A general copper-catalysed enantioconvergent C(sp3)-S cross-coupling via biomimetic radical homolytic substitution.

Although α-chiral C(sp3)-S bonds are of enormous importance in organic synthesis and related areas, the transition-metal-catalysed enantioselective C(sp3)-S bond construction still represents an underdeveloped domain probably due to the difficult heterolytic metal-sulfur bond cleavage and notorious catalyst-poisoning capability of sulfur nucleophiles. Here we demonstrate the use of chiral tridentate anionic ligands in combination with Cu(I) catalysts to enable a biomimetic enantioconvergent radical C(sp3)-S cross-coupling reaction of both racemic secondary and tertiary alkyl halides with highly transformable sulfur nucleophiles. This protocol not only exhibits a broad substrate scope with high enantioselectivity but also provides universal access to a range of useful α-chiral alkyl organosulfur compounds with different sulfur oxidation states, thus providing a complementary approach to known asymmetric C(sp3)-S bond formation methods. Mechanistic results support a biomimetic radical homolytic substitution pathway for the critical C(sp3)-S bond formation step.

Multi-apodization with cross-correlation combined with generalized sidelobe canceller applied to ultrasound imaging.

BACKGROUND: Beamforming is vital for medical ultrasound imaging systems. The generalized sidelobe canceller (GSC) beamforming can improve the image quality of lateral resolution, but its performance improvement in contrast and robustness is limited. OBJECTIVE: This paper proposes an improved generalized sidelobe canceller algorithm based on multi-apodization with cross-correlation (MAXB-IGSC), which aims to improve the contrast and robustness of ultrasound imaging while maintaining the high image resolution and background speckle quality of GSC. METHODS: The proposed MAXB-IGSC uses multiple pairs of complementary received apodization functions to process the echo data individually to obtain multiple pairs of data sets. The average of their normalized cross-correlation coefficients is then calculated and utilized to determine the adaptive subarray length of the GSC covariance matrix and weights the output of the improved GSC. RESULTS: The MAXB-IGSC improves the contrast ratio (CR) by 171.18% in anechoic cyst simulation and by 91.23%/130.97%/171.76% in geabr_0 (a dataset from the University of Michigan) experiment compared with GSC, respectively. Furthermore, MAXB-IGSC exhibits significant noise immunity, which greatly improves the robustness of the imaging. The technology also maintains the brightness and uniformity of the background speckle. CONCLUSION: The proposed MAXB-IGSC has potential for obtaining high-quality ultrasound images in clinical applications.

The roles of natural triterpenoid saponins against Alzheimer's disease.

The aging of the world population and increasing stress levels in life are the major cause of the increased incidence of neurological disorders. Alzheimer's disease (AD) creates a huge burden on the lives and health of individuals and has become a big concern for society. Triterpenoid saponins (TS), representative natural product components, have a wide range of pharmacological bioactivities such as anti-inflammation, antioxidation, antiapoptosis, hormone-like, and gut microbiota regulation. Notably, some natural TS exhibited promising neuroprotective activity that can intervene in AD progress, especially in the early stage. Recently, studies have indicated that TS play a pronounced positive role in the prevention and treatment of AD. This review discusses the recent research on the neuroprotection of TS and proceeds to detail the action mechanisms of TS against AD, hoping to provide a reference for drug development for anti-AD.

MYB112 connects light and circadian clock signals to promote hypocotyl elongation in Arabidopsis.

Ambient light and the endogenous circadian clock play key roles in regulating Arabidopsis (Arabidopsis thaliana) seedling photomorphogenesis. PHYTOCHROME-INTERACTING FACTOR 4 (PIF4) acts downstream of both light and the circadian clock to promote hypocotyl elongation. Several members of the R2R3-MYB transcription factor (TF) family, the most common type of MYB TF family in Arabidopsis, have been shown to be involved in regulating photomorphogenesis. Nonetheless, whether R2R3-MYB TFs are involved in connecting the light and clock signaling pathways during seedling photomorphogenesis remains unknown. Here, we report that MYB112, a member of the R2R3-MYB family, acts as a negative regulator of seedling photomorphogenesis in Arabidopsis. The light signal promotes the transcription and protein accumulation of MYB112. myb112 mutants exhibit short hypocotyls in both constant light and diurnal cycles. MYB112 physically interacts with PIF4 to enhance the transcription of PIF4 target genes involved in the auxin pathway, including YUCCA8 (YUC8), INDOLE-3-ACETIC ACID INDUCIBLE 19 (IAA19), and IAA29. Furthermore, MYB112 directly binds to the promoter of LUX ARRHYTHMO (LUX), the central component of clock oscillators, to repress its expression mainly in the afternoon and relieve LUX-inhibited expression of PIF4. Genetic evidence confirms that LUX acts downstream of MYB112 in regulating hypocotyl elongation. Thus, the enhanced transcript accumulation and transcriptional activation activity of PIF4 by MYB112 additively promotes the expression of auxin-related genes, thereby increasing auxin synthesis and signaling and fine-tuning hypocotyl growth under diurnal cycles.

Low complexity adaptive ultrasound image beamformer combined with improved multiphase apodization with cross-correlation.

In this paper, an ultrasound imaging method combined with low-complexity adaptive beamformer (LCA) and improved multiphase apodization with cross-correlation (IMPAX) is proposed to improve image resolution and contrast with low hardware cost. Firstly, the delayed echo signal is apodized by the LCA to obtain a narrow mainlobe width echo signal and LCA output. Then, multiple pairs of complementary square-wave phase apodizations are applied to the apodized echo signal to obtain corresponding signal pairs, which are used to calculate the normalized cross-correlation (NCC) matrix. Finally, the average value of the NCC matrices is filtered by 2-D means, and the filtered result is introduced as the weighting factor for the LCA output. The simulation and experimental results show that the proposed LCA-IMPAX can effectively reduce the mainlobe width, suppress clutter, and be robust to noise. Compared with DAS, LCA, and MPAX, for simulated point targets, the full-width at half-maximum (FWHM, -6dB) of LCA-IMPAX is reduced by 49.22%, 10.06%, and 48.67%, respectively. For simulated cyst, the CR is improved by 219.91%, 138.08%, and 103.44%, respectively. For experimental cysts, the CR is improved by an average of 145.00%, 136.14%, and 55.09%, respectively. The results of human heart data indicate that LCA-IMPAX has good imaging quality in vivo. Since the proposed method does not involve covariance matrix inversion, it can be applied in real-time imaging systems.

Design, synthesis and evaluation of a series of potential prodrugs of a Bruton's tyrosine kinase (BTK) inhibitor.

BTK has become a particularly attractive therapeutic target in autoimmune diseases and B-cell malignancies, making BTK inhibitors a valuable and important therapeutic option. We present the design, synthesis, and evaluation of a series of prodrugs of a BTK inhibitor with an insoluble 2,5-diaminopyrimidine structure. Tails containing different solubilizing groups were added to the parent molecule via an ester linkage. Prodrug 5a showed good aqueous solubility and could be efficiently converted to the parent in a human plasma stability study. The rational prodrug design was supported by molecular studies and a dramatically reduced BTK kinase-inhibitory potential. Taken together, the chemical, biological, and molecular studies suggest that prodrug derivatization of the 2,5-diaminopyrimidine scaffold could be a potential strategy for advancing this series of BTK inhibitors into the therapeutic arena.

MS/MS molecular networking-guided in-depth profiling of triterpenoid saponins from the fruit of Eleutherococcus senticosus and their neuroprotectivity evaluation.

INTRODUCTION: Eleutherococcus senticosus fruit (ESF) is a natural health supplement resource that has been extensively applied as a tonic for the nervous system. The structures and neural bioactivities of triterpenoid saponins (TS), which are the major constituents of ESF, have not been comprehensively analyzed thus far. OBJECTIVE: We conducted a complete in-depth MS/MS molecular networking (MN)-based targeted analysis of TS from the crude extract of ESF and investigated its neuroprotective value. METHODS: An MS/MS MN-guided strategy was used to rapidly present a series of precursor ions (PIs) of TS in a compound cluster as TS-targeted information used in the discovery and characterization of TS. In addition, a prepared TS-rich fraction of ESF was assayed for its restraining effects on ß-amyloid-induced inhibition of neurite outgrowth. RESULTS: A total of 87 TS were discovered using a PI tracking strategy, 28 of which were characterized as potentially undescribed structures according to their high-resolution MS values. Furthermore, the TS-rich fraction can significantly reduce ß-amyloid-induced damage to neural networks by promoting the outgrowth of neurites and axons. CONCLUSION: Our findings reveal the richness of TS in ESF and will accelerate their application in the treatment of neurodegenerative diseases.

Dual projection generalized sidelobe canceller based on mixed signal subspace for ultrasound imaging.

In this paper, we propose a dual projection generalized sidelobe canceller (DPGSC) based on mixed subspace (MS) for ultrasound imaging, which aims to improve the speckle signal-noise-ratio (sSNR) and decrease the dark-region artifacts. A mixed signal subspace based on the correlation between the desired steering vector and the eigenvectors is constructed to further optimize the desired steering vector and the final weight vector. The simulated and experimental results show that the proposed method can greatly improve the speckle uniformity. In the geabr_0 experiment, the standard deviation of background and sSNR of MS-DPGSC can be improved by 48.07% and 58.49% more than those of eigenspace-based generalized sidelobe canceller (ESGSC). Furthermore, for a hyperechoic target, the maximal improvement of contrast ratio is 95.29%. In terms of anechoic cyst, the contrast-to-noise ratio of MS-DPGSC is increased by 123.08% than that of ESGSC. The rat mammary tumor experimental data show that the proposed method has better comprehensive imaging effect than traditional generalized sidelobe cancellers and ESGSCs.

Depth-dependent apodization window based on Chebyshev polynomial for ultrasound imaging.

To improve the image resolution of a portable real-time ultrasound imaging device, this paper proposes a beamformer with composite apodization windows based on Chebyshev polynomial. By introducing the Chebyshev window, the level of sidelobe can be flexibly controlled. The value of weighting changes according to the detection depth and ultrasound attenuation such that it can attain better image resolution than traditional beamformers. The simulations and experiments indicate that the proposed method can flexibly narrow the mainlobe width while keeping the performance of the suppressing artifacts. The full width at half-maximum of this method is 14.1%-27.8% and 4.2%-25.0% narrower than those of traditional apodization methods in the field II simulations and Geabr_0 experiment, respectively.

Pharmacological effects of Eleutherococcus senticosus on the neurological disorders.

Eleutherococcus senticosus is a medicinal plant widely used in traditional medicine and edible remedies with effects on anti-fatigue, sleep improvement, and memory enhancement. Recently, the application of E. senticosus to neurological disorders has been a focus. However, its overall pharmacological effect on neural diseases and relevant mechanisms are needed in an in-depth summary. In this review, the traditional uses and the therapeutic effect of E. senticosus on the treatment of fatigue, depression, Alzheimer's disease, Parkinson's disease, and cerebral ischemia were summarized. In addition, the underlying mechanisms involved in the anti-oxidative damage, anti-inflammation, neurotransmitter modulation, improvement of neuronal growth, and anti-apoptosis were discussed. This review will accelerate the understanding of the neuroprotective effects brought from the E. senticosus, and impetus its development as a phytotherapy agent against neurological disorders.

Memory enhancement effect of saponins from Eleutherococcus senticosus leaves and blood-brain barrier-permeated saponins profiling using a pseudotargeted monitoring strategy.

Dried Eleutherococcus senticosus leaves (ESL), also known as Siberian ginseng tea, are beneficial for human neural disorders. Our previous studies showed that the aqueous extract of ESL enhanced memory in mice, and its saponin fraction (ESL-SAP) exhibited promising neuroprotective activities in vitro; however, the in vivo neurally related effect, bioactive material basis, and possible mechanism of action of ESL-SAP have not been investigated. Here, a series of memory and learning tests were carried out, and the results evidenced a significant enhancement effect of ESL-SAP. Furthermore, an in vivo saponin library-guided pseudotargeted strategy was established to support the rapid monitoring of 26 blood-brain barrier (BBB)-permeated saponins from ESL-SAP-administered rats. A further network pharmacology analysis was conducted on BBB-permeated compounds, which indicated that the in vivo mechanism of ESL-SAP might be effective through multiple targets and pathways, such as the AGE-RAGE signaling pathway and PI3K-Akt signaling pathway, to exert neuroprotective effects. Moreover, the molecular docking experiments demonstrated that key BBB-transferred saponins primarily interacted with targets HRAS, MAPK1, and MAPK8 to produce the neuroprotective effect.

Clinical application study of immediate implantation without bone grafting in maxillary molars: a clinical study with one-year follow up.

Our aim was to evaluate the clinical effect and feasibility of immediate implant placement combined with flap surgery with no bone grafting and non-submerged healing in the maxillary molar area. Thirty-five patients with failed single teeth in the molar area were selected. After minimally invasive extraction of the tooth, the flaps were elevated, and an implant inserted immediately; thereafter a healing abutment was connected. The mucoperiosteal flaps were sutured around the abutment without tension, and a permanent repair was performed six months later. During the study period, the implant survival rate, cone-beam computed tomography (CBCT) data, torque value, and the results of a subjective satisfaction survey conducted with a visual analogue scale (VAS), were evaluated to assess the procedure's therapeutic effect and feasibility. All 35 teeth were successfully implanted immediately after flap surgery. The mean (SD) torque value was 42.79 (5.70) N∙cm at the time of placement. During the six-month follow up and after one year of restoration, all 35 teeth showed no loosening, shedding of implants and restoration, or inflammation around the site. The mean (SD) value of the bony space around the implant immediately after the operation was 2.47 (0.56) mm. The bony spaces were filled with new bone after six months postoperatively. The mean (SD) VAS for satisfaction was 8.71 (1.05). Immediate implant placement combined with flap surgery without bone grafting and non-submerged healing is feasible for the maxillary molar area and produces a satisfactory clinical effect.

MRI-based observation of the size and morphology of temporomandibular joint articular disc and condyle in young asymptomatic adults.

OBJECTIVE: To investigate the size and morphology of the temporomandibular joint (TMJ) articular disc and condyle in young asymptomatic adults by using magnetic resonance imaging (MRI) and to provide a reference for clinical diagnosis and scientific study of temporomandibular disorders (TMD). METHODS: Overall, 93 undergraduate volunteers without TMD were enrolled from the freshmen pool at the Qingdao University. All participants underwent MRI of the oblique sagittal and oblique coronal TMJ planes. The articular disc and condyle were subsequently measured, and their morphology was evaluated. The obtained data were then grouped and analyzed statistically. Finally, intragroup correlation coefficient (ICC) was used to evaluate the interobserver measurement reliability. RESULTS: We totally received 186 TMJ imaging samples. Based on our analysis, disc's anterior band in young asymptomatic adult females were thicker than males of the same age (p = 0.024). Moreover, the media-lateral dimensions of the condylar head of adult females were shorter than males of equal age (P＜0.001). The bilateral articular disc morphology was the same in 72.4% of subjects while the condylar morphology was the same in 63.4% of participants. Finally, using measurement reliability assessment, we demonstrated that our conclusions are reliable (ICC ≥0.7). CONCLUSION: The thickness of the anterior band of the disc and the media-lateral dimensions of the condylar head were gender-related. Additionally, the morphology of the bilateral articular disc and condyle was different among the subset of young asymptomatic adults.

Efficient, Full Spectrum-Driven H2 Evolution Z-Scheme Co2P/CdS Photocatalysts with Co-S Bonds.

Exploring high-efficiency, low-cost, and stable photocatalysts that enable full solar spectrum including UV, visible, and near-infrared (NIR) light utilization for photocatalytic hydrogen generation still faces huge challenge. Herein, a Co2P/CdS Z-scheme photocatalyst without a noble metal is rationally fabricated to achieve ultrabroad UV-vis-NIR harvesting. Compared to Pt/CdS, CdS, and Co2P, the optimized Co2P/CdS exhibits much more outstanding performance with the H2 generation rates of 262.16, 66.98, and 3.93 mmol/g/h under solar, visible (780 nm > λ > 420 nm), and NIR (λ > 780 nm) light, respectively. Particularly, 10% Co2P/CdS displays a prominent apparent quantum efficiency value of 2.26% at 700 nm. The Z-scheme transform route can effectively enhance the separation of charge carriers in Co2P/CdS for UV-vis-driven HER, as confirmed by photoluminescence and photoelectrochemical measurements. More importantly, the Co-S bonds at the interface demonstrated by Fourier transform infrared, Raman (mapping), and X-ray photoelectron spectroscopy and density functional theory calculations can act as a "bridge" for charge transfer, thereby enhancing the full spectrum-driven H2 evolution. To the best of our knowledge, this is a rare research on full spectrum-driven photocatalytic HER without a noble metal.

Structure-based identification of novel CK2 inhibitors with a linear 2-propenone scaffold as anti-cancer agents.

Protein kinase CK2 has emerged as an attractive cancer therapeutic target. Previous studies have highlighted the challenge of optimizing CK2 ATP-competitive inhibitors that have low druggability due to their polycyclic ring scaffolds. Therefore the development of novel inhibitors with non-polycyclic scaffolds emerges as a promising strategy for drug discovery targeting CK2. In this current study, based on the similar predicted binding poses of the linear 2-propenone scaffold of isoliquiritigenin with that of the polycyclic inhibitor CX-4945, a series of 2-propenone derivatives containing an amine-substituted five-membered heterocycle and a benzoic acid were designed, synthesized and evaluated for their in vitro CK2 inhibition and anti-cancer activity. Compound 8b was found to be the most potent CK2 inhibitor (IC50 = 0.6 µM) with the anti-proliferative activity on HepG2 cancer cells (IC50 = 14 µM), compared to the activity of isoliquiritigenin (IC50 = 17 µM and 51 µM, respectively). Molecular docking was performed to understand the binding modes of the newly designed 2-propenone derivatives with CK2. Compound 8b formed the most favorable network of hydrogen bonds with both the hinge region and positive area. Our results indicate that CK2 derivatives with a linear 2-propenone scaffold are promising candidates for anti-cancer drug discovery.

Discovery of an Orally Available Janus Kinase 3 Selective Covalent Inhibitor.

JAK family kinases are important mediators of immune cell signaling and Janus Kinase 3 (JAK3) has long been indicated as a potential target for autoimmune disorders. Intensive efforts to develop highly selective JAK3 inhibitors have been underway for many years. However, because of JAK3's strong binding preference to adenosine 5'-triphosphate (ATP), a number of inhibitors exhibit large gaps between enzymatic and cellular potency, which hampers efforts to dissect the roles of JAK3 in cellular settings. Using a targeted covalent inhibitor approach, we discovered compound 32, which overcame ATP competition (1 mM) in the enzymatic assay, and demonstrated significantly improved inhibitory activity for JAK3-dependent signaling in mouse CTLL-2 and human peripheral blood mononuclear cells. Compound 32 also exhibited high selectivity within the JAK family and good pharmacokinetic properties. Thus, it may serve as a highly valuable tool molecule to study the overlapping roles of JAK family kinases in complex biological settings. Our study also suggested that for covalent kinase inhibitors, especially those targeting kinases with low Km ATP values, the reversible interactions between molecules and proteins should be carefully optimized to improve the overall potency.

Intravenous Injection of miR-34a Inhibitor Alleviates Diabetes Mellitus-Induced Vascular Endothelial Dysfunction by Targeting NOTCH1.

BACKGROUND: miR-34a is a multifunctional post-translational modulator, which is involved in several diabetes-related complications. However, miR-34a remains to be fully elucidated in the diabetic endothelium from rats. In this study, the role of miR-34a/NOTCH1 signaling in the progression of hyperglycemia-vascular endothelial dysfunction was investigated. METHODS: In intravenous injection of miR-34a mimics and inhibitors in streptozotocin (STZ)-induced diabetic rats, the biomarkers of endothelial dysfunction was measured. The targeted genes were predicted by a bioinformatics algorithm and confirmed by a dual luciferase reporter assay. The mRNA and protein levels were assayed by qRT-PCR and western blotting, respectively. Immunohistochemical staining was performed to measure NOTCH1 expression in the diabetic endothelium. RESULTS: miR-34a was significantly up-regulated, and NOTCH1 down-regulated, in the thoracic aorta from STZ-induced diabetic rats compared with control group. As compared to model group, the mRNA of NOTCH1 was significantly decreased or increased by miR-34a mimics or inhibitors ex vivo, respectively. Bioinformatics methods further demonstrated that NOTCH1 was a potential target of miR-34a, which was confirmed by dual-luciferase reporter assay. Moreover, both serum ET and NO were significantly increased in diabetic rats as compared to control group. miR-34a inhibitors ex vivo treatment resulted in significant down-regulation ofserum ET and NO levels in diabetic rats as compared to model group. CONCLUSION: These results provide evidence to support the use of miR-34a inhibitors as a therapeutic approach attenuating hyperglycemia-induced vascular endothelial dysfunction.

A Copper Catalyst with a Cinchona-Alkaloid-Based Sulfonamide Ligand for Asymmetric Radical Oxytrifluoromethylation of Alkenyl Oximes.

A copper-catalyzed asymmetric radical oxytrifluoromethylation of alkenyl oxime and Togni's reagent has been successfully developed, thereby providing straightforward access to CF3 -containing isoxazolines bearing α-tertiary stereocenters with excellent yield and enantioselectivity. The key to success is the rational design of cinchona-alkaloid-based sulfonamides as neutral/anionic hybrid ligands to effectively control the stereochemistry in copper-catalyzed reactions involving free alkyl radical species. The utility of this method is illustrated by efficient transformation of the products into useful chiral CF3 -containing 1,3-aminoalcohols.

Nicotinic Acid Receptor GPR109A Exerts Anti-Inflammatory Effects Through Inhibiting the Akt/mTOR Signaling Pathway in MIN6 Pancreatic ß cells.

OBJECTIVES: We found that activation of the nicotinic acid receptor GPR109A, expressed by the MIN6 murine pancreatic ß cell line, inhibits nitric oxide accumulation induced by IFN-γ and TNF-α, implicating an anti-inflammatory effect of GPR109A in MIN6 cells. Nevertheless, the mechanism of its anti-inflammatory effect is still unknown. In this study, we used palmitic acid to stimulate MIN6 cells to induce inflammatory cytokine production and explored the mechanism by which GPR109A exerts anti-inflammatory effects. MATERIALS AND METHODS: RT-PCR and immunocytochemical staining were used to detect the expression of GPR109A in MIN6 cells. Western blotting was used to detect the activation of the Akt/mTOR signaling pathway and expression of the inflammatory cytokine INF-γ, in MIN6 cells, following treatments with palmitic acid and palmitic acid+nicotinic acid, or with different concentrations of nicotinic acid and 3-hydroxybutyrate. RESULTS: In MIN6 cells, GPR109A transcripts and protein are expressed and GPR109A protein is mainly located in the cell membrane and cytoplasm. Palmitic acid enhanced the phosphorylation of Akt and p70S6K and elevated the expression of IFN-γ. Co-treatment with nicotinic acid, which is an agonist of GPR109A, inhibited the palmitic acid-induced phosphorylation of Akt, mTOR, and p70S6K, as well as the expression of IFN-γ. CONCLUSIONS: GPR109A may inhibit inflammatory cytokine production, induced by palmitic acid, by MIN6 cells possibly via inhibiting the Akt/mTOR signaling pathway.