The para-substituent effect and pH-dependence of the organometallic Baeyer–Villiger oxidation of rhenium–carbon bonds

We studied the Baeyer–Villiger (BV) type oxidation of phenylrhenium trioxide (PTO) by H2O2 in the aqueous phase using Quantum Mechanics (density functional theory with the M06 functional) focusing on how the solution pH and the para-substituent affect the Gibbs free energy surfaces. For both PTO and MTO (methylrhenium trioxide) cases, we find that for pH > 1 the BV pathway having OH− as the leaving group is lower in energy than the one involving simultaneous protonation of hydroxide. We also find that during this organometallic BV oxidation, the migrating phenyl is a nucleophile so that substituting functional groups in the para-position of phenyl with increased electron-donating character lowers the migration barrier, just as in organic BV reactions. However, this substituent effect also pushes electron density to Re, impeding HOO− coordination and slowing down the reaction. This is in direct contrast to the organic analog, in which para-substitution has an insignificant influence on 1,2-addition of peracids. Due to the competition of the two opposing effects and the dependence of the resting state on pH and concentration, the reaction rate of the organometallic BV oxidation is surprisingly unaffected by para-substitution

Functionalization of Rhenium Aryl Bonds by O-Atom Transfer

Aryltrioxorhenium (ArReO_3) has been demonstrated to show rapid oxy-functionalization upon reaction with O-atom donors, YO, to selectively generate the corresponding phenols in near quantitative yields. (18)^O-Labeling experiments show that the oxygen in the products is exclusively from YO. DFT studies reveal a 10.7 kcal/mol barrier (Ar = Ph) for oxy-functionalization with H_2O_2 via a Baeyer-Villiger type mechanism involving nudeophilic attack of the aryl group on an electrophilic oxygen of YO coordinated to rhenium

Green Tea Catechin, Epigallocatechin Gallate, Suppresses Signaling by the dsRNA Innate Immune Receptor RIG-I

The Innate immune system constitutes the first line of defense against pathogen infections. The Retinoic acid-inducible gene I (RIG-I) receptor recognizes triphosphorylated ssRNAs and dsRNA to initiate downstream signaling of interferon response. However, unregulated activity of these receptors could lead to autoimmune diseases. We seek to identify small molecules that can specifically regulate RIG-I signaling.Epigallocatechin gallate (EGCG), a polyphenolic catechin present in green tea, was identified in a small molecule screen. It was found to bind RIG-I and inhibits its signaling at low micromolar concentrations in HEK293T cells. Furthermore, EGCG dose-dependently inhibited the ATPase activity of recombinant RIG-I but did not compete with RIG-I interaction with RNA or with ATP. EGCG did not inhibit signaling by Toll-like receptors 3, 4, 9 or constitutive signaling by the adapter protein IPS-1. Structure activity relationship analysis showed that EGCG, its epimer GCG and a digallate-containing compound, theaflavin 3,3' digallate (TFDG) were potent RIG-I inhibitors. EGCG also inhibited IL6 secretion and IFN- β mRNA synthesis in BEAS-2B cells, which harbors intact endogenous RIG-I signaling pathway.EGCG and its derivatives could have potential therapeutic use as a modulator of RIG-I mediated immune responses

Crystal growth and magnetic structure of MnBi2Te4

Millimeter-sized MnBi$_2$Te$_4$ single crystals are grown out of Bi-Te flux and characterized by measuring magnetic and transport properties, scanning tunneling microscope (STM) and spectroscopy (STS). The magnetic structure of MnBi$_2$Te$_4$ below T$_N$ is determined by powder and single crystal neutron diffraction measurements. Below T$_N$=24\,K, Mn$^{2+}$ moments order ferromagnetically in the \textit{ab} plane but antiferromagnetically along the crystallographic \textit{c} axis. The ordered moment is 4.04(13) $\mu_{B}$/Mn at 10\,K and aligned along the crystallographic \textit{c}-axis. The electrical resistivity drops upon cooling across T$_N$ or when going across the metamagnetic transition in increasing fields below T$_N$. A critical scattering effect was observed in the vicinity of T$_N$ in the temperature dependence of thermal conductivity. However, A linear temperature dependence was observed for thermopower in the temperature range 2K-300K without any anomaly around T$_N$. These indicate that the magnetic order in Mn-Te layer has negligible effect on the electronic band structure, which makes possible the realization of proposed topological properties in MnBi$_2$Te$_4$ after fine tuning of the electronic band structure

On the flow-level stability of data networks without congestion control: the case of linear networks and upstream trees

In this paper, flow models of networks without congestion control are considered. Users generate data transfers according to some Poisson processes and transmit corresponding packet at a fixed rate equal to their access rate until the entire document is received at the destination; some erasure codes are used to make the transmission robust to packet losses. We study the stability of the stochastic process representing the number of active flows in two particular cases: linear networks and upstream trees. For the case of linear networks, we notably use fluid limits and an interesting phenomenon of "time scale separation" occurs. Bounds on the stability region of linear networks are given. For the case of upstream trees, underlying monotonic properties are used. Finally, the asymptotic stability of those processes is analyzed when the access rate of the users decreases to 0. An appropriate scaling is introduced and used to prove that the stability region of those networks is asymptotically maximized

Oxidative Aliphatic C-H Fluorination with Fluoride Ion Catalyzed by a Manganese Porphyrin

Despite the growing importance of fluorinated organic compounds in drug development, there are no direct protocols for the fluorination of aliphatic C-H bonds using conveniently handled fluoride salts. We have discovered that a manganese porphyrin complex catalyzes alkyl fluorination by fluoride ion under mild conditions in conjunction with stoichiometric oxidation by iodosylbenzene. Simple alkanes, terpenoids, and even steroids were selectively fluorinated at otherwise inaccessible sites in 50 to 60% yield. Decalin was fluorinated predominantly at the C2 and C3 methylene positions. Bornyl acetate was converted to exo-5-fluoro-bornyl acetate, and 5α-androstan-17-one was fluorinated selectively in the A ring. Mechanistic analysis suggests that the regioselectivity for C-H bond cleavage is directed by an oxomanganese(V) catalytic intermediate followed by F delivery via an unusual manganese(IV) fluoride that has been isolated and structurally characterized

Magneto-Driven Gradients of Diamagnetic Objects for Engineering Complex Tissues

Engineering complex tissues represents an extraordinary challenge and, to date, there have been few strategies developed that can easily recapitulate native‐like cell and biofactor gradients in 3D materials. This is true despite the fact that mimicry of these gradients may be essential for the functionality of engineered graft tissues. Here, a non‐traditional magnetics‐based approach is developed to predictably position naturally diamagnetic objects in 3D hydrogels. Rather than magnetizing the objects within the hydrogel, the magnetic susceptibility of the surrounding hydrogel precursor solution is enhanced. In this way, a range of diamagnetic objects (e.g., polystyrene beads, drug delivery microcapsules, and living cells) are patterned in response to a brief exposure to a magnetic field. Upon photo‐crosslinking the hydrogel precursor, object positioning is maintained, and the magnetic contrast agent diffuses out of the hydrogel, supporting long‐term construct viability. This approach is applied to engineer cartilage constructs with a depth‐dependent cellularity mirroring that of native tissue. These are thought to be the first results showing that magnetically unaltered cells can be magneto‐patterned in hydrogels and cultured to generate heterogeneous tissues. This work provides a foundation for the formation of opposing magnetic‐susceptibility‐based gradients within a single continuous material

Extension of in vivo half-life of biologically active molecules by XTEN protein polymers

AbstractXTEN™ is a class of unstructured hydrophilic, biodegradable protein polymers designed to increase the half-lives of therapeutic peptides and proteins. XTEN polymers and XTEN fusion proteins are typically expressed in Escherichia coli and purified by conventional protein chromatography as monodisperse polypeptides of exact length and sequence. Unstructured XTEN polypeptides have hydrodynamic volumes significantly larger than typical globular proteins of similar mass, thus imparting a bulking effect to the therapeutic payloads attached to them. Since their invention, XTEN polypeptides have been utilized to extend the half-lives of a variety of peptide- and protein-based therapeutics. Multiple clinical and preclinical studies and related drug discovery and development efforts are in progress. This review details the most current understanding of physicochemical properties and biological behavior of XTEN and XTENylated molecules. Additionally, the development path and status of several advanced drug discovery and development efforts are highlighted

Skeletal muscle power and fatigue at the tolerable limit of ramp-incremental exercise in COPD

Muscle fatigue (a reduced power for a given activation) is common following exercise in COPD. Whether muscle fatigue, and reduced maximal voluntary locomotor power, are sufficient to limit whole-body exercise in COPD is unknown. We hypothesized in COPD: 1) exercise is terminated with a locomotor muscle power reserve; 2) reduction in maximal locomotor power is related to ventilatory limitation; and 3) muscle fatigue at intolerance is less than age-matched controls. We used a rapid switch from hyperbolic to isokinetic cycling to measure the decline in peak isokinetic power at the limit of incremental exercise ('performance fatigue') in 13 COPD (FEV1 49±17 %pred) and 12 controls. By establishing the baseline relationship between muscle activity and isokinetic power, we apportioned performance fatigue into the reduction in muscle activation and muscle fatigue. Peak isokinetic power at intolerance was ~130% of peak incremental power in controls (274±73 vs 212±84W, p<0.05), but ~260% in COPD (187±141 vs 72±34W, p<0.05) - greater than controls (p<0.05). Muscle fatigue as a fraction of baseline peak isokinetic power was not different in COPD vs controls (0.11±0.20 vs 0.19±0.11). Baseline to intolerance, the median frequency of maximal isokinetic muscle activity was unchanged in COPD but reduced in controls (+4.3±11.6 vs -5.5±7.6%, p<0.05). Performance fatigue as a fraction of peak incremental power was greater in COPD vs controls and related to resting (FEV1/FVC) and peak exercise (V̇E/MVV) pulmonary function (r2=0.47, r2=0.55, p<0.05). COPD patients are more fatigable than controls, but this fatigue is insufficient to constrain locomotor power and define exercise intolerance