Comprehensive metabolome characterization and comparison between two sources of Dragon's blood by integrating liquid chromatography/mass spectrometry and chemometrics.

Dragon's Blood (DB) serves as a precious Chinese medicine facilitating blood circulation and stasis dispersion. Daemonorops draco (D. draco; Qi-Lin-Jie) and Dracaena cochinchinensis (D. cochinchinenesis; Long-Xue-Jie) are two reputable plant sources for preparing DB. This work was designed to comprehensively characterize and compare the metabolome differences between D. draco and D. cochinchinenesis, by integrating liquid chromatography/mass spectrometry and untargeted metabolomics analysis. Offline two-dimensional liquid chromatography/ion mobility-quadrupole time-of-flight mass spectrometry (2D-LC/IM-QTOF-MS), by utilizing a powerful hybrid scan approach, was elaborated for multicomponent characterization. Configuration of an XBridge Amide column and an HSS T3 column in offline mode exhibited high orthogonality (A0 0.80) in separating the complex components in DB. Particularly, the hybrid high-definition MSE-high definition data-dependent acquisition (HDMSE-HDDDA) in both positive and negative ion modes was applied for data acquisition. Streamlined intelligent data processing facilitated by the UNIFI™ (Waters) bioinformatics platform and searching against an in-house chemical library (recording 223 known compounds) enabled efficient structural elucidation. We could characterize 285 components, including 143 from D. draco and 174 from D. cochinchinensis. Holistic comparison of the metabolomes among 21 batches of DB samples by the untargeted metabolomics workflows unveiled 43 significantly differential components. Separately, four and three components were considered as the marker compounds for identifying D. draco and D. cochinchinenesis, respectively. Conclusively, the chemical composition and metabolomic differences of two DB resources were investigated by a dimension-enhanced analytical approach, with the results being beneficial to quality control and the differentiated clinical application of DB.

Aromaticity in Fully π-Conjugated Multicyclic Macrocycles.

The research on aromaticity has mainly focused on monocyclic [n]annulene-like systems or polycyclic aromatic hydrocarbons. For fully π-conjugated multicyclic macrocycles (MMCs), the electronic coupling between the individual constitutional macrocycles would lead to unique electronic structures and aromaticity. The studies on MMCs, however, are quite limited, presumably due to the great challenges to design and synthesize a fully π-conjugated MMC molecule. Herein, we report the facile synthesis of two MMCs (2TMC and 3TMC) in which two and three thiophene-based macrocycles are fused together by employing both intramolecular and intermolecular Yamamoto coupling reactions of a properly designed precursor (7). The monocyclic macrocycle (1TMC) was also synthesized as a model compound. The geometry, aromaticity, and electronic properties of these macrocycles at different oxidation states were investigated by X-ray crystallographic analysis, NMR, and theoretical calculations, which disclosed how the constitutional macrocycles interplay with each other and lead to unique aromatic/antiaromatic character. This study provides new insights into the complex aromaticity in MMC systems.

Clinical Utility of Plantar Pressure Measurements as Screening in Patients With Parkinson Disease With and Without Freezing of Gait History.

OBJECTIVE: To test the feasibility of objective assessments using the TekScan MatScan pressure mat plantar pressure measurement as a time-effective screening service for Parkinson disease (PD) with and without freezing of gait (FOG) history. DESIGN: Prospective cross-sectional study. SETTING: Largest medical center in southern Taiwan. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Plantar pressure measurements including average peak pressure (PP), contact area (CA), and pressure-time integral (PTI) in static and dynamic conditions as well as clinical scores during off-medication states. PARTICIPANTS: A total of 103 patients with PD and 22 age- and sex-matched volunteers without PD (N=125). RESULTS: Plantar pressure assessment including PP, CA, and PTI on the total foot areas between participants with PD and controls without PD in the static conditions are similar. Patients with PD presented higher PTI on total foot areas as well as hallux, midfoot area, and medial and lateral heels during dynamic conditions than controls without PD. The PP, CA, and PTI during the static condition and CA during the dynamic condition on the hallux showed statistical significance between PD with and without FOG history. Stepwise logistic regression after controlling with age and body mass index showed only PTI on hallux (static conditions) was significantly associated with the presence of FOG. The receiver operating characteristic curve analysis in diagnostic accuracy for FOG in PTI was statistically significant (P=.002; area under the curve, 0.71). CONCLUSIONS: FOG screening using the TekScan MatScan pressure mat plantar pressure measurement could serve as a time-effective screening service at the outpatient clinic. Based on our study, PTI may be valuable in auxiliary diagnosis.

The latest research progress on minimally invasive treatments for hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-related death worldwide. Due to the high prevalence of hepatitis B virus (HBV) infection in China, the incidence of HCC in China is high, and liver cirrhosis caused by chronic hepatitis also brings great challenges to treatment. This paper reviewed the latest research progress on minimally invasive treatments for HCC, including percutaneous thermal ablation and new nonthermal ablation techniques, and introduced the principles, advantages, and clinical applications of various therapeutic methods in detail. DATA SOURCES: The data of treatments for HCC were systematically collected from the PubMed, ScienceDirect, American Chemical Society and Web of Science databases published in English, using "minimally invasive" and "hepatocellular carcinoma" or "liver cancer" as the keywords. RESULTS: Percutaneous thermal ablation is still a first-line strategy for the minimally invasive treatment of HCC. The effect of microwave ablation (MWA) on downgrading treatment before liver transplantation is better than that of radiofrequency ablation (RFA), while RFA is more widely used in the clinical practice. High-intensity focused ultrasound (HIFU) is mainly used for the palliative treatment of advanced liver cancer. Electrochemotherapy (ECT) delivers chemotherapeutic drugs to the target cells while reducing the blood supply around HCC. Irreversible electroporation (IRE) uses a microsecond-pulsed electric field that induces apoptosis and necrosis and triggers a systemic immune response. The nanosecond pulsed electric field (nsPEF) has achieved a good response in the ablation of mice with HCC, but it has not been reported in China for the treatment of human HCC. CONCLUSIONS: A variety of minimally invasive treatments provide a sufficient survival advantage for HCC patients. Nonthermal ablation will lead to a new wave with its unique advantage of antitumor recurrence and metastasis.

Circumcoronenes.

Circumcoronene, a hexagonal graphene fragment with six zigzag edges, has been the focus of theoretical studies for many years, but its synthesis in solution has remained a challenge. In this study, we present a facile method for synthesizing three derivatives of circumcoronene using Brønsted/Lewis acid-mediated cyclization of vinyl ether or alkyne. Their structures were confirmed through X-ray crystallographic analysis. Bond length analysis, NMR measurement, and theoretical calculations showed that circumcoronene mostly follows Clar's bonding model and exhibits dominant local aromaticity. Its absorption and emission spectra are similar to those of the smaller hexagonal coronene due to its six-fold symmetry.

Bis-peri-dinaphtho-rylenes: Facile Synthesis via Radical-Mediated Coupling Reactions and their Distinctive Electronic Structures.

Polycyclic aromatic hydrocarbons (PAHs) with a one-dimensional (1D), ribbon-like structure have the potential to serve as both model compounds for corresponding graphene nanoribbons (GNRs) and as materials for optoelectronics applications. However, synthesizing molecules of this type with extended π-conjugation presents a significant challenge. In this study, we present a straightforward synthetic method for a series of bis-peri-dinaphtho-rylene molecules, wherein the peri-positions of perylene, quaterrylene, and hexarylene are fused with naphtho-units. These molecules were efficiently synthesized primarily through intramolecular or intermolecular radical coupling of in situ generated organic radical species. Their structures were confirmed using X-ray crystallographic analysis, which also revealed a slightly bent geometry due to the incorporation of a cyclopentadiene ring at the bay regions of the rylene backbones. Bond lengh analysis and theoretical calculations indicate that their electronic structures resemble pyrenacenes more than quinoidal rylenes. That is, the aromatic sextets are predominantly localized along the long axis of the skeletones. As the chain length increases, these molecules exhibit enhanced electronic absorption with a bathochromic shift, and multiple amphoteric redox waves. This study introduces a novel synthetic approach for generating 1D extended PAHs and GNRs, along with their structure-dependent electronic properties.

Fused Triangulene Dimers: Facile Synthesis by Intramolecular Radical-Radical Coupling and Application for Near-Infrared Lasers.

Large graphene-like molecules with four zigzag edges are ideal gain medium materials for organic near-infrared (NIR) lasers. However, synthesizing them becomes increasingly challenging as the molecular size increases. In this study, we introduce a new intramolecular radical-radical coupling approach and successfully synthesize two fused triangulene dimers (1 a/1 b) efficiently. X-ray crystallographic analysis of 1 a indicates that there is no intermolecular π-π stacking in the solid state. When the more soluble derivative 1 b is dispersed in polystyrene thin films, amplified spontaneous emission in the NIR region is observed. Using 1 b as the active gain material, we fabricate solution-processed distributed feedback lasers that exhibit a narrow emission linewidth at around 790 nm. The laser devices also exhibit low thresholds with high photostability. Our study provides a new synthetic strategy for extended nanographenes, which have diverse applications in electronics and photonics.

Discovery of Simple Diacylhydrazine-Functionalized Cinnamic Acid Derivatives as Potential Microtubule Stabilizers.

To develop novel microtubule-binding agents for cancer therapy, an array of N-cinnamoyl-N'-(substituted)acryloyl hydrazide derivatives were facilely synthesized through a two-step process. Initially, the antiproliferative activity of these title compounds was explored against A549, 98 PC-3 and HepG2 cancer cell lines. Notably, compound I23 exhibited the best antiproliferative activity against three cancer lines with IC50 values ranging from 3.36 to 5.99 µM and concurrently afforded a lower cytotoxicity towards the NRK-52E cells. Anticancer mechanism investigations suggested that the highly bioactive compound I23 could potentially promote the protofilament assembly of tubulin, thus eventually leading to the stagnation of the G2/M phase cell cycle of HepG2 cells. Moreover, compound I23 also disrupted cancer cell migration and significantly induced HepG2 cells apoptosis in a dosage-dependent manner. Additionally, the in silico analysis indicated that compound I23 exhibited an acceptable pharmacokinetic profile. Overall, these easily prepared N-cinnamoyl-N'-(substituted)acryloyl hydrazide derivatives could serve as potential microtubule-interacting agents, probably as novel microtubule-stabilizers.

Solution-Phase Synthesis and Isolation of An Aza-Triangulene and Its Cation in Crystalline Form.

Synthesis of triangulene and its derivatives is challenging due to their intrinsic high spin nature. Herein, we report solution-phase synthesis and isolation of a nitrogen-doped triangulene (i.e., aza-triangulene) (NT) and its cation (NT+ ) in single-crystal form. Notably, the cation NT+ can be regarded as an isoelectronic structure of the corresponding all-carbon triangulene. Both NT and NT+ show reasonable stability due to kinetic blocking by bulky and electron-withdrawing aryl substituents, and intramolecular donor-acceptor interaction. Bond length analysis, magnetic measurements and theoretical calculations reveal that the neutral NT has a doublet ground state with a zwitterionic character, while the cation NT+ exhibits a triplet ground state with a singlet-triplet energy gap of +0.84 kcal mol-1 . This study provides a rational strategy to access high-spin systems by heteroatom doping of pure π-conjugated polycyclic hydrocarbons.

Stablization of ACOs by NatB mediated N-terminal acetylation is required for ethylene homeostasis.

N-terminal acetylation (NTA) is a highly abundant protein modification catalyzed by N-terminal acetyltransferases (NATs) in eukaryotes. However, the plant NATs and their biological functions have been poorly explored. Here we reveal that loss of function of CKRC3 and NBC-1, the auxiliary subunit (Naa25) and catalytic subunit (Naa20) of Arabidopsis NatB, respectively, led to defects in skotomorphogenesis and triple responses of ethylene. Proteome profiling and WB test revealed that the 1-amincyclopropane-1-carboxylate oxidase (ACO, catalyzing the last step of ethylene biosynthesis pathway) activity was significantly down-regulated in natb mutants, leading to reduced endogenous ethylene content. The defective phenotypes could be fully rescued by application of exogenous ethylene, but less by its precursor ACC. The present results reveal a previously unknown regulation mechanism at the co-translational protein level for ethylene homeostasis, in which the NatB-mediated NTA of ACOs render them an intracellular stability to maintain ethylene homeostasis for normal growth and responses.

Development and preliminary testing of a probe-based duplex real-time PCR assay for the detection of African swine fever virus.

An outbreak of African swine fever (ASF) in China in 2018 caused substantial economic losses to the swine industry. To accurately diagnose clinical infection with ASF virus (ASFV), we developed a TaqMan probe-based duplex real-time PCR that simultaneously detected two discontinuous genes in the virus genome, thereby preventing the inaccurate results obtained with only one reaction. Two sets of ASFV gene-specific primers, along with two fluorescent TaqMan probes were designed to target conserved regions of the B646L and B438L genes. This method had high sensitivity and specificity, with a limit of detection of 10 copies/µL, and it did not cross-react with the genomes of other viral pathogens that affect pigs (i.e., CSFV, PRRSV, PEDV, PRV, PPV and PCV2). Overall, 180 clinical samples from ASFV-infected pig farms were used to compare this method with a commercial kit, which yielded excellent consistency (98.3%). This new diagnostic method should greatly improve the efficiency of ASFV surveillance and reduce economic losses, providing benefits for both animal and public health.

Projecting the Global Potential Distribution of Cydia pomonella (Lepidoptera: Tortricidae) Under Historical and RCP4.5 Climate Scenarios.

The codling moth Cydia pomonella (L.) (Lepidoptera: Tortricidae) is a destructive pest of apple (Malus domestica (Rosales: Rosaceae)), pear (Pyrus spp. (Rosales: Rosaceae)), and other pome tree fruits; outbreaks cause significant ecological and economic losses. In this study, we used CLIMEX model to predict and evaluate the global risk of C. pomonella based on historical climate data (1989-2018) and simulated future climate data (2071-2100) under the RCP4.5 scenarios. Cydia pomonella exhibited a wide distribution under both historical and future climate conditions. Climate change is predicted to expand the northern boundary of the potential distribution from approximately 60°N to 75°N. Temperature was the most dominant factor in climatic suitability for the pest. Combinations of multiple meteorological factors (relative humidity and precipitation) associated with a failure to break diapause in certain regions also affect suitability, particularly in northern South America and central Africa. Irrigation only had a slight impact on species favorability in some areas. The projections established in our study present insight into the global potential suitability of C. pomonella under climate change scenarios by the end of the 21st century. Farmers should be aware of the risk associated with the pest based on the results, which would provide guidance for quarantine agencies and trade negotiators worldwide.

Scholl Reaction of Perylene-Based Polyphenylene Precursors under Different Conditions: Formation of Hexagon or Octagon?

A planar dibenzo-peri-hexacene derivative (2) was synthesized via FeCl3 -mediated Scholl reaction from a cyclopenta-fused perylene (CP) based polyphenylene precursor (1). However, an unexpected octagon-containing, negatively curved molecule (3) was obtained in nearly quantitative yield when 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) and methanesulfonic acid (MeSO3 H) were used. Similar results were observed when two smaller-sized precursors containing one (4) or two CP units (5) were tested. X-ray crystallographic analysis also revealed that there is no close π-π stacking between neighboring π-conjugated skeletons. DFT calculations suggest a radical cation mechanism in the presence of FeCl3 while an arenium ion pathway for the DDQ/MeSO3 H mediated Scholl reaction, which can well explain the selective formation of hexagons and octagons under different conditions. The obtained compounds showed tunable optical and electrochemical properties.

Fused Quinoidal Dithiophene-Based Helicenes: Synthesis by Intramolecular Radical-Radical Coupling Reactions and Dynamics of Interconversion of Enantiomers.

A series of fused quinoidal dithiophene-based double and triple helicenes (1-M, 2-M, 2-M-Cl, 3-M, 3-M-Cl) were synthesized by intramolecular radical-radical coupling followed by oxidative dehydrogenation reaction. These helical molecules show dynamic interconversion of enantiomers in solution as revealed by variable-temperature NMR measurements, and the energy barriers are correlated to the substituents and topological structures. Notably, dynamic high performance liquid chromatography was used to quantitatively investigate the room-temperature racemization process between the (P,P,M)- and (P,M,M)- enantiomers of the triple helical 3-M-Cl, which gave an interconversion energy barrier in consistent with density functional theory calculations. Their optical and electrochemical properties are dependent on the fusion mode. Our studies provide both new synthetic strategy and new dynamic analytical method for helicenes with unique electronic structure.

S-shaped para-Quinodimethane-Embedded Double [6]Helicene and Its Charged Species Showing Open-Shell Diradical Character.

Helicenes and extended helical π-conjugated compounds have been widely studied, but most of the systems contain only aromatic benzene or heterocyclic rings, showing local aromatic character. Herein, new S-shaped double [6]helicene 1, which has two embedded para-quinodimethane (p-QDM) units, is reported. Due to the existence of a proaromatic quinoidal substructure, it has open-shell diradical character. Its model compound, C-shaped single [6]helicene 2 containing one p-QDM unit, was also synthesized and compared. Their ground-state structures and electronic properties were systematically studied by a combination of various experimental methods assisted by theoretical calculations. Compound 1 has a double-helical structure in the crystal, with the two terminal [6]helicene units bent in opposite directions (i.e., anti form). However, an anti/syn isomerization process with a moderate interconversion energy barrier was observed on the NMR timescale. Compound 1 shows amphoteric redox behavior. It also exhibits open-shell diradical character (y0 =12.1 %) and a small singlet-triplet gap. On the other hand, compound 2 has a typical closed-shell nature. The dication and dianion of 1 also show open-shell diradical character. The dianion of 2 and the tetraanion of 1 exhibit similar electronic structures to their respective isoelectronic structures, that is, [6]helicene and a double [6]helicene. This work provides some insights into the design and synthesis of stable helical π systems with open-shell diradical character and magnetic activity.

The trimeric Hef-associated nuclease HAN is a 3'→5' exonuclease and is probably involved in DNA repair.

Nucleases play important roles in nucleic acid metabolism. Some archaea encode a conserved protein known as Hef-associated nuclease (HAN). In addition to its C-terminal DHH nuclease domain, HAN also has three N-terminal domains, including a DnaJ-Zinc-finger, ribosomal protein S1-like, and oligonucleotide/oligosaccharide-binding fold. To further understand HAN's function, we biochemically characterized the enzymatic properties of HAN from Pyrococcus furiosus (PfuHAN), solved the crystal structure of its DHH nuclease domain, and examined its role in DNA repair. Our results show that PfuHAN is a Mn2+-dependent 3'-exonuclease specific to ssDNA and ssRNA with no activity on blunt and 3'-recessive double-stranded DNA. Domain truncation confirmed that the intrinsic nuclease activity is dependent on the C-terminal DHH nuclease domain. The crystal structure of the DHH nuclease domain adopts a trimeric topology, with each subunit adopting a classical DHH phosphoesterase fold. Yeast two hybrid assay confirmed that the DHH domain interacts with the IDR peptide of Hef nuclease. Knockout of the han gene or its C-terminal DHH nuclease domain in Haloferax volcanii resulted in increased sensitivity to the DNA damage reagent MMS. Our results imply that HAN nuclease might be involved in repairing stalled replication forks in archaea.

Benzidine/Quinoidal-Benzidine-Linked, Superbenzene-Based π-Conjugated Chiral Macrocycles and Cyclophanes.

Synthesis of fully conjugated cyclophanes containing large-size polycyclic aromatics is challenging. Now, three benzidine-linked, hexa-peri-hexabenzocoronene (superbenzene)-based ortho-, para-, and meta-cyclophanes are synthesized through intermolecular Yamamoto coupling reaction of structurally pre-organized precursors. Subsequent oxidative dehydrogenation gave the corresponding quinoidal benzidine-linked cyclophanes. Their geometries were confirmed by X-ray crystallographic analysis and their electronic properties were investigated by electronic absorption, cyclic voltammetry, and DFT calculations. The quinoidal benzidine-linked cyclophanes show thermally populated paramagnetic activity with a relatively large singlet-triplet energy gap. Two enantiomers for the ortho-cyclophanes (1-NH and 1-N) were isolated and their chiral figure-of-eight macrocyclic structures were identified. The cage-like cyclophanes 2-NH and 3-NH with concave surface can selectively encapsulate fullerene C70 .

Perylene-Fused, Aggregation-Free Polycyclic Aromatic Hydrocarbons for Solution-Processed Distributed Feedback Lasers.

Perylene-fused, aggregation-free polycyclic aromatic hydrocarbons with partial zigzag periphery (ZY-01, ZY-02, and ZY-03) were synthesized. X-ray crystallographic analysis reveals that there is no intermolecular π-π stacking in any of the three molecules, and as a result, they show moderate-to-high photoluminescence quantum yield in both solution and in the solid state. They also display the characteristic absorption and emission spectra of perylene dyes. ZY-01 and ZY-02 with a nearly planar π-conjugated skeleton exhibit amplified spontaneous emission (ASE) when dispersed in polystyrene thin films. Solution-processed distributed feedback lasers have been fabricated using ZY-01 and ZY-02 as active gain materials, both showing narrow emission linewidth (<0.4 nm) at wavelengths around 515 and 570 nm, respectively. In contrast, ZY-03 did not show ASE and lasing, presumably due to its highly twisted backbone, which facilitates nonradiative internal conversion and intersystem crossing.

Dicyclopenta[4,3,2,1- ghi:4',3',2',1'- pqr]perylene: A Bowl-Shaped Fragment of Fullerene C70 with Global Antiaromaticity.

Solution-phase synthesis of buckybowls remains a big challenge, and there are limited reports on the fragments of C70. Herein, we report a new basic subunit of C70 with C2v symmetry, the dicyclopenta[4,3,2,1- ghi:4',3',2',1'- pqr]perylene (2CP-Per). Its aryl-substituted derivative 2CP-Per-Ar was synthesized and shows a bowl-shaped geometry according to X-ray crystallographic analysis. A fast bowl-to-bowl inversion process was observed above 183 K by variable temperature nuclear magnetic resonance (NMR), with a small inversion energy barrier. 2CP-Per-Ar displays amphoteric redox behavior with a small electrochemical energy gap (1.29 eV). Different from many other aromatic buckybowls, 2CP-Per exhibits global antiaromaticity with a strong paratropic ring current associated with the 16π-electrons rim, as revealed by NMR measurements and theoretic calculations. Its dianion is aromatic, similar to its isoelectronic structure coronene. Its dication is predicted to be aromatic, with a [6]annulene-within-[14]annulene structure.

Bowl-Shaped Carbon Nanobelts Showing Size-Dependent Properties and Selective Encapsulation of C70.

The synthesis of carbon nanobelts (CNBs) with well-defined size and structure remains a challenging topic in nanocarbon chemistry and materials science. Herein, we report the synthesis, physical characterization, and supramolecular properties of two fully conjugated bowl-shaped CNBs (CNB1/CNB2), in which six/eight cyclopenta-rings are fused onto a macrocycle containing three/four alternately linked 2,7-pyrenyl and 2,7-phenanthryl units. The existence of five-membered rings results in a bowl-shaped geometry, as revealed by X-ray crystallographic analysis and density functional theory calculations. Both molecules contain an alternate aromatic phenanthrene- co-quinoidal pyrene structure to satisfy Clar's aromatic sextet rule. The smaller size CNB1 has a deeper bowl depth ( d = 4.997 Å) than CNB2 ( d = 3.682 Å) and cannot undergo bowl-to-bowl (BTB) inversion below 373 K in toluene. However, the larger size CNB2 shows a smaller BTB inversion barrier (∼12 kcal/mol) at the coalescent temperature (248 K), which was estimated by variable-temperature NMR measurements. Both compounds exhibit a small energy gap and amphoteric redox behavior with multiple redox waves. The dications of CBN1 and CBN2, and the tetracation of CBN2, are experimentally accessible by chemical oxidation with NO·SbF6, all displaying unusual open-shell singlet diradical character with a small singlet-triplet energy gap (Δ ES-T = -2.71 kcal/mol for CBN12+, -2.50 kcal/mol for CBN22+, and -2.00 kcal/mol for CBN24+). The dications are globally aromatic while the tetracations are globally antiaromatic according to NMR measurements and theoretical calculations (anisotropy of the induced current density, nucleus independent chemical shift, and 2D isochemical shielding surface). The small bowl-shaped CNB1 demonstrates selective encapsulation of fullerene C70 over C60, with a large association constant ( Ka = 8.066 × 105 M-1 in toluene). However, the larger size CNB2 does not exhibit any encapsulation with both C60 and C70.