Bioinspired Collective Total Synthesis of (±)-Rhynchines A-E.

Herein, we present the first racemic total synthesis of the structurally complex monoterpene indole alkaloids rhynchines A-E, starting from commercially available methyl nicotinate and 3-(2-bromoethyl)-1H-indole. The success of our synthesis is attributed to the utilization of a bioinspired synthetic strategy, which facilitated the rapid construction of the pentacyclic core skeleton of the target molecules through biomimetic skeletal rearrangement and late-stage C-H oxidative cyclization. Additionally, silica-gel-promoted tautomerization played a crucial role as a strategic element in the chemical synthesis of rhynchines A and B.

A Bayesian model-based reduced major axis regression.

Reduced major axis (RMA) regression, widely used in the fields of zoology, botany, ecology, biology, spectroscopy, and among others, outweighs the ordinary least square regression by relaxing the assumption that the covariates are without measurement errors. A Bayesian implementation of the RMA regression is presented in this paper, and the equivalence of the estimates of the parameters under the Bayesian and the frequentist frameworks is proved. This model-based Bayesian RMA method is advantageous since the posterior estimates, the standard deviations, as well as the credible intervals of the estimates can be obtained through Markov chain Monte Carlo methods directly. In addition, it is straightforward to extend to the multivariate RMA case. The performance of the Bayesian RMA approach is evaluated in the simulation study, and, finally, the proposed method is applied to analyze a dataset in the plantation.

Bioinspired Total Synthesis of Cephalotaxus Diterpenoids and Their Structural Analogues.

Herein, we present a unified chemical synthesis of three subgroups of cephalotaxus diterpenoids. Key to the success lies in adopting a synthetic strategy that is inspired by biosynthesis but is opposite in nature. By employing selective one-carbon introduction and ring expansion operations, we have successfully converted cephalotane-type C18 dinorditerpenoids (using cephanolide B as a starting material) into troponoid-type C19 norditerpenoids and intact cephalotane-type C20 diterpenoids. This synthetic approach has enabled us to synthesize cephinoid H, 13-oxo-cephinoid H, 7-oxo-cephinoid H, fortalpinoid C, 7-epi-fortalpinoid C, cephanolide E, and 13-epi-cephanolide E. Furthermore, through the development of an intermolecular asymmetric Michael reaction between ß-oxo esters and ß-substituted enones, we have achieved the enantioselective synthesis of advanced intermediates within our synthetic sequence, thus formally realizing the asymmetric total synthesis of the cephalotaxus diterpenoids family.

Sirt6 regulates the proliferation of neural precursor cells and cortical neurogenesis in mice.

Sirt6, a member of the class III histone deacetylases (HDACs), functions in the regulation of genomic stability, DNA repair, cancer, metabolism and aging. Sirt6 deficiency is lethal, and newborn SIRT6-null cynomolgus monkeys show unfinished brain development. After the generation of a cortex-specific Sirt6 conditional knockout mouse model, we investigated the specific deletion of Sirt6 in NPCs at E10.5. This study found that Sirt6 deficiency causes excessive proliferation of neural precursor cells (NPCs) and retards differentiation. The results suggest that endogenous Sirt6 in NPCs regulates histone acetylation and limits stemness-related genes, including Notch1, in order to participate in NPC fate determination. These findings help elucidate Sirt6's role in brain development and in NPC fate determination while providing data on species generality and differentiation.

Tetraphenylethene-Based Cross-Linked Conjugated Polymer Nanoparticles for Efficient Detection of 2,4,6-Trinitrophenol in Aqueous Phase.

The cross-linked conjugated polymer poly(tetraphenylethene-co-biphenyl) (PTPEBP) nanoparticles were prepared by Suzuki-miniemulsion polymerization. The structure, morphology, and pore characteristics of PTPEBP nanoparticles were characterized by FTIR, NMR, SEM, and nitrogen adsorption and desorption measurements. PTPEBP presents a spherical nanoparticle morphology with a particle size of 56 nm; the specific surface area is 69.1 m2/g, and the distribution of the pore size is centered at about 2.5 nm. Due to the introduction of the tetraphenylethene unit, the fluorescence quantum yield of the PTPEBP nanoparticles reaches 8.14% in aqueous dispersion. Combining the porosity and nanoparticle morphology, the fluorescence sensing detection toward nitroaromatic explosives in the pure aqueous phase has been realized. The Stern-Volmer quenching constant for 2,4,6-trinitrophenol (TNP) detection is 2.50 × 104 M-1, the limit of detection is 1.07 µM, and the limit of quantification is 3.57 µM. Importantly, the detection effect of PTPEBP nanoparticles toward TNP did not change significantly after adding other nitroaromatic compounds, indicating that the anti-interference and selectivity for TNP detection in aqueous media is remarkable. In addition, the spike recovery test demonstrates the potential of PTPEBP nanoparticles for detecting TNP in natural environmental water samples.

N4BP1 mediates RAM domain-dependent notch signaling turnover during neocortical development.

Notch signaling pathway activity, particularly fluctuations in the biologically active effector fragment NICD, is required for rapid and efficient dynamic regulation of proper fate decisions in stem cells. In this study, we identified NEDD4-binding protein 1 (N4BP1), which is highly expressed in the developing mouse cerebral cortex, as a negative modulator of Notch signaling dynamics in neural progenitor cells. Intriguingly, N4BP1 regulated NICD stability specifically after Notch1 S3 cleavage through ubiquitin-mediated degradation that depended on its RAM domain, not its PEST domain, as had been extensively and previously described. The CoCUN domain in N4BP1, particularly the "Phe-Pro" motif (862/863 amino acid), was indispensable for mediating NICD degradation. The Ring family E3 ligase Trim21 was, in contrast to other NEDD4 family members, required for N4BP1-regulated NICD degradation. Overexpression of N4BP1 in cortical neural progenitors promoted neural stem cell differentiation, whereas neural progenitor cells lacking N4BP1 were sensitized to Notch signaling, resulting in the maintenance of stem-like properties in neural progenitor cells and lower production of cortical neurons.

Total Synthesis of Metaphanine and Oxoepistephamiersine.

Herein, we report a concise and divergent synthesis of the complex hasubanan alkaloids metaphanine and oxoepistephamiersine from commercially available and inexpensive cyclohexanedione monoethylene acetal. Our synthesis features a palladium-catalyzed cascade cyclization reaction to set the tricyclic carbon framework of the desired molecules, a regioselective Baeyer-Villiger oxidation followed by a MeNH2 triggered skeletal reorganization cascade to construct the benzannulated aza[4.4.3]propellane, and a strategically late-stage regio-/diastereoselective oxidative annulation of sp3 C-H bond to form the challenging THF ring system and hemiketal moiety in a single step. In addition, a highly enantioselective alkylation of cyclohexanedione monoethylene acetal paved the way for the asymmetric synthesis of target molecular.

Pea Starch-Lauric Acid Complex Alleviates Dextran Sulfate Sodium-Induced Colitis in C57BL/6J Mice.

The previous documentation has shown the role of resistant starch in promoting intestinal health, while the effect of starch-lipid complex (RS5) on colitis remains unclear. This study aimed to investigate the effect and potential mechanism of RS5 in colitis. We prepared RS5 complexes by combining pea starch with lauric acid. Mice with dextran sulfate sodium-induced colitis were treated with either RS5 (3.25 g/kg) or normal saline (10 mL/kg) for seven days, and the effects of pea starch-lauric acid complex on mice were observed. The RS5 treatment significantly attenuated weight loss, splenomegaly, colon shortening, and pathological damage in mice with colitis. Compare with the DSS group, cytokines levels, such as tumor necrosis factor-α and interleukin-6 in both serum and colon tissue was significantly decreased in RS5 treatment group, while the gene expression of interleukin-10 and the expression of mucin 2, zonula occludens-1, Occludin, and claudin-1 in the colon was significantly upregulated in RS5 treatment group. In addition, RS5 treatment altered the gut microbiota structure of colitis mice by increasing the abundance of Bacteroides and decreasing Turicibacter, Oscillospira, Odoribacter, and Akkermansia. The dietary composition could be exploited to manage colitis by attenuating inflammation, restoring the intestinal barrier, and regulating gut microbiota.

Supercapacitive performance of C-axis preferentially oriented TiO2 nanotube arrays decorated with MoO3 nanoparticles.

Highly ordered TiO2 nanotube arrays (TNTAs) have received great attention owing to their high surface area, stability and direct transport pathways. The TNTAs, modified with other materials exhibiting enhanced conductivity and capacitance have been considered to be promising anode materials for supercapacitors. In this work, MoO3/carbon@different crystallography-oriented TiO2 nanotube arrays (CTNTAs) were synthesized by an anodizing method and electrochemical deposition. The structure and morphology of the samples were characterized by X-ray diffraction (XRD), field emission scanning electron microscopy (FE-SEM), high-resolution transmission electron microscopy (HR-TEM) and X-ray photoelectron spectroscopy (XPS). The electrochemical performance was tested by cyclic voltammogram (CV) and galvanostatic charge-discharge (GDC) tests. The results indicated that MoO3/carbon@(004) preferentially oriented TiO2 nanotube array electrodes have the advantages of combining p-TNTAs and MoO3 nanoparticles and exhibit high electrochemical performance and cycling stability. The highest specific capacitance of the MoO3-p-CTNTA electrode achieved is 194 F g-1 at a current density of 1 A g-1.

Psychological responses and dietary changes of residents during the local outbreak of COVID-19 in the post-epidemic era: A cross-sectional study.

The coronavirus disease 2019 (COVID-19) pandemic has had a dramatic impact on the psychological state and dietary behavior of individuals. Many previous studies have discussed the psychological and dietary problems during the first COVID-19 pandemic. However, few papers have discussed them during the local COVID-19 outbreak in the post-epidemic era. To explore the psychological responses and the influencing factors, dietary changes and the relationship with psychological responses during the local COVID-19 outbreak in the post-epidemic era. Methods: A total 3790 residents were surveyed by online questionnaire to collect information about social demography, health status, local outbreak related information, lifestyle changes, anxiety and depression. Binary logistic regression was used to discuss the influencing factors of anxiety and depression. Kendall tau-b correlation coefficient was used to discuss the relationship between anxiety, depression and dietary changes. Self-perceived physical condition, chronic disease, lockdown or quarantine, fear of COVID-19, changes in smoking, drinking and physical activity were the influencing factors of anxiety and depression. The top 3 foods with increased intake were drinking water, fresh fruits and fresh vegetables, while the top 3 foods with reduced intake were puffed foods, fried foods and sugary foods. Dietary changes were correlated with generalized anxiety disorder-7 and patient health questionnaire-9 scores. These findings provide experience and clues for local governments to improve the psychological status and dietary habits of residents during the local COVID-19 outbreak in the post-pandemic era.

Metabolomic profiles in a green alga (Raphidocelis subcapitata) following erythromycin treatment: ABC transporters and energy metabolism.

A recent study showed that erythromycin (ERY) exposure caused hormesis in a model alga (Raphidocelis subcapitata) where the growth was promoted at an environmentally realistic concentration (4 µg/L) but inhibited at two higher concentrations (80 and 120 µg/L), associated with opposite actions of certain signaling pathways (e.g., xenobiotic metabolism, DNA replication). However, these transcriptional alterations remain to be investigated and verified at the metabolomic level. This study uncovered metabolomic profiles and detailed toxic mechanisms of ERY in R. subcapitata using untargeted metabolomics. The metabolomic analysis showed that metabolomic pathways including ABC transporters, fatty acid biosynthesis and purine metabolism were associated with growth promotion in algae treated with 4 µg/L ERY. An overcompensation was possibly activated by the low level of ERY in algae where more resources were reallocated to efficiently restore the temporary impairments, ultimately leading to the outperformance of growth. By contrast, algal growth inhibition in the 80 and 120 µg/L ERY treatments was likely attributed to the dysfunction of metabolomic pathways related to ABC transporters, energy metabolism and metabolism of nucleosides. Apart from binding of ERY to the 50S subunit of ribosomes to inhibit protein translation as in bacteria, the data presented here indicate that inhibition of protein translation and growth performance of algae by ERY may also result from the suppression of amino acid biosynthesis and aminoacyl-tRNA biosynthesis. This study provides novel insights into the dose-dependent toxicity of ERY on R. subcapitata.

The Ash2l SDI Domain Is Required to Maintain the Stability and Binding of DPY30.

ASH2L and DPY30 are important for the assembly and catalytic activity of the complex associated with SET1 (COMPASS), which catalyzes histone methylation and regulates gene expression. However, the regulations among COMPASS components are not fully understood. Here, we leveraged a mouse model and cell lines to observe the outcome of Ash2l depletion and found a significant decrease in DPY30. Analyzing ASH2L ChIP-seq and RNA-seq data excluded transcriptional and translational regulation of ASH2L to DPY30. The decrease in DPY30 was further attributed to the degradation via the ubiquitin-mediated proteasomal pathway. We also verified that three amino acids in the ASH2L Sdc1 DPY30 interaction (SDI) domain are essential for the recognition and binding of DPY30. Lastly, we unexpectedly observed that overexpression of DPY30 in Ash2l-depleted cells rescued the decrease in Ccnd1 and the abnormal cell cycle, which indicates that DPY30 can participate in other complexes to regulate gene expression. Overall, our results, for the first time, reveal that the existence of DPY30 relies on the binding with ASH2L, with degradation of DPY30 via the ubiquitin-proteasome system, and they further indicate that the function of DPY30 can be independent of ASH2L.

Integrated comparison of growth and oxidative stress induced by tylosin in two freshwater algae Chlorella vulgaris and Raphidocelis subcapitata.

Two model algae, Chlorella vulgaris (C. vulgaris) and Raphidocelis subcapitata (R. subcapitata), are commonly used in registration procedures to evaluate compounds with antimicrobial capacity. However, it has been found that these two algae show considerable differences in sensitivity when exposed to antibiotics. The selection of a suitable test species plays a crucial role in assessing the environmental hazards and risks of a compound, as the balance between oxidative stress and antioxidants is a key factor for alga growth. This study was conducted to investigate the status of oxidative stress and mechanism of antioxidant defense system of algae under antibiotic stress. Different tylosin (TYN) exposure-concentrations were used for the tests in this study. Oxidative stress biomarkers (malondialdehyde (MDA)), non-enzymatic antioxidants (reduced glutathione (GSH)), antioxidant enzymes (superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GP), glutathione S-transferase (GST)) and photosynthetic pigments were measured to determine the status of the antioxidant defense system. With increasing TYN concentration, the growth of R. subcapitata was significantly inhibited, while there was no effect on C. vulgaris. When the growth of R. subcapitata was inhibited, the content of MDA was significantly increased and the antioxidant system was activated, which indicated a significant increase in the activity of SOD and CAT.

Clinical characteristics of primary Fallopian tube carcinoma: A single-institution retrospective study of 57 cases.

OBJECTIVE: To analyze the clinical profile and prognosis of primary Fallopian tube cancer (PFTC) in order to improve earlier diagnosis. METHODS: In this retrospective study, 57 women with PFTC were assessed from 2006 to 2016. Pathology, clinical index, recurrence, and survival were analyzed. RESULTS: Mean age was 57.35 ± 9.01 years, and 73% (19/26) of the patients with early-stage PFTC (I/II) were aged less than 60 years. Of patients who presented with abnormal vaginal bleeding, 75% (9/12) were at an early stage and their condition was often misdiagnosed as endometrial carcinoma preoperatively. In patients with Stages I/II and Stages III/IV PFTC, 59.09% (13/22) and 96.43% (27/28), respectively, had adnexal masses on color Doppler ultrasonography. The 5-year overall survival (OS) and disease-free survival rates were 69.23% and 44.23%, respectively, and univariate analysis showed that tumor stage and residual tumor size significantly affected the two survival rates. CONCLUSION: Primary Fallopian tube cancer is more likely to be misdiagnosed in patients aged less than 60 years or those presenting with vaginal bleeding at the premenopausal stage. Magnetic resonance imaging, cervical smear, and endometrial brush may be helpful for early PFTC diagnosis. Satisfactory cytoreductive surgery is critical because tumor stage and residual tumor size are significantly associated with the OS rate.

Transcriptomic analysis of Raphidocelis subcapitata exposed to erythromycin: The role of DNA replication in hormesis and growth inhibition.

The occurrence of hormesis in the algal growth inhibition test is a major challenge in the dose-response characterization, whereas the molecular mechanism remains unraveled. The aim of this study is therefore to investigate the changes in the molecular pathways in a model green alga Raphidocelis subcapitata treated with erythromycin (ERY; 4, 80, 120 µg L-1) by transcriptomic analysis. After 7 day exposure, ERY at 4 µg L-1 caused hormetic effects (21.9 %) on cell density, whereas 52.0 % and 65.4 % were inhibited in two higher exposures. By using adj p < 0.05 and absolute log2 fold change> 1 as a cutoff, we identified 218, 950, and 2896 differentially expressed genes in 4, 80, 120 µg L-1 treatment groups, respectively. In two higher ERY treated groups, genes involved in phases I, II & III metabolism processes and porphyrin and chlorophyll metabolism pathway were consistently suppressed. Interestingly, genes (e.g., pri2, mcm2, and mcm6) enriched in DNA replication process were up-regulated in 4 µg L-1 group, whereas these genes were all repressed in 120 µg L-1 group. Alteration trend in gene expression was consistent with algal growth. Taken together, our results unveiled the molecular mechanism of action in ERY- stimulated/ inhibited growth in green alga.

HCF-1 promotes cell cycle progression by regulating the expression of CDC42.

The eukaryotic cell cycle involves a highly orchestrated series of events in which the cellular genome is replicated during a synthesis (S) phase and each of the two resulting copies are segregated properly during mitosis (M). Host cell factor-1 (HCF-1) is a transcriptional co-regulator that is essential for and has been implicated in basic cellular processes, such as transcriptional regulation and cell cycle progression. Although a series of HCF-1 transcriptional targets have been identified, few functional clues have been provided, especially for chromosome segregation. Our results showed that HCF-1 activated CDC42 expression by binding to the -881 to -575 region upstream of the CDC42 transcription start site, and the regulation of CDC42 expression by HCF-1 was correlated with cell cycle progression. The overexpression of a spontaneously cycling and constitutively active CDC42 mutant (CDC42F28L) rescued G1 phase delay and multinucleate defects in mitosis upon the loss of HCF-1. Therefore, these results establish that HCF-1 ensures proper cell cycle progression by regulating the expression of CDC42, which indicates a possible mechanism of cell cycle coordination and the regulation mode of typical Rho GTPases.

Mendelian randomization analyses of genetically predicted circulating levels of cytokines with risk of breast cancer.

To determine whether genetically predicted circulating levels of cytokines are associated with risk of overall breast cancer (BC), estrogen receptor (ER)-positive and ER-negative BC, we conducted two-sample MR analyses using data from the most comprehensive genome-wide association studies (GWAS) on cytokines in 8293 Finnish participants and the largest BC GWAS from the Breast Cancer Association Consortium (BCAC) with totally 122,977 BC cases and 105,974 healthy controls. We systematically screened 41 cytokines (of which 24 cytokines have available instruments) and identified that genetically predicted circulating levels (1-SD increase) of MCP1 (OR: 1.08; 95% CIs: 1.03-1.12; P value: 3.55 × 10-4), MIP1b (OR: 1.02; 95% CIs: 1.01-1.04; P value: 2.70 × 10-3) and IL13 (OR: 1.06; 95% CIs: 1.03-1.10; P value: 3.33 × 10-4) were significantly associated with increased risk of overall BC, as well as ER-positive BC. In addition, higher levels of MIP1b and IL13 were also significantly associated with increased risk of ER-negative BC. These findings suggest the crucial role of cytokines in BC carcinogenesis and potential of targeting specific inflammatory cytokines for BC prevention.

Bioinformatics analyses and biological function of lncRNA ZFPM2-AS1 and ZFPM2 gene in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) remains one of the most lethal malignant tumors worldwide; however, the etiology of HCC still remains poorly understood. In the present study, cancer-omics databases, including The Cancer Genome Atlas, GTEx and Gene Expression Omnibus, were systematically analyzed in order to investigate the role of the long non-coding RNA (lncRNA) zinc finger protein, FOG family member 2-antisense 1 (ZFPM2-AS1) and the zinc finger protein, FOG family member 2 (ZFPM2) gene in the occurrence and progression of HCC. It was identified that the expression levels of lncRNA ZFPM2-AS1 were significantly increased in HCC tissues, whereas expression levels of the ZFPM2 gene were significantly decreased in HCC tissues compared with normal liver tissues. Higher expression levels of ZFPM2-AS1 were significantly associated with a less favorable prognosis of HCC, whereas higher expression levels of the ZFPM2 gene were associated with a more favorable prognosis of HCC. Genetic alterations in the ZFPM2 gene may contribute to a worse prognosis of HCC. Validation of the GSE14520 dataset also demon stared that ZFPM2 gene expression levels were significantly decreased in HCC tissues (P<0.001). The receiver operating characteristic (ROC) analysis of the ZFPM2 gene indicated high accuracy of this gene in distinguishing between HCC tissues and non-tumor tissues. The areas under the ROC curves were >0.8. Using integrated strategies, the present study demonstrated that lncRNA ZFPM2-AS1 and the ZFPM2 gene may contribute to the occurrence and prognosis of HCC. These findings may provide a novel understanding of the molecular mechanisms underlying the occurrence and prognosis of HCC.

Reduced graphene oxide/TiO2(B) nanocomposite-modified separator as an efficient inhibitor of polysulfide shuttling in Li-S batteries.

The shutting effect in lithium-sulfur (Li-S) batteries hinders their widespread application, which can be restrained effectively by a modified separator. In this work, a composite of reduced graphene oxide and beta-phase TiO2 nanoparticles (RGO/TiO2(B)) is designed as a separator modification material for improving the electrochemical behavior of Li-S batteries. The TiO2(B) nanoparticles are in situ prepared and tightly adhere to the RGO layer. A series of examinations demonstrated that the RGO/TiO2(B)-coated separator efficiently inhibits the polysulfide shuttling phenomenon by the cooperative effect of physical adsorption and chemical binding. Specifically, as modified separators, a comparison between TiO2(B) and anatase TiO2(A) each composited with RGO has been conducted. The TiO2(B) sample not only exhibits a superior blocking character of migrating polysulfides, but also enhances battery electrochemical kinetics by fast Li ion diffusion.

Bayesian Meta-Regression Model Using Heavy-Tailed Random-effects with Missing Sample Sizes for Self-thinning Meta-data.

Motivated by the self-thinning meta-data, a random-effects meta-analysis model with unknown precision parameters is proposed with a truncated Poisson regression model for missing sample sizes. The random effects are assumed to follow a heavy-tailed distribution to accommodate outlying aggregate values in the response variable. The logarithm of the pseudo-marginal likelihood (LPML) is used for model comparison. In addition, in order to determine which self-thinning law is more supported by the meta-data, a measure called "Plausibility Index (PI)" is developed. A simulation study is conducted to examine empirical performance of the proposed methodology. Finally, the proposed model and the PI measure are applied to analyze a self-thinning meta-data set in details.