Nickel-Catalyzed Asymmetric Hydroaryloxy- and Hydroalkoxycarbonylation of Cyclopropenes.

The asymmetric Reppe carbonylation reactions provide a straightforward access to α-chiral carbonyl compounds. The reported paradigms predominantly adopted precious palladium as the catalyst. Here we report a nickel-catalyzed asymmetric carbonylation of cyclopropenes with phenyl formate and CO/ROH, respectively. This asymmetrical synthetic protocol features high atom economy, good functional group tolerance, which rapidly constructs polysubstituted cyclopropanecarboxylic derivatives with excellent diastereo- and enantioselectivity. The synthetic utility is demonstrated by facile conversion of the chiral products into bioactive molecules such as (-)-Tranylcypromine and (-)-Lemborexant.

Palladium-Catalyzed C-P(III) Bond Formation by Coupling ArBr/ArOTf with Acylphosphines.

Palladium-catalyzed C-P bond formation reaction of ArBr/ArOTf using acylphosphines as differential phosphination reagents is reported. The acylphosphines show practicable reactivity with ArBr and ArOTf as the phosphination reagents, though they are inert to the air and moisture. The reaction affords trivalent phosphines directly in good yields with a broad substrate scope and functional group tolerance. This reaction discloses the acylphosphines' capability as new phosphorus sources for the direct synthesis of trivalent phosphines.

Group I CDAs are responsible for a selective CHC-independent cuticular barrier in Locusta migratoria.

Chitin deacetylases including CDA1 and CDA2, containing a chitin deacetylase domain and an LDL domain, have been reported to be essential for cuticle structure differentiation in different insect species. However, it is yet unexplored whether CDA1 and CDA2 activity is needed for the function of the cuticle as a barrier against pathogen and xenobiotics penetration. In this study, we studied the efficiency of fungal infection in the migratory locust Locusta migratoria in dependence of LmCDA1 and LmCDA2 function. Second instar nymphs injected with dsRNA against LmCDA1 and LmCDA2 transcripts were less resistant against the infection by the fungus Metarhizium anisopliae than control nymphs. At the same time, permeability to organophosphorus pesticides was increased in these nymphs. Interestingly, the CHC amounts at the cuticle surface were unaffected upon LmCDA1 and LmCDA2 reduction. These results suggest that the barrier function of the locust cuticle not only depends on surface CHCs, but also on an intact procuticle.

The impact of COVID-19 on higher education building energy use and implications for future education building energy studies.

Although COVID-19 has significantly changed the higher educational sector, there are few studies revealing how this pandemic has changed the energy use of higher education buildings. This study was conducted not only to disclose the energy use change under COVID-19 but also to identify the corresponding facilities management strategies for future learning and teaching delivery modes under virtual campuses. This study collected the energy use data of 122 buildings across five campuses in Griffith University, located in Southeast Queensland, Australia, during the COVID-19 academic year (February 17, 2020, to February 21, 2021) and during a typical normal academic year (February 18, 2019, to February 16, 2020) by PI Vision Platform, and compared the data using the t-test and multiple linear regression. The results indicated that learning and administration activities became off campus during the pandemic, while research activities remained on campus. During the COVID-19 academic year, an amount of 9,646,933 kWh energy or around 24.88 kWh/m2 of energy use intensity was saved, which accounted for 16% of the total energy use per academic year. Specifically, the shutting down of air conditioning in academic buildings, administration buildings, retail buildings and teaching buildings during COVID-19 saved 4,566 kWh (1.13 kWh/m2), 966 kWh (0.8 kWh/m2), 1,472 kWh (1.4 kWh/m2) and 860 kWh (1.3 kWh/m2) of electricity use per week, respectively, which accounted for 51.5%, 44.3%, 48.3% and 57.1% of total energy use per week during this period, respectively. Based on this analysis and the changing educational environment, this study also speculated on the energy implications of future teaching and learning practices, which provided guidance to the facilities management under virtual campuses.

Nickel-Catalyzed Migratory Hydrocyanation of Internal Alkenes: Unexpected Diastereomeric-Ligand-Controlled Regiodivergence.

A regiodivergent nickel-catalyzed hydrocyanation of a broad range of internal alkenes involving a chain-walking process is reported. When appropriate diastereomeric biaryl diphosphite ligands are applied, the same starting materials can be converted to either linear or branched nitriles with good yields and high regioselectivities. DFT calculations suggested that the catalyst architecture determines the regioselectivity by modulating electronic and steric interactions. In addition, moderate enantioselectivities were observed when branched nitriles were produced.

Isolation, identification and characterization of propionic acid bacteria associated with autistic spectrum disorder.

Autism spectrum disorder (ASD) seriously affects children's health. Recently, propionic acid (PA) has been reported to play a significant role in the formation of ASD. In this study, we investigated the community structure of PA-related bacteria in healthy and ASD children by isolation and culture, while a group of representative PA-related bacteria were identified and characterized based on colony morphological observation, physiological and biochemical tests, as well as living/dead cells staining analysis and 16S rRNA gene sequencing. The results showed that the number of PA-related bacteria in healthy children was >100-fold higher than that in ASD children, while compared to healthy children, greater diversity was found in PA-associated bacteria from ASD children. The sensitivity of the representative strains to PA was affected by bacterial species, PA concentration and incubation time. The decrease of pH value was found in PA-resistant Lactobacillus plantarum strain 6-1 but not in PA-sensitive Enterococcus lactis strain 4-1, while biofilm formation of both strains were unaffected by PA. Furthermore, PA inhibited the propagation of the two selected bacteria rather than killed them, while the greater inhibitory effect was observed on strain 4-1. Overall, the result is of great significance for revealing the role of PA-related bacteria in development of ASD.

Enantioselective Nickel-Catalyzed Migratory Hydrocyanation of Nonconjugated Dienes.

Metal-catalyzed chain-walking reactions have recently emerged as a powerful strategy to functionalize remote positions in organic molecules. However, a chain-walking protocol for nonconjugated dienes remains scarcely reported, and developments are currently ongoing. In this Communication, a nickel-catalyzed asymmetric hydrocyanation of nonconjugated dienes involving a chain-walking process is demonstrated. The reaction exhibits excellent regio- and chemoselectivity, and a wide range of substrates were tolerated, delivering the products in high yields and enantioselectivities. Deuterium-labeling experiments support the chain-walking process, which involves an iterative ß-H elimination and reinsertion processes. Gram-scale synthesis, regioconvergent experiments, and downstream transformations gave further insights into the high potential of this transformation.

Access to 1,3-Dinitriles by Enantioselective Auto-tandem Catalysis: Merging Allylic Cyanation with Asymmetric Hydrocyanation.

Enantioselective auto-tandem catalysis represents a challenging yet highlight attractive topic in the field of asymmetric catalysis. In this context, we describe a dual catalytic cycle that merges allylic cyanation and asymmetric hydrocyanation. The one-pot conversion of a broad array of allylic alcohols into their corresponding 1,3-dinitriles proceeds in good yield with high enantioselectivity. The products are densely functionalized and can be easily transformed to chiral diamines, dinitriles, diesters, and piperidines. Mechanistic studies clearly support a novel sequential cyanation/hydrocyanation pathway.

Helicoidal Organization of Chitin in the Cuticle of the Migratory Locust Requires the Function of the Chitin Deacetylase2 Enzyme (LmCDA2).

In the three-dimensional extracellular matrix of the insect cuticle, horizontally aligned microfibrils composed of the polysaccharide chitin and associated proteins are stacked either parallel to each other or helicoidally. The underlying molecular mechanisms that implement differential chitin organization are largely unknown. To learn more about cuticle organization, we sought to study the role of chitin deacetylases (CDA) in this process. In the body cuticle of nymphs of the migratory locust Locusta migratoria, helicoidal chitin organization is changed to an organization with unidirectional microfibril orientation when LmCDA2 expression is knocked down by RNA interference. In addition, the LmCDA2-deficient cuticle is less compact suggesting that LmCDA2 is needed for chitin packaging. Animals with reduced LmCDA2 activity die at molting, underlining that correct chitin organization is essential for survival. Interestingly, we find that LmCDA2 localizes only to the initially produced chitin microfibrils that constitute the apical site of the chitin stack. Based on our data, we hypothesize that LmCDA2-mediated chitin deacetylation at the beginning of chitin production is a decisive reaction that triggers helicoidal arrangement of subsequently assembled chitin-protein microfibrils.

Identification and characterization of two CYP9A genes associated with pyrethroid detoxification in Locusta migratoria.

Cytochrome P450s (CYPs) constitute one of the largest gene super families and distribute widely in all living organisms. In this study, the full-length cDNA sequences of two LmCYP9A genes (LmCYP9AQ1 and LmCYP9A3) were cloned from Locusta migratoria. We analyzed the expression patterns of two LmCYP9A genes in various tissues and different developmental stages using real-time quantitative PCR. Then we evaluated the detoxification functions of the two LmCYP9A genes by testing mortalities with four kinds of pyrethroid treatment after RNA interference (RNAi), respectively. Combining with docking structure of two LmCYP9A genes, their detoxification properties were extensively analyzed. The full-length cDNAs of LmCYP9AQ1 and LmCYP9A3 putatively encoded 525 and 524 amino acid residues, respectively. Both LmCYP9A genes were expressed throughout the developmental stages. The expression of LmCYP9AQ1 in the brain was higher than that in other examined tissues, whereas the LmCYP9A3 was mainly expressed in the fat body. The mortalities of nymphs exposed to deltamethrin and permethrin increased from 27.7% to 77.7% and 27.7% to 58.3%, respectively, after dsLmCYP9A3 injection. While the mortalities of nymphs exposed to fluvalinate increased from 29.8% to 53.0% after LmCYP9AQ1 was silenced using RNA interference. Our results suggested that the two LmCYP9A genes may be involved in different pyrethroid insecticide detoxification in L. migratoria.

Identification and functional analysis of a cytochrome P450 gene CYP9AQ2 involved in deltamethrin detoxification from Locusta migratoria.

A 1578-bp cDNA of a cytochrome P450 gene (CYP9AQ2) was sequenced from the migratory locust, Locusta migratoria. It contains an open reading frame (ORF) of 1557 bp that encodes 519 amino acid residues. As compared with other known insect cytochrome P450 enzymes, the overall structure of its deduced protein is highly conserved. The expression of CYP9AQ2 was relatively higher in nymphal stages than in egg and adult stages, and the highest expression was found in fourth-instar nymphs, which was 8.7-fold higher than that of eggs. High expression of CYP9AQ2 was observed in foregut, followed by hindgut, Malpighian tubules, brain and fat bodies, which were 75~142-fold higher than that in hemolymph. Low expression was found in midgut, gastric cecum and hemolymph. The expression of CYP9AQ2 was up-regulated by deltamethrin at the concentrations of 0.04, 0.08, and 0.12 µg/mL and the maximal up-regulation was 2.6-fold at LD10 (0.04 µg/mL). RNA interference-mediated silencing of CYP9AQ2 led to an increased mortality of 25.3% when the nymphs were exposed to deltamethrin, suggesting that CYP9AQ2 plays an important role in deltamethrin detoxification in L. migratoria. Computational docking studies suggested that hydroxylation of the phenoxybenzyl moiety might be one of the deltamethrin metabolic pathways by CYP9AQ2.

Ultra-high pressure improved gelation and digestive properties of Tai Lake whitebait myofibrillar protein.

This study investigated the effects of ultra-high pressure (UHP) at different levels on the physicochemical properties, gelling properties, and in vitro digestion characteristics of myofibrillar protein (MP) in Tai Lake whitebait. The α-helix gradually unfolded and transformed into ß-sheet as the pressure increased from 0 to 400 MPa. In addition, the elastic modulus (G') and viscous modulus (G'') of the 400 MPa-treated MP samples increased by 4.8 and 3.8 times, respectively, compared with the control group. The gel properties of the MP also increased significantly after UHP treatment, e.g., the gel strength increased by a 4.8-fold when the pressure reached 400 Mpa, compared with the control group. The results of in vitro simulated digestion showed that the 400 MPa-treated MP gel samples showed a 1.8-fold increase in digestibility and a 69.6 % decrease in digestible particle size compared with the control group.

Knickkopf (LmKnk) is required for chitin organization in the foregut of Locusta migratoria.

The foregut, located at the front of the digestive tract, serves a vital role in insects by storing and grinding food into small particles. The innermost layer of the foregut known as the chitinous intima, comes into direct contact with the food and acts as a protective barrier against abrasive particles. Knickkopf (Knk) is required for chitin organization in the chitinous exoskeleton, tracheae and wings. Despite its significance, little is known about the biological function of Knk in the foregut. In this study, we found that LmKnk was stably expressed in the foregut, and highly expressed before molting in Locusta migratoria. To ascertain the biological function of LmKnk in the foregut, we synthesized specific double-stranded LmKnk (dsLmKnk) and injected it into locusts. Our findings showed a significant decrease in the foregut size, along with reduced food intake and accumulation of residues in the foregut after dsLmKnk injection. Morphological observations revealed that newly formed intima became thinner and lacked chitin lamella. Furthermore, fluorescence immunohistochemistry revealed that LmKnk was located in the apical region of new intima and epithelial cells. Taken together, this study provides insights into the biological function of LmKnk in the foregut, and identifies the potential target gene for exploring biological pest management strategies.

A Stackelberg Game-Theoretic Exploration Rendering Robustness and Optimality for Performance Improvement of Fuzzy Mechanical Systems.

We consider mechanical systems with uncertainty. The uncertainty may be time varying. The bound of the uncertainty is described by its fuzzy characteristics. To design a feasible control, we start with a robust phase, which renders a control scheme that guarantees the system performance regardless of the actual value of the uncertainty. This robust phase is then followed by an optimal phase. There are design parameters in the control, which can be fine-tuned. We proposed multiple performance objectives. The goal of the choice of the control design parameters is to minimize the performance objectives. However, since these objectives are nonconciliating (meaning one's minimum is not the other one's minimum), we invoke the Stackelberg strategy for the optimal parameters. The game strategy mimics two players: one is the leader and one is the follower. Through the interplay between the two players, we show how to select the design parameters. The design procedure in both robust and optimal phases is demonstrated by a coupled inverted pendulum system.

Highly Diastereoselective Synthesis of Polysubstituted Cyclopropanecarbonitriles via Palladium-Catalyzed Cyanoesterification of Cyclopropenes.

We herein develop a highly diastereoselective synthesis of cyano-substituted cyclopropanes via palladium-catalyzed direct cyanoesterification of cyclopropenes, which features mild reaction conditions, good functional group compatibility, and simple operation. This transformation represents a stepwise, highly atom economic, and scalable protocol for obtaining synthetically useful cyclopropanecarbonitriles.

Membrane-disruptive homo-polymethacrylate with both hydrophobicity and pH-sensitive protonation for selective cancer therapy.

The membrane-disruptive strategy, which involves host defense peptides and their mimetics, is a revolutionary cancer treatment based on broad-spectrum anticancer activities. However, clinical application is limited by low selectivity towards tumors. In this context, we have established a highly selective anticancer polymer, i.e. poly(ethylene glycol)-poly(2-azepane ethyl methacrylate) (PEG-PAEMA), that can mediate the membrane-disruptive activity via a subtle pH change between physiological pH and tumor acidity for selective cancer treatment. Specifically, the resulting PEG-PAEMA can assemble into neutral nanoparticles and silence the membrane-disruptive activity at physiological pH and disassemble into cationic free-chains or smaller nanoparticles with potent membrane-disruptive activity after the protonation of the PAEMA block due to tumor acidity, resulting in high selectivity towards tumors. Dramatically, PEG-PAEMA exhibited a >200-fold amplification in hemolysis and <5% in IC50 against Hepa1-6, SKOV3 and CT-26 cells at pH 6.7 as compared to those at pH 7.4, thanks to the selective membrane-disruptive mechanism. Moreover, mid- and high-dose PEG-PAEMA demonstrated higher anticancer efficacy than an optimal clinical prescription (bevacizumab plus PD-1) and, significantly, had few side effects on major organs in the tumor-bearing mice model, agreeing with the highly selective membrane-disruptive activity in vivo. Collectively, this work showcases the latent anticancer pharmacological activity of the PAEMA block, and also brings new hope for selective cancer therapy.

Smart anti-vascular nanoagent induces positive feedback loop for self-augmented tumor accumulation.

How to achieve efficient drug accumulation in the tumor with low vascular density is a great challenge but the key to push the limit of anti-vascular therapeutic efficacy. Herein, we report a charge-reversible nanoparticles of gambogenic acid (CRNP-GNA) that would induce the positive feedback loop between increased tumor vascular permeability and improved drug accumulation. This positive feedback loop would remarkably improve tumor vascular permeability for efficient drug accumulation through few residue vessels. As compared to its charge-irreversible analogue in the latter injections, the accumulation in tumor and vascular permeability and retention indexes (VPRI) in CRNP-GNA group respectively boosted from nearly equal to 8.32 and 60 times, while its tumorous microvessel density decreased from nearly equal to only 7%. The self-augmented accumulation consequently amplified the antitumor efficacy via multiple pathways of anti-angiogenesis, vascular disruption and pro-apoptosis, where 5 out of 6 tumors in animal models were completely cured by CRNP-GNA. This work confirms that the underlying positive feedback loop for anti-vascular therapy could be induced by charge-reversible drug delivery nanosystem to achieve efficient and self-augmented drug accumulation even in the tumor with few vessels. It provides a novel strategy to conquer the dilemma between anti-vascular efficacy and drug accumulation.

Nickel-Catalyzed Enantioselective Hydrothiocarbonylation of Cyclopropenes.

Hydrothiocarbonylation of olefins using carbon monoxide and thiols is a powerful method to synthesize thioesters from simple building blocks. Owing to the intrinsic challenges of catalyst poisoning, transition-metal-catalyzed asymmetric thiocarbonylation, particularly when utilizing earth abundant metals, remains rare in the literature. Herein, we report a nickel-catalyzed enantioselective hydrothiocarbonylation of cyclopropenes for the synthesis of a diverse collection of functionalized thioesters in good to excellent yields with high stereoselectivity. This new method employs an inexpensive, air-stable nickel(II) precursor, which provides enhanced catalyst fidelity against CO poisoning compared to nickel(0) catalysts.

Regioselective Hydrodeoxygenation of α-Diketones with Phosphites under Visible-Light Catalysis.

Novel regioselective hydrodeoxygenation of α-diketones with phosphites as the deoxygenation reagent was realized via visible-light photoredox catalysis. Broad substrate scope and high functional group compatibility were obtained. Unsymmetric α-diketones were selectively reduced at the carbonyls of higher electrophilicity. This unique regioselectivity compared with available methods makes it a practical complementary approach for the monohydrodeoxygenation of α-diketones.