Rational Design of Bipolar Host and Thermally Activated Delayed Fluorescence Materials in Donor-Acceptor Molecular Architecture: A Theoretical Study.

Donor-acceptor (D-A) molecules have drawn massive attention recently in the design of high-performance materials, but the underlying reasons for the magic abilities of D-A architecture in building very different organic semiconductors are still unclear. Here, based on a series of experimentally bipolar host and thermally activated delayed fluorescence (TADF) molecules with the same donor but different acceptor units, it was found that TADF emitters have more effective charge transfer between donor and acceptor units than bipolar host molecules. More efficient conjugation effects between the donor and acceptor units of host materials were identified from the lower dihedral angles of the D-A structure, smaller and even negative charge transfer amount, shorter charge-transfer length, and larger hole-electron overlap extent. These findings with in-depth insights into different interaction models of donor and acceptor units shed important light on the molecular design of TADF emitters and bipolar materials in a D-A architecture.

Fluorido-bridged robust metal-organic frameworks for efficient C2H2/CO2 separation under moist conditions.

The modern technology for acetylene production is inevitably accompanied by the contamination of carbon dioxide and moisture impurities. Metal-organic frameworks (MOFs), with rational configurations of fluorine as the hydrogen-bonding acceptor (HBA), exhibit excellent affinities to capture acetylene from the gas mixtures. Currently, most research studies feature anionic fluorine groups as structural pillars (e.g., SiF6 2-, TiF6 2-, NbOF5 2-), whereas in situ insertion of fluorine into metal clusters is rather challenging. Herein, we report a unique fluorine-bridged Fe-MOF, i.e., DNL-9(Fe), which is assembled by mixed-valence FeIIFeIII clusters and renewable organic ligands. The fluorine species in the coordination-saturated structure offer superior C2H2-favored adsorption sites facilitated by hydrogen bonding, with a lower C2H2 adsorption enthalpy than other reported HBA-MOFs, demonstrated by static/dynamic adsorption tests and theoretical calculations. Importantly, DNL-9(Fe) shows exceptional hydrochemical stability under aqueous, acidic, and basic conditions, and its intriguing performance for C2H2/CO2 separation was even maintained at a high relative humidity of 90%.

A Spatiotemporal Deep Learning Approach for Unsupervised Anomaly Detection in Cloud Systems.

Anomaly detection is a critical task for maintaining the performance of a cloud system. Using data-driven methods to address this issue is the mainstream in recent years. However, due to the lack of labeled data for training in practice, it is necessary to enable an anomaly detection model trained on contaminated data in an unsupervised way. Besides, with the increasing complexity of cloud systems, effectively organizing data collected from a wide range of components of a system and modeling spatiotemporal dependence among them become a challenge. In this article, we propose TopoMAD, a stochastic seq2seq model which can robustly model spatial and temporal dependence among contaminated data. We include system topological information to organize metrics from different components and apply sliding windows over metrics collected continuously to capture the temporal dependence. We extract spatial features with the help of graph neural networks and temporal features with long short-term memory networks. Moreover, we develop our model based on variational auto-encoder, enabling it to work well robustly even when trained on contaminated data. Our approach is validated on the run-time performance data collected from two representative cloud systems, namely, a big data batch processing system and a microservice-based transaction processing system. The experimental results show that TopoMAD outperforms some state-of-the-art methods on these two data sets.

Inactivated vaccine effectiveness against symptomatic COVID-19 in Fujian, China during the Omicron BA.2 outbreak.

Objective: More than 90% of the Chinese population have completed 2 doses of inactivated COVID-19 vaccines in Mainland China. However, after China government abandoned strict control measures, many breakthrough infections appeared, and vaccine effectiveness against Omicron BA.2 infection was uncertain. This study aims to investigate the real-world effectiveness of widely used inactivated vaccines during the wave of Omicron variants. Methods: Test-negative case-control study was conducted in this study to analyze the vaccine effectiveness against symptomatic disease caused by the Omicron variant (BA.2) in Fujian, China. Conditional logistic regression was selected to estimate the vaccine effectiveness. Results: The study found the vaccine effectiveness against symptomatic COVID-19 is 32.46% (95% CI, 8.08% to 50.37%) at 2 to 8 weeks, and 27.05% (95% CI, 1.23% to 46.12%) at 12 to 24 weeks after receiving booster doses of the inactivated vaccine. Notably, the 3-17 years group had higher vaccine effectiveness after 2 doses than the 18-64 years and over 65 years groups who received booster doses. Conclusion: Inactivated vaccines alone may not offer sufficient protection for all age groups before the summer of 2022. To enhance protection, other types of vaccines or bivalent vaccines should be considered.

Constructing high-performance TADF polymers from non-TADF monomers: a computational investigation.

Thermally activated delayed fluorescence (TADF) polymers excelling in simple, low-cost and large-area solution process ability have attracted tremendous attention recently, but it remains a great challenge for the design of such materials due to the lack of reliable molecular construction guidelines. Here we perform a systematic computational investigation on the construction of TADF polymers from non-TADF monomers to elucidate the effects of polymerization sites, substituent positions and substituent types. The results indicate that the polymerization of 3,6-carbazole-based monomers with different substituents is efficient to build TADF polymers due to their facile π-conjugation extendability. Especially, polymers with para-phenyl-substituted monomers are promising in light of their separated frontier molecular orbitals for small ΔEST with favorable energy levels, bipolar charge transport properties and relatively strong absorption/emission intensity, which should be highly attractive for experimental investigations. These findings and insights are important in revealing the structure-property relation of TADF polymers made from non-TADF monomers with important clues for understanding the construction mechanism and molecular design principles of TADF polymers.

Oral administration of Lactococcus lactis WHH2078 alleviates depressive and anxiety symptoms in mice with induced chronic stress.

Depression is a mood disorder with a high prevalence rate globally, which is associated with abnormalities in 5-hydroxytryptamine (5-HT) metabolism. Emerging evidence suggests that certain probiotics that modulate 5-HT metabolism confer beneficial effects on depression. In this study, in vitro enterochromaffin RIN14B cells were used for screening potential antidepressant probiotic Lactococcus lactis strains. The L. lactis strain WHH2078 increased to high levels the 5-HT precursor 5-hydroxytryptophan (5-HTP) and the expression of tryptophan hydroxylase 1 (Tph1), which converts tryptophan to 5-HTP in RIN14B cells. The oral administration of WHH2078 (1 × 109 CFU mL-1) in mice with induced chronic unpredictable mild stress (CUMS) for 5 weeks significantly ameliorated depressive and anxiety-like behaviors in the tail suspension test, forced swim test, sucrose preference test, and open field test. Besides, WHH2078 significantly reduced the serum corticosterone level and restored the central levels of 5-HT, 5-HTP, and brain-derived neurotrophic factor in CUMS-induced mice. Moreover, WHH2078 also reversed the 5-HTP levels in the serum and colon, accompanied by an upregulation in colonic Tph1 gene expression. Using 16S rRNA high-throughput sequencing of feces, WHH2078 was shown to improve the CUMS-induced gut microbial dysbiosis, through restoring alpha diversity and the abundances of Firmicutes and Bacteroidetes. In summary, these results indicate that WHH2078 can alleviate rodent depressive and anxiety-like behaviors in response to CUMS, which is associated with the improvement of 5-HT metabolism and modulation of the gut microbiome composition. Therefore, supplementation of the L. lactis strain WHH2078 with antidepressant properties may serve as a promising therapeutic strategy for chronic stress-induced depression.

Heteroatom-bridged heterofluorenes: a theoretical study on molecular structures and optoelectronic properties.

Heteroatom incorporation is highly effective in tuning the molecular structures and optoelectronic properties of conjugated organic molecules. Here, we performed systematic theoretical studies on heteroatom-bridged heterofluorenes (BXFs) constructed by double heteroatom bridges of biphenyl to reveal the effects of heavily incorporated heteroatoms on molecular architecture and π-conjugation for different optoelectronic properties. Nine novel BXFs in three series were investigated and all of them exhibit promising potential optoelectronic properties owing to their highly fused molecular structure with heavy π-conjugation, although the introduction of different types and numbers of heteroatoms will lead to varied properties. Moreover, spiropolymers of BSiF and BGeF polymerized at the bridging position were also designed for the first time and found to have attractive optoelectronic properties of poly(BXF)s inherited from their monomers, demonstrating further the effectiveness of the bis-heteroatom introduction strategy in the construction of high-performance optoelectronic polymers. This heteroatom introduction strategy in constructing highly rigid π-conjugated materials could be applicable to other systems, representing a new concept advance to design novel conjugated small molecules and polymers for high-performance optoelectronic applications.

Tuning Intramolecular Conformation and Packing Mode of Host Materials through Noncovalent Interactions for High-Efficiency Blue Electrophosphorescence.

Molecular conformation plays an important role in tuning the packing modes of organic optoelectronic materials to achieve enhanced and/or balanced charge transport. Here, we introduce the noncovalent intramolecular interactions to the host materials of phosphorescent organic light-emitting diodes (PhOLEDs). Different numbers and/or positions of intramolecular CH···N noncovalent interactions were constructed by using different N-heterocycles of pyridine, pyrimidine, and pyrazine as acceptor units and carbazole as the donor unit in a donor-acceptor-donor (D-A-D) motif. Thus, designed D-A-D molecules were synthesized facilely through a one-step Ullmann reaction in high yields, showing varied intramolecular interactions to regulate the molecular conformation significantly. Impressively, owing to the quasi-parallel molecular conformation, which is beneficial for forming facile transporting channels of both holes and electrons, the newly designed host material of 9,9'-(pyridine-2,5-diyl)bis(9H-carbazole) exhibits good device performance of blue PhOLEDs with current, power, and external quantum efficiencies up to 33.0 cd A-1, 32.1 lm W-1, and 16.3%, respectively. This work highlights the significant importance of the noncovalent interactions in designing advanced organic semiconductors for high-performance optoelectronic devices.

Direct population of triplet excited states through singlet-triplet transition for visible-light excitable organic afterglow.

Invoking efficient afterglow in metal-free organic molecules represents an important material advancement. However, organic afterglow suffers from low intensity and efficiency and generally needs to be excited by UV light owing to its spin-forbidden phosphorescent nature that essentially requires facile intersystem crossing (ISC). Here, we propose a strategy to bypass the traditional ISC through facilitating singlet-triplet transition to directly populate triplet excited states from the ground state by combining synergetic effects of both heavy/hetero-atom incorporation and aromatic aggregation. Verified by systematic experimental and computational investigations, this unique singlet-to-triplet absorption results in a much improved organic afterglow quantum efficiency up to 9.5% with a prolonged lifetime of 0.25 s under visible-light irradiation. Fundamentally, this work illustrates for the first time the great potential of the direct population method to red-shift the excitation wavelength and improve the afterglow efficiency, offering important clues for the development of triplet-state involved organic optoelectronic technologies.

Synthesis and Application of Perylene-Embedded Benzoazoles for Small-Molecule Organic Solar Cells.

Two new building blocks of perylene-embedded benzoazoles containing both rigid 2D-conjugated aromatic rings and flexible branched alkyl chains were designed and facilely synthesized in high yields for organic solar cells (OSCs). With a typical acceptor of diketopyrrolopyrrole, small molecular OSC donors constructed in an acceptor-fused donor-acceptor motif exhibit excellent solubility, stability, and light absorption with tunable frontier orbitals, leading to a power conversion efficiency of up to 2.88% in preliminary OSCs.

6-Benzhydryl-4-amino-quinolin-2-ones as Potent Cannabinoid Type 1 (CB1) Receptor Inverse Agonists and Chemical Modifications for Peripheral Selectivity.

A novel series of 6-benzhydryl-4-amino-quinolin-2-ones was discovered as cannabinoid type 1 receptor (CB1R) inverse agonists based on the high-throughput screening hit, compound 1a. Structure-activity relationships were studied to improve in vitro/in vivo pharmacology and restrict distribution to the peripheral circulation. We adopted several strategies such as increasing topological polar surface area, incorporating discrete polyethylene glycol side chains, and targeting P-glycoprotein (P-gp) to minimize access to the brain. Compound 6a is a P-gp substrate and a potent and highly selective CB1R inverse agonist, demonstrating excellent in vivo metabolic stability and a low brain to plasma ratio. However, brain receptor occupancy studies showed that compound 6a may accumulate in brain with repeat dosing. This was evidenced by compound 6a inhibiting food intake and inducing weight loss in diet-induced obese mice. Thus, a strategy based on P-gp efflux may not be adequate for peripheral restriction of the disclosed quinolinone series.

Resonance-Activated Spin-Flipping for Efficient Organic Ultralong Room-Temperature Phosphorescence.

Triplet-excited-state-involved photonic and electronic properties have attracted tremendous attention for next-generation technologies. To populate triplet states, facile intersystem crossing (ISC) for efficient exciton spin-flipping is crucial, but it remains challenging in organic molecules free of heavy atoms. Here, a new strategy is proposed to enhance the ISC of purely organic optoelectronic molecules using heteroatom-mediated resonance structures capable of promoting spin-flipping at large singlet-triplet splitting energies with the aid of the fluctuation of the state energy and n-orbital component upon self-adaptive resonance variation. Combined experimental and theoretical investigations confirm the key contributions of the resonance variation to the profoundly promoted spin-flipping with ISC rate up to ≈107 s-1 in the rationally designed NPX (X = O or S) resonance molecules. Importantly, efficient organic ultralong room-temperature phosphorescence (OURTP) with simultaneously elongated lifetime and improved efficiency results overcoming the intrinsic competition between the OURTP lifetime and efficiency. With the spectacular resonance-activated OURTP molecules, time-resolved and color-coded quick response code devices with multiple information encryptions are realized, demonstrating the fundamental significance of this approach in boosting ISC dynamically for advanced optoelectronic applications.

Discovery of Orally Efficacious Tetrahydrobenzimidazoles as TGR5 Agonists for Type 2 Diabetes.

We have discovered a novel series of tetrahydrobenzimidazoles 3 as TGR5 agonists. Initial structure-activity relationship studies with an assay that measured cAMP levels in murine enteroendocrine cells (STC-1 cells) led to the discovery of potent agonists with submicromolar EC50 values for mTGR5. Subsequent optimization through methylation of the 7-position of the core tetrahydrobenzimidazole ring resulted in the identification of potent agonists for both mTGR5 and hTGR5 (human enteroendocrine NCI-H716 cells). While the lead compounds displayed low to moderate exposure after oral dosing, they significantly reduced blood glucose levels in C57 BL/6 mice at 30 mg/kg and induced a 13-22% reduction in the area under the blood glucose curve (AUC)0-120 min in oral glucose tolerance tests (OGTT).

Evaluation of anti-diabetic effect and gall bladder function with 2-thio-5-thiomethyl substituted imidazoles as TGR5 receptor agonists.

A novel series of 2-thio-5-thiomethyl substituted imidazoles was discovered to be potent TGR5 agonists that possessed glucose-lowering effects while inhibiting gall bladder emptying in mice.

Tetrahydroindazole derivatives as potent and peripherally selective cannabinoid-1 (CB1) receptor inverse agonists.

A series of potent and receptor-selective cannabinoid-1 (CB1) receptor inverse agonists has been discovered. Peripheral selectivity of the compounds was assessed by a mouse tissue distribution study, in which the concentrations of a test compound in both plasma and brain were measured. A number of peripherally selective compounds have been identified through this process. Compound 2p was further evaluated in a 3-week efficacy study in the diet-induced obesity (DIO) mouse model. Beneficial effects on plasma glucose were observed from the compound-treated mice.

Tetrahydropyrazolo[4,3-c]pyridine derivatives as potent and peripherally selective cannabinoid-1 (CB1) receptor inverse agonists.

Peripherally restricted CB1 receptor inverse agonists hold potential as useful therapeutics to treat obesity and related metabolic diseases without causing undesired CNS-mediated adverse effects. We identified a series of tetrahydropyrazolo[4,3-c]pyridine derivatives as potent and highly peripherally selective CB1 receptor inverse agonists. This discovery was achieved by introducing polar functional groups into the molecule, which increase the topological polar surface area and reduce its brain-penetrating ability.

Arterial antithrombotic activity of rivaroxaban, an orally active factor Xa inhibitor, in a rat electrolytic carotid artery injury model of thrombosis.

Rivaroxaban, an oral, direct factor Xa inhibitor, has been approved in several countries for thromboprophylaxis after elective hip or knee arthroplasty based on favorable benefit-risk profile and improved efficacy compared to enoxaparin in reducing the composite of symptomatic and asymptomatic deep vein thrombosis, nonfatal pulmonary embolism, and all-cause mortality. Given the potential therapeutic utility of factor Xa inhibition in arterial thrombosis, we evaluated the antithrombotic activity of rivaroxaban in a model of arterial thrombosis in anesthetized rats in which thrombotic occlusion was induced by electrolytic injury of the carotid artery. Rivaroxaban, 0.3, 1 or 3 mg/kg, enoxaparin, 10 mg/kg, or vehicle were infused intravenously to anesthetized rats and time to occlusion as well as coagulation parameters monitored following carotid electrolytic injury. Although the lowest dose of rivaroxaban (0.3 mg/kg) did not prolong occlusion time compared to vehicle, rivaroxaban at 1 or 3 mg/kg prevented occlusion in all vessels during the 30-min observation period (median occlusion time >30 min), which was greater than that following a single dose of enoxaparin infused at a dose of 10 mg/kg (median time to occlusion = 21.6 min). Rivaroxaban was also effective following oral dosing at 3 mg/kg. Rivaroxaban's antithrombotic activity was paralleled by dose-dependent increases in prothrombin time (PT) and activated clotting time (ACT) without significant changes in activated partial thromboplastin time. Rivaroxaban also markedly increased Russell's viper venom time (RVVT) and decreased thrombin-antithrombin complex concentrations at all doses. These findings support the potential utility of rivaroxaban in arterial thrombotic disorders such as acute coronary syndrome, stroke and peripheral arterial disease.

Torcetrapib produces endothelial dysfunction independent of cholesteryl ester transfer protein inhibition.

OBJECTIVE: Torcetrapib, a prototype cholesteryl ester transfer protein (CETP) inhibitor with potential for decreasing atherosclerotic disease, increased cardiovascular events in clinical trials. The identified hypertensive and aldosterone-elevating actions of torcetrapib may not fully account for this elevated cardiovascular risk. Therefore, we evaluated the effects of torcetrapib on endothelial mediated vasodilation in vivo. METHODS AND RESULTS: In vivo endothelial mediated vasodilation was assessed using ultrasound imaging of acetylcholine-induced changes in rabbit central ear artery diameter. Torcetrapib, in addition to producing hypertension and baseline vasoconstriction, markedly inhibited acetylcholine-induced vasodilation. A structurally distinct CETP inhibitor, JNJ-28545595, did not affect endothelial function despite producing similar degrees of CETP inhibition and high-density lipoprotein elevation. Nitroprusside normalized torcetrapib's basal vasoconstriction and elicited dose-dependent vasodilation of norepinephrine preconstricted arteries in torcetrapib-treated animals, indicating torcetrapib did not impair smooth muscle function. CONCLUSIONS: Torcetrapib significantly impairs endothelial function in vivo, independent of CETP inhibition and high-density lipoprotein elevation. Given the well-documented association of endothelial dysfunction with cardiovascular disease and risk, this activity of torcetrapib may have contributed to increased cardiovascular risk in clinical trials.

Thrombogenic collagen-mimetic peptides: Self-assembly of triple helix-based fibrils driven by hydrophobic interactions.

Collagens are integral structural proteins in animal tissues and play key functional roles in cellular modulation. We sought to discover collagen model peptides (CMPs) that would form triple helices and self-assemble into supramolecular fibrils exhibiting collagen-like biological activity without preorganizing the peptide chains by covalent linkages. This challenging objective was accomplished by placing aromatic groups on the ends of a representative 30-mer CMP, (GPO)(10), as with l-phenylalanine and l-pentafluorophenylalanine in 32-mer 1a. Computational studies on homologous 29-mers 1a'-d' (one less GPO), as pairs of triple helices interacting head-to-tail, yielded stabilization energies in the order 1a' > 1b' > 1c' > 1d', supporting the hypothesis that hydrophobic aromatic groups can drive CMP self-assembly. Peptides 1a-d were studied comparatively relative to structural properties and ability to stimulate human platelets. Although each 32-mer formed stable triple helices (CD) spectroscopy, only 1a and 1b self-assembled into micrometer-scale fibrils. Light microscopy images for 1a depicted long collagen-like fibrils, whereas images for 1d did not. Atomic force microscopy topographical images indicated that 1a and 1b self-organize into microfibrillar species, whereas 1c and 1d do not. Peptides 1a and 1b induced the aggregation of human blood platelets with a potency similar to type I collagen, whereas 1c was much less effective, and 1d was inactive (EC(50) potency: 1a/1b >> 1c > 1d). Thus, 1a and 1b spontaneously self-assemble into thrombogenic collagen-mimetic materials because of hydrophobic aromatic interactions provided by the special end-groups. These findings have important implications for the design of biofunctional CMPs.