Versatile Landscape of Low-k Polyimide: Theories, Synthesis, Synergistic Properties, and Industrial Integration.

The development of microelectronics and large-scale intelligence nowadays promotes the integration, miniaturization, and multifunctionality of electronic and devices but also leads to the increment of signal transmission delays, crosstalk, and energy consumption. The exploitation of materials with low permittivity (low-k) is crucial for realizing innovations in microelectronics. However, due to the high permittivity of conventional interlayer dielectric material (k ∼ 4.0), it is difficult to meet the demands of current microelectronic technology development (k < 3.0). Organic dielectric materials have attracted much attention because of their relatively low permittivity owing to their low material density and low single bond polarization. Polyimide (PI) exhibits better application potential based on its well permittivity tunability (k = 1.1-3.2), high thermal stability (>500 °C), and mechanical property (modulus of elasticity up to 3.0-4.0 GPa). In this review, based on the synergistic relationship of dielectric parameters of materials, the development of nearly 20 years on low-k PI is thoroughly summarized. Moreover, process strategies for modifying low-k PI at the molecular level, multiphase recombination, and interface engineering are discussed exhaustively. The industrial application, technological challenges, and future development of low-k PI are also analyzed, which will provide meaningful guidance for the design and practical application of multifunctional low-k materials.

Discovery of Aurovertin B as a Potent Metastasis Inhibitor against Triple-Negative Breast Cancer: Elucidating the Complex Role of the ATF3-DUSP1 Axis.

Triple-negative breast cancer (TNBC) is characterized by high mortality rates primarily due to its propensity for metastasis. Addressing this challenge necessitates the development of effective antimetastatic therapies. This study aimed to identify natural compounds with potential antimetastatic properties mainly based on the high-throughput phenotypic screening system. This system, utilizing luciferase reporter gene assays combined with scratch wound assays, evaluates compounds based on their influence on the epithelial-mesenchymal transition (EMT) marker E-cadherin. Through this approach, aurovertin B (AVB) was revealed to have significant antimetastatic capability. Notably, AVB exhibited substantial metastasis suppression in many TNBC cell lines, including MDA-MB-231, HCC1937 and 4T1. Also, its remarkable antimetastatic activity was demonstrated in vivo via the orthotopic breast cancer mouse model. Further exploration revealed a pronounced association between AVB-induced upregulation of DUSP1 (dual-specificity phosphatase 1) and its inhibitory effect on TNBC metastasis. Additionally, microarray analysis conducted to elucidate the underlying mechanism of the AVB-DUSP1 interaction identified ATF3 (activating transcription factor 3) as a critical transcription factor instrumental in DUSP1 transcriptional activation. This discovery, coupled with observations of enhanced ATF3-DUSP1 expression and consequent reduction in TNBC metastatic foci in response to AVB, provides novel insights into the molecular mechanisms driving metastasis in TNBC. Significance Statement We construct a high-throughput phenotypic screening system utilizing EMT marker E-cadherin promoter luciferase reporter gene combined with scratch wound assays. Aurovertin B was revealed to possess significant antimetastatic activity through this approach, which was further demonstrated via in vivo and in vitro experiments. The discovery of the regulatory role of the ATF3-DUSP1 pathway enriches our understanding of TNBC metastasis mechanism and suggests the potential of ATF3 and DUSP1 as biomarkers for diagnosing TNBC metastasis.

Predicting Microvascular Invasion in Hepatocellular Carcinoma Using CT-based Radiomics Model.

Background Prediction of microvascular invasion (MVI) may help determine treatment strategies for hepatocellular carcinoma (HCC). Purpose To develop a radiomics approach for predicting MVI status based on preoperative multiphase CT images and to identify MVI-associated differentially expressed genes. Materials and Methods Patients with pathologically proven HCC from May 2012 to September 2020 were retrospectively included from four medical centers. Radiomics features were extracted from tumors and peritumor regions on preoperative registration or subtraction CT images. In the training set, these features were used to build five radiomics models via logistic regression after feature reduction. The models were tested using internal and external test sets against a pathologic reference standard to calculate area under the receiver operating characteristic curve (AUC). The optimal AUC radiomics model and clinical-radiologic characteristics were combined to build the hybrid model. The log-rank test was used in the outcome cohort (Kunming center) to analyze early recurrence-free survival and overall survival based on high versus low model-derived score. RNA sequencing data from The Cancer Image Archive were used for gene expression analysis. Results A total of 773 patients (median age, 59 years; IQR, 49-64 years; 633 men) were divided into the training set (n = 334), internal test set (n = 142), external test set (n = 141), outcome cohort (n = 121), and RNA sequencing analysis set (n = 35). The AUCs from the radiomics and hybrid models, respectively, were 0.76 and 0.86 for the internal test set and 0.72 and 0.84 for the external test set. Early recurrence-free survival (P < .01) and overall survival (P < .007) can be categorized using the hybrid model. Differentially expressed genes in patients with findings positive for MVI were involved in glucose metabolism. Conclusion The hybrid model showed the best performance in prediction of MVI. © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Summers in this issue.

An imaging-based machine learning model outperforms clinical risk scores for prognosis of cirrhotic variceal bleeding.

OBJECTIVES: To develop and validate a machine learning model based on contrast-enhanced CT to predict the risk of occurrence of the composite clinical endpoint (hospital-based intervention or death) in cirrhotic patients with acute variceal bleeding (AVB). METHODS: This retrospective study enrolled 330 cirrhotic patients with AVB between January 2017 and December 2020 from three clinical centers. Contrast-enhanced CT and clinical data were collected. Centers A and B were divided 7:3 into a training set and an internal test set, and center C served as a separate external test set. A well-trained deep learning model was applied to segment the liver and spleen. Then, we extracted 106 original features of the liver and spleen separately based on the Image Biomarker Standardization Initiative (IBSI). We constructed the Liver-Spleen (LS) model based on the selected radiomics features. The performance of LS model was evaluated by receiver operating characteristics and calibration curves. The clinical utility of models was analyzed using decision curve analyses (DCA). RESULTS: The LS model demonstrated the best diagnostic performance in predicting the composite clinical endpoint of AVB in patients with cirrhosis, with an AUC of 0.782 (95% CI 0.650-0.882) and 0.789 (95% CI 0.674-0.878) in the internal test and external test groups, respectively. Calibration curves and DCA indicated the LS model had better performance than traditional clinical scores. CONCLUSION: A novel machine learning model outperforms previously known clinical risk scores in assessing the prognosis of cirrhotic patients with AVB CLINICAL RELEVANCE STATEMENT: The Liver-Spleen model based on contrast-enhanced CT has proven to be a promising tool to predict the prognosis of cirrhotic patients with acute variceal bleeding, which can facilitate decision-making and personalized therapy in clinical practice. KEY POINTS: • The Liver-Spleen machine learning model (LS model) showed good performance in assessing the clinical composite endpoint of cirrhotic patients with AVB (AUC ≥ 0.782, sensitivity ≥ 80%). • The LS model outperformed the clinical scores (AUC ≤ 0.730, sensitivity ≤ 70%) in both internal and external test cohorts.

Structurally Diverse Sesquiterpenoids from the Genus of Ainsliaea.

The genus of Ainsliaea embraces approximately 70 recognized species, many of which have been used to treat various diseases in folklore medicines. As the main metabolites of Ainsliaea plants, Ainsliaea sesquiterpenoids have drawn considerable attention in related scientific communities due to their intriguing structures and a variety of bioactivities. In this review, we intend to provide a full-aspect coverage of sesquiterpenoids reported from the genus of Ainsliaea, including 145 monomeric sesquiterpenoids and 30 oligomeric ones. Multiple aspects will be summarized, including their classification, distributions, structures, bioactivities, and biomimetic syntheses. In addition, their possible biosynthetic pathway will be discussed in detail.

[Research progress on chemical structures and pharmacological effects of natural cytisine and its derivatives].

Cytisine derivatives are a group of alkaloids containing the structural core of cytisine, which are mainly distributed in Fabaceae plants with a wide range of pharmacological activities, such as resisting inflammation, tumors, and viruses, and affecting the central nervous system. At present, a total of 193 natural cytisine and its derivatives have been reported, all of which are derived from L-lysine. In this study, natural cytisine derivatives were classified into eight types, namely cytisine type, sparteine type, albine type, angustifoline type, camoensidine type, cytisine-like type, tsukushinamine type, and lupanacosmine type. This study reviewed the research progress on the structures, plant sources, biosynthesis, and pharmacological activities of alkaloids of various types.

Coordination of Polyketide Release and Multiple Detoxification Pathways for Tolerable Production of Fungal Mycotoxins.

Efficient biosynthesis of microbial bioactive natural products (NPs) is beneficial for the survival of producers, while self-protection is necessary to avoid self-harm resulting from over-accumulation of NPs. The underlying mechanisms for the effective but tolerable production of bioactive NPs are not well understood. Herein, in the biosynthesis of two fungal polyketide mycotoxins aurovertin E (1) and asteltoxin, we show that the cyclases in the gene clusters promote the release of the polyketide backbone, and reveal that a signal peptide is crucial for their subcellular localization and full activity. Meanwhile, the fungus adopts enzymatic acetylation as the major detoxification pathway of 1. If intermediates are over-produced, the non-enzymatic shunt pathways work as salvage pathways to avoid excessive accumulation of the toxic metabolites for self-protection. These findings provided new insight into the interplay of efficient backbone release and multiple detoxification strategies for the production of fungal bioactive NPs.

Euphorbia diterpenoids: isolation, structure, bioactivity, biosynthesis, and synthesis (2013-2021).

Covering: 2013 to 2021As the characteristic metabolites of Euphorbia plants, Euphorbia diterpenoids have always been a hot topic in related science communities due to their intriguing structures and broad bioactivities. In this review, we intent to provide an in-depth and extensive coverage of Euphorbia diterpenoids reported from 2013 to the end of 2021, including 997 new Euphorbia diterpenoids and 78 known ones with latest progress. Multiple aspects will be summarized, including their occurrences, chemical structures, bioactivities, and syntheses, in which the structure-activity relationship and biosynthesis of this class will be discussed for the first time.

Tetrodecadazinone, a novel tetrodecamycin-pyridazinone hybrid with anti-liver fibrosis activity from Streptomyces sp. HU051.

Tetrodecadazinone (1), a novel tetrodecamycin-pyridazinone hybrid possessing a new 1,2-dimethyl-1-(2-methylnonyl)decahydronaphthalene skeleton, and 4-hydroxydihydrotetrodecamycin (2) were separated from a culture of Streptomyces sp. HU051, together with a known compound, dihydrotetrodecamycin (3). Diverse spectroscopic approaches were applied to assign the structures of 1-3, and the structure of 1 was further confirmed by single crystal X-ray diffraction analysis. Compound 1 is the first example of a pyridazinone-containing natural product. Biosynthetically, 1 is proposed to be derived from a Michael addition reaction of a PKS-derived tetrodecamycin and a piperazic-acid-derived pyridazinone. Biological evaluation revealed 1 could reduce the expressions of extracellular matrix proteins (fibronectin and collagen I) and α-smooth muscle actin (α-SMA) in transforming growth factor-ß (TGF-ß1)-activated LX-2 cells. Preliminary mechanism study showed 1 exerted its anti-liver fibrosis effect by regulating TGF-ß1/Smad2/3 signaling pathway.

Temperature might increase the hospital admission risk for rheumatoid arthritis patients in Anqing, China: a time-series study.

Temperature has been studied in relation to many health outcomes. However, few studies have explored its effect on the risk of hospital admission for rheumatoid arthritis (RA). A distributed lag non-linear model (DLNM) was used to analyze associations between mean temperature, diurnal temperature range (DTR), temperature change between neighboring days (TCN), and daily admissions for RA from 2015 to 2019 in Anqing, China. Subgroup analyses based on age, gender, rheumatoid factors, and admission route were performed. In total, 1456 patients with RA were hospitalized. Regarding the cumulative-lag effects of extreme cold temperature (5th percentile = 3℃), the risks of admissions for RA were increased and highest at lag 0-11 (RR = 2.68, 95% CI: 1.23-5.86). Exposing to low (5th percentile = 1.9℃) and high (95th percentile = 14.2℃) DTRs both had increased risks of RA admission, with highest RRs of 1.40 (95% CI: 1.03-1.91) and 1.24 (95% CI: 1.0-1.53) at lag 0 day, respectively. As for TCN, the marginal risk of admission in RA patients was found when exposed to high TCN (95th percentile = 2.9℃) with the largest single-day effect at lag 10 (RR = 1.11, 95% CI: 1.01-1.23). In subgroup analyses, females were more susceptible to extreme cold temperature, low and high DTRs, and high TCN. In regard to extreme cold temperature, significant risk of hospital admission in females only appeared at lag 2 (RR = 1.48, 95% CI: 1.02-2.15) and lag 0-2 (RR = 2.35, 95% CI: 1.11-4.95). It is clear that RA patients exposed to changing temperature may increase risks of admission.

New Jatrophane-Type Diterpenoids from Euphorbia kansui as Potential MDR Reversal Agents.

A serial jatrophane-type diterpenoids, comprised with three undescribed compounds kanesulones C-E (1-3) and four known ones (4-7), were obtained from the roots of Euphorbia kansui. The structures of compounds 1-3 were elucidated by detailed interpretation of their spectroscopic data, especially 2D-NMR and HR-ESI-MS, the absolute configuration of 1 was revealed by single crystal X-ray diffraction. These isolates were assayed for their multidrug resistance reversing activities on human breast adenocarcinoma cell line MCF-7/ADR. Compound 1 possessed potential as low toxic MDR modulator that could promote the efficacy of anticancer drug adriamycin ca. 85-fold at 5 µM, as 12 times stronger than the positive drug verapamil.

Synthesizing Photoluminescent Au28 (SCH2 Ph-t Bu)22 Nanoclusters with Structural Features by Using a Combined Method.

We present a method for atomically precise nanocluster synthesis. As an illustration, we introduced the reducing-ligand induction combined method and synthesized a novel nanocluster, which was determined to be Au28 (SCH2 Ph-t Bu)22 with the same number of gold atoms as existing Au28 (SR)20 nanoclusters but different ligands (hetero-composition-homo-size). Compared with the latter, the former has distinct properties and structures. In particular, a novel kernel evolution pattern is reported, i.e., the quasi-linear growth of Au4 -tetrahedron by sharing one vertex and structural features, including a tritetrahedron kernel with two bridging thiolates and two Au6 (SCH2 Ph-t Bu)6 hexamer chair-like rings on the kernel surface were also first reported, which endow Au28 (SCH2 Ph-t Bu)22 with the best photoluminescence quantum yield among hydrophobic thiolated gold nanoclusters so far, probably due to the enhanced charge transfer from the bi-ring to the kernel via Au-Au bonds.

Unravelling the Structure of a Medium-Sized Metalloid Gold Nanocluster and its Filming Property.

Unravelling the structure of thiolated metalloid gold nanoclusters in the medium-sized range by single crystal X-ray crystallography (SCXC) is challenging. Herein, we successfully synthesized a novel Au67 (SR)35 nanocluster, and unravelled its single crystal structure by SCXC, which features a mix-structured Au48 kernel protected by one Au4 (SR)5 staple and fifteen Au(SR)2 staples. Unprecedentedly, this structure can be thermally induced to aggregate into larger nanoparticles and self-deposit to form a gold nanoparticles film onto the walls of a vial or other substrates such as quartz, mica or ceramic, which can be developed into a facile, substrate-universal and scalable filming method. The film exhibits high sensitivity, uniformity and recyclability as a surface-enhanced Raman scattering (SERS) substrate and can be applied for detecting multiple organic pollutants.

Natural disesquiterpenoids: an update.

Covering: July 2010 to August 2019. Previous review: Nat. Prod. Rep., 2011, 28, 594The review covers recent progress on the isolation, identification, bioactivity and biomimetic synthesis of natural dimeric sesquiterpenoids, along with a detailed discussion of the biogenesis of these metabolites. Structural revisions are included.

Streptomyces albogriseolus SY67903 Produces Eunicellin Diterpenoids Structurally Similar to Terpenes of the Gorgonian Muricella sibogae, the Bacterial Source.

Microeunicellols A (1) and B (2), two undescribed eunicellin diterpenoids, were isolated from the culture of a bacterial symbiont, Streptomyces albogriseolus SY67903. Their structures, including absolute configurations revealed by spectroscopic data and single-crystal X-ray diffraction analysis, are closely related with the diterpenoids from its host, a South China Sea gorgonian, Muricella sibogae. This is the first report of eunicellin diterpenoids, commonly coral-derived, from a bacterial symbiont of coral. The chemical metabolic relationship between the bacterium and its host is discussed. Biological evaluation revealed that compound 1 possessed cytotoxicities against several human cancer cell lines.

Ordered and Isomerically Stable Bicyclic Peptide Scaffolds Constrained through Cystine Bridges and Proline Turns.

Bicyclic peptides are attractive scaffolds for the design of potent protein binders and new therapeutics. However, peptide bicycles constrained through disulfide bonds are rarely stable or tolerant to sequence manipulation owing to disulfide isomerization, especially for peptides lacking a regular secondary structure. Herein, we report the discovery and identification of a class of bicyclic peptide scaffolds with ordered but irregular secondary structures. These peptides have a conserved cysteine/proline framework for directing the oxidative folding into a fused bicyclic structure that consists of four irregular turns and a 310 helix (characterized by NMR spectroscopy). This work shows that bicyclic peptides can be stabilized into ordered structures by manipulating both the disulfide bonds and proline-stabilized turns. In turn, this could inspire the design and engineering of multicyclic peptides with new structures and benefit the development of novel protein binders and therapeutics.

Synthesis and anti-tumor activity study of water-soluble PEG-celastrol coupling derivatives as self-assembled nanoparticles.

To improve the drug-ability of celastrol, a series of PEGylation celastrol (PEGC) were designed and synthesized by conjugation with different kinds of polyethylene glycols (PEGs) with celastrol. Most of PEGCs could easily dissolve in water. In particular, one of them (DC1000) could be dispersed in water to form nanoparticles by self-assembly. The cytotoxic evaluation of PEGCs revealed that some of PEGCs showed more potent cytotoxicity than celastrol, and the molecular weight of PEG parts in PEGCs had apparent influence on their cytotoxic activity. Anti-tumor evaluation in vivo showed DC1000 had higher tumor inhibition rate and better safety than celastrol by intravenous administration with equivalent molar weight. These results revealed PEGylation might be an efficient and economical method to improve the water solubility and safety of celastrol and similar natural products.

Cytotoxic Spliceostatin Analogs from Pseudomonas sp.

Two new spliceostatin analogs, designed as spliceostatins J and K (1 and 2), were isolated and identified from the culture of Pseudomonas sp., along with two known ones, FR901464 (3) and spliceostatin E (4). Their structures were elucidated by detailed interpretation of their spectroscopic data, especially 2D-NMR and HR-ESI-MS. Spliceostatin J (1) represented the first example of spliceostatins bearing an unusual hexahydrofuro[3,4-b]furan moiety. Biological assay showed all the isolated compounds except 1 displayed potent cytotoxic activities against two cancer cell lines (MDA-MB-231 and A-549). Structure-activity-relationship studies revealed that the tetrahydropyran ring in spliceostatin analogs was necessary for their bioactive retention.

New Immunomodulating Polyhydroxypregnane Glycosides from the Roots of Cynanchum otophyllum C.K.Schneid.

Seven new polyhydroxypregnane glycosides, named cynotophyllosides P-V, together with three known analogs were isolated from the roots of Cynanchum otophyllum C.K.Schneid. Their structures were elucidated by a variety of spectroscopic techniques, as well as acid-catalyzed hydrolysis. All isolates were tested for their immunological activities in vitro against Con A- and LPS-induced proliferation of mice splenocytes. Immunoenhancing (for 1, 9) and immunosuppressive (for 2) activities were observed. Furthermore, cynotophylloside R (3) showed immunomodulatory as it enhanced the proliferation of splenocytes in low concentration and suppressed immune cells in concentration more than 1.0 µg/ml.

Biotransformation of Huperzine B by a Fungal Endophyte of Huperzia serrata.

The biotransformation of huperzine B (hupB), one of the characteristic bioactive constituents of the medicinal plant Huperzia serrata, by a fungal endophyte of the host plant was studied. One new compound, 8α,15α-epoxyhuperzine B (1), along with two known oxygenated hupB analogs, 16-hydroxyhuperzine B (2) and carinatumin B (3), was isolated and identified. The structures of all the isolates were deduced by spectroscopic methods including NMR, MS, IR, and UV spectra. The known compounds 2 and 3 were obtained from a microbial source for the first time. To the best of our knowledge, it is the first report on the microbial transformation of hupB and would facilitate further structural modification of hupB by chemo-enzymatic method. In the LPS-induced neuro-inflammation injury assay, 8α,15α-epoxyhuperzine B (1) exhibited moderate neuroprotective activity by increasing the viability of U251 cell lines with an EC50 of 40.1 nm.