Optimal flexibility for conformational transitions in macromolecules

Conformational transitions in macromolecular complexes often involve the reorientation of lever-like structures. Using a simple theoretical model, we show that the rate of such transitions is drastically enhanced if the lever is bendable, e.g. at a localized "hinge''. Surprisingly, the transition is fastest with an intermediate flexibility of the hinge. In this intermediate regime, the transition rate is also least sensitive to the amount of "cargo'' attached to the lever arm, which could be exploited by molecular motors. To explain this effect, we generalize the Kramers-Langer theory for multi-dimensional barrier crossing to configuration dependent mobility matrices.Comment: 4 pages, 4 figure

Non-Alcoholic Steatohepatitis: Limited Available Treatment Options but Promising Drugs in Development and Recent Progress Towards a Regulatory Approval Pathway

The prevalence of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) is increasing world-wide in parallel to the increase of the obesity epidemic. Insulin resistance (IR) and the accumulation of triglyceride-derived toxic lipid metabolites play a key role in its pathogenesis. Multiple biomarkers are being evaluated for the non-invasive diagnosis of NASH. However, a percutaneous liver biopsy is still the gold standard method; the minimal diagnostic criteria include the presence of \u3e5 % macrovesicular steatosis, inflammation, and liver cell ballooning. Several pharmaceutical agents have been evaluated for the treatment of NASH; however, no single therapy has been approved so far. Due to the increasing prevalence and the health burden, there is a high need to develop therapeutic strategies for patients with NASH targeting both those with early-stage disease as well as those with advanced liver fibrosis. There are unique challenges in the design of studies for these target populations. Collaborative efforts of health authorities, medical disease experts, and the pharmaceutical industry are ongoing to align options for a registrational pathway. Several companies pursuing different mechanisms of action are nearing the end of phase II with their candidates. This manuscript reviews those compounds with a variety of mode of actions that have been evaluated and/or are currently being tested with the goal of achieving a NAFLD/NASH indication

A New Geographic Locality and Three New Host Records for Neobenedenia melleni (MacCallum) (Monogenea: Capsalidae)

A new geographic locality record and three new host records for Neobenedenia melleni (MacCallum, 1921) (Monogenea: Capsalidae) are provided. Specimens of N. melleni were collected from the skin of three Florida pompano, Trachinotus carolinus (Linnaeus, 1166)(Carangidae),caught in the northern Gulf of Mexico off Horn Island, Mississippi; from the skin of a bluering angelfish, Pomacanthus annularis (Bloch, 1157) (Pomacanthidae), in the Shark Reef Aquarium at Mandalay Bay, Las Vegas, Nevada; from the skin of a rock greenling, Hexagrammos lagocephalus (Pallas, 1810) (Hexagrammidae), in the Alaska SeaLife Center, Seward, Alaska; and from the skin of two blue-barred ribbon gobies, Oxymetopon cyanoctenosum Klausewitz and Condé, 1981 (Microdesmidae), in a tropical fish clearinghouse in Hayward, California. This is the first published record of the parasite from a microdesmid or wild carangid. Prior to this report, no specimen of N. melleni had been reported from a wild-caught fish in the Gulf of Mexico. The presence of N. melleni in the Gulf of Mexico is particularly noteworthy because this monogenean is a known pathogen of cultured fishes in netpens and recirculating seawater systems

Quasispecies evolution in general mean-field landscapes

I consider a class of fitness landscapes, in which the fitness is a function of a finite number of phenotypic "traits", which are themselves linear functions of the genotype. I show that the stationary trait distribution in such a landscape can be explicitly evaluated in a suitably defined "thermodynamic limit", which is a combination of infinite-genome and strong selection limits. These considerations can be applied in particular to identify relevant features of the evolution of promoter binding sites, in spite of the shortness of the corresponding sequences.Comment: 6 pages, 2 figures, Europhysics Letters style (included) Finite-size scaling analysis sketched. To appear in Europhysics Letter

Reply to Jensen and Kowalik: Consideration of mixed infections is central to understanding HCMV intrahost diversity.

Kowalik and Jensen (1) have reported that intra-host variation in HCMV approaches levels similar to those of HCV, with fast mutation rates mooted as one explanation (2).While we discussed that HCMV mutation rates were postulated as an explanation for high diversity, the focus of our work is on observed inconsistencies in nucleotide diversity between and within patients (3). Kowalik and Jensen did calculate HCMV mutation rates to be similar to MCMV but maintained that this could underestimate the true levels (2). In contrast, our study showed that in the absence of mixed infections, HCMV is no more diverse than other DNA viruses, and considerably less so than chronic RNA viruses. This simple conclusion is different to that of Kowalik and Jensen and had not been stated prior to our publication.N

Constructing amino acid residue substitution classes maximally indicative of local protein structure

Using an information theoretic formalism, we optimize classes of amino acid substitution to be maximally indicative of local protein structure. Our statistically-derived classes are loosely identifiable with the heuristic constructions found in previously published work. However, while these other methods provide a more rigid idealization of physicochemically constrained residue substitution, our classes provide substantially more structural information with many fewer parameters. Moreover, these substitution classes are consistent with the paradigmatic view of the sequence-to-structure relationship in globular proteins which holds that the three-dimensional architecture is predominantly determined by the arrangement of hydrophobic and polar side chains with weak constraints on the actual amino acid identities. More specific constraints are imposed on the placement of prolines, glycines, and the charged residues. These substitution classes have been used in highly accurate predictions of residue solvent accessibility. They could also be used in the identification of homologous proteins, the construction and refinement of multiple sequence alignments, and as a means of condensing and codifying the information in multiple sequence alignments for secondary structure prediction and tertiary fold recognition. © 1996 Wiley-Liss, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/38523/1/3_ftp.pd

Single-ion and exchange anisotropy effects and multiferroic behavior in high-symmetry tetramer single molecule magnets

We study single-ion and exchange anisotropy effects in equal-spin $s_1$ tetramer single molecule magnets exhibiting $T_d$, $D_{4h}$, $D_{2d}$, $C_{4h}$, $C_{4v}$, or $S_4$ ionic point group symmetry. We first write the group-invariant quadratic single-ion and symmetric anisotropic exchange Hamiltonians in the appropriate local coordinates. We then rewrite these local Hamiltonians in the molecular or laboratory representation, along with the Dzyaloshinskii-Moriay (DM) and isotropic Heisenberg, biquadratic, and three-center quartic Hamiltonians. Using our exact, compact forms for the single-ion spin matrix elements, we evaluate the eigenstate energies analytically to first order in the microscopic anisotropy interactions, corresponding to the strong exchange limit, and provide tables of simple formulas for the energies of the lowest four eigenstate manifolds of ferromagnetic (FM) and anitiferromagnetic (AFM) tetramers with arbitrary $s_1$. For AFM tetramers, we illustrate the first-order level-crossing inductions for $s_1=1/2,1,3/2$, and obtain a preliminary estimate of the microscopic parameters in a Ni$_4$ from a fit to magnetization data. Accurate analytic expressions for the thermodynamics, electron paramagnetic resonance absorption and inelastic neutron scattering cross-section are given, allowing for a determination of three of the microscopic anisotropy interactions from the second excited state manifold of FM tetramers. We also predict that tetramers with symmetries $S_4$ and $D_{2d}$ should exhibit both DM interactions and multiferroic states, and illustrate our predictions for $s_1=1/2, 1$.Comment: 30 pages, 14 figures, submitted to Phys. Rev.

Magnetohydrodynamic Turbulence and Reconnection in the Magnetotail

We have used a global MHD simulation with high spatial resolution to investigate the origin and properties of turbulence in the plasma sheet. In this simulation we imposed a steady southward IMF with a magnitude of 5 nT at the upstream simulation boundary for more than three hours followed by ninety minutes of northward IMF of the same magnitude. The solar wind number density was 20 cm-3, the thermal pressure was 20 pPa, and the velocity was 500 km/s in the x direction. The moderately high dynamic pressure confined the magnetotail to the high-grid resolution region. Even for these nominal solar wind parameters and steady driving the plasma sheet became turbulent. The power spectral densities and probability distribution functions computed from the simulations were comparable to those obtained from spacecraft observations. The largest scale vortices were associated with reconnection outflows and, in the southward IMF case, with the diversion of high speed flows in the near-Earth region. Both time and space domain analyses revealed that there were three scales present, the large scale of the driving processes, the intermediate inertial scale and the dissipative scale

Turbulence in a global magnetohydrodynamic simulation of the Earth's magnetosphere during northward and southward interplanetary magnetic field

We report the results of MHD simulations of Earth's magnetosphere for idealized steady solar wind plasma and interplanetary magnetic field (IMF) conditions. The simulations feature purely northward and southward magnetic fields and were designed to study turbulence in the magnetotail plasma sheet. We found that the power spectral densities (PSDs) for both northward and southward IMF had the characteristics of turbulent flow. In both cases, the PSDs showed the three scale ranges expected from theory: the energy-containing scale, the inertial range, and the dissipative range. The results were generally consistent with in-situ observations and theoretical predictions. While the two cases studied, northward and southward IMF, had some similar characteristics, there were significant differences as well. For southward IMF, localized reconnection was the main energy source for the turbulence. For northward IMF, remnant reconnection contributed to driving the turbulence. Boundary waves may also have contributed. In both cases, the PSD slopes had spatial distributions in the dissipative range that reflected the pattern of resistive dissipation. For southward IMF there was a trend toward steeper slopes in the dissipative range with distance down the tail. For northward IMF there was a marked dusk-dawn asymmetry with steeper slopes on the dusk side of the tail. The inertial scale PSDs had a dusk-dawn symmetry during the northward IMF interval with steeper slopes on the dawn side. This asymmetry was not found in the distribution of inertial range slopes for southward IMF. The inertial range PSD slopes were clustered around values close to the theoretical expectation for both northward and southward IMF. In the dissipative range, however, the slopes were broadly distributed and the median values were significantly different, consistent with a different distribution of resistivity

Entanglement entropy and quantum phase transitions in quantum dots coupled to Luttinger liquid wires

We study a quantum phase transition which occurs in a system composed of two impurities (or quantum dots) each coupled to a different interacting (Luttinger-liquid) lead. While the impurities are coupled electrostatically, there is no tunneling between them. Using a mapping of this system onto a Kondo model, we show analytically that the system undergoes a Berezinskii-Kosterlitz-Thouless quantum phase transition as function of the Luttinger liquid parameter in the leads and the dot-lead interaction. The phase with low values of the Luttinger-liquid parameter is characterized by an abrupt switch of the population between the impurities as function of a common applied gate voltage. However, this behavior is hard to verify numerically since one would have to study extremely long systems. Interestingly though, at the transition the entanglement entropy drops from a finite value of $\ln(2)$ to zero. The drop becomes sharp for infinite systems. One can employ finite size scaling to extrapolate the transition point and the behavior in its vicinity from the behavior of the entanglement entropy in moderate size samples. We employ the density matrix renormalization group numerical procedure to calculate the entanglement entropy of systems with lead lengths of up to 480 sites. Using finite size scaling we extract the transition value and show it to be in good agreement with the analytical prediction.Comment: 12 pages, 9 figure