.

      Authors established that HDAC6, through its ZnF-UBP domain but not its deacetylase activity domain, was essential for the uncoating step during the infectious process.

    31. An inhibitor of the deacetylase activity of HDAC6,

      This study reported the design and synthesis of a potent and selective HDAC6 inhibitor.

    32. We generated a mutant cell line HDAC6 (ZnFm-W1116A) with a mutation in the corresponding mouse HDAC6 ZnF-UBP

      In a previous work, scientists investigated whether ubiquitin chain binding affects HDAC6 activity. To generate a ubiquitin-chain binding deficient mutant of HDAC6, they mutated several residues in the BUZ finger that were predicted to make contacts with ubiquitin. It was found that W1182A point mutation markedly disrupted the ability of HDAC6 to bind free ubiquitin chains.

    33. A point mutation W1182A in the human HDAC6 ZnF-UBP disrupts binding of free Ub chains

      In a previous work, scientists investigated whether ubiquitin chain binding affects HDAC6 activity. To generate a ubiquitin-chain binding deficient mutant of HDAC6, they mutated several residues in the BUZ finger that were predicted to make contacts with ubiquitin. It was found that W1182A point mutation markedly disrupted the ability of HDAC6 to bind free ubiquitin chains.

    34. point mutations

      Point mutation is a technique in which a single base nucleotide is replaced with another nucleotide. As a result, the mutant protein has a different primary sequence with respect to the wild-type protein.

    35. Fig. 1 IAV requires the Ub-binding function of HDAC6 for capsid uncoating.

      In this figure the authors showed the results obtained when they investigated HDAC6 role in IAV entry.

      Panel A: The top part shows a cartoon of IAV entry that consists of multiple steps. The authors studied what step HDAC6 was critical during the virus host cell entry. Bottom part shows quantitative analysis graphs, each corresponding to the above step of IAV entry under investigation.

      Panel A (endocytosis): The authors measured the amount of HA-stained spots per cell in wild type MEFs (WT MEF) compared to HADC5 Knock-out MEFs (HDAC6 KO). The third bar represents WT MEFs that were treated with dynasore (Dyn) in order to stop the endocytosis process. Depletion of HDAC6 did not influence the endocytosis step.

      Panel A (HA-Acidification): In this step HDAC6 KO MEFS did not show any difference with respect to the wild type cells. It was concluded that HDAC6 does not influence this step of the virus infection.

      Panel A (Fusion): fusion of capsid to endosome membrane is not affected by the lack of HDAC6 in knock-out MEF cells as shown in graph.

      Panel A (Uncoating): Measuring the amount of cells with dispersed M1, the authors noticed that cells lacking HDAC6 dispersed less M1. This observation led to the conclusion that HDAC6 was fundamental for the uncoating process.

      Panel A (vRNP import): Indeed, As vRNP import represents the step following uncoating, HDAC6 KO MEFs showed less NP-positive nuclei because the previous uncoating step was reduced.

      In analyzing HA Acidification, Fusion, Uncoating and vRNP import, the authors used BafA1, which is a drug that is able to block uncoating, as a control for their experiment.

      Panel B is a graphical representation of the 2 deacetylase catalytic domains of HDAC6 and the zinc-finger ubiquitin binding domain that is close to the C-terminus of the enzyme.

      Panel C HDAC6 (WTr) (light gray bar) was a line of HDAC6 KO MEFs able to express again HDAC6. HDAC6 (HDm) (blue bar) was a line of HDAC6 KO MEFs expressing HDAC6 mutated in its deacetylase domain. HDAC6 (ZnFm) (purple bar) was a line of HDAC6 KO MEFs expressing HDAC6 with a mutation in its zinc-finger domain. The authors evaluated the effect of these mutations on the uncoating capacity of IAV. Depletion of deacetylase activity of HDAC6 did not influence the uncoating. Instead, loss of zinc-finger ubiquitin binding domain was detrimental for the uncoating.

      The two asterisks on top of the purple bar indicate that this result is statistically significant, that is a result that is caused by something other than mere random chance.

      Panel D: life in technicolor!!! These experiments were performed using the confocal microscopy technique. Fluorescent dye molecules bind to specific parts of the cell, so that only those parts are visualized. Fluorescent dyes are chemical compounds that re-emit light upon light excitation (light absorption).<br> The following video, created by Northwest Missouri State University, explains the basics of confocal microscopy. https://www.youtube.com/watch?v=jUAvneBhDcQ

      The authors observed that after 2.5 hours from infection, M1 is dispersed inside WT MEFs, indicating that uncoating has occurred. Instead, M1 is confined inside vacuoles when cells lack HDAC6 and the mutant cells in which HDAC6 lacks the Zinc-finger ubiquitin binding region, meaning that the uncoating hasn't occurred.

    36. zinc-finger

      Zinc finger is any small, functional, independently folded protein domain that requires coordination of one or more zinc ions to stabilize its structure and is essential for DNA- or RNA-binding protein-protein interactions and membrane association. http://www.ncbi.nlm.nih.gov/pubmed/11179890

    37. we used HDAC6 KO MEFs that had been rescued either with WT HDAC6 (WTr) or with HDAC6s with point mutations either in the two deacetylase domains (HDm)

      Following the observation that HDAC6 was implicated in the viral uncoating, next question that the authors asked was: knowing that HDAC6 has deacetylase activity domains as well as ubiquitin binding domain, what HDAC6 function is critical in the uncoating? To study these functions separately, the authors re-introduced WT HDAC6 or HDAC6 point mutated for etheir deacetylase or ubiquitin binding domain in HDAC6 knock-out MEFs

    38. HDAC6 was required after fusion

      HDAC6 plays an important role during IAV infection after the fusion of the virus capsid to the endosome membrane.

    39. we induced fusion of the virus directly with the plasma membrane (PM), a process that allows delivery of viral capsids into the cytosol without endocytosis

      Authors ran a second experiment to confirm the involvement of HDAC6 after the fusion step. In this experiment, they bypassed the endocytosis process by means of pH change.

    40. It was apparent that HDAC6 played a role in the release of viral capsids from the cytosolic surface of endosomes, the dissociation of M1 from vRNPs, and the dispersion of capsid components in the cytosol.

      The authors drew the conclusion that HDAC6 was playing an important role in helping the viral uncoating.

    41. However, capsid uncoating and nuclear import of vRNPs were reduced to 22 and 17%, respectively (Fig. 1A). In HDAC6-depleted A549 cells, uncoating was reduced to 21% compared with controls, with no effect on HA acidification or fusion

      Because the host cell entry comprises multiple steps, the authors investigated which one was affected by the depletion of HDAC6. They noticed that HDAC6 has a function specifically during the uncoating and the vRNPs import.

    42. viral titers

      Viral titer is a way to express concentration. It refers to the concentration of viruses in a sample.

    43. intratracheally

      IAV was introduced into the trachea of mice.

    44. infection was reduced to 30%, and viral titers to 48%, compared with wild-type (WT) MEFs

      To determine whether HDAC6 was involved with virus infection, the author examined mutant cells in which HDAC6 expression was silenced. The author observed that when HDAC6 is absent, viral infection and concentration were reduced.

    45. RNA interference (RNAi)

      RNAi is a biological process in which RNA molecules inhibit gene expression, typically by causing the destruction of specific mRNA molecules. The final result is the depletion of specific target proteins.

    46. aggresome

      Aggresomes are dynamic structures, formed of improperly folded proteins.

    47. ubiquitin

      Ubiquitin is a small regulatory protein that has been found in almost all eukaryotic cells. Ubiquitin binds to proteins and labels them for destruction.

    48. tubulin

      Tubulin is the protein that polymerizes into long chains or filaments that form microtubules, hollow fibers which serve as a skeletal system for living cells.

    49. we noticed that another histone deacetylase, HDAC6, was also required for infection

      Connect to Learning Standards: http://www.nap.edu/openbook.php?record_id=13165&page=69

      Progression for explanation. In a previous study, the authors observed that HDAC6 was required for viral infection. As a consequence, they continued to study the function of HDAC6 in deep detail.

    50. While analyzing the role of HDAC8 and HDAC3 in endosome maturation and IAV penetration

      In a previous work, the authors found the histone deacetylase 8 was required for centrosome cohesion and influenza A virus entry.

    51. hemagglutinin

      Hemagglutinin is a glycoprotein found on the surface of the influenza viruses. It is responsible for binding the virus to cells.

    52. conformational change

      A conformational change is a change in the shape of a macromolecule, often induced by environmental factors.

    53. endosomes

      Endosomes are membrane-bound vesicles, formed via a complex family of processes collectively known as endocytosis, and found in the cytoplasm of virtually every animal cell.

    54. host cell

      A host cell is a living cell invaded by or capable of being invaded by an infectious agent (as a bacterium or a virus).

    55. helical viral ribonucleoproteins (vRNPs)

      The genome of influenza A viruses consists of eight segments of single-stranded, negative-sense RNA that are encapsidated as individual rod-shaped ribonucleoprotein complexes (RNPs). Each RNP contains a viral RNA, a viral polymerase and multiple copies of the viral nucleoprotein (NP).

    56. supramacromolecular

      A supramolecular complex is a well-defined assembly of molecules held together by noncovalent bonds. While a supramolecular assembly can be simply composed of two molecules (e.g., a DNA double helix), it is more often used to denote larger complexes of molecules that form sphere-, rod-, or sheetlike species.

    57. capsid

      A capsid is the protein shell of a virus. The capsid encloses the genetic material of the virus.

    58. single-stranded, negative-sense RNA genome

      Viral RNA with a base sequence complementary to that of mRNA; during replication it serves as a template for the transcription of viral complementary RNA. Negative-sense (3' to 5') viral RNA cannot be translated into protein directly. Instead, it must first be transcribed into a positive-sense RNA (5' to 3') which acts as an mRNA. Some viruses (influenza, for example) have negative-sense genomes and so must carry an RNA polymerase inside the virion.

    59. With the risk of an influenza pandemic growing, it is increasingly important to understand virus-host interactions in detail and to develop new antiviral strategies (1).

      http://www.nap.edu/openbook.php?record_id=13165&page=43

      Science can contribute to meeting many of the major challenges that confront society today, such as preventing and treating disease.

    60. Influenza A virus uses the aggresome processing machinery for host cell entry

      Fighting the influenza A virus (IAV) still remains a great challenge, and there is a real and urgent need for developing new antiviral medicines. Until now, scientists did not know how the virus was able to release its viral genetic material, which is well protected inside a shell, the capsid. A group of scientists discovered that IAV uses the waste disposal system of the host cell for breaking apart the capsid. The presence of a protein, ubiquitin, on the surface of the capsid makes the host cell perceive the IAV as an aggregate of proteins to waste. Then, a histone deacetylase 6 (HDAC6)-dependent pathway, along with cellular transport factors such as dynein and myosin 10, come into play for disposing the virus. The final result is the opening of the capsid followed by the host cell infection. Understanding the molecular mechanisms underlying IAV infection could lead to advances in medicine. HDAC6, as well as other proteins, were suggested as potential targets for the development of new antiviral therapeutics.

    61. Influenza A virus uses the aggresome processing machinery for host cell entry

      Title: Mimicking a bundle of waste: Influenza A virus strategic attack.

    1. and does meet the needs of faculty who depend on graduate students as research assistants.

      Aye, there's the rub

    2. However, these efforts are limited in scope and primarily take the form of adding offerings to an already overcrowded curriculum.

      Yes. If we added all the things that graduate students needed to learn to the curriculum, we wouldn't have to worry about careers at all, as they would be students for their entire careers.

    3. All available evidence suggests that over 60% of new Ph.D.s in science in the United States will not have careers in academic research, yet graduate training in science has followed the same basic format for almost 100 years, heavily focused on producing academic researchers.

      Would be nice to be able to track down this reference, because this is a rather startling statistic. Although I suppose that in any highly competitive field, e.g., acting, sports, the percentages of those actually pursuing what they were trained for might be even lower?

    1. Keep in mind that the person asking for feedback is making themselves vulnerable by asking for your opinion, and you should deliver your feedback in a way that relays your best intentions.

      This is an important point to keep in mind.

    1. coalescence

      Coalescence is a merging of two units. For example, here the authors consider that Middle East or China are unlikely centers of dog origin because such a scenario would require that ancient wolves and dogs from these areas are united by a common ancestor.

    2. two-phase bottleneck

      A population bottleneck is the reduction of the population size, followed by an expansion, e.g. a small group leaves the first population and immigrates elsewhere.

      This reduction often leads to the loss of genetic diversity in the population; it is called the founder effect.

    3. The first wasat the origin of the domestication process, and thesecond was more recent during breed formationover the past several hundred years

      Previously, the DNA analysis of the genome of prehistoric wolves and dogs support the idea of a two-step domestication process. The first one was the evolution of wolves through a mutually beneficial relationship with humans, sharing food and space. The second one was the active breeding of dogs by humans in order to select dogs which were adapted to the current needs (hunting, tracking, pet).

      Furthermore, there are two main hypotheses to explain the first domestication step (http://www.americanscientist.org/issues/pub/early-canid-domestication-the-farm-fox-experiment):

      1) “Self-domestication” by the wolves: Some wolves lived in the vicinity of the camps of the nomadic hunter-gatherers to eat the garbage left by the prehistoric people. Those that were less anxious thrived and continued to follow the humans, generation after generation, and gradually the first dogs emerged from this group.

      2) The prehistoric people actively selected wolf pups and let only the most docile ones reproduce. After several generations, the first dogs emerged. This hypothesis has been being tested in Novosibirsk since 1959, where foxes are being bred for “tamability.”

    4. G. Larson, J. Burger,Trends Genet.29, 197–205 (2013).

      This study is about animal domestication. It explains that the dog is the only animal domesticated before the advent of agriculture. It also discuss the limits of mtDNA analysis.

    5. Our findings support the conclusion thatthe mitochondrial legacy of dogs derives fromwolves of European origin.

      The authors observe: I) The process of domestication began in Europe between 18,800 and 32,100 years ago;

      II) The population of proto-dog moved with human populations.

      Therefore, the authors concluded of the European origin of the modern dogs.

    6. from which dogs derive

      This entire sentence should be selected, but when I try, I don't pop up an annotation box. It seems to be the first four words (gray wolf (Canis lupus) that is the problem. Encountered something similar below.

    7. ourresults imply that some of the earliest putative dogremains, such as the Goyet dog from Belgium (2)or Altai Mountain specimen from Russia

      Some domestication did not work, which is why we find traces of domesticated dogs that do not exist today.

      This is based on the mitochondrial DNA; the autosomal DNA has not been analyzed yet.

    8. Nonetheless, ourmtDNA genome tree shows that three of four
    9. We generated com-plete and partial mitochondrial genomes from18 prehistoric canids and 20 modern wolves ofEurasian and American origin (Table 1 and tableS2) by performing DNA capture followed by high-throughput sequencing

      This technique allows the authors to determine the precise order of nucleotides within specific regions of a DNA sample.

      high-throughout means that large volumes of DNA can be sequenced quickly.

    10. tochastic effects

      Stochasticity is randomness; in this context, the fact that several lineages mixed resulted in different offspring but each did not recapitulate all the characteristics of its ancestors.

    11. centers of dog origins fromgenetic data have been proposed, including theMiddle East and East Asia

      In ref. 5, a genome-wide array of SNP between dogs and wolves suggest that dogs originate from Middle East.

      However, ref. 6, the comparison between dog and wolf mitochondrial DNA suggests East Asia as the center of dog origin.

    12. phylogenetically

      A phylogeny is the method to resolve the evolutionary history of a group of species. The relationship between these species can be inferred from various statistical analyses that estimate the genetic relatedness of each species to one another, depending on their differences either in DNA or protein material.

    13. mitochondrialgenomes

      DNA located in the mitochondria. All animal mitochondrial genomes, with a few exceptions, contain the same 37 genes, making them useful as a model for genome evolution.

      Specifically, the comparison of mitochondrial gene arrangements in animals has been critical to inferring ancient evolutionary relationships.

    14. phenotypic variation

      Phenotypic variation is the variability of all observable or measurable characteristics of the individual animals.

    1. phenotypic variation

      Phenotypic variation is the variability of all observable or measurable characteristics of the individual animals.

    2. Dogs are one of the best known examplesof domestication, the process of speciesmodification over time by human-inducedselection

      Check out a Science special issue on Dogs: http://www.sciencemag.org/site/extra/dogs/

    3. onset of domesticationthere 18,800 to 32,100 years ago.

      Wolves were domesticated much earlier than thought. Researchers discovered that wolves were domesticated by European hunter-gatherers between 19,000 and 32,000 years ago. The analysis cannot, however, be used to determine the origin of the dog, argues a Danish DNA scientist.

      http://sciencenordic.com/wolves-became-domesticated-dogs-much-earlier-thought

    4. ere compared withcomplete mitochondrial genome sequences from49 wolves; 77 dogs, including divergent dog breedssuch as Basenji and Dingo; three recently publishedChinese indigenous dogs (7); and four coyotestotaling 148 mitochondrial genomes.

      The authors collected the mtDNA sequences previously published by other teams in order to get more data to analyze and a larger diversity of samples.

    5. e generated com-plete and partial mitochondrial genomes from18 prehistoric canids and 20 modern wolves ofEurasian and American origin (Table 1 and tableS2) by performing DNA capture followed by high-throughput sequencing

      This technique allows the authors to determine the precise order of nucleotides within specific regions of a DNA sample.

      high-throughout means that large volumes of DNA can be sequenced quickly.

    6. DNA extracted from the earliest canids showingphenotypic evidence of domestication

      Some of the phenotypic adaptation can be observed, such as: shorter fangs and claws alteration of some brain areas.

      By comparing the DNA of phenotypically domesticated canids and actual dogs and identifying the genes which are responsible of the domesticate phenotype, it is possible to understand which genes have been altered by domestication and when they have been altered.

    7. centers of dog origins fromgenetic data have been proposed, including theMiddle East and East Asia

      In ref. 5, a genome-wide array of SNP between dogs and wolves suggest that dogs originate from Middle East.

      However, ref. 6, the comparison between dog and wolf mitochondrial DNA suggests East Asia as the center of dog origin.

    8. putative

      Commonly accepted.

    9. tochastic effects

      Stochasticity is randomness; in this context, the fact that several lineages mixed resulted in different offspring but each did not recapitulate all the characteristics of its ancestors.

    10. phenotypic variation

      Phenotypic variation is the variability of all observable or measurable characteristics of the individual animals.

    11. Molecular dating

      Molecular dating is a technique that allows biologists to determine the divergence time for two genes or for two species. It is based on the theory of the molecular clock stating that mutations accumulate in organisms at a stable speed.

      Thus, if you compare genes or protein sequences in different species, you can, assuming you know the speed of variation for these sequences, estimate the age of the last common ancestor.

    12. phylogenetically

      A phylogeny is the method to resolve the evolutionary history of a group of species. The relationship between these species can be inferred from various statistical analyses that estimate the genetic relatedness of each species to one another, depending on their differences either in DNA or protein material.

    13. mitochondrial genomes

      DNA located in the mitochondria. All animal mitochondrial genomes, with a few exceptions, contain the same 37 genes, making them useful as a model for genome evolution.

      Specifically, the comparison of mitochondrial gene arrangements in animals has been critical to inferring ancient evolutionary relationships.

    1. High-resolution mapping of intracellular fluctuations using carbon nanotubes

      Hi Jeremy: Can you see this?

    1. The cytoplasm of eukaryotic cells is a highlydynamic composite polymer material.
    2. The motion of probe particles trackedinside cells has been classified as subdiffusive,diffusive, or superdiffusive. Such classifications,however, obscure the distinction between ther-mally driven and nonequilibrium fluctuationsand are inadequate to identify intracellular ma-terial properties
    3. To track the dynamics of the cytoskeletonwithout introducing invasive probes, we specif-ically targeted short SWNTs (~100 to 300 nm;fig. S2) to the endogenous kinesin-1 motor Kif5cin cultured COS-7 cells (see supplementary ma-terials).
    4. eukaryotic cells
    5. near-infrared luminescence
    6. Noninvasive
    7. supramolecular
    8. dynamics
    9. Cells
    1. Wanting to establish his priority of discovery, but not yet ready to reveal what he had found, he sent to Kepler (and others) the following jumble of letters, which he informed them was a coded description of his latest discovery:   smaismrmilmepoetaleumibunenugttauiras   It was not uncommon in those days for scientists to communicate (or rather, to avoid communicating) their discoveries by means of coded expressions.

      Think I've annotated this before, but sitting at a conference on Open Science where it was suggested that science used to be open. Not really!

    1. Colectica® is the fastest way to design, document, and publish your statistical data and survey research using open data standards.

      We should consider adding this to the SciCrunch Registry, even though it is a commercial tool.

    1. Borgman offers case studies of data practices in the sciences, the social sciences, and the humanities, and then considers the implications of her findings for scholarly practice and research policy.
    2. Big Data, Little Data, No Data
    1. Acetylcholine excites cells in the suprachiasmatic nucleus, so cholinergic transmission of more Acetylcholine into the suprachiasmatic nucleus should support the formation of a time memor

      awkward phrasing.

    1. high-mol-wt ubiquitin conjugates (HMWUC) above 40 kDa increased, whereas free ubiquitin and ubiquitinated histone 2A decreased slightly after 4 h and 24 h of reperfusion.

      See paper by Hu et al., published in 2000.

    1. The MyConnectome project is characterizing how the brain of one person changes over the course of an entire year. It is almost certainly the most ambitious study of a single living person’s brain ever attempted. The data will provide new insights into the dynamics of brain activity and their relationship to bodily metabolism and psychological function.

      Add to SciCrunch Registry

    1. Innovators can compensate in their education by seeking narrower expertise, but narrowing expertise will reduce their individual capacities, with implications for the organization of innovative activity - a greater reliance on teamwork - and negative implications for growth

      Interesting, but perhaps ignores technology?

      Paul Groth: Downside of teamwork = communication overhead.

    2. The Burden of Knowledge and the 'Death of the Renaissance Man': Is Innovation Getting Harder?

      Read this paper

    1. The changes of ubi-proteins also occur, although to a less extent, in the surviving neuronal populations.

      In doing some research, I see that a paper was published in 1991 by Hayashi and colleagues on ubiquitin and esteem. They showed by immunoblot: "high-mol-wt ubiquitin conjugates (HMWUC) above 40 kDa increased, whereas free ubiquitin and ubiquitinated histone 2A decreased slightly after 4 h and 24 h of reperfusion", consistent with the findings of this study.

    2. Correspondence should be addressed to Dr. Bing-Ren Hu, Laboratory of Neurochemistry, Center for the Study of Neurological Disease, Queen's Medical Center, 1356 Lusitana Street, 8th Floor, Honolulu, HI 96813. E-mail: bhu@cns.queens.org.

      Dr. Hu is now at the University of Maryland.

    3. B. R. Hu and B. K. Siesjö, unpublished data)

      Was this study ever published?

    4. In this study, we demonstrated that intracellular membranous proteins were severely aggregated in dying CA1 neurons but not in neurons destined to survive after transient cerebral ischemia.

      Around this time, it was becoming apparent that abnormal protein aggregates were a hallmark of neurodegenerative disease. I think this was one of the first studies to suggest that they were associated with ischemic cell death.

    1. This clearly showed that the areas we found to be crucial to musical memory are among the least affected by advanced Alzheimer’s in the entire brain.

      That makes me happy somehow; that there is preservation of something that gives people such happiness.

    2. Because there are few neuroimaging studies of long-term musical memory, and none that met our rigorous standards, we had to devise a novel experimental paradigm, and an appropriate analysis strategy, to locate brain areas most crucial to this human capability.

      I am rather surprised, given the size of the neuroimaging literature, that this is the case.

    1. We have a tool that can be used to assess the level of a patient’s activation and engagement: the Patient Activation Measure. But of course that activated patient needs to engage with a receptive clinician. There ought to be a parallel tool that we could use to measure the clinician’s receptivity to and engagement with an activated patient — a tool that should include a measure that can identify the clinician who is able to activate a patient.

      Yes, I think this is a very important point. The clinician has to be receptive to an activated patient, but the clinician should invite activation from patients.

    2. The desired outcome ought to be determined by taking patient desires and preferences into account.

      It's a shame that this has to be stated, but it is the most important thing.

    3. orry, orthopedic surgeons; it’s just a hypothetical example …

      My old neuropsychology mentor used to say that as long as you could walk out the door, a neurologist thought you were fine. Never mind that you neglected the left half of your body. So although perhaps hypothetical, the tendency to focus on individual symptoms and ignore other issues through specialization is very real.

    4. I am on a life-long search for a handful of good measures that would prove to be predictive of everything else that matters; I am not convinced that these take us too far down the path in that direction.

      But I don't think that the two are disconnected and perhaps that's a topic for further study. Does sloppy and rude office practice reflect on the quality of the doctor? Practices that are managed professionally and are of high quality generally attract and keep the best employees, I should think. I wouldn't want to work for a hack.

    5. What other measures like these should we be considering?

      Good doctors should be willing to refer you for a second opinion and should not become hostile when you suggest that you want one.

    6. This, shall we say, inflamed Casey’s ire, as an engaged patient and patient activist. She noted that in many cases a patient with a chronic condition is in fact more expert in her condition — and certainly in the ins and outs of what works or doesn’t work for them in managing her condition — than a clinician new to the case. There is an oft-cited statistic that it takes 17 years for new medical science to filter from journal article to accepted everyday practice. Nobody wants to wait that long for her health care to catch up with the state of the art. An engaged patient is more likely to do the research, do the legwork, and surface ideas directly relevant to her case. Some clinicians, of course, are open to the notion that they can “Let Patients Help.”

      And, as my recent veterinary experience showed, owners are sometimes more expert than doctors. In this case, I had seen the condition before and knew the cause, whereas the doctor had not. After much trauma to my cat and many unnecessary tests, it turned out to be exactly what I said it was. So if a doctor hasn't seen something before, is s/he likely to diagnose and treat it correctly?