Biocompatible hydroxy double salt tablet formulations

Generally, commercial extended release tablets are core-based, which can cause problems for certain patients if they split them prior to ingestion. There is a need to develop non-core-based extended release tablets. We have previously reported the synthesis of two new biocompatible hydroxy double salts (HDSs), [Mg2Zn3(OH)8]Cl2⋅3.4H2O (MgZn–Cl) and [Fe2.4Zn2.6(OH)8]Cl2⋅2H2O (FeZn–Cl) (J. Mater. Chem. B 2016, 4, 5789), and found them to be good candidates for the extended release of diclofenac (Dic), ibuprofen (SI) and valproate (Val) (Appl. Clay. Sci. 2022, 221, 106456). Here we build on these previous results and report scale-up synthesis of MgZn–Cl and FeZn–Cl loaded with Dic, SI, and Val. The scaled-up products were blended with excipients and formulated into non-core based tablets. The post-compression parameters of the HDS-based tablets were assessed against the pharmacopeia requirements (friability, weight, and dose uniformity) and all passed the tests. Drug release studies were carried out using the paddle method (USPII) in conditions representative of the gastrointestinal tract. The HDS tablets were found to meet the pharmacopeia requirements for modified release dosage forms and showed similar release profiles to current commercial formulations. It is thus possible to develop modified release non-core based tablets using HDSs. These have additional benefits over standard commercial tablets, because the presence of the essential elements Zn, Fe and/or Mg in the layers can compensate for deficiencies induced over long-term treatment, and enhance therapeutic efficacy in some cases. Furthermore, the buffering effect of the HDS layers has the potential to prevent the gastric irritation often associated with the use of non-steroidal anti-inflammatory drugs

Forest structure, stand composition, and climate-growth response in montane forests of Jiuzhaigou National Nature Reserve, China.

Montane forests of western China provide an opportunity to establish baseline studies for climate change. The region is being impacted by climate change, air pollution, and significant human impacts from tourism. We analyzed forest stand structure and climate-growth relationships from Jiuzhaigou National Nature Reserve in northwestern Sichuan province, along the eastern edge of the Tibetan plateau. We conducted a survey to characterize forest stand diversity and structure in plots occurring between 2050 and 3350 m in elevation. We also evaluated seedling and sapling recruitment and tree-ring data from four conifer species to assess: 1) whether the forest appears in transition toward increased hardwood composition; 2) if conifers appear stressed by recent climate change relative to hardwoods; and 3) how growth of four dominant species responds to recent climate. Our study is complicated by clear evidence of 20(th) century timber extraction. Focusing on regions lacking evidence of logging, we found a diverse suite of conifers (Pinus, Abies, Juniperus, Picea, and Larix) strongly dominate the forest overstory. We found population size structures for most conifer tree species to be consistent with self-replacement and not providing evidence of shifting composition toward hardwoods. Climate-growth analyses indicate increased growth with cool temperatures in summer and fall. Warmer temperatures during the growing season could negatively impact conifer growth, indicating possible seasonal climate water deficit as a constraint on growth. In contrast, however, we found little relationship to seasonal precipitation. Projected warming does not yet have a discernible signal on trends in tree growth rates, but slower growth with warmer growing season climates suggests reduced potential future forest growth

Three-dimensional FEM derived elastic Green's functions for the coseismic deformation of the 2005 M_w 8.7 Nias-Simeulue, Sumatra earthquake

Using finite element models (FEMs), we examine the sensitivity of surface displacements to the location of fault slip, topography, and three-dimensional variations in elastic moduli in the context of a 2-D infinite thrust fault. We then evaluate the impact of these factors and fault geometry on surface displacements and estimates of the distribution of coseismic slip associated with the 2005 M_w 8.7 Nias-Simeulue, Sumatra earthquake. Topographic effects can be significant near the trench, where bathymetric gradients are highest and the fault is closest to the free surface. Variations in Young's modulus can significantly alter predicted deformation. Surface displacements are relatively insensitive to perturbations in Poisson's ratio for shear sources, but may play a stronger role when the source has a dilatational component. If we generate synthetic displacements using a heterogeneous elastic model and then use an elastic half-space or layered earth model to estimate the slip distribution and fault geometry, we find systematic residuals of surface displacements and different slip patterns compared to the input fault slip model. The coseismic slip distributions of the 2005 earthquake derived from the same fault geometry and different material models show that the rupture areas are narrower in all tested heterogeneous elastic models compared to that obtained using half-space models. This difference can be understood by the tendency to infer additional sources in elastic half-space models to account for effects that are intrinsically due to the presence of rheological gradients. Although the fit to surface observations in our preferred 3-D FEM model is similar to that from a simple half-space model, the resulting slip distribution may be a more accurate reflection the true fault slip behavior

Transcription-translation coupling: direct interactions of RNA polymerase with ribosomes and ribosomal subunits.

In prokaryotes, RNA polymerase and ribosomes can bind concurrently to the same RNA transcript, leading to the functional coupling of transcription and translation. The interactions between RNA polymerase and ribosomes are crucial for the coordination of transcription with translation. Here, we report that RNA polymerase directly binds ribosomes and isolated large and small ribosomal subunits. RNA polymerase and ribosomes form a one-to-one complex with a micromolar dissociation constant. The formation of the complex is modulated by the conformational and functional states of RNA polymerase and the ribosome. The binding interface on the large ribosomal subunit is buried by the small subunit during protein synthesis, whereas that on the small subunit remains solvent-accessible. The RNA polymerase binding site on the ribosome includes that of the isolated small ribosomal subunit. This direct interaction between RNA polymerase and ribosomes may contribute to the coupling of transcription to translation

QCD Approach to B->D \pi Decays and CP Violation

The branching ratios and CP violations of the $B\to D\pi$ decays, including both the color-allowed and the color-suppressed modes, are investigated in detail within QCD framework by considering all diagrams which lead to three effective currents of two quarks. An intrinsic mass scale as a dynamical gluon mass is introduced to treat the infrared divergence caused by the soft collinear approximation in the endpoint regions, and the Cutkosky rule is adopted to deal with a physical-region singularity of the on mass-shell quark propagators. When the dynamical gluon mass $\mu_g$ is regarded as a universal scale, it is extracted to be around $\mu_g = 440$ MeV from one of the well-measured $B\to D\pi$ decay modes. The resulting predictions for all branching ratios are in agreement with the current experimental measurements. As these decays have no penguin contributions, there are no direct $CP$ asymmetries. Due to interference between the Cabibbo-suppressed and the Cabibbo-favored amplitudes, mixing-induced CP violations are predicted in the $B\to D^{\pm}\pi^{\mp}$ decays to be consistent with the experimental data at 1-$\sigma$ level. More precise measurements will be helpful to extract weak angle $2\beta+\gamma$.Comment: 21pages,5 figures,3 tables, typos corrected and numerical result for one of decay channels is improve

Flame Enhancement and Quenching in Fluid Flows

We perform direct numerical simulations (DNS) of an advected scalar field which diffuses and reacts according to a nonlinear reaction law. The objective is to study how the bulk burning rate of the reaction is affected by an imposed flow. In particular, we are interested in comparing the numerical results with recently predicted analytical upper and lower bounds. We focus on reaction enhancement and quenching phenomena for two classes of imposed model flows with different geometries: periodic shear flow and cellular flow. We are primarily interested in the fast advection regime. We find that the bulk burning rate v in a shear flow satisfies v ~ a*U+b where U is the typical flow velocity and a is a constant depending on the relationship between the oscillation length scale of the flow and laminar front thickness. For cellular flow, we obtain v ~ U^{1/4}. We also study flame extinction (quenching) for an ignition-type reaction law and compactly supported initial data for the scalar field. We find that in a shear flow the flame of the size W can be typically quenched by a flow with amplitude U ~ alpha*W. The constant alpha depends on the geometry of the flow and tends to infinity if the flow profile has a plateau larger than a critical size. In a cellular flow, we find that the advection strength required for quenching is U ~ W^4 if the cell size is smaller than a critical value.Comment: 14 pages, 20 figures, revtex4, submitted to Combustion Theory and Modellin

DNA Cleaving "Tandem-Array" Metallopeptides Activated With KHSO5: Towards the Development of Multi-Metallated Bioactive Conjugates and Compounds

Amino terminal peptides of the general form Gly-Gly-His have been used to introduce single sites of metal binding and redox activity into a wide range of biomolecules to create bioactive compounds and conjugates capable of substrate oxidation. We report here that Gly-Gly-His-like peptides linked in a tandem fashion can also be generated leading to multi-metal binding arrays. While metal binding by the native Gly-Gly-His motif (typically to Cu(2+), Ni(2+), or Co(2+)) requires a terminal peptide amine ligand, previous work has demonstrated that an ornithine (Orn) residue can be substituted for the terminal Gly residue to allow solid-phase peptide synthesis to continue via the side chain N-δ. This strategy thus frees the Orn residue N-α for metal binding and permits placement of a Gly-Gly-His-like metal binding domain at any location within a linear, synthetic peptide chain. As we show here, this strategy also permits the assembly of tandem arrays of metal binding units in linear peptides of the form: NH2-Gly-Gly-His-[(δ)-Orn-Gly-His]n-(δ)-Orn-Gly-His-CONH2 (where n = 0, 1, and 2). Metal binding titrations of these tandem arrays monitored by UV-vis and ESI-MS indicated that they bind Cu(2+), Ni(2+), or Co(2+) at each available metal binding site. Further, it was found that these systems retained their ability to modify DNA oxidatively and to an extent greater than their parent M(II)•Gly-Gly-His. These findings suggest that the tandem array metallopeptides described here may function with increased efficiency as "next generation" appendages in the design of bioactive compounds and conjugates

The Radial Orbit Instability in Collisionless N-Body Simulations

Using a suite of self-gravitating, collisionless N-body models, we systematically explore a parameter space relevant to the onset and behavior of the radial orbit instability (ROI), whose strength is measured by the systemic axis ratios of the models. We show that a combination of two initial conditions, namely the velocity anisotropy and the virial ratio, determines whether a system will undergo ROI and exactly how triaxial the system will become. A third initial condition, the radial shape of the density profile, plays a smaller, but noticeable role. Regarding the dynamical development of the ROI, the instability a) begins after systems collapse to their most compact configuration and b) evolves fastest when a majority of the particles have radially anisotropic orbits while there is a lack of centrally-concentrated isotropic orbits. We argue that this is further evidence that self-reinforcing torques are the key to the onset of the ROI. Our findings support the idea that a separate orbit instability plays a role in halting the ROI.Comment: accepted for publication in ApJ. 9 figures in emulateapj styl

Self-consistent theory of reversible ligand binding to a spherical cell

In this article, we study the kinetics of reversible ligand binding to receptors on a spherical cell surface using a self-consistent stochastic theory. Binding, dissociation, diffusion and rebinding of ligands are incorporated into the theory in a systematic manner. We derive explicitly the time evolution of the ligand-bound receptor fraction p(t) in various regimes . Contrary to the commonly accepted view, we find that the well-known Berg-Purcell scaling for the association rate is modified as a function of time. Specifically, the effective on-rate changes non-monotonically as a function of time and equals the intrinsic rate at very early as well as late times, while being approximately equal to the Berg-Purcell value at intermediate times. The effective dissociation rate, as it appears in the binding curve or measured in a dissociation experiment, is strongly modified by rebinding events and assumes the Berg-Purcell value except at very late times, where the decay is algebraic and not exponential. In equilibrium, the ligand concentration everywhere in the solution is the same and equals its spatial mean, thus ensuring that there is no depletion in the vicinity of the cell. Implications of our results for binding experiments and numerical simulations of ligand-receptor systems are also discussed.Comment: 23 pages with 4 figure