Next-generation high-throughput DNA sequencing techniques are opening fascinating opportunities in the life sciences. Novel fields and applications in biology and medicine are becoming a reality, ...beyond the genomic sequencing which was original development goal and application. Serving as examples are: personal genomics with detailed analysis of individual genome stretches; precise analysis of RNA transcripts for gene expression, surpassing and replacing in several respects analysis by various microarray platforms, for instance in reliable and precise quantification of transcripts and as a tool for identification and analysis of DNA regions interacting with regulatory proteins in functional regulation of gene expression. The next-generation sequencing technologies offer novel and rapid ways for genome-wide characterisation and profiling of mRNAs, small RNAs, transcription factor regions, structure of chromatin and DNA methylation patterns, microbiology and metagenomics. In this article, development of commercial sequencing devices is reviewed and some European contributions to the field are mentioned. Presently commercially available very high-throughput DNA sequencing platforms, as well as techniques under development, are described and their applications in bio-medical fields discussed.
Investment Banking: Institutions, Politics, and Law provides an economic rationale for the dominant role of investment banks in the capital markets, and uses it to explain both the historical ...evolution of the investment banking industry and also recent changes to its organization. Although investment decisions rely upon price-relevant information, it is impossible to establish property rights over it and hence is very hard to coordinate its exchange. The authors argue that investment banks help to resolve this problem by managing "information marketplaces," within which extra-legal institutions support the production and dissemination of information that is important to investors. Reputations and relationships are more important in fulfilling this role than financial capital. The authors substantiate their theory with reference to the industry's evolution during the last three centuries. They show how investment banking networks were formed, and identify the informal contracts that they supported. This historical development points to tensions between the relational contracting of investment banks and the regulatory impulses of the State, thus providing some explanation for the periodic large-scale State intervention in the operation of capital markets. Their theory also provides a technological explanation for the massive restructuring of the capital markets in recent decades, which the authors argue can be used to think about the likely future direction of the investment banking industry. Available in OSO: http://www.oxfordscholarship.com/oso/public/content/economicsfinance/019929657X/toc.html
Early and persistent activation of complement is considered to play a key role in the pathogenesis of COVID-19. Complement activation products orchestrate a proinflammatory environment that might be ...critical for the induction and maintenance of a severe inflammatory response to SARS-CoV-2 by recruiting cells of the cellular immune system to the sites of infection and shifting their state of activation towards an inflammatory phenotype. It precedes pathophysiological milestone events like the cytokine storm, progressive endothelial injury triggering microangiopathy, and further complement activation, and causes an acute respiratory distress syndrome (ARDS). To date, the application of antiviral drugs and corticosteroids have shown efficacy in the early stages of SARS-CoV-2 infection, but failed to ameliorate disease severity in patients who progressed to severe COVID-19 pathology. This report demonstrates that lectin pathway (LP) recognition molecules of the complement system, such as MBL, FCN-2 and CL-11, bind to SARS-CoV-2 S- and N-proteins, with subsequent activation of LP-mediated C3b and C4b deposition. In addition, our results confirm and underline that the N-protein of SARS-CoV-2 binds directly to the LP- effector enzyme MASP-2 and activates complement. Inhibition of the LP using an inhibitory monoclonal antibody against MASP-2 effectively blocks LP-mediated complement activation. FACS analyses using transfected HEK-293 cells expressing SARS-CoV-2 S protein confirm a robust LP-dependent C3b deposition on the cell surface which is inhibited by the MASP-2 inhibitory antibody. In light of our present results, and the encouraging performance of our clinical candidate MASP-2 inhibitor Narsoplimab in recently published clinical trials, we suggest that the targeting of MASP-2 provides an unsurpassed window of therapeutic efficacy for the treatment of severe COVID-19.
Obstacles on the surface of microtubules can lead to defective cargo transport, proposed to play a role in neurological diseases such as Alzheimer’s. However, little is known about how motor ...proteins, which follow individual microtubule protofilaments (such as kinesin-1), deal with obstacles on the molecular level. Here, we used rigor-binding mutants of kinesin-1 as roadblocks to permanently obstruct individual microtubule binding sites and studied the movement of individual kinesin-1 motors by single-molecule fluorescence and dark-field scattering microscopy in vitro. In the presence of roadblocks, kinesin-1 often stopped for ∼0.4 s before either detaching or continuing to move, whereby the latter circumvention events occurred in >30% after a stopping event. Consequently, and in agreement with numerical simulations, the mean velocity, mean run length, and mean dwell time of the kinesin-1 motors decreased upon increasing the roadblock density. Tracking individual kinesin-1 motors labeled by 40 nm gold particles with 6 nm spatial and 1 ms temporal precision revealed that ∼70% of the circumvention events were associated with significant transverse shifts perpendicular to the axis of the microtubule. These side-shifts, which occurred with equal likelihood to the left and right, were accompanied by a range of longitudinal shifts suggesting that roadblock circumvention involves the unbinding and rebinding of the motors. Thus, processive motors, which commonly follow individual protofilaments in the absence of obstacles, appear to possess intrinsic circumvention mechanisms. These mechanisms were potentially optimized by evolution for the motor’s specific intracellular tasks and environments.
We investigate whether analyst behavior influenced banks' likelihood of winning underwriting mandates for a sample of 16,625 U.S. debt and equity offerings in 1993-2002. We control for the strength ...of the issuer's investment banking relationships with potential competitors for the mandate, prior lending relationships, and the endogeneity of analyst behavior and the bank's decision to provide analyst coverage. Although analyst behavior was influenced by economic incentives, we find no evidence that aggressive analyst behavior increased their bank's probability of winning an underwriting mandate. The main determinant of the lead-bank choice is the strength of prior underwriting and lending relationships.
We present results for the strange contribution to the electromagnetic form factors of the nucleon computed on the coordinated lattice simulation ensembles with Nf=2+1 flavors of O(a)-improved Wilson ...fermions and an O(a)-improved vector current. Several source-sink separations are investigated in order to estimate the excited-state contamination. We calculate the form factors on six ensembles with lattice spacings in the range of a=0.049–0.086 fm and pion masses in the range of mπ=200–360 MeV, which allows for a controlled chiral and continuum extrapolation. In the computation of the quark-disconnected contributions, we employ hierarchical probing as a variance-reduction technique.
Standards in Pupillography Kelbsch, Carina; Strasser, Torsten; Chen, Yanjun ...
Frontiers in neurology,
02/2019, Letnik:
10
Journal Article
Recenzirano
Odprti dostop
The number of research groups studying the pupil is increasing, as is the number of publications. Consequently, new standards in pupillography are needed to formalize the methodology including ...recording conditions, stimulus characteristics, as well as suitable parameters of evaluation. Since the description of intrinsically photosensitive retinal ganglion cells (ipRGCs) there has been an increased interest and broader application of pupillography in ophthalmology as well as other fields including psychology and chronobiology. Color pupillography plays an important role not only in research but also in clinical observational and therapy studies like gene therapy of hereditary retinal degenerations and psychopathology. Stimuli can vary in size, brightness, duration, and wavelength. Stimulus paradigms determine whether rhodopsin-driven rod responses, opsin-driven cone responses, or melanopsin-driven ipRGC responses are primarily elicited. Background illumination, adaptation state, and instruction for the participants will furthermore influence the results. This standard recommends a minimum set of variables to be used for pupillography and specified in the publication methodologies. Initiated at the 32nd International Pupil Colloquium 2017 in Morges, Switzerland, the aim of this manuscript is to outline standards in pupillography based on current knowledge and experience of pupil experts in order to achieve greater comparability of pupillographic studies. Such standards will particularly facilitate the proper application of pupillography by researchers new to the field. First we describe general standards, followed by specific suggestions concerning the demands of different targets of pupil research: the afferent and efferent reflex arc, pharmacology, psychology, sleepiness-related research and animal studies.
Bioluminescence is a phenomenon that has fascinated mankind for centuries. Today the phenomenon and its sibling, chemiluminescence, have impacted society with a number of useful applications in ...fields like analytical chemistry and medicine, just to mention two. In this review, a molecular-orbital perspective is adopted to explain the chemistry behind chemiexcitation in both chemi- and bioluminescence. First, the uncatalyzed thermal dissociation of 1,2-dioxetane is presented and analyzed to explain, for example, the preference for triplet excited product states and increased yield with larger nonreactive substituents. The catalyzed fragmentation reaction and related details are then exemplified with substituted 1,2-dioxetanone species. In particular, the preference for singlet excited product states in that case is explained. The review also examines the diversity of specific solutions both in Nature and in artificial systems and the difficulties in identifying the emitting species and unraveling the color modulation process. The related subject of excited-state chemistry without light absorption is finally discussed. The content of this review should be an inspiration to human design of new molecular systems expressing unique light-emitting properties. An appendix describing the state-of-the-art experimental and theoretical methods used to study the phenomena serves as a complement.
We present results for the isovector electromagnetic form factors of the nucleon computed on the coordinated lattice simulations ensembles with Nf=2+1 flavors of O(a)-improved Wilson fermions and an ...O(a)-improved vector current. The analysis ncludes ensembles with four lattice spacings and pion masses ranging from 130 up o 350 MeV and mainly targets the low-Q2 region. In order to remove any bias rom nsuppressed excited-state contributions, we investigate several source-sink eparations between 1.0 and 1.5 fm and apply the summation method as well as xplicit two-state fits. The chiral interpolation is performed by applying covariant hiral perturbation theory including vector mesons directly to our form factor data, hus avoiding an auxiliary parametrization of the Q2 dependence. At the physical oint, we obtain μ=4.71(11)stat(13)sys for the nucleon isovector magnetic moment, in good agreement with the experimental value and ⟨r2M⟩=0.661(30)stat(11)sys fm2 for the corresponding square radius, again in good agreement with the alue inferred from the ep-scattering determination Bernauer et al., Phys. Rev. ett. 105, 242001 (2010) of the proton radius. Our estimate for the isovector electric charge radius, ⟨r2E⟩=0.800(25)stat(22)sys fm2, however, is in slight tension with the larger value inferred from the aforementioned ep-scattering data, while being in agreement with the value derived from the 2018 CODATA average for the proton charge radius.
When intense lightwaves accelerate electrons through a solid, the emerging high-order harmonic (HH) radiation offers key insights into the material
. Sub-optical-cycle dynamics-such as dynamical ...Bloch oscillations
, quasiparticle collisions
, valley pseudospin switching
and heating of Dirac gases
-leave fingerprints in the HH spectra of conventional solids. Topologically non-trivial matter
with invariants that are robust against imperfections has been predicted to support unconventional HH generation
. Here we experimentally demonstrate HH generation in a three-dimensional topological insulator-bismuth telluride. The frequency of the terahertz driving field sharply discriminates between HH generation from the bulk and from the topological surface, where the unique combination of long scattering times owing to spin-momentum locking
and the quasi-relativistic dispersion enables unusually efficient HH generation. Intriguingly, all observed orders can be continuously shifted to arbitrary non-integer multiples of the driving frequency by varying the carrier-envelope phase of the driving field-in line with quantum theory. The anomalous Berry curvature warranted by the non-trivial topology enforces meandering ballistic trajectories of the Dirac fermions, causing a hallmark polarization pattern of the HH emission. Our study provides a platform to explore topology and relativistic quantum physics in strong-field control, and could lead to non-dissipative topological electronics at infrared frequencies.
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