The development of enantioselective alkyl–alkyl cross‐couplings with coinstantaneous formation of a stereogenic center without the use of sensitive organometallic species is attractive yet ...challenging. Herein, we report the intermolecular regio‐ and enantioselective formal hydrofunctionalizations of acrylamides, forging a stereogenic center α‐position to the newly formed Csp3–Csp3 bond for the first time. The use of a newly developed chiral ligand enables the electronically‐reversed formal hydrofunctionalizations, including hydroalkylation, hydrobenzylation, and hydropropargylation, offering an efficient way to access diverse enantioenriched amides with a tertiary α‐stereogenic carbon center which is facile to racemize. This operationally simple protocol allows for the anti‐Markovnikov enantioselective hydroalkylation, and unprecedented hydrobenzylation, hydropropargylation under mild conditions with excellent functional group compatibility, delivering a wide range of amides with excellent levels of enantioselectivity.
Alkyl–alkyl bond‐forming with coinstantaneous formation of a stereogenic center is attractive yet challenging. Herein, the intermolecular, regio‐ and enantioselective formal hydrofunctionalization of alkenes to forge a stereogenic center in the α‐position to the newly formed alkyl–alkyl bond is reported for the first time, providing a facile access to a wide range of α‐branched chiral amides with broad functional group tolerance.
Quantum resources construct new avenues to explore the cosmos. Considering bipartite-qubit detectors subjected to scalar fields in an expanding spacetime, quantum resources (including quantum ...coherence, quantum discord, Bell-nonlocality, and nonlocal advantage of quantum coherence) of the system are characterized. The influences of various cosmic parameters on these quantum resources are investigated. Besides, we use the filtering operation to propose a strategy that can be used to control these quantum resources. The results reveal that quantum coherence and quantum discord can not disappear at different expansion rapidity, expansion volumes, and particle masses of scalar field. Conversely, one can not capture Bell-nonlocality and nonlocal advantage of quantum coherence at higher expansion rapidity, larger expansion volume, and smaller particle mass. The dissipation of quantum resources can be resisted via the filtering operation. One can use the filtering operation to remarkably strengthen these quantum resources of the system.
Bacillus subtilis relies on biofilms for survival in harsh environments. Extracellular polymeric substance (EPS) is a crucial component of biofilms, yet the dynamics of EPS production in single cells ...remain elusive. To unveil the modulation of EPS synthesis, we built a minimal network model comprising the SinI‐SinR‐SlrR module, Spo0A, and EPS. Stochastic simulations revealed that antagonistic interplay between SinI and SinR enables EPS production in bursts. SlrR widens these bursts and increases their frequency by stabilizing SinR‐SlrR complexes and depleting free SinR. DNA replication and chromosomal positioning of key genes dictate pulsatile changes in the slrR:sinR gene dosage ratio (gr) and Spo0A‐P levels, each promoting EPS production in distinct phases of the cell cycle. As the cell cycle lengthens with nutrient stress, the duty cycle of gr pulsing decreases, whereas the amplitude of Spo0A‐P pulses elevates. This coordinated response facilitates keeping a constant proportion of EPS‐secreting cells within colonies across diverse nutrient conditions. Our results suggest that bacteria may ‘encode’ eps expression through strategic chromosomal organization. This work illuminates how stochastic protein interactions, gene copy number imbalance, and cell‐cycle dynamics orchestrate EPS synthesis, offering a deeper understanding of biofilm formation.
Background and Aims EUS-guided biliary drainage (EUS-BD) has emerged as an alternative procedure after failed ERCP. However, limited data on the efficacy and safety of EUS-BD are available. ...Therefore, a systematic review was conducted to evaluate the efficacy and safety of EUS-BD and to evaluate transduodenal (TD) and transgastric (TG) approaches. Methods PubMed and EMBASE were searched to identify relevant studies published in the English language for inclusion in this systematic review and meta-analysis. Data from eligible studies were combined to calculate the cumulative technical success rate (TSR), functional success rate (FSR), and adverse-event rate of EUS-BD and the pooled odds ratio of TSR, FSR, and adverse-event rate of the TD approach when compared with the TG approach. Results Forty-two studies with 1192 patients were included in this study, and the cumulative TSR, FSR, and adverse-event rate were 94.71%, 91.66%, and 23.32%, respectively. The common adverse events associated with EUS-BD were bleeding (4.03%), bile leakage (4.03%), pneumoperitoneum (3.02%), stent migration (2.68%), cholangitis (2.43%), abdominal pain (1.51%), and peritonitis (1.26%). Ten studies were included in the meta-analysis for comparative evaluation of TD and TG approaches for EUS-BD. Compared with the TG approach, the pooled odds ratio of the TSR, FSR, and adverse-event rate of the TD approach were 1.36 (95% CI, .66-2.81; P > .05), .84 (95% CI, .50-1.42; P > .05), and .61 (95% CI, .36-1.03; P > .05), respectively, which indicated no significant difference in the TSR, FSR, and adverse-event rate between the 2 groups. Conclusions Although it is associated with significant morbidity, EUS-BD is an effective alternative procedure for relieving biliary obstruction. There was no significant difference between the TD and TG approaches for EUS-BD.
Mutations or aberrant upregulation of EZH2 occur frequently in human cancers, yet clinical benefits of EZH2 inhibitor (EZH2i) remain unsatisfactory and limited to certain hematological malignancies. ...We profile global posttranslational histone modification changes across a large panel of cancer cell lines with various sensitivities to EZH2i. We report here oncogenic transcriptional reprogramming mediated by MLL1’s interaction with the p300/CBP complex, which directs H3K27me loss to reciprocal H3K27ac gain and restricts EZH2i response. Concurrent inhibition of H3K27me and H3K27ac results in transcriptional repression and MAPK pathway dependency in cancer subsets. In preclinical models encompassing a broad spectrum of EZH2-aberrant solid tumors, a combination of EZH2 and BRD4 inhibitors, or a triple-combination including MAPK inhibition display robust efficacy with very tolerable toxicity. Our results suggest an attractive precision treatment strategy for EZH2-aberrant tumors on the basis of tumor-intrinsic MLL1 expression and concurrent inhibition of epigenetic crosstalk and feedback MAPK activation.
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•Epigenetic signature profiling in ∼100 tumor lines with different EZH2i sensitivities•MLL1-p300/CBP-mediated H3K27ac gain and oncogenic reprogramming limit EZH2i response•H3K27ac co-inhibition improves EZH2i efficacy but activates MAPK in some cancers•MLL1 level and inhibiting feedback MAPK activation expand EZH2i utility and precision
Epigenetic crosstalk targeting together with MLL1-based stratification and inhibiting feedback MAPK activation expand EZH2 inhibitors’ therapeutic utility and efficacy in patient-derived solid tumor models.
The electrochemical nitrogen reduction reaction (NRR) offers a sustainable solution towards ammonia production but suffers poor reaction performance owing to preferential catalyst–H formation and the ...consequential hydrogen evolution reaction (HER). Now, the Pt/Au electrocatalyst d‐band structure is electronically modified using zeolitic imidazole framework (ZIF) to achieve a Faradaic efficiency (FE) of >44 % with high ammonia yield rate of >161 μg mgcat−1 h−1 under ambient conditions. The strategy lowers electrocatalyst d‐band position to weaken H adsorption and concurrently creates electron‐deficient sites to kinetically drive NRR by promoting catalyst–N2 interaction. The ZIF coating on the electrocatalyst doubles as a hydrophobic layer to suppress HER, further improving FE by >44‐fold compared to without ZIF (ca. 1 %). The Pt/Au‐NZIF interaction is key to enable strong N2 adsorption over H atom.
A kinetically driven ambient nitrogen reduction reaction has a Faradaic efficiency of over 44 % and an ammonia yield rate of over 161 μg mgcat−1 h−1. It employs a zeolitic imidazole framework to induce electron‐deficient sites on the catalyst and a lower d‐band to weaken catalyst–H interactions whilst promoting the catalyst–N2 interaction.
Porphyry copper deposits account for more than 80% of the world’s total Cu resources. However, the formation mechanism and controlling factors of porphyry copper deposits remain obscure. Previous ...studies have revealed that porphyry copper deposits are usually associated with oxidized, calc-alkalic, adakitic shallow intrusive rocks. Here we show that hematite–magnetite intergrowths are commonly found in porphyry copper deposits, suggesting high and fluctuating oxygen fugacity (fO2). Oxidation promotes the destruction of sulfides in the magma source, and thereby increases initial chalcophile element concentrations. Sulfide remains undersaturated during the evolution of oxidized sulfur-enriched magmas where sulfate is the dominant sulfur species, leading to high chalcophile element concentrations in evolved magmas. The final porphyry copper mineralization is controlled by sulfate reduction, which starts with magnetite crystallization, accompanied by decreasing pH and correspondingly increasing fO2. Hematite forms once sulfate reduction lowers the pH sufficiently and the fO2 reaches the hematite–magnetite oxygen fugacity buffer, which in turn increases the pH for a given fO2. The oxidation of ferrous iron during the crystallization of magnetite and hematite is the causal process of sulfate reduction and consequent mineralization. Therefore, the initial pH and fO2 ranges of porphyries favorable for porphyry copper mineralization are defined by the hematite–magnetite oxygen fugacity buffer and SO42−–HS−–S3− reaction lines. Adakitic rocks have higher initial contents of copper, sulfur and iron than normal arc rocks, and thus are the best candidates for porphyry copper deposits. These provide a plausible explanation for the formation of copper porphyry deposits. The hematite–magnetite intergrowth marks the upper limits of fO2 favorable for the mineralization, and thus may be a powerful tool for future prospecting of large porphyry copper deposits.
Sulfur is an attractive cathode material in energy storage devices since its high theoretical capacity of 1672 mAh g−1. However, practical application of lithium sulfur (Li–S) batteries can be ...achieved only when the major barriers, including the insulating nature of element sulfur and shuttling effect of polysulfides (Li2Sx, x = 3–8), are tackled. Here, nitrogen, sulfur-codoped (N,S-codoped) sponge-like graphene, which presents a high reversible capacity, is used as electroactive interlayer for Li–S batteries to address these issues. An impressive high capacity of 2193.2 mAh g−1 can be obtained for the sulfur cathodes with such an interlayer at the rate of 0.2C, and it can be stably maintained at 829.4 mAh g−1 at the rate of 6C, for which the contribution from the electroactive interlayer is ca. 30.0%. High energy density of 418.5 Wh Kg−1 still can be released at the power density of 4.55 kW kg−1 (6C) based on the total mass of the sulfur cathode and interlayer for the assembled Li–S batteries.
N,S-codoped sponge-like graphene, which presents a high reversible capacity to offer extra capacity, and contains rich doping heteroatoms to restrict the dissolution of polysulfide, is used as electroactive interlayer for Li–S batteries. By this method, the sulfur cathode shows an ultrahigh discharge capacity and superior high rate performance. Display omitted
•Electroactive N,S-codoped graphene as interlayer for Li–S batteries is reported.•N,S-codoped graphene presents a high discharge capacity and good conductivity.•High rate capability and discharge capacity is obtained using such interlayer.•High energy density of 1106.5 Wh Kg−1 is obtained based on cathode and interlayer.•Energy density of 418.5 Wh Kg−1 can be released at power density of 4.55 kW kg−1.
Of the seven P2X receptor subtypes, P2X4 receptor (P2X4R) is widely distributed in the central nervous system, including in neurons, astrocytes, and microglia. Accumulating evidence supports roles ...for P2X4R in the central nervous system, including regulating cell excitability, synaptic transmission, and neuropathic pain. However, little information is available about the distribution and function of P2X4R in the peripheral nervous system. In this study, we find that P2X4R is mainly localized in the lysosomes of Schwann cells in the peripheral nervous system. In cultured Schwann cells, TNF‐a not only enhances the synthesis of P2X4R protein but also promotes P2X4R trafficking to the surface of Schwann cells. TNF‐a‐induced BDNF secretion in Schwann cells is P2X4R dependent. in vivo experiments reveal that expression of P2X4R in Schwann cells of injured nerves is strikingly upregulated following nerve crush injury. Moreover, overexpression of P2X4R in Schwann cells by genetic manipulation promotes motor and sensory functional recovery and accelerates nerve remyelination via BDNF release following nerve injury. Our results suggest that enhancement of P2X4R expression in Schwann cells after nerve injury may be an effective approach to facilitate the regrowth and remyelination of injured nerves.
Main Points
P2X4R is mainly localized in the lysosomes of Schwann cells and the expression of P2X4R in Schwann cells is strikingly upregulated following nerve crush injury.
Overexpression of P2X4R in Schwann cells by genetic manipulation promotes motor and sensory functional recovery as well as accelerates nerve remyelination via BDNF release following nerve injury.
Rare Earth Elements (REE) are essential to modern society but the origins of many large REE deposits remain unclear. The U-Th-Pb ages, chemical compositions and C, O and Mg isotopic compositions of ...Bayan Obo, the world's largest REE deposit, indicate a protracted mineralisation history with unusual chemical and isotopic features. Coexisting calcite and dolomite are in O isotope disequilibrium; some calcitic carbonatite samples show highly varied δ26 Mg which increases with increasing Si and Mg; and ankerite crystals show decreases in Fe and REE from rim to centre, with highly varied REE patterns. These and many other observations are consistent with an unusual mineralisation process not previously considered; protracted fluxing of calcitic carbonatite by subduction-released high-Si fluids during the closure of the Palaeo-Asian Ocean. The fluids leached Fe and Mg from the mantle wedge and scavenged REE, Nb and Th from carbonatite, forming the deposit through metasomatism of overlying sedimentary carbonate.