Type I [4σ+4π] versus [4σ+4π-1] Cycloaddition To Access Medium-Sized Carbocycles and Discovery of a Liver X Receptor ß-Selective Ligand.

Transition-metal-catalyzed [4+4] cycloaddition leading to cyclooctanoids has centered on dimerization between 1,3-diene-type substrates. Herein, we describe a [4σ+4π-1] and [4σ+4π] cycloaddition strategy to access 7/8-membered fused carbocycles through rhodium-catalyzed coupling between the 4σ-donor (benzocyclobutenones) and pendant diene (4π) motifs. The two pathways can be controlled by adjusting the solvated CO concentration. A broad range (>40 examples) of 5-6-7 and 5-6-8 polyfused carbocycles was obtained in good yields (up to 90 %). DFT calculations, kinetic monitoring and 13C-labeling experiments were carried out, suggesting a plausible mechanism. Notably, one 5-6-7 tricycle was found to be a very rare, potent, and selective ligand for the liver X receptor ß (KD=0.64 µM), which is a potential therapeutic target for cholesterol-metabolism-related fatal diseases.

Pushing the thinness limit of silver films for flexible optoelectronic devices via ion-beam thinning-back process.

Reducing the silver film to 10 nm theoretically allows higher transparency but in practice leads to degraded transparency and electrical conductivity because the ultrathin film tends to be discontinuous. Herein, we developed a thinning-back process to address this dilemma, in which silver film is first deposited to a larger thickness with high continuity and then thinned back to a reduced thickness with an ultrasmooth surface, both implemented by a flood ion beam. Contributed by the shallow implantation of silver atoms into the substrate during deposition, the thinness of silver films down to 4.5 nm can be obtained, thinner than ever before. The atomic-level surface smooth permits excellent visible transparency, electrical conductivity, and the lowest haze among all existing transparent conductors. Moreover, the ultrathin silver film exhibits the unique robustness of mechanical flexibility. Therefore, the ion-beam thinning-back process presents a promising solution towards the excellent transparent conductor for flexible optoelectronic devices.

A pH-responsive, injectable and self-healing chitosan-coumarin hydrogel based on Schiff base and hydrogen bonds.

Smart hydrogels have shown great potential applications in disease treatment due to their controlled and local drug-release ability. Herein, a smart hydrogel with pH-responsive, injectable, and self-healing properties for controlled release of taxifolin (TFL) was prepared by freezing-thawing and photo-crosslinking methods. The crosslinking network of hydrogels (CS-CA hydrogels) was constructed by the hydrogen bonds, Schiff base bonds, and cyclobutane rings using chitosan (CS) and coumarin (CA) as raw materials. The CS-CA hydrogel demonstrated a compressive strength of 1.04 MPa, a self-healing efficiency of 99.9 %, and could maintain structural and functional integrity after injection. In addition, the drug release rate and shape of the CS-CA hydrogels were tunable due to its pH sensitivity. The TFL cumulative release reached 60 % within 12 h at pH = 4, and after equilibration, the cumulative release of TFL at pH = 4 (80 %) was significantly higher than at pH = 9.2 (50 %). The CCK8 experiment showed that the resulting hydrogel had no cytotoxicity. Meanwhile, subcutaneous implantation experiments in mice showed that the CS-CA hydrogels had favorable biodegradability and compatibility.

Enantioselective Total Syntheses of (-)-Caulamidine D and (-)-Isocaulamidine D and Their Absolute Configuration Reassignment.

The first enantioselective total syntheses of (-)-caulamidine D (5) and (-)-isocaulamidine D (6) were accomplished. Their absolute configurations were unambiguously elucidated through X-ray crystallography. The isolated natural samples of both 5 and 6 are determined to be the TFA salts instead of the neutral forms. It took 16 steps (longest linear sequence) to divergently access both 5 and 6 following a unified strategy. The key reactions include (1) development and application of an asymmetric Meerwein-Eschenmoser-Claisen rearrangement to construct the challenging C10, C23 consecutive stereocenters and (2) application of a cascade 6-exo-dig/6-exo-tet amine/nitrile cyclization reaction.

Solar Light Management Enabled by Dual-Responsive Smart Window.

Smart windows with tunable optical properties for energy-saving and privacy protection applications are receiving increasing attention. However, current studies of smart windows either involve the use of complex material preparation processes and complex device systems for window switching or continue to face several challenges, including low luminous transmittance, low luminous and solar modulation, and narrow wavelength range management problems. Here, we report a dual-responsive smart window that achieves solar light management in the range of 200-2500 nm. This smart window is fabricated by combining a reversible thermoresponsive hydrogel that acts as a thermochromic material with a ZnO/Ag/ZnO multilayer film that acts as a transparent heater. The as-prepared smart window can modulate solar light over a range from ultraviolet to infrared and achieves active responses to high-temperature weather, with passive responses being produced through electrical heating. The smart window shows high luminous transmittance (81.7%) and high luminous modulation (81.6%), together with an outstanding solar modulation performance (62.9%). In outdoor demonstrations, the as-prepared smart window exhibited a promising temperature regulation ability under strong solar irradiation. Therefore, the proposed smart window promises to provide a simple and effective energy management technology for buildings.

Enhanced Stability and Function of Probiotic Streptococcus thermophilus with Self-Encapsulation by Increasing the Biosynthesis of Hyaluronan.

The harsh conditions of the gastrointestinal tract limit the potential health benefits of oral probiotics. It is promising that oral bioavailability is improved by strengthening the self-protection of probiotics. Here, we report the encapsulation of a probiotic strain by endogenous production of hyaluronan to enhance the effects of oral administration of the strain. The traditional probiotic Streptococcus thermophilus was engineered to produce hyaluronan shells by using traceless genetic modifications and clustered regularly interspaced short palindromic repeat interference. After oral delivery to mice in the form of fermented milk, hyaluronan-coated S. thermophilus (204.45 mg/L hyaluronan in the milk) exhibited greater survival and longer colonization time in the gut than the wild-type strain. In particular, the engineered probiotic strain could also produce hyaluronan after intestinal colonization. Importantly, S. thermophilus self-encapsulated with hyaluronan increased the number of goblet cells, mucus production, and abundance of the microorganisms related to the biosynthesis of short-chain fatty acids, resulting in the enhancement of the intestinal barrier. The coating formed by endogenous hyaluronan provides an ideal reference for the effective oral administration of probiotics.

Combined targeted therapy and immunotherapy in anaplastic thyroid carcinoma with distant metastasis: A case report.

BACKGROUND: Anaplastic thyroid carcinoma (ATC), also called undifferentiated thyroid cancer, is the least common but most aggressive and deadly thyroid gland malignancy of all thyroid cancers[1]. It has poor prognosis, and is the leading cause of death from malignant thyroid tumors. The one-year survival rate is 20%, with a median overall survival (OS) of only 5 mo[2]. The aim of this report is to provide our experience in the diagnosis and treatment of ATC. CASE SUMMARY: A patient with a thyroid mass underwent surgical treatment after developing symptoms of hoarseness. The resected tumor was pathologically diagnosed as ATC. Imaging examination revealed organ and lymph node metastasis. After multiple cycles of chemotherapy and local radiotherapy, the metastases were not relieved and gradually increased in size and new metastases appeared. The patient immediately received immunotherapy combined with targeted therapy. During treatment, immune-related adverse reactions occurred, which were improved after symptomatic treatment, and tolerated by the patient. The OS of the patient was more than 30 mo after immunotherapy combined with targeted therapy. CONCLUSION: For metastatic ATC, surgical treatment, radiotherapy and chemotherapy have no significant effect on remission of the disease. However, immunotherapy has made a breakthrough in the treatment of ATC.

Recent Advances in Copper-Doped Titanium Implants.

Titanium (Ti) and its alloys have been extensively used as implant materials in clinical practice due to their high corrosion resistance, light weight and excellent biocompatibility. However, the insufficient intrinsic osteogenic capacity of Ti and its alloys impedes bone repair and regeneration, and implant-related infection or inflammation remains the leading cause of implant failure. Bacterial infections or inflammatory diseases constitute severe threats to human health. The physicochemical properties of the material are critical to the success of clinical procedures, and the doping of Cu into Ti implants has been confirmed to be capable of enhancing the bone repair/regeneration, angiogenesis and antibacterial capability. This review outlines the recent advances in the design and preparation of Cu-doped Ti and Ti alloy implants, with a special focus on various methods, including plasma immersion implantation, magnetron sputtering, galvanic deposition, microarc oxidation and sol-gel synthesis. More importantly, the antibacterial and mechanical properties as well as the corrosion resistance and biocompatibility of Cu-doped Ti implants from different methods are systematically reviewed, and their prospects and limitations are also discussed.

Au@Ag Nanorods-PDMS Wearable Mouthguard as a Visualized Detection Platform for Screening Dental Caries and Periodontal Diseases.

The development of easy-to-use, low-cost, and visualized detection platforms for screening human dental caries and periodontal diseases is in urgent demand. In this work, a Au@Ag nanorods-poly(dimethylsiloxane) (Au@Ag NRs-PDMS) wearable mouthguard, which can visualize the tooth lesion sites through the color change of it at the corresponding locations, is presented. The Au@Ag NRs-PDMS composite exhibits a distinct color response to hydrogen sulfide (H2 S) gas generated by bacterial decay at the lesion sites. Moreover, the Au@Ag NRs-PDMS mouthguard is demonstrated to own desired mechanical properties, excellent chemical stability, as well as good biocompatibility, and can accurately locate the lesion sites in human oral cavity. These findings suggest that the mouthguard has the potential to be utilized on a large scale to help people self-monitor their oral health in daily life, and treat oral diseases locally.

Analysis of the clinicopathological characteristics and prognosis of triple-positive breast cancer and HER2-positive breast cancer-A retrospective study.

Background: Adjuvant chemotherapy and targeted therapy have become standard postoperative therapeutic modalities for human epidermal growth factor receptor 2 (HER2)-positive breast cancer(HER2-positive,HR-negative), including triple-positive breast cancer(HER2-positive,HR-positive). However, these two types of breast cancer differ in terms of pathogenesis. This article analyzes these two types of breast cancer by comparing their prognoses. Methods: The clinicopathological characteristics of 135 patients, including 60 patients with triple-positive breast cancer and 75 patients with HER2-positive breast cancer, were analyzed to compare the disease-free survival (DFS) and overall survival (OS) of the two groups over a 5-year period. A multifactorial Cox risk model was constructed by grouping age, menstrual status, maximum tumor diameter, number of lymph node metastases, pathological staging, and Ki-67 staining results. All statistical data were analyzed in detail using SPSS25.0 statistical software. Results: The 5-year OS rates of patients with breast cancer in the triple-positive and HER2-positive groups were 96.7% and 82.7%, respectively, and the 5-year DFS rates were 90% and 73.3%, respectively. The Cox results revealed that molecular staging was an independent factor affecting recurrent metastasis and survival of breast cancer patients (hazard ratio [HR] =2.199, 95% confidence interval [CI], 1.296-8.266; HR = 9.994, 95% CI, 2.019-49.465). Conclusion: The 5-year DFS and OS rates were significantly better in the triple-positive group than in the HER2-positive group. Subgroups received different prognosis for different chemotherapy regimens. Breast cancer patients should be treated according to the risk of recurrence with symptomatic treatment and precise regulation.

Patterns of tree species richness in Southwest China.

As a region known for its high species richness, southwest China plays an important role in preserving global biodiversity and ensuring ecological security in the Yangtze, Mekong, and Salween river basins. However, relatively few studies focus on the response of tree species richness to climate change in this part of China. This study determined the main tree species in southwest China using the Vegetation Map of China and the Flora of China. From simulations of 1970 to 2000 and three forecasts of future benign, moderate, and extreme climate warming anticipated during 2061 to 2080, this study used a maximum entropy model (MaxEnt) to simulate main tree species richness in southwest China. Regions with a peak species richness at intermediate elevations were typically dominated by complex mountainous terrain, such as in the Hengduan Mountains. Likewise, regions with the smallest richness were low-elevation areas, including the Sichuan Basin, and the high-elevation Sichuan-Tibet region. Annual precipitation, minimum temperature of the coldest month, temperature seasonality, and elevation were the most critical factors in estimating tree species richness in southwest China. During future 2061 to 2080 climate scenarios, tree species tended to migrate towards higher elevations as mean temperatures increased. For climate change scenarios RCP2.6-2070 (benign) and RCP4.5-2070 (moderate), the main tree species richness in the study area changed little. During the RCP8.5-2070 extreme scenario, tree species richness decreased. This study provides useful guidance to plan and implement measures to conserve biodiversity.

Application of Rare-Earth Elements and Comparison to Molecular Markers in Oil-Source Correlation of Tight Oil: A Case Study of Chang 7 of the Upper Triassic Yanchang Formation in Longdong Area, Ordos Basin, China.

The biomarker features of 10 Chang 7 crude oil samples were investigated by gas chromatography-mass spectrometry (GC-MS), and the rare-earth element (REE) compositions of 16 Chang 7 and Chang 8 crude oil samples were determined by inductively coupled plasma-mass spectrometry (ICP-MS) for the first time in Longdong area. Oil-source correlation analysis was improved by biomarkers and REEs. The distribution and relative ratios of a series of biomarker parameters in saturated hydrocarbons and aromatic hydrocarbons of crude oil samples indicate that Chang 7 tight oil has already reached the mature stage. The organic matter mainly comes from lower aquatic organisms of algae, with some contribution of micro-organisms and bacteria, while the forming environment of tight oil is mainly the transitional environment of sub-oxidizing to sub-reducing. The V/(V + Ni) and Ni/Co ratios of crude oil samples suggest that the specific redox conditions of Chang 71 and Chang 72 samples were slightly oxic, while Chang 73 and Chang 8 samples were formed under an anoxic environment. The results of both biomarker-based and REE-based oil-source correlation analysis indicate that Chang 71 and Chang 72 tight oils come from Chang 7 mudstone, while most of the Chang 73 tight oils are from Chang 7 oil shale, with part of mixed from Chang 7 mudstone. This recognition may indicate that Chang 7 mudstone and oil shale are two relatively independent hydrocarbon self-generation and near-storage systems. The analysis results demonstrate that the REE composition in crude oil is an efficient and accurate tool for oil-source correlation in the petroleum system.

Plasmon-Emitter Hybrid Nanostructures of Gold Nanorod-Quantum Dots with Regulated Energy Transfer as a Universal Nano-Sensor for One-step Biomarker Detection.

Recently, biosensing based on weak coupling in plasmon-emitter hybrid nanostructures exhibits the merits of simplicity and high sensitivity, and attracts increasing attention as an emerging nano-sensor. In this study, we propose an innovative plasmon-regulated fluorescence resonance energy transfer (plasmon-regulated FRET) sensing strategy based on a plasmon-emitter hybrid nanostructure of gold nanorod-quantum dots (Au NR-QDs) by partially modifying QDs onto the surfaces of Au NRs. The Au NR-QDs showed good sensitivity and reversibility against refractive index change. We successfully employed the Au NR-QDs to fabricate nano-sensors for detecting a cancer biomarker of alpha fetoprotein with a limit of detection of 0.30 ng/mL, which displays that the sensitivity of the Au NR-QDs nano-sensor was effectively improved compared with the Au NRs based plasmonic sensing. Additionally, to demonstrate the universality of the plasmon-regulated FRET sensing strategy, another plasmon-emitter hybrid nano-sensor of Au nano-prism-quantum dots (Au NP-QDs) were constructed and applied for detecting a myocardial infarction biomarker of cardiac troponin I. It was first reported that the change of absorption spectra of plasmonic structure in a plasmon-emitter hybrid nanostructure was employed for analytes detection. The plasmon-regulated FRET sensing strategy described herein has potential utility to develop general sensing platforms for chemical and biological analysis.

Enhancing the production of tacrolimus by engineering target genes identified in important primary and secondary metabolic pathways and feeding exogenous precursors.

Tacrolimus has been widely used as a powerful novel immunosuppressant. The objective of this study was to improve the production of tacrolimus by engineering the target genes of important primary and secondary metabolic pathways and feeding exogenous precursors. Based on the metabonomics analysis, the shikimic acid pathway is an important primary metabolic pathway for the producing tacrolimus. Combined overexpression of shikimate kinase and dehydroquinic acid synthetase genes led to a 33.1% enhancement of tacrolimus production compared to parent strain. To predict the most efficient targets in secondary metabolic pathways for improving the production of tacrolimus, a genome-scale dynamic metabolic network model was used. A knockout of the D-lactate dehydrogenase gene, combined with the overexpression of tryptophane synthase and aspartate 1-decarboxylase genes, led to a 29.8% enhancement of tacrolimus production compared to the parent strain. Finally, we investigated the impact of the genetic manipulations on transcription levels, cell growth, cell morphology and production of tacrolimus by qRT-PCR and scanning electron microscopy to reveal the relationship between the growth of strains, the effects of engineering and fermentation. As the efficient synthesis of tacrolimus requires a rich supply of external substrates, the efficiency of the metabolic pathways that convert these substances is extremely important. The combined addition of three external substrates such as shikimic acid, alanine and the n-dodecane increased tacrolimus production by 49.5%. The insights obtained in this study will help further elucidate the mechanisms by which the identified target genes promote the activity of important primary and secondary metabolic pathways for tacrolimus biosynthesis and provide a new feeding strategy to improve tacrolimus production.

Manipulating the expression of SARP family regulator BulZ and its target gene product to increase tacrolimus production.

Tacrolimus (FK506), an effective immunosuppressant, is widely used in the treatment of autoimmune diseases. In this study, we identified that BulZ, a Streptomyces antibiotic regulatory protein (SARP) family regulator, acted as a positive regulator for spore differentiation and tacrolimus production. A knockout of bulZ resulted in a 47.5% decrease of tacrolimus production and a delay of spore differentiation. Using quantitative real-time PCR (qRT-PCR) analysis and electrophoretic mobility shift assays (EMSAs), it was found that BulZ directly activated the transcriptions of bulZ and bulS2, a putative γ-butyrolactone (GBL) synthetase, and bulS2 was shown to play a positive role in tacrolimus biosynthesis. Meanwhile, BulZ was able to indirectly regulate the transcriptions of the cluster-linked activator genes tcs7 and fkbN, as well as the GBL receptor gene bulR1. STSU_RS22595, which encoded a WhiB family transcriptional regulator, was found to be a previously unknown potential target gene of BulZ based on a whole-genome search of the conserved sequence (5'-TSVAVVVNVNBTSRAGNN-3') of the SARP-binding motifs. Although overexpression of STSU_RS22595 did not result in an obvious enhancement of tacrolimus yield, STSU_RS22595 might have important effects on the spore differentiation process. Finally, co-overexpression of bulZ and its target gene bulS2 improved tacrolimus production by 36% compared to the control strain, reaching 324 mg/L. The insights obtained in this study will help further elucidate the regulatory mechanism of tacrolimus biosynthesis and provide new avenues for further improvement of tacrolimus production.

Distinct transduction modes of arginine-rich cell-penetrating peptides for cargo delivery into tumor cells.

The application of cell-penetrating peptides (CPPs) for delivering various cargo molecules with biological functions into cells has gained much attention in recent years. However, the internalization mechanisms and delivery properties of CPP-cargo remains controversial. In this study, low- and high-molecular-weight cargoes attached to arginine-rich CPPs were employed: the former was the fluorescein isothiocyanate-labeled nona-arginine (CPP-FITC), and the latter was the fluorescently labeled nona-arginine-avidin complex (CPP-avidin). We measured the intracellular trafficking of CPP-FITC and CPP-avidin in four cancer cell lines in a series of microenvironments altered by the presence or absence of serum, different temperatures and different incubation times. The results revealed that CPP-cargo delivery exhibited no specificity toward any cell line, but the levels were found to be related to cell type and cargo. Furthermore, their endocytic mechanisms were investigated via incubation with related endocytic inhibitors. Two different types of CPP-cargo were required to cross the plasma membrane to bind to cell surface-associated heparan sulfate proteoglycans in a time-dependent manner. CPPs and small cargoes attached to CPP may enter cells rapidly via direct translocation in addition to the endocytic route. Translocation of large components linked to CPP tended to be mediated by macropinocytosis in an energy-dependent manner with slower rates for larger compounds. In contrast, the clathrin-dependent pathway is not essential to the translocation of either type of CPP-cargo.

[Comparison of mechanisms and cellular uptake of cell-penetrating peptide on different cell lines].

Cell-penetrating peptide (CPP) can be used in pharmaceutics as a highly efficient drug delivery transporter. In this study, four tumor cell lines (MCF-7, MDA-MB-231, C6, and B16F10) were used to observe the uptake of fluorescein isothiocyanate (FITC) labeled CPP and the effects of time and concentration of CPP on cell penetration was studied. The CPP exocytosis on C6 cell line was observed, and its exocytosis kinetics was described by zero order equation. In addition, low-temperature condition (4 degrees C) and endocytosis inhibitors were utilized to investigate the mechanism of CPP uptake by cells. Low-temperature condition did not show significantly inhibition on CPP uptake. Heparin, a membrane glycoprotein receptor inhibitor, showed strong inhibition effect (only 3%-10% of the control) on CPP uptake. Chlorpromazine, chloroquine and 5-(N-ethyl-N-isopropyl)-amiloride (EIPA) showed little effect on CPP uptake. This study indicated that CPP penetration had little selectivity on cell type, but the amount and rate of CPP penetration into cells were related to the type of cell lines. The adsorption of CPP on cell membrane induced by sulfate proteoglycan plays an important role on CPP penetration.