Persulfate promoted carbamoylation of N-arylacrylamides and N-arylcinnamamides with 4-carbamoyl-Hantzsch esters.

Carbamoyl-Hantzsch esters were used as carbamoyl radical precursors for oxidative carbamoylation of N-arylacrylamides and N-arylcinnamamides in the presence of inexpensive persulfates. This protocol can be applied to a broad range of substrates with various functional groups, providing a variety of 3,3-disubstituted oxindoles and 3,4-disubstituted dihydroquinolin-2(1H)-ones in moderate to good yields via an intermolecular addition/cyclization process.

Plastic pollution in croplands threatens long-term food security.

Plastic pollution is a global concern given its prevalence in aquatic and terrestrial ecosystems. Studies have been conducted on the distribution and impact of plastic pollution in marine ecosystems, but little is known on terrestrial ecosystems. Plastic mulch has been widely used to increase crop yields worldwide, yet the impact of plastic residues in cropland soils to soil health and crop production in the long term remained unclear. In this paper, using a global meta-analysis, we found that the use of plastic mulch can indeed increase crop yields on average by 25%-42% in the immediate season due to the increase of soil temperature (+8%) and moisture (+17%). However, the unabated accumulation of film residues in the field negatively impacts its physicochemical properties linked to healthy soil and threatens food production in the long term. It has multiple negative impacts on plant growth including crop yield (at the mean rate of -3% for every additional 100 kg/ha of film residue), plant height (-2%) and root weight (-5%), and soil properties including soil water evaporation capacity (-2%), soil water infiltration rate (-8%), soil organic matter (-0.8%) and soil available phosphorus (-5%) based on meta-regression. Using a nationwide field survey of China, the largest user of plastic mulch worldwide, we found that plastic residue accumulation in cropland soils has reached 550,800 tonnes, with an estimated 6%-10% reduction in cotton yield in some polluted sites based on current level of plastic residue content. Immediate actions should be taken to ensure the recovery of plastic film mulch and limit further increase in film residue loading to maintain the sustainability of these croplands.

Copper/B2pin2-Catalyzed Difluoroalkylation of Methylenecyclopropanes with Bromodifluorinated Acetates and Acetamides: One-Pot Synthesis of CF2-Containing Dihydronaphthalene Derivatives.

Novel copper/B2pin2-catalyzed difluoroalkylation of methylenecyclopropanes with bromodifluorinated acetates and acetamides via a tandem radical process involving ring-opening/intramolecular cyclization has been reported. This protocol is not only tolerated to a diverse range of substrates but also applicable to the synthesis of useful difluoromethylated compounds. Moreover, the reaction could be performed on a gram scale with a high yield, which opens up the possibility for practical applications.

Lightweight Splint Design for Individualized Treatment of Distal Radius Fracture.

A systematic design approach is proposed for medical splints for individualized treatment of the distal radius fracture. An initial split structural model is first constructed by 3D scanning of an injured limb. Based on the biomechanical theory and clinical experiences, the topology optimization method is applied to design the splint structure. The optimized lightweight splint is realized by additive manufacturing using polylactic acid. Compared to the traditional designs for the distal radius fracture, the optimized design by the proposed approach exhibits a weight reduction of more than 40%. Besides, the mechanical properties of the splint meet the requirements of medical treatment according to the simulation results. Numerical examples are provided to demonstrate the applicability of the approach.

Controlled Growth of Metal-Organic Frameworks on Polymer Brushes.

Polymer brushes are for the first time used to induce the synthesis of metal-organic frameworks (MOFs). The semi-fixed polymer chains provide a confined environment, which allows a mild growth of MOFs in between polymer chains to give surface-attached spherical MOF nanoparticles, in contrast to the larger MOF cubes/plates formed simultaneously in solution. Polymer brushes bearing carboxylate acid functionalities are indispensable for the formation of surface bound MOFs, while no MOF nanoparticles are observed on neutral polymer brushes. Characterization of the resultant MOF/polymer brushes hybrid film indicates the formation of crystalline MOF structure. The dimension of surface-attached MOFs can be fine-tuned from 20 nm to 1.4 µm simply by varying the structural parameter of polymer brushes and the nucleation duration. The method is not only applicable to the synthesis of MOF-5 and MIL-125, but shows great potential for the preparation of other surface-attached MOFs.

Topology optimization for optical projection lithography with manufacturing uncertainties.

This article presents a topology optimization approach for micro- and nano-devices fabricated by optical projection lithography. Incorporating the photolithography process and the manufacturing uncertainties into the topology optimization process results in a binary mask that can be sent directly to manufacturing without additional optical proximity correction (OPC). The performance of the optimized device is robust toward the considered process variations. With the proposed unified approach, the design for photolithography is achieved by considering the optimal device performance and manufacturability at the same time. Only one optimization problem is solved instead of two as in the conventional separate procedures by (1) blueprint design and (2) OPC. A micro-gripper design example is presented to demonstrate the potential of this approach.

Zn-Mediated Fragmentation of N-Alkoxyphthalimides Enabling the Synthesis of gem-Difluoroalkenes.

Zn-mediated generation of alkoxyl radicals from N-alkoxyphthalimides emerged as an efficient approach for forming diverse and valuable alkyl radicals through ß-scission or a hydrogen atom transfer process. The alkyl radical species can be further trapped by α-trifluoromethyl alkenes to construct a series of gem-difluoroalkenes.

Polyoxometalate solution passivation enabling dendrite-free and high-performance zinc anodes in aqueous zinc-ion batteries.

Zinc metal anodes in aqueous electrolytes commonly face challenges such as dendrite growth and undesirable side reactions, limiting their application in the field of aqueous zinc-ion batteries (AZIBs) for energy storage. Drawing inspiration from industrial practices involving molybdenum salt solutions for metal modification, a polyoxometalate solution was formulated as a passivation solution for zinc anodes (referred to as MO solution). The formed passivation layer, referred to as the MO layer, exhibited a uniform and protective nature with a thickness of approximately 10 µm. The experimental results demonstrated that this passivation layer effectively suppressed side reactions at the zinc anode interface, as evidenced by lower corrosion current density for MO-Zn anodes. Additionally, the newly plated Zn was uniformly deposited atop the MO layer, ensuring coating integrity and inhibiting dendrite growth. As a result, under more demanding conditions such as a larger current of 8 mA cm-2, the MO-Zn anode displayed an extended cycle life exceeding 420 h in a symmetric battery, with an overpotential as low as 98 mV. This performance significantly outperformed that of commercially available pure Zn foils (with a cycle life of 60 h and an overpotential of 192 mV). Notably, a self-made Na-doped V2O5 served as the cathode (referred to as NaVO), forming the MO-Zn//NaVO full battery. Even under high current test conditions of 2 A/g, the specific capacity of the MO-Zn//NaVO full battery remained substantial at 152.83 mAh/g after 1000 cycles. Furthermore, pouch batteries assembled with NaVO//MO-Zn successfully illuminated small bulbs. This study offers a viable optimization strategy for AZIB anodes and demonstrates the potential of using polyoxometalate solution for etching zinc anodes to inhibit dendrite growth and interfacial corrosion of zinc metal anodes.

Activation of hydrogen peroxide by ionic liquids: mechanistic studies and application in the epoxidation of olefins.

Imidazolium-based ionic liquids that contain perrhenate anions are very efficient reaction media for the epoxidation of olefins with H2O2 as an oxidant, thus affording cyclooctene in almost quantitative yields. The mechanism of this reaction does not follow the usual pathway through peroxo complexes, as is the case with long-known molecular transition-metal catalysts. By using in situ Raman, FTIR, and NMR spectroscopy and DFT calculations, we have shown that the formation of hydrogen bonds between the oxidant and perrhenate activates the oxidant, thereby leading to the transfer of an oxygen atom onto the olefin demonstrating the special features of an ionic liquid as a reaction environment. The influence of the imidazolium cation and the oxidant (aqueous H2O2, urea hydrogen peroxide, and tert-butyl hydrogen peroxide) on the efficiency of the epoxidation of cis-cyclooctene were examined. Other olefinic substrates were also used in this study and they exhibited good yields of the corresponding epoxides. This report shows the potential of using simple complexes or salts for the activation of hydrogen peroxide, owing to the interactions between the solvent medium and the active complex.

Safety, Tolerability, and Pharmacokinetics of Recombinant Human Neuregulin-1 in Healthy Chinese Subjects.

BACKGROUND: We investigated the safety, tolerability, and pharmacokinetics of intravenous recombinant human Neuregulin-1 (rhNRG-1), a DNA recombinant protein for the treatment of chronic heart failure, in healthy Chinese volunteers following single and multiple dose administration. METHODS AND RESULTS: To evaluate the safety and tolerance after single-dosing escalation, 28 subjects were divided into six groups (0.2, 0.4, 0.8, 1.2, 1.6, and 2.4 µg/kg) to receive an intravenous (IV) infusion of rhNRG-1 over 10 min by a randomized, open-label design. Only the 1.2 µg/kg dose group obtained pharmacokinetic parameters: Cmax was 7.645 (24.21) ng/mL, AUC0-t was 97.088 (21.41) min·ng/mL. To assess the safety and pharmacokinetics after multiple-dosing, 32 subjects were divided into four groups (0.2, 0.4, 0.8, and 1.2 µg/kg) to receive a 10-min IV infusion of rhNRG-1 for five consecutive days. After multiple dosing of 1.2 µg/kg, the Cmax value at day 5 was 8.838 (51.6) ng/mL and the AUC0-t value at day 5 was 109.890 (32.99) min·ng/mL. RhNRG-1 is rapidly cleared from the blood and has a short t1/2 of about 10 min. The adverse events related to rhNRG-1 mainly included flat or inverted T wave and gastrointestinal reactions, all of which were mild. CONCLUSIONS: It is concluded that rhNRG-1 is safe and well tolerated in healthy Chinese subjects at the dosing levels used in this study. The severity and frequency of adverse events did not increase with the prolongation of administration time. CLINICAL TRIAL REGISTRATION: Chinese Clinical Trial Registry ( http://www.chictr.org.cn ) Identifier No. ChiCTR2000041107.

Neuregulin 1 sustains the gene regulatory network in both trabecular and nontrabecular myocardium.

RATIONALE: The cardiac gene regulatory network (GRN) is controlled by transcription factors and signaling inputs, but network logic in development and it unraveling in disease is poorly understood. In development, the membrane-tethered signaling ligand Neuregulin (Nrg)1, expressed in endocardium, is essential for ventricular morphogenesis. In adults, Nrg1 protects against heart failure and can induce cardiomyocytes to divide. OBJECTIVE: To understand the role of Nrg1 in heart development through analysis of null and hypomorphic Nrg1 mutant mice. METHODS AND RESULTS: Chamber domains were correctly specified in Nrg1 mutants, although chamber-restricted genes Hand1 and Cited1 failed to be activated. The chamber GRN subsequently decayed with individual genes exhibiting decay patterns unrelated to known patterning boundaries. Both trabecular and nontrabecular myocardium were affected. Network demise was spatiotemporally dynamic, the most sensitive region being the central part of the left ventricle, in which the GRN underwent complete collapse. Other regions were partially affected with graded sensitivity. In vitro, Nrg1 promoted phospho-Erk1/2-dependent transcription factor expression, cardiomyocyte maturation and cell cycle inhibition. We monitored cardiac pErk1/2 in embryos and found that expression was Nrg1-dependent and levels correlated with cardiac GRN sensitivity in mutants. CONCLUSIONS: The chamber GRN is fundamentally labile and dependent on signaling from extracardiac sources. Nrg1-ErbB1/4-Erk1/2 signaling critically sustains elements of the GRN in trabecular and nontrabecular myocardium, challenging our understanding of Nrg1 function. Transcriptional decay patterns induced by reduced Nrg1 suggest a novel mechanism for cardiac transcriptional regulation and dysfunction in disease, potentially linking biomechanical feedback to molecular pathways for growth and differentiation.

Cross-dehydrogenative Coupling of N-Aryl Tetrahydroisoquinolines Catalyzed by an Anthraquinone-containing Polymeric Photosensitizer.

This work reports the photocatalytic application of an anthraquinone-containing polymeric photosensitizer (AQ-PHEMA) in the visible light-induced cross-dehydrogenative-coupling of N-aryl tetrahydroisoquinolines with several nucleophiles, including nitromethane, 1-methyl-2-alkyl ketone and dialkyl (aryl) phosphine oxide. The results revealed that the reaction could be catalyzed by AQ-PHEMA efficiently to afford a series of 1-substituted-2-aryl-1,2,3,4-tetrahydroisoquinolines in good to excellent yields with nice substrate tolerance under aerobic conditions at room temperature. The practical application potential was also showcased by a gram-scale synthesis. More importantly, the utilization of AQ-PHEMA as a heterogeneous photosensitizer also showed nice recyclability and reusability of the catalyst, whereas AQ-PHEMA can be easily separated and reused for at least 8 times without significant loss of photocatalytic activity.

Mn(III)-Mediated Radical Cyclization of o-Alkenyl Aromatic Isocyanides with Boronic Acids: Access to N-Unprotected 2-Aryl-3-cyanoindoles.

The synthesis of N-unprotected 2-aryl-3-cyanoindoles was realized via the Mn(III)-mediated radical cascade cyclization of o-alkenyl aromatic isocyanides with boronic acids. A possible mechanism involving a sequential intermolecular radical addition, intramolecular cyclization, and cleavage of the C-C bond under mild reaction conditions is proposed. Mechanism studies show that H2O or O2 might provide the oxygen source for the elimination of benzaldehyde.

Ruthenium(II)-Catalyzed C-C/C-N Coupling of 2-Arylquinazolinones with Vinylene Carbonate: Access to Fused Quinazolinones.

In this work, ruthenium(II)-catalyzed C-C/C-N annulation of 2-arylquinazolinones with vinylene carbonate is reported to synthesize fused quinazolinones. This catalytic system tolerates a wide range of substrates with excellent functional-group compatibility. In this transformation, the vinylene carbonate acts as an ethynol surrogate without any external oxidant involved. Furthermore, preliminary mechanistic studies were conducted, and a plausible catalytic cycle was also proposed.

Photoredox Generation of N-Centered Hydrazonyl Radicals Enables the Construction of Dihydropyrazole-Fused gem-Difluoroalkenes.

An efficient visible-light-promoted N-radical-mediated tandem radical cyclization/defluorinated alkylation of ß,γ-unsaturated hydrazones, and α-trifluoromethyl alkenes is described. This protocol provides a general and effective route to synthesize various dihydropyrazole-fused gem-difluoroalkenes at moderate to excellent yields under redox-neutral, metal-free, and mild conditions.

Neuregulin-1/ErbB signaling: a druggable target for treating heart failure.

Neuregulin-1s are widely expressed signaling molecules that are involved in cell differentiation, proliferation, growth, survival, and apoptosis. They transmit their signals by interacting with cell membrane receptors of the ErbB family, resulting in the activation of intracellular signaling cascades, which participate in various physiological and etiological processes. Besides their essential function in the development of the heart and the physiology of cardiac pumping, there is emerging evidence for the involvement of neuregulin-1/ErbB signals in human disease, including heart failure. These reasons prompt the development of new therapeutic agents based on neuregulin-1.

Neuregulin signaling and heart failure.

Neuregulin-1 (NRG-1), a ligand of receptor tyrosine kinases of the ErbB family, plays a critical role in cardiovascular development and maintenance of adult heart function. Results from cellular, animal, and clinical experiments have shown NRG-1 to be a promising drug candidate for restoring cardiac function after cardiac injury. Various mechanisms have been suggested to be involved in this process, such as improving sarcomeric structure or cell-cell adhesion, promoting proliferation and survival of cardiac myocytes, balancing Ca(2+) homeostasis, modulating inotropic effects, promoting angiogenesis, and preventing atherosclerosis. However, the contribution of these effects to the restoration of cardiac function remains to be estimated, and it may depend on the specific events that led to heart failure. Meanwhile, distinct and crossed signaling pathways downstream of NRG-1 may play a role in these underlying mechanisms, resulting in a complicated network of signaling mediating the function of NRG-1.

[Establishment of an ErbB3- and ErbB4-specific ligand screening system, and a screen of neuregulin-1 mutants].

Neuregulin-1 (NRG1), now in a phase II clinical trial, has beneficial effects on heart failure patients through the activation of ErbB2/ErbB4 receptor pair. To decrease the side effect of NRG1 on activating ErbB3, a mutation screen was carried out to get NRG1 mutants, which have more specific binding to ErbB2/ErbB4 receptor pair. Two CHO stable cell lines were constructed, which express ErbB2/ErbB3 or ErbB2/ErbB4 receptor pair, respectively. The ErbB2/ErbB4 cell line showed similar characteristics in ligand-binding activity and the activation of downstream signaling molecules, such as the AKT and PI3K to the primary neonatal rat ventricular myocytes (NRVM), which endogenously expresses ErbB2/ErbB4. Both cell lines have good dose-response. Thirty-one NRG1 mutants were successfully expressed in Escherichia coli and purified. Their ability to stimulate the downstream signaling was measured by detecting AKT phosphorylation. Some mutants showed more specific activation activity in ErbB2/ErbB4 cells. Further study on five of these mutants demonstrated that the change of the activation activity is associated with that of their binding activities to ErbB2/ErbB4 and ErbB2/ErbB3. Four of the candidates are more specific ligands for ErbB2/ErbB4 activation, and thus may serve as more potent drug candidates for heart failure.

Anti-inflammatory effect of fucoxanthin on dextran sulfate sodium-induced colitis in mice.

The anti-inflammatory activities of fucoxanthin, a marine carotenoid derived from the macroalgae and microalgae, have been demonstrated in the previous studies. However, the effect of fucoxanthin on ulcerative colitis (UC), an inflammatory bowel disease, was still unclear. In this study, we evaluated the in vivo anti-inflammatory effect of fucoxanthin on dextran sulfate sodium(DSS)-induced colitis in mice. Fucoxanthin at the doses of 50 and 100 mg/kg/day significantly protected against DSS-induced gradual loss of body weight, exhibited inhibitory effects on the DSS-induced increase of disease activity index and colon shortening. Moreover, fucoxanthin treatment resulted in a marked amelioration of the histological damage in the colon, and reduced the colonic PGE2 levels in colitic mice. In addition, the DSS-induced overexpressions of inflammation-related molecules including COX-2 and NF-κB were significantly decreased in fucoxanthin-treated mice. These finding suggested that the use of fucoxanthin provides a new and attractive alternative to control UC.