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

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

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

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

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

Electrically driven single electron spin resonance in a slanting Zeeman field

The rapidly rising fields of spintronics and quantum information science have led to a strong interest in developing the ability to coherently manipulate electron spins. Electron spin resonance (ESR) is a powerful technique to manipulate spins that is commonly achieved by applying an oscillating magnetic field. However, the technique has proven very challenging when addressing individual spins. In contrast, by mixing the spin and charge degrees of freedom in a controlled way through engineered non-uniform magnetic fields, electron spin can be manipulated electrically without the need of high-frequency magnetic fields. Here we realize electrically-driven addressable spin rotations on two individual electrons by integrating a micron-size ferromagnet to a double quantum dot device. We find that the electrical control and spin selectivity is enabled by the micro-magnet's stray magnetic field which can be tailored to multi-dots architecture. Our results demonstrate the feasibility of manipulating electron spins electrically in a scalable way.Comment: 25 pages, 6 figure

Nanoscale spin rectifiers controlled by the Stark effect

The control of orbital and spin state of single electrons is a key ingredient for quantum information processing, novel detection schemes, and, more generally, is of much relevance for spintronics. Coulomb and spin blockade (SB) in double quantum dots (DQDs) enable advanced single-spin operations that would be available even for room-temperature applications for sufficiently small devices. To date, however, spin operations in DQDs were observed at sub-Kelvin temperatures, a key reason being that scaling a DQD system while retaining an independent field-effect control on the individual dots is very challenging. Here we show that quantum-confined Stark effect allows an independent addressing of two dots only 5 nm apart with no need for aligned nanometer-size local gating. We thus demonstrate a scalable method to fully control a DQD device, regardless of its physical size. In the present implementation we show InAs/InP nanowire (NW) DQDs that display an experimentally detectable SB up to 10 K. We also report and discuss an unexpected re-entrant SB lifting as a function magnetic-field intensity

Performance of the 2007 WHO Algorithm to diagnose Smear-negative Pulmonary Tuberculosis in a HIV prevalent setting

The 2007 WHO algorithm for diagnosis of smear-negative pulmonary tuberculosis (PTB) including Mycobacterium tuberculosis (MTB) culture was evaluated in a HIV prevalent area of Kenya

The breadth of primary care: a systematic literature review of its core dimensions

Background: Even though there is general agreement that primary care is the linchpin of effective health care delivery, to date no efforts have been made to systematically review the scientific evidence supporting this supposition. The aim of this study was to examine the breadth of primary care by identifying its core dimensions and to assess the evidence for their interrelations and their relevance to outcomes at (primary) health system level. Methods: A systematic review of the primary care literature was carried out, restricted to English language journals reporting original research or systematic reviews. Studies published between 2003 and July 2008 were searched in MEDLINE, Embase, Cochrane Library, CINAHL, King's Fund Database, IDEAS Database, and EconLit. Results: Eighty-five studies were identified. This review was able to provide insight in the complexity of primary care as a multidimensional system, by identifying ten core dimensions that constitute a primary care system. The structure of a primary care system consists of three dimensions: 1. governance; 2. economic conditions; and 3. workforce development. The primary care process is determined by four dimensions: 4. access; 5. continuity of care; 6. coordination of care; and 7. comprehensiveness of care. The outcome of a primary care system includes three dimensions: 8. quality of care; 9. efficiency care; and 10. equity in health. There is a considerable evidence base showing that primary care contributes through its dimensions to overall health system performance and health. Conclusions: A primary care system can be defined and approached as a multidimensional system contributing to overall health system performance and health