Enhanced J-protein interaction and compromised protein stability of mtHsp70 variants lead to mitochondrial dysfunction in Parkinsons disease

Parkinsons disease (PD) is the second most prevalent progressive neurological disorder commonly associated with impaired mitochondrial function in dopaminergic neurons. Although familial PD is multifactorial in nature, a recent genetic screen involving PD patients identified two mitochondrial Hsp70 variants (P509S and R126W) that are suggested in PD pathogenesis. However, molecular mechanisms underlying how mtHsp70 PD variants are centrally involved in PD progression is totally elusive. In this article, we provide mechanistic insights into the mitochondrial dysfunction associated with human mtHsp70 PD variants. Biochemically, the R126W variant showed severely compromised protein stability and was found highly susceptible to aggregation at physiological conditions. Strikingly, on the other hand, the P509S variant exhibits significantly enhanced interaction with J-protein cochaperones involved in folding and import machinery, thus altering the overall regulation of chaperone-mediated folding cycle and protein homeostasis. To assess the impact of mtHsp70 PD mutations at the cellular level, we developed yeast as a model system by making analogous mutations in Ssc1 ortholog. Interestingly, PD mutations in yeast (R103W and P486S) exhibit multiple in vivo phenotypes, which are associated with omitochondrial dysfunction', including compromised growth, impairment in protein translocation, reduced functional mitochondrial mass, mitochondrial DNA loss, respiratory incompetency and increased susceptibility to oxidative stress. In addition to that, R103W protein is prone to aggregate in vivo due to reduced stability, whereas P486S showed enhanced interaction with J-proteins, thus remarkably recapitulating the cellular defects that are observed in human PD variants. Taken together, our findings provide evidence in favor of direct involvement of mtHsp70 as a susceptibility factor in PD.

Evolution of quantum discord and its stability in two-qubit NMR systems

We investigate evolution of quantum correlations in ensembles of two-qubit nuclear spin systems via nuclear magnetic resonance techniques. We use discord as a measure of quantum correlations and the Werner state as an explicit example. We, first, introduce different ways of measuring discord and geometric discord in two-qubit systems and then describe the following experimental studies: (a) We quantitatively measure discord for Werner-like states prepared using an entangling pulse sequence. An initial thermal state with zero discord is gradually and periodically transformed into a mixed state with maximum discord. The experimental and simulated behavior of rise and fall of discord agree fairly well. (b) We examine the efficiency of dynamical decoupling sequences in preserving quantum correlations. In our experimental setup, the dynamical decoupling sequences preserved the traceless parts of the density matrices at high fidelity. But they could not maintain the purity of the quantum states and so were unable to keep the discord from decaying. (c) We observe the evolution of discord for a singlet-triplet mixed state during a radio-frequency spin-lock. A simple relaxation model describes the evolution of discord, and the accompanying evolution of fidelity of the long-lived singlet state, reasonably well.

Thermo-mechanical stability of a cellular assembly of carbon nanotubes in air

Carbon nanotubes (CNT) in bulk form offer outstanding structural and functional properties, and are shown to remain viscoelastic over a wide temperature range (77-1273 K) under inert conditions. We examine the quasi-static and dynamic compressive mechanical response of these cellular CNT materials in ambient air up to a temperature of 773 K. In uniaxial quasi-static compression, several displacement bursts are noted at large strains. These are results of the slippage and zipping of the CNT, and lead to significant mechanical energy absorption. Results of the dynamic mechanical analysis experiments show no degradation in storage modulus and loss coefficient for up to 20 h at 673 K. Hence, these stable cellular CNT structures can be utilized up to a maximum temperature of 673 K in air, which is much higher than the best polymers. (C) 2012 Elsevier Ltd. All rights reserved.

Seismic stability of a long unsupported circular tunnel

The stability of a long unsupported circular tunnel (opening) in a cohesive frictional soil has been assessed with the inclusion of pseudo-static horizontal earthquake body forces. The analysis has been performed under plane strain conditions by using upper bound finite element limit analysis in combination with a linear optimization procedure. The results have been presented in the form of a non-dimensional stability number (gamma H-max/c); where H = tunnel cover, c refers to soil cohesion and gamma(max) is the maximum unit weight of soil mass which the tunnel can support without collapse. The results have been obtained for various values of H/D (D = diameter of the tunnel), internal friction angle (phi) of soil, and the horizontal earthquake acceleration coefficient (alpha(h)). The computations reveal that the values of the stability numbers (i) decrease quite significantly with an increase in alpha(h), and (ii) become continuously higher for greater values of H/D and phi. As expected, the failure zones around the periphery of the tunnel becomes always asymmetrical with an inclusion of horizontal seismic body forces. (c) 2012 Elsevier Ltd. All rights reserved.

Role of Specific Cations and Water Entropy on the Stability of Branched DNA Motif Structures

DNA three-way junctions (TWJs) are important intermediates in various cellular processes and are the simplest of a family of branched nucleic acids being considered as scaffolds for biomolecular nanotechnology. Branched nucleic acids are stabilized by divalent cations such as Mg2+, presumably due to condensation and neutralization of the negatively charged DNA backbone. However, electrostatic screening effects point to more complex solvation dynamics and a large role of interfacial waters in thermodynamic stability. Here, we report extensive computer simulations in explicit water and salt on a model TWJ and use free energy calculations to quantify the role of ionic character and strength on stability. We find that enthalpic stabilization of the first and second hydration shells by Mg2+ accounts for 1/3 and all of the free energy gain in 50% and pure MgCl2 solutions, respectively. The more distorted DNA molecule is actually destabilized in pure MgCl2 compared to pure NaCl. Notably, the first shell, interfacial waters have very low translational and rotational entropy (i.e., mobility) compared to the bulk, an entropic loss that is overcompensated by increased enthalpy from additional electrostatic interactions with Mg2+. In contrast, the second hydration shell has anomalously high entropy as it is trapped between an immobile and bulklike layer. The nonmonotonic entropic signature and long-range perturbations of the hydration shells to Mg2+ may have implications in the molecular recognition of these motifs. For example, we find that low salt stabilizes the parallel configuration of the three-way junction, whereas at normal salt we find antiparallel configurations deduced from the NMR. We use the 2PT analysis to follow the thermodynamics of this transition and find that the free energy barrier is dominated by entropic effects that result from the decreased surface area of the antiparallel form which has a smaller number of low entropy waters in the first monolayer.

Stability of developing film flow down an inclined surface

Film flows on inclined surfaces are often assumed to be of constant thickness, which ensures that the velocity profile is half-Poiseuille. It is shown here that by shallow water theory, only flows in a portion of Reynolds number-Froude number (Re-Fr) plane can asymptotically attain constant film thickness. In another portion on the plane, the constant thickness solution appears as an unstable fixed point, while in other regions the film thickness seems to asymptote to a positive slope. Our simulations of the Navier-Stokes equations confirm the predictions of shallow water theory at higher Froude numbers, but disagree with them at lower Froude numbers. We show that different regimes of film flow show completely different stability behaviour from that predicted earlier. Supercritical decelerating flows are shown to be always unstable, whereas accelerating flows become unstable below a certain Reynolds number for a given Froude number. Subcritical flows on the other hand are shown to be unstable above a certain Reynolds number. In some range of parameters, two solutions for the base flowexist, and the attached profile is found to be more stable. All flows except those with separation become more stable as they proceed downstream. (C) 2012 American Institute of Physics. http://dx.doi.org/10.1063/1.4758299]

Seismic Stability and Liquefaction Analysis of Tailings Dam

Proper analysis for safe design of tailings earthen dam is necessary under static loading and more so under earthquake conditions to reduce damages of important geotechnical structure. This paper presents both static and seismic analyses of a typical section of tailings earthen dam constructed by downstream method and located at a site in eastern part India to store non-radioactive nuclear waste material. The entire analysis is performed using geotechnical softwares FLAC(3D) and TALREN 4. Results are obtained for various possible conditions of the reservoir to investigate the stability under both static and seismic loading condition using 1989 Loma Prieta earthquake acceleration-time history. FLAC(3D) analyses indicate the critical maximum displacement at crest of the proposed tailings dam section is 5.5 cm under the static loading but it increases to about 16.24 cm under seismic loading. The slope stability analyses provide the minimum value of factor of safety for seismic loading as 1.5 as compared to 2.31 for static loading. Amplification of base seismic acceleration is also observed. The liquefaction potential analysis in FLAC(3D) indicates considerable loss of shear strength in the tailings portion of the proposed earthen dam section with significantly high values of pore pressure ratio.

Precision and long-term stability of clumped-isotope analysis of CO2 using a small-sector isotope ratio mass spectrometer

RATIONALE The ratio of the measured abundance of 13C18O bonding CO2 to its stochastic abundance, prescribed by the delta 13C and delta 18O values from a carbonate mineral, is sensitive to its growth temperature. Recently, clumped-isotope thermometry, which uses this ratio, has been adopted as a new tool to elucidate paleotemperatures quantitatively. METHODS Clumped isotopes in CO2 were measured with a small-sector isotope ratio mass spectrometer. CO2 samples digested from several kinds of calcium carbonates by phosphoric acid at 25 degrees C were purified using both cryogenic and gas-chromatographic separations, and their isotopic composition (delta 13C, delta 18O, Delta 47, Delta 48 and Delta 49 values) were then determined using a dual-inlet Delta XP mass spectrometer. RESULTS The internal precisions of the single gas Delta 47 measurements were 0.005 and 0.02 parts per thousand (1 SE) for the optimum and the routine analytical conditions, respectively, which are comparable with those obtained using a MAT 253 mass spectrometer. The long-term variations in the Delta 47 values for the in-house working standard and the heated CO2 gases since 2007 were close to the routine, single gas uncertainty while showing seasonal-like periodicities with a decreasing trend. Unlike the MAT 253, the Delta XP did not show any significant relationship between the Delta 47 and delta 47 values. CONCLUSIONS The Delta XP gave results that were approximately as precise as those of the MAT 253 for clumped-isotope analysis. The temporal stability of the Delta XP seemed to be lower, although an advantage of the Delta XP was that no dependency of delta 47 on Delta 47 was found. Copyright (c) 2012 John Wiley & Sons, Ltd.

Stability of Adult Emergence and Activity/Rest Rhythms in Fruit Flies Drosophila melanogaster under Semi-Natural Condition

Here we report the results of a study aimed at examining stability of adult emergence and activity/rest rhythms under seminatural conditions (henceforth SN), in four large outbred fruit fly Drosophila melanogaster populations, selected for emergence in a narrow window of time under laboratory (henceforth LAB) light/dark (LD) cycles. When assessed under LAB, selected flies display enhanced stability in terms of higher amplitude, synchrony and accuracy in emergence and activity rhythms compared to controls. The present study was conducted to assess whether such differences in stability between selected and control populations, persist under SN where several gradually changing time-cues are present in their strongest form. The study revealed that under SN, emergence waveform of selected flies was modified, with even more enhanced peak and narrower gate-width compared to those observed in the LAB and compared to control populations in SN. Furthermore, flies from selected populations continued to exhibit enhanced synchrony and accuracy in their emergence and activity rhythms under SN compared to controls. Further analysis of zeitgeber effects revealed that enhanced stability in the rhythmicity of selected flies under SN was primarily due to increased sensitivity to light because emergence and activity rhythms of selected flies were as stable as controls under temperature cycles. These results thus suggest that stability of circadian rhythms in fruit flies D. melanogaster, which evolved as a consequence of selection for emergence in a narrow window of time under weak zeitgeber condition of LAB, persists robustly in the face of day-to-day variations in cycling environmental factors of nature.

Structure of SAICAR synthetase from Pyrococcus horikoshii OT3: Insights into thermal stability

The first native crystal structure of Phosphoribosylaminoimidazole-succinocarboxamide synthetase (SAICAR synthetase) from a hyperthermophilic organism Pyrococcus horikoshii OT3 was determined in two space groups H3 (Type-1: Resolution 2.35 angstrom) and in C222(1) (Type-2: Resolution 1.9 angstrom). Both are dimeric but Type-1 structure exhibited hexameric arrangement due to the presence of cadmium ions. A comparison has been made on the sequence and structures of all SAICAR synthetases to better understand the differences between mesophilic, thermophilic and hyperthermophilic SAICAR synthetases. These SAICAR synthetases are reasonably similar in sequence and three-dimensional structure; however, differences were visible only in the subtler details of percentage composition of the sequences, salt bridge interactions and non-polar contact areas. (c) 2012 Elsevier B.V. All rights reserved.

Parabolized stability equation models for predicting large-scale mixing noise of turbulent round jets

Parabolized stability equation (PSE) models are being deve loped to predict the evolu-tion of low-frequency, large-scale wavepacket structures and their radiated sound in high-speed turbulent round jets. Linear PSE wavepacket models were previously shown to be in reasonably good agreement with the amplitude envelope and phase measured using a microphone array placed just outside the jet shear layer. 1,2 Here we show they also in very good agreement with hot-wire measurements at the jet center line in the potential core,for a different set of experiments. 3 When used as a model source for acoustic analogy, the predicted far field noise radiation is in reasonably good agreement with microphone measurements for aft angles where contributions from large -scale structures dominate the acoustic field. Nonlinear PSE is then employed in order to determine the relative impor-tance of the mode interactions on the wavepackets. A series of nonlinear computations with randomized initial conditions are use in order to obtain bounds for the evolution of the modes in the natural turbulent jet flow. It was found that n onlinearity has a very limited impact on the evolution of the wavepackets for St≥0. 3. Finally, the nonlinear mechanism for the generation of a low-frequency mode as the difference-frequency mode 4,5 of two forced frequencies is investigated in the scope of the high Reynolds number jets considered in this paper.

Effect of leachate recirculation and extent of degradation on the stability of bioreactor landfill slopes

The stability of a bioreactor landfill slope is influenced by the quantity and method of leachate recirculation as well as on the degree of decomposition. Other factors include properties variation of waste material and geometrical configurations, i.e., height and slope of landfills. Conventionally, the stability of slopes is evaluated using factor of safety approach, in which the variability in the engineering properties of MSW is not considered directly and stability issues are resolved from past experiences and good engineering judgments. On the other hand, probabilistic approach considers variability in mathematical framework and provides stability in a rational manner that helps in decision making. The objective of the present study is to perform a parametric study on the stability of a bioreactor landfill slope in probabilistic framework considering important influencing factors, such as, variation in MSW properties, amount of leachate recirculation, and age of degradation, in a systematic manner. The results are discussed in the light of existing relevant regulations, design and operation issues.

Live Soap: Stability, Order, and Fluctuations in Apolar Active Smectics

We construct a hydrodynamic theory of noisy, apolar active smectics in bulk suspension or on a substrate. Unlike purely orientationally ordered active fluids, active apolar smectics can be dynamically stable in Stokesian bulk suspensions. Smectic order in these systems is quasilong ranged in dimension d = 2 and long ranged in d = 3. We predict reentrant Kosterlitz-Thouless melting to an active nematic in our simplest model in d = 2, a nonzero second-sound speed parallel to the layers in bulk suspensions, and that there are no giant number fluctuations in either case. We also briefly discuss possible instabilities in these systems. DOI: 10.1103/PhysRevLett.110.118102

Pseudo-Static and Pseudo-Dynamic Stability Analysis of Tailings Dam Under Seismic Conditions

In this paper the seismic slope stability analyses are performed for a typical section of 44 m high water retention type tailings earthen dam located in the eastern part of India, using both the conventional pseudo-static and recent pseudo-dynamic methods. The tailings earthen dam is analyzed for different upstream conditions of reservoir like filled up with compacted and non-compacted dumped waste materials with different water levels of the pond tailings portion. Phreatic surface is generated using seepage analysis in geotechnical software SEEP/W and that same is used in the pseudo-static and pseudo-dynamic analyses to make the approach more realistic. The minimum values of factor of safety using pseudo-static and pseudo-dynamic method are obtained as 1.18 and 1.09 respectively for the chosen seismic zone in India. These values of factor of safety show clearly the demerits of conventional pseudo-static analysis compared to recent pseudo-dynamic analysis, where in addition to the seismic accelerations, duration, frequency of earthquake, body waves traveling during earthquake and amplification effects are considered.