[1] The stable oxygen isotope ratio (δ 18 O) in precipitation is an integrated tracer of atmospheric processes worldwide. Since the 1990s, an intensive effort has been dedicated to studying precipitation isotopic composition at more than 20 stations in the Tibetan Plateau (TP) located at the convergence of air masses between the westerlies and Indian monsoon. In this paper, we establish a database of precipitation δ

Growth of lithium metal dendrites would trigger disastrous battery failure and hence hinder the practicality of Li-metal anode. The concept of this work lies in utilizing the highly ordered angstrom-scale pores in metal-organic framework (MOF) to regulate the Li-ion transport in pristine liquid electrolyte. By using the MOF-modified electrolyte, the selective Li-ion transport and the consequent homogeneous Li electrodeposition are realized, thus enabling a high-power dendrite-free Li-metal anode.

arising from inhomogeneous Li electrodeposition is a typical problem in lithium secondary batteries, which will give rise to a series of unfavorable effects, including aggravated adverse reactions, evolution of dead Li from dendrites, increased polarization and large volume change. [4,5] What's worse, thorns of Li dendrites can pierce the separators and contact with cathode, thus leading to an internal short circuit and safety hazards. [6] The polysulfides shuttle is a common phenomenon in Li-S batteries. [7] To be specific, the soluble intermediate polysulfide species generated from sulfur cathode can pass through the separator to lithium anode and react with the Li-metal to form insoluble Li 2 S and Li 2 S 2 on the surface of anode, resulting in surface passivation of Li metal anode. [8] Apart from the deterioration of Li metal anode, the polysulfides shuttle also leads to the irreversible loss of active materials due to the consumption of polysulfides and a high interfacial resistance between anode and electrolyte because of the formed unstable solid-electrolyte interphase. [9] Many efforts have been devoted to address these issues. [2,10] One of the widely applied approaches to restrain polysulfides shuttle is confining sulfur in the porous hosts so that the generated intermediate polysulfides can be immobilized by physical adsorption and/or chemical binding. [11] Despite improved cycling performance of Li-S batteries can be achieved to some degree by the encapsulation approaches, it is hardly to completely prevent the dissolution of polysulfides especially in the case of high sulfur loading due to the limited adsorption capacity and binding sites. [12] Another efficient way to prevent the reaction between polysulfides and Li metal is constructing a protective layer on the surface of Li metal, which also can effectively inhibit the growth of Li dendrites. [13] However, an excess solid-electrolyte interphase (SEI) layer on the surface of Li metal will ineluctably lead to a high interfacial resistance between the anode and electrolyte, causing poor rate performance. In these respects, it seems that functional separators are more reliable strategies for achieving high performance Li-S batteries, on account of the fact that separator is an essential component in battery systems. [14] The separator in batteries not only can act as an electronic insulator to prevent Lithium-sulfur (Li-S) batteries are considered a promising candidate for next-generation energy storage devices due to their ultrahigh theoretical energy density (≈2600 Wh kg −1 ). However, the uncontrolled growth of Li dendrites and the adverse effect of polysulfide shuttling seriously hinder their practical applications. Herein, a metal organic framework based membrane (MOF@PVDF-HFP) with good flexibility is designed and fabricated by a facial vacuum filtration strategy. The highly uniform pore sizes of MOF particles facilitate homogenous Li-ion fluxes, fundamentally inhibiting the growth of Li dendrites and resulting in stable Li plating/stripin...

Midazolam (MDZ) oxidation by recombinant CYP3A4 purified from Escherichia coli and 30 mutants generated at 15 different substrate recognition site positions has been studied to determine the role of individual residues in regioselectivity and to investigate the possible existence of multiple binding sites. Initial results showed that oxidation of MDZ by CYP3A4 causes time-and concentration-dependent enzyme inactivation with K I and k inact values of 5.8 M and 0.15 min Ϫ1 , respectively. The different time courses of MDZ hydroxylation by mutants that predominantly formed 1Ј-OH MDZ as opposed to 4-OH MDZ provided strong evidence that the 1Ј-OH MDZ pathway leads to CYP3A4 inactivation. Correlational analysis of 1Ј-OH formation versus 4-OH formation by the mutants supports the inference that the two metabolites result from the binding of MDZ at two separate sites. Thus, substitution of residues Phe-108, Ile-120, Ile-301, Phe-304, and Thr-309 with a larger amino acid caused an increase in the ratio of 1Ј-OH/4-OH MDZ formation, whereas substitution of residues Ser-119, Ile-120, Leu-210, Phe-304, Ala-305, Tyr-307, and Thr-309 with a smaller amino acid decreased this ratio. Kinetic analyses of nine key mutants revealed that the alteration in regioselectivity is caused by a change in kinetic parameters (V max and K M ) for the formation of both metabolites in most cases. The study revealed the role of various active-site residues in the regioselectivity of MDZ oxidation, identified the metabolic pathway that leads to enzyme inactivation, and provided an indication that the two proposed MDZ binding sites in CYP3A4 may be partially overlapping.Midazolam (MDZ) is one of the most commonly used drugs for sedation in emergency rooms (see Nordt and Clark, 1997 and references therein). It is also used as a safe and effective drug for the treatment of generalized seizure, status epilepticus, and acute agitation. The biotransformation of MDZ is mediated by at least three different CYP3A enzymes: 3A4, 3A5, and 3A7 (Gorski et al., 1994;Kuehl et al., 2001). Although CYP3A7 is predominantly expressed in fetal tissues, CYP3A4 and CYP3A5 represent the majority of the total hepatic and intestinal P450 content in adults (Guengerich, 1995). These enzymes are of particular clinical significance because of their ability to metabolize a large number of therapeutic agents of very diverse structures (Guengerich, 1995). Moreover, intestinal CYP3A accounts for significant first-pass metabolism of ingested drugs. Because of the large number of therapeutic agents that alter CYP3A expression or activity, a significant potential for drug-drug interactions exists (Fuhr et al., 1996). In particular, CYP3A4 is known to exhibit both homotropic and heterotropic cooperativity, which could influence drug metabolism and excretion or bioactivation (Schwab et al

Asia's high plateaus are sensitive to climate change and have been experiencing rapid warming over the past few decades. We found 99 new lakes and extensive lake expansion on the Tibetan Plateau during the last four decades, 1970–2013, due to increased precipitation and cryospheric contributions to its water balance. This contrasts with disappearing lakes and drastic shrinkage of lake areas on the adjacent Mongolian Plateau: 208 lakes disappeared, and 75% of the remaining lakes have shrunk. We detected a statistically significant coincidental timing of lake area changes in both plateaus, associated with the climate regime shift that occurred during 1997/1998. This distinct change in 1997/1998 is thought to be driven by large‐scale atmospheric circulation changes in response to climate warming. Our findings reveal that these two adjacent plateaus have been changing in opposite directions in response to climate change. These findings shed light on the complex role of the regional climate and water cycles and provide useful information for ecological and water resource planning in these fragile landscapes.

The structural basis of species differences in cytochrome P450 2B-mediated hydroxylation of 2,2',3,3',6,6'-hexachlorobiphenyl (236HCB) was evaluated by using 14 site-directed mutants of cytochrome P450 2B1 and three point mutants of 2B11 expressed in Escherichia coli. To facilitate metabolite identification, seven possible products, including three hydroxylated and four dihydroxylated hexachlorobiphenyls, were synthesized by direct functionalization of precursors and Ullmann and crossed Ullmann reactions. HPLC and GC/MS analysis and comparison with authentic standards revealed that 2B1, 2B11, and all their mutants produced 4, 5-dihydroxy-236HCB and 5-hydroxy-236HCB, while 2B11 L363V and 2B1 I114V mutants also catalyzed hydroxylation at the 4-position. The amount of products formed by 2B1 mutants I114V, F206L, L209A, T302S, V363A, V363L, V367A, I477A, I477L, G478S, I480A, and I480L was smaller than that of the wild type. I477V exhibited unaltered 236HCB metabolism, and I480V produced twice as much dihydroxy product as the wild type. For 2B11, substitution of Val-114 or Asp-290 with Ile decreased the product yields. Replacement of Leu-363 with Val dramatically altered the profile of 236HCB metabolites. In addition to an increase in the overall level of hydroxylation, the mutant mainly catalyzed hydroxylation at the 4-position. Incubation of P450 2B1 with 5-hydroxy-236HCB produced 4,5-dihydroxy-236HCB, which indicates that 4,5-dihydroxy-236HCB may be formed by a direct hydroxylation of 5-hydroxy-236HCB. The findings from this study demonstrate the importance of residues 114, 206, 209, 302, 363, 367, 477, 478, and 480 in 2B1 and 114, 290, and 363 in 2B11 for 236HCB metabolism.

Tibetans are well adapted to the hypoxic environments at high altitude, yet the molecular mechanism of this adaptation remains elusive. We reported comprehensive genetic and functional analyses of EPAS1, a gene encoding hypoxia inducible factor 2α (HIF-2α) with the strongest signal of selection in previous genome-wide scans of Tibetans. We showed that the Tibetan-enriched EPAS1 variants down-regulate expression in human umbilical endothelial cells and placentas. Heterozygous EPAS1 knockout mice display blunted physiological responses to chronic hypoxia, mirroring the situation in Tibetans. Furthermore, we found that the Tibetan version of EPAS1 is not only associated with the relatively low hemoglobin level as a polycythemia protectant, but also is associated with a low pulmonary vasoconstriction response in Tibetans. We propose that the down-regulation of EPAS1 contributes to the molecular basis of Tibetans’ adaption to high-altitude hypoxia.

Anionic redox reveals to be a promising strategy to effectively improve the energy density of layered metal oxide cathodes for sodium-ion batteries. However, lattice oxygen loss and derived structural distortion severely hinder its practical application. Herein, combined with anionic and cationic redox activities, we developed a layered structure P2-type Na0.66Li0.22Ti0.15Mn0.63O2 cathode, delivering an initial discharge capacity of 228 mAh g–1 and highly reversible structural evolution as well as improved cyclability. On the basis of comprehensive comparison with Ti-free P2-Na0.66Li0.22Mn0.78O2, both oxygen-related negative behaviors (irreversible O2 evolution and superoxo-related parasitic production) and Mn-related Jahn–Teller distortion have been effectively restrained by simultaneously suppressing both oxygen loss and the participation of Mn4+/Mn3+ redox. Not limited to discovering excess capacity derived from anionic oxidation up charging, our findings not only highlight an effective strategy to stabilize anionic and cationic redox activities but also pave the way for the further improvement of Na-deficient layered materials for high-energy sodium-ion batteries.