1,694 research outputs found
Functional anatomy of the middle and inner ears of the red fox, in comparison to domestic dogs and cats
Anatomical middle and inner ear parameters are often used to predict hearing sensitivities of mammalian species. Given that ear morphology is substantially affected both by phylogeny and body size, it is interesting to consider whether the relatively small anatomical differences expected in related species of similar size have a noticeable impact on hearing. We present a detailed anatomical description of the middle and inner ears of the red fox Vulpes vulpes, a widespread, wild carnivore for which a behavioural audiogram is available. We compare fox ears to those of the well‐studied and similarly sized domestic dog and cat, taking data for dogs and cats from the literature as well as providing new measurements of basilar membrane (BM) length and hair cell numbers and densities in these animals. Our results show that the middle ear of the red fox is very similar to that of dogs. The most obvious difference from that of the cat is the lack of a fully formed bony septum in the bulla tympanica of the fox. The cochlear structures of the fox, however, are very like those of the cat, whereas dogs have a broader BM in the basal cochlea. We further report that the mass of the middle ear ossicles and the bulla volume increase with age in foxes. Overall, the ear structures of foxes, dogs and cats are anatomically very similar, and their behavioural audiograms overlap. However, the results of several published models and correlations that use middle and inner ear measurements to predict aspects of hearing were not always found to match well with audiogram data, especially when it came to the sharper tuning in the fox audiogram. This highlights that, although there is evidently a broad correspondence between structure and function, it is not always possible to draw direct links when considering more subtle differences between related species
Solution of the Dyson--Schwinger equation on de Sitter background in IR limit
We propose an ansatz which solves the Dyson-Schwinger equation for the real
scalar fields in Poincare patch of de Sitter space in the IR limit. The
Dyson-Schwinger equation for this ansatz reduces to the kinetic equation, if
one considers scalar fields from the principal series. Solving the latter
equation we show that under the adiabatic switching on and then off the
coupling constant the Bunch-Davies vacuum relaxes in the future infinity to the
state with the flat Gibbons-Hawking density of out-Jost harmonics on top of the
corresponding de Sitter invariant out-vacuum.Comment: 20 pages, including 4 pages of Appendix. Acknowledgements correcte
Catalytic activation of pre-substrates via dynamic Fragment assembly on Protein templates
Sensitive detection of small molecule fragments binding to defined sites of
biomacromolecules is still a considerable challenge. Here we demonstrate that
protein-binding fragments are able to induce enzymatic reactions on the
protein surface via dynamic fragment ligation. Fragments binding to the S1
pocket of serine proteases containing a nitrogen, oxygen or sulphur
nucleophile are found to activate electrophilic pre-substrates through a
reversible, covalent ligation reaction. The dynamic ligation reaction
positions the pre-substrate molecule at the active site of the protein thereby
inducing its enzymatic cleavage. Catalytic activation of pre-substrates is
confirmed by fluorescence spectroscopy and by high-performance liquid
chromatography. The approach is investigated with 3 pre-substrates and 14
protein-binding fragments and the specific activation and the templating
effect exerted by the enzyme is quantified for each protease–fragment–pre-
substrate combination. The described approach enables the site-specific
identification of protein-binding fragments, the functional characterization
of enzymatic sites and the quantitative analysis of protein template-assisted
ligation reactions. View full text Subject terms: Chemical sciences Chemical
biology Medicinal chemistry At a glance Figures First | 1-4 of 6 | Last View
all figures left The concept of pre-substrate activation by protein-binding
fragments. Figure 1 Proof-of-concept. Figure 2 Structure of potential pre-
substrates 1–3 and S1-binding fragments 4–17. Figure 3 Model for the
activation of pre-substrates by nucleophilic protein-binding fragments. Figure
4 Activation of pre-substrate 3. Figure 5 Three-fragment assembly. Figure 6
right Compounds Genes and Proteins References Abstract• References• Author
information• Supplementary information Rees, D. C., Congreve, M., Murray, C.
W. & Carr, R. Fragment-based lead discovery. Nat. Rev. Drug Discov. 3, 660–672
(2004). CAS ISI PubMed Article Hajduk, P. J. & Greer, J. A decade of fragment-
based drug design: strategic advances and lessons learned. Nat. Rev. Drug
Discov. 6, 211–219 (2007). CAS ISI PubMed Article Erlanson, D. A., McDowell,
R. S. & O’Brien, T. Fragment-based drug discovery. J. Med. Chem. 47, 3463–3482
(2004). CAS ISI PubMed Article Fattori, D., Squarcia, A. & Bartoli, S.
Fragment-based approach to drug lead discovery. Drugs RD 9, 217–227 (2008).
ISI Article Rademann, J. Organic protein chemistry: drug discovery through the
chemical modification of proteins. Angew. Chem. Int. Ed. 43, 4554–4556 (2004).
Article Corbett, P. T. et al. Dynamic combinatorial chemistry. Chem. Rev. 106,
3652–3711 (2006). CAS ISI PubMed Article Erlanson, D. A. Fragment-based lead
discovery: a chemical update. Curr. Opin. Biotechnol. 17, 643–652 (2006). CAS
ISI PubMed Article Schmidt, M. F. & Rademann, J. Dynamic template-assisted
strategies in fragment-based drug discovery. Trends Biotechnol. 27, 512–521
(2009). CAS ISI PubMed Article Shuker, S. B., Hajduk, P. J., Meadows, R. P. &
Fesik, S. W. Discovering high-affinity ligands for proteins: SAR by NMR.
Science 274, 1531–1534 (1996). CAS ISI PubMed Article Vongvilai, P., Angelin,
M., Larsson, R. & Ramström, O. Dynamic combinatorial resolution: direct
asymmetric lipase-mediated screening of dynamic nitroaldol library. Angew.
Chem. Int. Ed. 46, 948–950 (2007). CAS Article Nienaber, V. L. et al.
Discovering novel ligands for macromolecules using X-ray crystallographic
screening. Nat. Biotechnol. 18, 1105–1108 (2000). CAS ISI PubMed Article
Blundell, T. L., Jhoti, H. & Abell, C. High-throughput crystallography for
lead discovery in drug design. Nat. Rev. Drug Discov. 1, 45–54 (2002). CAS ISI
PubMed Article Sharff, A. & Jhoti, H. High-throughput crystallographyto
enhance drug discovery. Curr. Opin. Chem. Biol. 7, 340–345 (2003). CAS ISI
PubMed Article Sanders, W. J. et al. Discovery of potent inhibitors of
dihydroneopterin aldolase using CrystaLEAD high-throughput X-ray
crystallographic screening and structure-directed lead optimization. J. Med.
Chem. 47, 1709–1718 (2004). CAS ISI PubMed Article Patterson, A. W., Wood, W.
J. L. & Ellman, J. A. Substrate activity screening (SAS): a general procedure
for the preparation and screening of a fragment-based non-peptidic protease
substrate library for inhibitor discovery. Nat. Protoc. 2, 424–433 (2007). ISI
PubMed Article Mares-Guia, M. & Shaw, E. Substrate side chain guanidines as
model of the binding of amidines and studies on the active center of trypsin.
J. Biol. Chem. 240, 1579–1585 (1965). CAS PubMed Schmidt, M. F. et al.
Sensitized detection of inhibitory fragments and iterative development of non-
peptidic protease inhibitors by dynamic ligation screening. Angew. Chem. Int.
Ed. 47, 3275–3278 (2008). Article Schmidt, M. F., El-Dahshan, A., Keller, S. &
Rademann, J. Selective identification of cooperatively binding fragments in a
high-throughput ligation assay enables development of a picomolar caspase-3
inhibitor. Angew. Chem. Int. Ed. 48, 6346–6349 (2009). CAS Article Schmidt, M.
F., Groves, M. & Rademann, J. Dynamic substrate enhancement for the
identification of specific, second-site-binding fragments targeting a set of
protein tyrosine phosphatases. Chembiochem 12, 2640–2646 (2011). ISI PubMed
Article Al-Gharabli, S. I. et al. An efficient method for the synthesis of
peptide aldehyde libraries employed in the discovery of reversible SARS
coronavirus main protease (SARS-CoV Mpro) inhibitors. Chembiochem 7, 1048–1055
(2006). ISI PubMed Article Reek J. N. H., Otto S. (eds)Dynamic Combinatorial
Chemistry Wiley-VCH (2010). Osowska, K. & Miljanic, O. S. Oxidative kinetic
self-sorting of a dynamic imine library. J. Am. Chem. Soc. 133, 724–727
(2011). ISI PubMed Article Hermann, A. Dynamic mixtures and combinatorial
libraries: imines as probes for molecular evolution at the interface between
chemistry and biology. Org. Biomol. Chem. 7, 3195–3204 (2009). PubMed Article
Meyer, C. D., Joiner, C. S. & Stoddart, J. F. Template-directed synthesis
employing reversible imine bond formation. Chem. Soc. Rev. 36, 1705–1723
(2007). CAS ISI PubMed Article Rodriguez-Decampo, Z. & Otto, S. Orthogonal or
simultaneous use of disulfide and hydrazone exchange in dynamic covalent
chemistry in aqueous solution. Chem. Commun. 5301–5303 (2008). Dirksen, A.,
Yegneswaran, S. & Dawson, P. E. Bisaryl hydrazones as exchangeable
biocompatible linkers. Angew. Chem. Int. Ed. 49, 2023–2027 (2010). CAS Article
Soutullo, M. D., O’Brien, R. A., Gaines, K. E. & Davis, J. H. Jr
Constitutional dynamic systems of ionic and molecular liquids. Chem. Commun.
2529–2531 (2009). Drahonovsky, D. & Lehn, J.-M. Hemiacetals in dynamic
covalent chemistry: formation, exchange, selection and modulation processes.
J. Org. Chem. 74, 8428–8432 (2009). ISI PubMed Article Caraballo, R., Dong,
H., Ribeiro, J. P., Jimenez-Barbero, J. & Ramström, O. Direct STD NMR
identification of β-galactosidase inhibitors from a virtual dynamic
hemithioacetal system. Angew. Chem. Int. Ed. 49, 589–593 (2010). Article
Cacciapaglia, R., Di Stefano, S. & Mandolini, L. Metathesis reaction of
formaldehyde acetals: an easy entry into the dynamic covalent chemistry of
cyclophane formation. J. Am. Chem. Soc. 127, 13666–13671 (2005). ISI PubMed
Article Berkovich-Berger, D. & Lemcoff, N. G. Facile acetal dynamic
combinatorial library. Chem. Commun. 1686–1688 (2008). Larsson, R., Pei, Z. &
Ramström, O. Catalytic self-screening of cholinesterase substrates from a
dynamic combinatorial thioester library. Angew. Chem. Int. Ed. 43, 3716–3718
(2004). Article Shi, B. & Greaney, M. F. Reversible Michael addition of thiols
as a new tool for dynamic combinatorial chemistry. Chem. Commun. 886–888
(2005). de Candia, M., Lopopolo, G. & Altomare, C. Novel factor Xa inhibitors:
a patent review. Expert Opin. Ther. Pat. 19, 1535–1580 (2009). PubMed Article
Schröder Leiros, H.-H. et al. Trypsin specificity as elucidated by LIE
calculations, X-ray structures, and association constant measurements. Protein
Sci. 13, 1056–1070 (2004). PubMed Article List, B., Lerner, R. A. & Barbas, C.
F. III Proline-catalyzed direct asymmetric aldol reactions. J. Am. Chem. Soc.
122, 2395–2396 (2000). CAS ISI Article Wilhelms, N., Kuchat, S. & Lehn, J.-M.
Organocatalysis of C=N/C=N and C=C/C=N exchange in dynamic covalent chemistry.
Helv. Chim. Acta 95, 2635–2651 (2012). ISI Article Khatik, G. L., Kumar, R. &
Chakraborti, A. K. Catalyst-free conjugate addition of thiols to
α,β-unsaturated carbonyl compounds in water. Org. Lett. 8, 2433–2436 (2006).
PubMed Article Hoyle, C. E. & Bowman, C. N. Thiol-ene click chemistry. Angew.
Chem. Int. Ed. 49, 1540–1573 (2010). CAS ISI Article Download references
Author information Abstract• References• Author information• Supplementary
information Affiliations Institute of Pharmacy, Medicinal Chemistry,
University of Leipzig, Brüderstraße 34, 04103 Leipzig, Germany Edyta Burda &
Jörg Rademann Institute of Pharmacy, Medicinal Chemistry, Freie Universität
Berlin, Königin-Luise-Straße 2+4, 14195 Berlin, Germany Jörg Rademann
Contributions J.R. and E.B. conceived and designed the experiments, E.B.
performed the experiments. Both authors discussed the results and co-wrote the
manuscript. Competing financial interests The authors declare no competing
financial interests. Corresponding author Correspondence to: Jörg Rademann
Supplementary information Abstract• References• Author information•
Supplementary information PDF files Supplementary Information (915 KB)
Supplementary Figures 1-11, Supplementary Methods and Supplementary
References. Additional data 3-Oxo-(N-(4-methyl-2-oxo-2H-
chromen-7-yl)-propanoylamide N-(4-Methyl-2-oxo-2H-chromen-7-yl)-acrylamide
3-((2-Aminoethyl)thio)-N-(4-methyl-2-oxo-2H-chromen-7-yl)propanamide npj
Genomic Medicine - Open for Submissions Science jobs Science events
NatureEvents Directory The 1st Annual Translational Microbiome Conference 14
May 2015 — 15 May 2015 Boston, MA, United States rTMS for depression, OCD and
new developments: 2-day rTMS course 19 November 2015 — 20 November 2015
Bijleveldsingel 34, Nijmegen, Netherlands Human Health in the Face of Climate
Change: Science, Medicine, and Adaptation 14 May 2015 — 15 May 2015 Carrer d'
Isaac Newton, 26, Barcelona, Spain Post a free event More science events
Discover more LIF negatively regulates tumour-suppressor p53 through
Stat3/ID1/MDM2 in colorectal cancers Nature Communications 17 Oct 2014
Interlocked loops trigger lineage specification and stable fates in the
Drosophila nervous system Nature Communications 28 Jul 2014 O-GlcNAc-
modification of SNAP-29 regulates autophagosome maturation Nature Cell Biology
24 Nov 2014 Most read Nature.com Open innovation Pavillion Intravenous
Sustained Release Drug Delivery Technology Deadline: Mar 21 2015 Reward:
20,000 USD
Data collection in outdoor field studies is problematic and inefficient
without a reliable wireless internet connection. The… Powered by:innocentive
Sensitive detection of small molecule fragments binding to defined sites of
biomacromolecules is still a considerable challenge. Here we demonstrate that
protein-binding fragments are able to induce enzymatic reactions on the
protein surface via dynamic fragment ligation. Fragments binding to the S1
pocket of serine proteases containing a nitrogen, oxygen or sulphur
nucleophile are found to activate electrophilic pre-substrates through a
reversible, covalent ligation reaction. The dynamic ligation reaction
positions the pre-substrate molecule at the active site of the protein thereby
inducing its enzymatic cleavage. Catalytic activation of pre-substrates is
confirmed by fluorescence spectroscopy and by high-performance liquid
chromatography. The approach is investigated with 3 pre-substrates and 14
protein-binding fragments and the specific activation and the templating
effect exerted by the enzyme is quantified for each protease–fragment–pre-
substrate combination. The described approach enables the site-specific
identification of protein-binding fragments, the functional characterization
of enzymatic sites and the quantitative analysis of protein template-assisted
ligation reactions.1\. Auflag
Asymmetric correlation matrices: an analysis of financial data
We analyze the spectral properties of correlation matrices between distinct
statistical systems. Such matrices are intrinsically non symmetric, and lend
themselves to extend the spectral analyses usually performed on standard
Pearson correlation matrices to the realm of complex eigenvalues. We employ
some recent random matrix theory results on the average eigenvalue density of
this type of matrices to distinguish between noise and non trivial correlation
structures, and we focus on financial data as a case study. Namely, we employ
daily prices of stocks belonging to the American and British stock exchanges,
and look for the emergence of correlations between two such markets in the
eigenvalue spectrum of their non symmetric correlation matrix. We find several
non trivial results, also when considering time-lagged correlations over short
lags, and we corroborate our findings by additionally studying the asymmetric
correlation matrix of the principal components of our datasets.Comment: Revised version; 11 pages, 13 figure
Maximal entropy random walk in community finding
The aim of this paper is to check feasibility of using the maximal-entropy
random walk in algorithms finding communities in complex networks. A number of
such algorithms exploit an ordinary or a biased random walk for this purpose.
Their key part is a (dis)similarity matrix, according to which nodes are
grouped. This study encompasses the use of the stochastic matrix of a random
walk, its mean first-passage time matrix, and a matrix of weighted paths count.
We briefly indicate the connection between those quantities and propose
substituting the maximal-entropy random walk for the previously chosen models.
This unique random walk maximises the entropy of ensembles of paths of given
length and endpoints, which results in equiprobability of those paths. We
compare performance of the selected algorithms on LFR benchmark graphs. The
results show that the change in performance depends very strongly on the
particular algorithm, and can lead to slight improvements as well as
significant deterioration.Comment: 7 pages, 4 figures, submitted to European Physical Journal Special
Topics following the 4-th Conference on Statistical Physics: Modern Trends
and Applications, July 3-6, 2012 Lviv, Ukrain
Renal cell carcinoma drug and cell therapy: today and tomorrow
The paper also looks at clinically applicable targeted immune drugs and the principle of their effect on tumorous cells. Besides, modern clinical studies of cell drugs have been considere
Portfolio Optimization and the Random Magnet Problem
Diversification of an investment into independently fluctuating assets
reduces its risk. In reality, movement of assets are are mutually correlated
and therefore knowledge of cross--correlations among asset price movements are
of great importance. Our results support the possibility that the problem of
finding an investment in stocks which exposes invested funds to a minimum level
of risk is analogous to the problem of finding the magnetization of a random
magnet. The interactions for this ``random magnet problem'' are given by the
cross-correlation matrix {\bf \sf C} of stock returns. We find that random
matrix theory allows us to make an estimate for {\bf \sf C} which outperforms
the standard estimate in terms of constructing an investment which carries a
minimum level of risk.Comment: 12 pages, 4 figures, revte
Casimir effect for massless minimally coupled scalar field between parallel plates in de Sitter spacetime
Casimir effect for massless minimally coupled scalar field is studied. An
explicit answer for de Sitter spacetime is obtained and analized. Cosmological
implications of the result are discussed.Comment: 7 pages, 2 figure
The Okun Misery Index in the European Union Countries from 2000 to 2009
The study is composed of four main parts and a summary. The first part, introduction, discusses various measures of the economic system's efficiency that are used in practice. Part two emphasises that the GDP per capita according to purchasing power parity still remains the most popular among those measures. Further, it presents the ranking of the European Union countries taking that measure into account, the research period being 1999-2009. Part three points out that it is also the level of poverty (misery) that determines the economic system's efficiency. That level can be measured by means of various indicators, among others, the so called HPI-2 index calculated by the UN. It will be the Okun misery index, however, computed as the sum of inflation and unemployment rates that will be presented as an alternative being of interest from the macroeconomic point of view. The ranking of the European Union member states according to that measure in the 2000-2004 and 2005-2009 periods will be provided in part four. The article will end in a summary containing synthetic conclusions drawn from earlier observations.Opracowanie składa się z czterech części zasadniczych i podsumowania. W punkcie pierwszym omówiono różnorodne mierniki sprawności systemu gospodarczego wykorzystywane w praktyce. W części drugiej podkreślono, iż nadal najpopularniejszym z nich jest PKB per capita według parytetu siły nabywczej. Zgodnie z tym miernikiem przedstawiono ranking państw Unii Europejskiej w latach 1999-2009. W punkcie trzecim podkreślono, że o sprawności systemu gospodarczego decyduje także poziom ubóstwa. Może być on mierzony różnymi wskaźnikami, m.in. tzw. indeksem HPI-2 obliczanym przez ONZ. Jako ciekawą z makroekonomicznego punktu widzenia alternatywę ukazano jednak miarę wskaźnika ubóstwa Okuna obliczanego poprzez zsumowanie stopy inflacji i stopy bezrobocia. Ranking państw Unii Europejskiej według tej miary w okresach 2000-2004 oraz 2005-2009 zaprezentowano w części czwartej. Całość zamknięto podsumowaniem, w którym zawarto syntetyczne wnioski z przeprowadzonych obserwacji
Levy targeting and the principle of detailed balance
We investigate confined L\'{e}vy flights under premises of the principle of
detailed balance. The master equation admits a transformation to L\'{e}vy -
Schr\"{o}dinger semigroup dynamics (akin to a mapping of the Fokker-Planck
equation into the generalized diffusion equation). We solve a stochastic
targeting problem for arbitrary stability index of L\'{e}vy drivers:
given an invariant probability density function (pdf), specify the jump - type
dynamics for which this pdf is a long-time asymptotic target. Our
("-targeting") method is exemplified by Cauchy family and Gaussian target
pdfs. We solve the reverse engineering problem for so-called L\'{e}vy
oscillators: given a quadratic semigroup potential, find an asymptotic pdf for
the associated master equation for arbitrary
- …