Considering product life cycle characteristics and industry background in environmental impact analysis and application: a case study of a television.

Life cycle assessment (LCA) is widely used to evaluate product's life cycle environmental impact and identify the environmental weaknesses. However, it is difficult for existing LCA software to perform flexible LCA analysis based on the product life cycle characteristics and industry background. Meanwhile, under the existing LCA research model, product designers and manufacturers are usually not LCA evaluators, resulting in a certain time gap between the evaluation results and product improvement. Designers with less experience in green design often find it difficult to identify high environmental impact links in products at different life cycle stages and product levels, and updated products are challenging to meet various environmental restrictions. This paper establishes a multi-module product life cycle analysis model that combines product industry background that includes basic information, assessment information, structural information, and restriction information to achieve the multi-scenario of product LCA in different dimensions in a typical domain. The calculated mechanism of the dynamic power emission factor is built according to the service time and space dimensions. The proposed method forms an integrated environmental performance evaluation of household appliance (EPEHA) system. A software assessment and an optimization method are proposed to improve the EPEHA system. The results of this study show that these proposed methods can improve the timeliness and diversity of results analysis of product LCA in the field of household appliances in China. The universal data exchange format and simple operation interface of the EPEHA system enable people related to the product to quickly understand the environmental impact of the product in different scenarios, even if they lack green design knowledge and professional software training.

The detection methods currently available for protein aggregation in neurological diseases.

Protein aggregation is a pathological feature in various neurodegenerative diseases and is thought to play a crucial role in the onset and progression of neurological disorders. This pathological phenomenon has attracted increasing attention from researchers, but the underlying mechanism has not been fully elucidated yet. Researchers are increasingly interested in identifying chemicals or methods that can effectively detect protein aggregation or maintain protein stability to prevent aggregation formation. To date, several methods are available for detecting protein aggregates, including fluorescence correlation spectroscopy, electron microscopy, and molecular detection methods. Unfortunately, there is still a lack of methods to observe protein aggregation in situ under a microscope. This article reviews the two main aspects of protein aggregation: the mechanisms and detection methods of protein aggregation. The aim is to provide clues for the development of new methods to study this pathological phenomenon.

Clinical Efficacy and Adverse Effects of Bevacizumab in Combination with Chemotherapy for Metastatic Colorectal Cancer.

Objective: This study aims to investigate the efficacy of bevacizumab (BEV) in combination with chemotherapy for metastatic colorectal cancer (mCRC). Methods: A cohort of 121 patients diagnosed with mCRC and admitted to our hospital from May 2018 to October 2019 were selected for the study. The control group, comprising 64 patients, received chemotherapy alone, while the research group, consisting of 57 patients, underwent a combination of BEV and chemotherapy. Comparative analyses included an assessment of clinical outcomes, monitoring of tumor markers including Carcinoembryonic Antigen (CEA), Cancer Antigen 74-2 (CA74-2), and Carbohydrate Antigen 19-9 (CA19-9) before and after treatment, and a count of adverse effects during the treatment phase. A 3-year post-discharge follow-up was conducted to compare the survival prognosis between the two groups. Results: The research group exhibited a significantly higher objective response rate (ORR) and clinical benefit rate (CBR) compared to the control group (P < .05). Furthermore, CEA, CA74-2, and CA19-9 post-treatment levels were markedly lower in the research group (P < .05). No notable difference in the incidence of adverse reactions was observed between the two groups (P > .05). Importantly, the 3-year overall survival prognosis was superior in the research group (P < .05). Within the research group, patients treated with BEV combined with the XELIRI regimen chemotherapy demonstrated a higher CBR rate (P < .05). Conclusions: The combination of BEV and chemotherapy proves to be highly effective in treating mCRC, significantly enhancing the prognostic survival cycle of patients. This treatment modality holds promise for future clinical applications in managing patients with mCRC.

The PKA-CREB1 axis regulates coronavirus proliferation by viral helicase nsp13 association.

The COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has posed a worldwide threat in the past 3 years. Although it has been widely and intensively investigated, the mechanism underlying the coronavirus-host interaction requires further elucidation, which may contribute to the development of new antiviral strategies. Here, we demonstrated that the host cAMP-responsive element-binding protein (CREB1) interacts with the non-structural protein 13 (nsp13) of SARS-CoV-2, a conserved helicase for coronavirus replication, both in cells and in lung tissues subjected to SARS-CoV-2 infection. The ATPase and helicase activity of viral nsp13 were shown to be potentiated by CREB1 association, as well as by Protein kinase A (PKA)-mediated CREB1 activation. SARS-CoV-2 replication is significantly suppressed by PKA Cα, cAMP-activated protein kinase catalytic subunit alpha (PRKACA), and CREB1 knockdown or inhibition. Consistently, the CREB1 inhibitor 666-15 has shown significant antiviral effects against both the WIV04 strain and the Omicron strain of the SARS-CoV-2. Our findings indicate that the PKA-CREB1 signaling axis may serve as a novel therapeutic target against coronavirus infection. IMPORTANCE: In this study, we provide solid evidence that host transcription factor cAMP-responsive element-binding protein (CREB1) interacts directly with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) helicase non-structural protein 13 (nsp13) and potentiate its ATPase and helicase activity. And by live SARS-CoV-2 virus infection, the inhibition of CREB1 dramatically impairs SARS-CoV-2 replication in vivo. Notably, the IC50 of CREB1 inhibitor 666-15 is comparable to that of remdesivir. These results may extend to all highly pathogenic coronaviruses due to the conserved nsp13 sequences in the virus.

The efficacy-associated biomarkers for immune checkpoint inhibitors in gastrointestinal cancer: a literature review.

Background and Objective: Immune checkpoint inhibitors (ICIs) have been widely applied and studied in the treatment of gastrointestinal (GI) cancers, and have achieved good results. However, in clinical practice, it has been observed that only some patients respond well to ICIs, and some patients may experience various degrees of adverse reactions during the treatment. Timely evaluation of the potential therapeutic effects and adverse reactions of ICIs for patients has important clinical significance. This review aimed to summarize recent progress regarding efficacy-associated biomarkers for ICIs in GI cancer. Methods: The literature on ICI treatment in GI cancers was searched in the PubMed, Embase, and Cochrane Library databases for publications up to April 2023. Key Content and Findings: Clinical practice and research has gradually revealed some biomarkers related to the treatment of GI cancers with ICIs, which can be roughly divided into three types: biomarkers that predict the effectiveness of ICIs treatment, biomarkers associated with resistance to ICIs, and biomarkers associated with immune related adverse events (irAEs). This review article provides a literature review on biomarkers related to the efficacy of ICIs in the treatment of GI cancers. Conclusions: According to existing clinical research results, there are multiple biomarkers that can be used for predicting and monitoring the efficacy and risk of adverse events of ICIs in the treatment of digestive system malignant tumors.

Acellular dermal matrix-assisted tissue expansion for giant congenital melanocytic nevi of the extremities and trunk in pediatric patients.

BACKGROUND: Tissue expansion for treating giant congenital melanocytic nevi (GCMN) is a commonly employed surgical method. However, the procedure's efficacy is often hindered by anatomical and histological characteristics as well as blood supply, particularly in the extremities and trunk. Enhancing expansion efficiency while reducing complications is thus a topic to be investigated, especially for pediatric patients undergoing rapid physical and psychological development with higher risks of non-compliance to medical instructions. OBJECT: To explore the effectiveness of expansion in extremities and trunk by immobilizing the acellular dermal matrix (ADM) in the gravitational force zone of inflating expanders. METHODS: All patients involved in this research underwent ADM-assisted tissue expansion in either the extremities or trunk. ADM was fully flattened, securely fixed to the lower pole of the expander, and subsequently attached to the inner surface of the expanding flap. RESULTS: From 2021 to 2023, a total of nine pediatric patients with GCMN underwent the ADM-assisted tissue expansion. All patients achieved the desired expanding volume without experiencing petechiae, ecchymosis, or skin ulceration in the ADM-covered area. The process was well tolerated by all patients, with no reports of itching, pain, allergic reaction, or fever. During the flap transfer, the ADM was observed to be firmly adhered to the expanding flap with discernible capillary network. CONCLUSION: ADM-assisted tissue expansion demonstrates promise in augmenting expansion efficiency and reducing the time needed for surgical intervention in the extremities and trunk, thereby presenting significant clinical value for pediatric patients afflicted with GCMN.

Diagnostic performance of serum galactomannan and ß-D-glucan for invasive aspergillosis in suspected patients: A meta-analysis.

BACKGROUND: Serum galactomannan (GM) and ß-D-glucan (BG) are known markers of invasive aspergillosis (IA). The aim of this meta-analysis was to evaluate the efficiency of serum GM and BG as diagnostic markers of symptomatic IA infection and compare the performance of the combined tests with that of either test individually. METHODS: A literature search was carried out using PubMed, Web of Science, and EMBASE databases to include relevant studies published in English up to May 2023. The quality assessment was performed using Review Manager 5.3 software. A bivariate model was applied to pool diagnostic parameters using Stata 14.0 software. We used Cochrane I2 index to assess heterogeneity and identify the potential source of heterogeneity by meta-regression. Paired t tests were used to compare the value of GM and BG for IA diagnosis when used in combination or alone. RESULTS: Sixteen studies were eligible for inclusion in the meta-analysis. For proven or probable IA, serum GM and BG yielded a pooled sensitivity of 0.53 (95% CI 0.40-0.66) vs 0.72 (95% CI 0.61-0.81) and a pooled specificity of 0.94 (95% CI 0.91-0.97) vs 0.82 (95% CI 0.73-0.88). The area under the curve (AUC) of ROC was 0.90 (95% CI 0.87-0.92) vs 0.83 (95% CI 0.80-0.86) for all studies. The pooled sensitivity and specificity for IA diagnosis by combined GM and BG assays (GM/BG) were 0.84 (95% CI 0.69-0.86) and 0.76 (95% CI 0.69-0.81), respectively. The sensitivity of the combined GM/BG test to diagnose IA was higher than of the GM or BG test alone. CONCLUSION: Serum GM and BG tests had a relatively high accuracy for IA diagnosis in suspected patients. The diagnostic accuracy of both assays is comparable, and the diagnostic sensitivity is further improved by the combined detection of the 2 markers.

Targeting MET in NSCLC: An Ever-Expanding Territory.

MET protooncogene (MET) alterations are known driver oncogenes in NSCLC. Since the identification of MET as a potential therapeutic target, extensive clinical trials have been performed. As a result, MET-targeted therapies, including MET tyrosine kinase inhibitors, monoclonal antibodies, and MET antibody-drug conjugates now play important roles in the standard treatment of MET-altered NSCLC; they have considerably improved the outcomes of patients with tumors that harbor MET oncogenic drivers. Although clinical agents are currently available and numerous other options are in development, particular challenges in the field require attention. For example, the therapeutic efficacy of each drug remains unsatisfactory, and concomitantly, the resistance mechanisms are not fully understood. Thus, there is an urgent need for optimal drug sequencing and combinations, along with a thorough understanding of treatment resistance. In this review, we describe the current landscape of pertinent clinical trials focusing on MET-targeted strategies and discuss future developmental directions in this rapidly expanding field.

Textured Potassium Sodium Niobate Lead-Free Ceramics with High d33 and Qm for Meeting High-Power Applications.

Potassium sodium niobate (KNN) lead-free piezoceramics have garnered significant attention for their environmentally friendly attributes, desired piezoelectric activity (d33), and high Curie temperature (Tc). However, the limited applicability of most KNN systems in high-power apparatus, including ultrasonic motors, transformers, and resonators, persists due to the inherent low mechanical quality factor (Qm). Herein, we proposed an innovative strategy for achieving high Qm accompanied by desirable d33 via synergistic chemical doping and texturing in KNN piezoceramics. Comprehensive electrical measurements along with quantitative structural characterization at multilength scales reveal that the excellent electromechanical properties (kp = 0.58, d33 ∼ 134 pC·N-1, Qm = 582, and Tc ∼ 415 °C) originate from the high <001> texturing degree, nanodomain, as well as acceptor hardening. Our findings provide an insight and guidance for achieving high-power performance in lead-free KNN-based piezoceramics, which were expected to be used in advanced transducer technology.

EGR1 transcriptionally regulates SVEP1 to promote proliferation and migration in human coronary artery smooth muscle cells.

A low-frequency variant of sushi, von Willebrand factor type A, EGF, and pentraxin domain-containing protein 1 (SVEP1) is associated with the risk of coronary artery disease, as determined by a genome-wide association study. SVEP1 induces vascular smooth muscle cell proliferation and an inflammatory phenotype to promote atherosclerosis. In the present study, qRT‒PCR demonstrated that the mRNA expression of SVEP1 was significantly increased in atherosclerotic plaques compared to normal tissues. Bioinformatics revealed that EGR1 was a transcription factor for SVEP1. The results of the luciferase reporter assay, siRNA interference or overexpression assay, mutational analysis and ChIP confirmed that EGR1 positively regulated the transcriptional activity of SVEP1 by directly binding to its promoter. EGR1 promoted human coronary artery smooth muscle cell (HCASMC) proliferation and migration via SVEP1 in response to oxidized low-density lipoprotein (ox-LDL) treatment. Moreover, the expression level of EGR1 was increased in atherosclerotic plaques and showed a strong linear correlation with the expression of SVEP1. Our findings indicated that EGR1 binding to the promoter region drive SVEP1 transcription to promote HCASMC proliferation and migration.

The effects of low-dose IL-2 on Th17/Treg cell imbalance in primary biliary cholangitis mouse models.

BACKGROUND/AIMS: Primary biliary cholangitis (PBC) is a chronic cholestatic liver disease. The imbalance of Th17/Treg cells has been reported in PBC patients. Low-dose IL-2 can alleviate disease severity through modulating CD4 + T cell subsets in patients with autoimmune diseases. Hence, the present study aimed to examine the effects and mechanism of low-dose IL-2 in PBC mouse models. METHODS: PBC models were induced in female C57BL/6 mice by two immunizations with 2OA-BSA at two-week intervals, and poly I: C every three days. PBC mouse models were divided into the IL-2 treated and untreated groups and low-dose IL-2 was injected at three different time points. Th17 and Tregs were analyzed by flow cytometry, and the related cytokines were analyzed by ELISA. Liver histopathology was examined by H&E and immunohistochemical staining. RESULTS: Twelve weeks after modeling, the serum AMA was positive and the ALP was significantly increased in PBC mouse models (P<0.05). The pathology showed lymphocyte infiltration in the portal area, damage, and reactive proliferation of the small bile duct (P<0.05). The flow cytometric showed the imbalance of Th17/Treg cells in the liver of PBC mouse models, with decreased Treg cells, increased Th17 cells, and Th17/Treg ratio (P < 0.05). After the low-dose IL-2 intervention, biochemical index and liver pathologies showed improvement at 12 weeks. Besides, the imbalance of Th17 and Treg cells recovered. Public database mining showed that Th17 cell differentiation may contribute to poor response in PBC patients. CONCLUSION: Low-dose IL-2 can significantly improve liver biochemistry and pathology by reversing the imbalance of Th17 and Treg cells, suggesting that it may be a potential therapeutic target for PBC.

The Pendulum Movement of Orbital Fat and Retro-Orbicularis Oculi Fat: A New Strategy for Correction of Sunken Eyelid Deformity in Revision Upper Blepharoplasty for Asian Patients.

BACKGROUND: With an increasing number of East Asians undergoing blepharoplasty, the number of patients with secondary upper eyelid deformities is increasing. The sunken eyelid deformity is a common deformity after upper blepharoplasty in Asians due to over-resection, retraction, or atrophy of the nasal and central orbital fat pads. Herein, we present a novel procedure, the pendulum movement of orbital fat and retro-orbicularis oculi fat ("POR" technique), for correction of sunken eyelid deformity in secondary Asian blepharoplasty. METHODS: Patients who underwent secondary upper blepharoplasty with the POR technique by the senior author between January 2020 and October 2021 were identified retrospectively. Those with fewer than 6 months of follow-up were excluded. Patient charts and images were reviewed for demographic data, comorbidities, concomitant eyelid deformities, and postoperative complications. Pre- and postoperative aesthetics, including degree of sunken eyelid deformity, were assessed by two independent raters and by self-reported patient satisfaction. RESULTS: Forty-nine consecutive patients were identified, all of whom were female and had grade I or II sunken eyelid deformity. Median follow-up was 8 months. Concomitant deformities included high tarsal crease (N = 31 patients, 63.3%), ptosis (N = 13, 26.5%), and upper eyelid retraction (N = 5, 10.2%). Almost patients had improvement in their eyelid volume, and 95.9% had improvement in their aesthetic rating. Approximately 93.9% of patients were satisfied with the outcome. CONCLUSIONS: The POR technique is an effective technique for correction of sunken eyelid deformity and can be utilized in conjunction with other techniques during secondary blepharoplasty. LEVEL OF EVIDENCE III: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Association of spinal-pelvic parameters with recurrence of lumbar disc herniation after endoscopic surgery: a retrospective case-control study.

PURPOSE: This study aimed to investigate the relationship between spinal-pelvic parameters and recurrence of lumbar disc herniation (rLDH) after percutaneous endoscopic lumbar discectomy (PELD) through a retrospective case-control study. METHODS: Patients who underwent PELD for single-segment LDH at our hospital were included in this study. The relationship between sagittal balance parameters of the spine and recurrence was analysed through correlation analysis, and ROC curves were plotted. The baseline characteristics, sagittal balance parameters of the spine and radiological parameters of the case and control groups were compared, and the relationship between sagittal balance parameters of the spine and recurrence of rLDH after PELD was determined through univariate and multivariate logistic regression analysis. RESULTS: Correlation analysis showed that PI and ∆PI-LL were negatively correlated with grouping (r = -0.090 and -0.120, respectively, P = 0.001 and 0.038). ROC curve analysis showed that the area under the curve (ROC-AUC) for predicting rLDH based on PI was 0.65 (CI95% = 0.598, 0.720), with a cut-off of 50.26°. The ROC-AUC for predicting rLDH based on ∆PI-LL was 0.56 (CI95% = 0.503, 0.634), with a cut-off of 28.21°. Multivariate logistic regression analysis showed that smoking status (OR = 2.667, P = 0.008), PI ≤ 50.26 (OR = 2.161, P = 0.009), ∆PI-LL ≤ 28.21 (OR = 3.185, P = 0.001) and presence of Modic changes (OR = 4.218, P = 0.001) were independent risk factors, while high DH (OR = 0.788, P = 0.001) was a protective factor. CONCLUSION: PI < 50.26 and ∆PI-LL < 28.21 were risk factors for recurrence of lumbar disc herniation after spinal endoscopic surgery and had some predictive value for post-operative recurrence.

Serine and arginine rich splicing factor 1­regulated microtubule interacting and trafficking domain containing 1 affects colorectal cancer progression and ferroptosis.

As the third most common type of cancer globally, colorectal cancer (CC) is a prevalent digestive malignancy, with the second highest mortality rate among all types of cancer. It has been reported that microtubule interacting and trafficking domain containing 1 (MITD1) serves a pivotal role in the initiation and progression of diverse types of tumors. Nevertheless, the underlying mechanism of MITD1 in CC has not been previously investigated. The ENCORI and GEPIA databases were used to investigate the expression levels of MITD1 in patients with CC. Immunohistochemistry was used to detect the expression of MITD1 in cancer tissues obtained from patients with CC, while its mRNA and protein expression levels in CC cell lines were determined by reverse transcription-quantitative PCR and western blot analysis, respectively. Subsequently, MITD1 was knocked down in CC cells using an interference plasmid and Cell Counting Kit 8, colony formation, as well as EdU assays were performed to assess cell proliferation. Concurrently, wound healing and Transwell assays were performed to evaluate the migration and invasion abilities of CC cells. Lipid reactive oxygen species (ROS) levels were determined by BODIPY 581/591 C11 staining. In addition, the levels of oxidative stress markers and those of total iron were measured using the corresponding kits. Furthermore, the association between serine and arginine rich splicing factor 1 (SRSF1) and MITD1 was verified by RNA immunoprecipitation and actinomycin D experiments. Finally, to further uncover the mechanism of MITD1, SRSF1 was overexpressed and MITD1 was silenced in CC cells. The results demonstrated that the expression of MITD1 was abnormally elevated in CC tissues and CC cell lines. MITD1 silencing distinctly diminished CC cell viability, increased CC cell ferroptosis and attenuated their invasion and migration abilities. In addition, MITD1 knockdown significantly increased the expression of lipid ROS and total iron levels in CC cells. Additionally, the results showed that SRSF1 could stabilize MITD1 mRNA expression in CC cells. Finally, it was revealed that SRSF1 could regulate MITD1 and affect the progression of CC and ferroptosis via p53/solute carrier family 7 member 11 (SLC7A11)/glutathione peroxidase 4 (GPX4) signaling. Overall, the results of the current study indicated that SRSF1-regulated MITD1 could affect CC progression and ferroptosis, probably via the p53/SLC7A11/GPX4 signaling pathway.

Interactions among the composition changes in fungal communities and the main mycotoxins in simulated stored wheat grains.

BACKGROUND: There are significant food safety risks associated with wheat spoilage due to fungal growth and mycotoxin contamination. Nevertheless, a few studies have examined how stored wheat grain microbial communities and mycotoxins vary in different storage conditions. In this study, changes in deoxynivalenol (DON) and deoxynivalenol-3-glucoside (D3G) content were measured with ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS), and an amplicon sequence analysis of fungi was performed on stored wheat grains from different storage conditions using high-throughput sequencing. The detailed interactions among the composition changes in the fungal community and the DON content of simulated stored wheat grains were also analyzed. RESULTS: Alternaria, Fusarium, Mrakia, and Aspergillus were the core fungal taxa, and the fungal communities of samples stored under different conditions were observed to be different. Aspergillus relative abundances increased, whereas Fusarium decreased. This led to an increase in the content of DON. The content of DON increased about 67% with 12% moisture and at 25 °C after 2 months of storage, which was influenced by the stress response of Fusarium. Correlations in fungal and mycotoxins changes were observed. There may be potential value in these findings for developing control strategies to prevent mildew infestations and mycotoxins contamination during grain storage. CONCLUSION: In storage, the more the fungal community composition and the relative abundance of Fusarium change, the more mycotoxins will be produced. We should therefore reduce competition between fungal communities through pre-storage treatment and through measures during storage. © 2023 Society of Chemical Industry.

Constructing a model including the cryptic sulfur cycle in Chesapeake Bay requires judicious choices for key processes and parameters.

A new biogeochemical model for Chesapeake Bay has been developed by merging two published models - the ECB model of Da et al. (2018) that has been calibrated for the Bay but only simulates nitrogen, carbon and oxygen and the BioRedoxCNPS model of al Azhar et al. (2014) and Hantsoo et al. (2018) that includes cryptic sulfur cycling. Comparison between these models shows that judicious choices are required for key processes and parameters. This manuscript documents the sources of differences between the two published models in order to select the most realistic configuration for our new model.•This study focuses on three sets of differences-processes only included in ECB (burial and dissolved organic matter), processes only included in BioRedoxCNPS (explicit dynamics for hydrogen sulfide, sulfate and nitrite, light attenuation that does not include CDOM or sediments), and differences in parameters common to the two codes.•Sensitivity studies that highlight particular choices (absorption by dissolved organic matter, nitrification rates, stoichiometric ratios) are also shown.•The new model includes sulfur cycling and has comparable skill in predicting oxygen as ECB, but also has improved simulation of nitrogen species compared with both original codes.

Four New Species of Strobilomyces (Boletaceae, Boletales) from Hainan Island, Tropical China.

Strobilomyces, one of the most noticeable genera of Boletaceae (Boletales), is both ecologically and economically important. Although many studies have focused on Strobilomyces in China, the diversity still remains incompletely understood. In the present study, several collections of Strobilomyces from Hainan Island, tropical China were studied based on morphology and molecular phylogenetic analyses. Four species are described as new, viz. S. baozhengii, S. conicus, S. hainanensis, and S. pachycystidiatus. Detailed descriptions, color photos of fresh basidiomata, and line drawings of microstructures of the four species are presented.

Knockdown of ZEB1 Inhibits Hypertrophic Scarring through Suppressing the Wnt/ß-catenin Signaling Pathway in a Mouse Model.

BACKGROUND: Hypertrophic scars (HS) cause functional impairment and cosmetic deformities following surgeries or burns (30% to 94%). There is no target therapy yet because the pathogenesis of HS progression is not well-known. In tissue fibrosis, Zinc finger E-box binding homeobox 1 (ZEB1) abnormal upregulation is an important cause for extracellular matrix (ECM) overexpression, which is the main molecular change in HS. Therefore, we hypothesized that ZEB1-knockdown inhibits HS formation. METHODS: ZEB1 expression in human HS and TGF-ß1-induced fibroblasts were identified by PCR and western blotting. ZEB1 was knockdown by siRNA in HS fibroblasts (HSFs) and mouse HS model (C57/BL6, male, 8-12 weeks). After 8-hour-transfection, HSFs were subjected to PCR, western blotting and CCK-8, apoptosis, migration and contraction assays. Mice HS were analyzed by HE staining, PCR and western blotting after 56 days. RESULTS: ZEB1 was upregulated in HS tissue (2.0-fold; p < 0.001). ZEB1 knockdown inhibited HSFs activity (0.6 to 0.7-fold; p < 0.001), the expression of fibrotic markers (0.4 to 0.6-fold; p < 0.001) and ß-catenin, cyclinD1 and c-Myc expression (0.5-fold; p < 0.001). In mouse HS models, HS skin thickness was thinner (1.60 ± 0.40 mm vs. 4.04 ± 0.36 mm; p < 0.001) after ZEB1 knockdown. CONCLUSIONS: Knockdown of ZEB1 inhibits HS formation both in vitro and in vivo. However, this is an in vitro/mouse model and more validation is needed. CLINICAL RELEVANCE STATEMENT: The discovery of ZEB1 as a mediator of HS formation might be a potential therapeutic target in HS treatment.

Catalytic Asymmetric Polycyclization of Tertiary Enamides with Silyl Enol Ethers: Total Synthesis of (-)-Cephalocyclidin A.

A catalytic enantioselective polycyclization of tertiary enamides with terminal silyl enol ethers has been developed by virtue of Cu(OTf)2 catalysis with a novel spiropyrroline-derived oxazole (SPDO) ligand. This tandem reaction offers an effective approach to assemble bicyclic and tricyclic N-heterocycles bearing both aza- and oxa-quaternary stereogenic centers, which are primal subunits in a range of natural alkaloids. Strategic application of this methodology and a late-stage radical cyclization as key steps have been showcased in the concise total synthesis of (-)-cephalocyclidin A.