Amyloid-like fibrils from a domain-swapping protein feature a parallel, in-register conformation without native-like interactions

The formation of amyloid-like fibrils is characteristic of various diseases, but the underlying mechanism and the factors that determine whether, when, and how proteins form amyloid, remain uncertain. Certain mechanisms have been proposed based on the three-dimensional or runaway domain swapping, inspired by the fact that some proteins show an apparent correlation between the ability to form domain-swapped dimers and a tendency to form fibrillar aggregates. Intramolecular β-sheet contacts present in the monomeric state could constitute intermolecular β-sheets in the dimeric and fibrillar states. One example is an amyloid-forming mutant of the immunoglobulin binding domain B1 of streptococcal protein G, which in its native conformation consists of a four-stranded β-sheet and one α-helix. Under native conditions this mutant adopts a domainswapped dimer, and it also forms amyloid-like fibrils, seemingly in correlation to its domain-swapping ability. We employ magic angle spinning solid-state NMR and other methods to examine key structural features of these fibrils. Our results reveal a highly rigid fibril structure that lacks mobile domains and indicate a parallel in-register β-sheet structure and a general loss of native conformation within the mature fibrils. This observation contrasts with predictions that native structure, and in particular intermolecular β-strand interactions seen in the dimeric state, may be preserved in "domain-swapping" fibrils. We discuss these observations in light of recent work on related amyloidforming proteins that have been argued to follow similar mechanisms and how this may have implications for the role of domain-swapping propensities for amyloid formation. © 2011 by The American Society for Biochemistry and Molecular Biology, Inc

The aggregation-enhancing huntingtin N-terminus is helical in amyloid fibrils

The 17-residue N-terminus (httNT) directly flanking the polyQ sequence in huntingtin (htt) N-terminal fragments plays a crucial role in initiating and accelerating the aggregation process that is associated with Huntington's disease pathogenesis. Here we report on magic-angle-spinning solid-state NMR studies of the amyloid-like aggregates of an htt N-terminal fragment. We find that the polyQ portion of this peptide exists in a rigid, dehydrated amyloid core that is structurally similar to simpler polyQ fibrils and may contain antiparallel β-sheets. In contrast, the httNT sequence in the aggregates is composed in part of a well-defined helix, which likely also exists in early oligomeric aggregates. Further NMR experiments demonstrate that the N-terminal helical segment displays increased dynamics and water exposure. Given its specific contribution to the initiation, rate, and mechanism of fibril formation, the helical nature of httNT and its apparent lack of effect on the polyQ fibril core structure seem surprising. The results provide new details about these disease-associated aggregates and also provide a clear example of an amino acid sequence that greatly enhances the rate of amyloid formation while itself not taking part in the amyloid structure. There is an interesting mechanistic analogy to recent reports pointing out the early-stage contributions of transient intermolecular helix-helix interactions in the aggregation behavior of various other amyloid fibrils. © 2011 American Chemical Society

Effective Field Theory for Few-Nucleon Systems

We review the effective field theories (EFTs) developed for few-nucleon systems. These EFTs are controlled expansions in momenta, where certain (leading-order) interactions are summed to all orders. At low energies, an EFT with only contact interactions allows a detailed analysis of renormalization in a non-perturbative context and uncovers novel asymptotic behavior. Manifestly model-independent calculations can be carried out to high orders, leading to high precision. At higher energies, an EFT that includes pion fields justifies and extends the traditional framework of phenomenological potentials. The correct treatment of QCD symmetries ensures a connection with lattice QCD. Several tests and prospects of these EFTs are discussed.Comment: 55 pages, 18 figures, to appear in Ann. Rev. Nucl. Part. Sci. 52 (2002

Coupling molecular spin states by photon-assisted tunneling

Artificial molecules containing just one or two electrons provide a powerful platform for studies of orbital and spin quantum dynamics in nanoscale devices. A well-known example of these dynamics is tunneling of electrons between two coupled quantum dots triggered by microwave irradiation. So far, these tunneling processes have been treated as electric dipole-allowed spin-conserving events. Here we report that microwaves can also excite tunneling transitions between states with different spin. In this work, the dominant mechanism responsible for violation of spin conservation is the spin-orbit interaction. These transitions make it possible to perform detailed microwave spectroscopy of the molecular spin states of an artificial hydrogen molecule and open up the possibility of realizing full quantum control of a two spin system via microwave excitation.Comment: 13 pages, 9 figure

Matrix interpretation of multiple orthogonality

In this work we give an interpretation of a (s(d + 1) + 1)-term recurrence relation in terms of type II multiple orthogonal polynomials.We rewrite this recurrence relation in matrix form and we obtain a three-term recurrence relation for vector polynomials with matrix coefficients. We present a matrix interpretation of the type II multi-orthogonality conditions.We state a Favard type theorem and the expression for the resolvent function associated to the vector of linear functionals. Finally a reinterpretation of the type II Hermite- Padé approximation in matrix form is given

Glauber theory of initial- and final-state interactions in (p,2p) scattering

We develop the Glauber theory description of initial- and final-state interactions (IFSI) in quasielastic A(p,2p) scattering. We study the IFSI-distortion effects both for the inclusive and exclusive conditions. In inclusive reaction the important new effect is an interaction between the two sets of the trajectories which enter the calculation of IFSI-distorted one-body density matrix for inclusive (p,2p) scattering and are connected with incoherent elastic rescatterings of the initial and final protons on spectator nucleons. We demonstrate that IFSI-distortions of the missing momentum distribution are large over the whole range of missing momentum both for inclusive and exclusive reactions and affect in a crucial way the interpretation of the BNL data on (p,2p) scattering. Our numerical results show that in the region of missing momentum p_{m}\lsim 100-150 MeV/c the incoherent IFSI increase nuclear transparency by 5-10\%. The incoherent IFSI become dominant at p_{m}\gsim 200 MeV/c.Comment: Accepted in Z. Phys.A, Latex, 26 pages, uuencoded 9 figure

The Potential of Blockchain Technology for Health Information Exchange: Experimental Study From Patients’ Perspectives

Background: Nowadays, a number of mechanisms and tools are being used by health care organizations and physicians to electronically exchange the personal health information of patients. The main objectives of different methods of health information exchange (HIE) are to reduce health care costs, minimize medical errors, and improve the coordination of interorganizational information exchange across health care entities. The main challenges associated with the common HIE systems are privacy concerns, security risks, low visibility of system transparency, and lack of patient control. Blockchain technology is likely to disrupt the current information exchange models utilized in the health care industry. Objective: Little is known about patients’ perceptions and attitudes toward the implementation of blockchain-enabled HIE networks, and it is still not clear if patients (as one of the main HIE stakeholders) are likely to opt in to the applications of this technology in HIE initiatives. Thus, this study aimed at exploring the core value of blockchain technology in the health care industry from health care consumers’ views. Methods: To recognize the potential applications of blockchain technology in health care practices, we designed 16 information exchange scenarios for controlled Web-based experiments. Overall, 2013 respondents participated in 16 Web-based experiments. Each experiment described an information exchange condition characterized by 4 exchange mechanisms (ie, direct, lookup, patient-centered, and blockchain), 2 types of health information (ie, sensitive vs nonsensitive), and 2 types of privacy policy (weak vs strong). Results: The findings show that there are significant differences in patients’ perceptions of various exchange mechanisms with regard to patient privacy concern, trust in competency and integrity, opt-in intention, and willingness to share information. Interestingly, participants hold a favorable attitude toward the implementation of blockchain-based exchange mechanisms for privacy protection, coordination, and information exchange purposes. This study proposed the potentials and limitations of a blockchain-based attempt in the HIE context. Conclusions: The results of this research should be of interest to both academics and practitioners. The findings propose potential limitations of a blockchain-based HIE that should be addressed by health care organizations to exchange personal health information in a secure and private manner. This study can contribute to the research in the blockchain area and enrich the literature on the use of blockchain in HIE efforts. Practitioners can also identify how to leverage the benefit of blockchain to promote HIE initiatives nationwide

Management of Skin Toxicity Related to the Use of Imatinib Mesylate (STI571, Glivec™) for Advanced Stage Gastrointestinal Stromal Tumours

Skin toxicity is a common side-effect of treatment with imatinib mesylate (STI571, Glivec™) in advanced gastrointestinal stromal tumours (GIST) and chronic myeloid leukaemia. The optimal duration of treatment with imatinib mesylate in GIST has not yet been established, as durable remissions have been observed in patients. It is, therefore, important to develop strategies to deal with common side-effects of what may be a long-term treatment. Here we report the case of a patient with advanced GIST who developed a cutaneous drug reaction secondary to imatinib mesylate and the various management options that may be employed depending upon the severity of the toxicity. The case and literature are discussed

Nonequilibrium Singlet-Triplet Kondo Effect in Carbon Nanotubes

The Kondo-effect is a many-body phenomenon arising due to conduction electrons scattering off a localized spin. Coherent spin-flip scattering off such a quantum impurity correlates the conduction electrons and at low temperature this leads to a zero-bias conductance anomaly. This has become a common signature in bias-spectroscopy of single-electron transistors, observed in GaAs quantum dots as well as in various single-molecule transistors. While the zero-bias Kondo effect is well established it remains uncertain to what extent Kondo correlations persist in non-equilibrium situations where inelastic processes induce decoherence. Here we report on a pronounced conductance peak observed at finite bias-voltage in a carbon nanotube quantum dot in the spin singlet ground state. We explain this finite-bias conductance anomaly by a nonequilibrium Kondo-effect involving excitations into a spin triplet state. Excellent agreement between calculated and measured nonlinear conductance is obtained, thus strongly supporting the correlated nature of this nonequilibrium resonance.Comment: 21 pages, 5 figure