Conservation genomics of the critically endangered Chinese pangolin.

The Chinese pangolin (Manis pentadactyla, MP) has been extensively exploited and is now on the brink of extinction, but its population structure, evolutionary history, and adaptive potential are unclear. Here, we analyzed 94 genomes from three subspecies of the Chinese pangolin and identified three distinct genetic clusters (MPA, MPB, and MPC), with MPB further divided into MPB1 and MPB2 subpopulations. The divergence of these populations was driven by past climate change. For MPB2 and MPC, recent human activities have caused dramatic population decline and small population size as well as increased inbreeding, but not decrease in genomic variation and increase in genetic load probably due to strong gene flow; therefore, it is crucial to strengthen in situ habitat management for these two populations. By contrast, although human activities have a milder impact on MPA, it is at high risk of extinction due to long-term contraction and isolation, and genetic rescue is urgently needed. MPB1 exhibited a relatively healthy population status and can potentially serve as a source population. Overall, our findings provide novel insights into the conservation of the Chinese pangolin and biogeography of the mammals of eastern Asia.

LIMA1 links the E3 ubiquitin ligase RNF40 to lipid metabolism.

LIMA1 is a LIM domain and Actin binding 1 protein that acts as a skeleton protein to promote cholesterol absorption, which makes it an ideal target for interfering with lipid metabolism. However, the detailed regulation of LIMA1 remains unclear. Here, we identified that ring finger protein 40 (RNF40), an E3 ubiquitin ligase previously known as an epigenetic modifier to increase H2B ubiquitination, mediated the ubiquitination of LIMA1 and thereby promoted its degradation in a proteasome-dependent manner. Fraction studies revealed that the 1-166aa fragment of LIMA1 was indispensable for the interaction with RNF40, and at least two domains of RNF40 might mediate the association of RNF40 with LIMA1. Notably, treatment with simvastatin dramatically decreased the levels of CHO and TG in control cells rather than cells with overexpressed LIMA1. Moreover, RNF40 significantly decreased lipid content, which could be reversed by LIMA1 overexpression. These findings suggest that E3 ubiquitin ligase RNF40 could directly target LIMA1 and promote its protein degradation in cytoplasm, leading to the suppression of lipid accumulation mediated by LIMA1. Collectively, this study unveils that RNF40 is a novel E3 ubiquitin ligase of LIMA1, which underpins its high therapeutic value to combat dysregulation of lipid metabolism.

Financial Development and Energy Environmental Performance: Evidence from China's Regional Economies.

Financial development makes many contributions to promoting economic growth. With the deterioration of the ecological environment, scholars have begun to consider the role of financial development in sustainable economic development. This paper investigates the influence of financial development on China's energy environmental performance (EEP) by utilizing panel data from 2002 to 2017. The findings demonstrate that financial development has a significant impact on regional EEP, and the results remain robust through a series of assessments. The technological innovation level and human capital are the transmission paths through which financial development affects regional EEP. Furthermore, using the difference-in-differences (DID) method, we not only prove the causal relationship between financial development and EEP but also show that the allocation of financial assets can significantly affect energy consumption efficiency. Finally, heterogeneity analysis shows that financial development has varying impacts on energy efficiency in distinct regions across China. The influence of financial development on EEP displays a clear "Matthew Effect". To the best of our knowledge, our findings offer greater insight into the energy-saving and emission-reduction effects of financial development.

The Relationship between the Dietary Inflammatory Index (DII) and Metabolic Syndrome (MetS) in Middle-Aged and Elderly Individuals in the United States.

(1) Background: With the aging demographic shift in society, there is a growing number of middle-aged and elderly individuals affected by metabolic syndrome (MetS), a risk factor contributing to all causes of mortality. Inflammation plays a crucial role in the development of MetS. This study aims to examine the correlation between MetS and pro-inflammatory diets in middle-aged and elderly individuals, utilizing the Dietary Inflammation Index (DII) as a measure. (2) Methods: Data were extracted from the 2007-2016 National Health and Nutrition Examination Survey (NHANES) database for individuals who were 45 years of age or older. The DII was determined for each participant through 24-h dietary recall interviews. The relationship between DII and MetS was assessed using binary logistic regression analysis, and the association between DII and MetS-related indicators was further explored through generalized linear model (GLM) and quantile regression analysis. (3) Results: A total of 3843 middle-aged and elderly individuals were included in the study. After controlling for confounding factors, the highest quartile of DII was associated with a higher risk of MetS (ORQ4:Q1 = 1.339; 95% CI: 1.013, 1.769; p for trend = 0.018). The top DII quartile also increased the risk of reduced HDL-C (ORQ4:Q1 = 1.499; 95% CI: 1.005, 2.234; p for trend = 0.048) and raised FG (ORQ4:Q1 = 1.432; 95% CI: 1.095, 1.873; p for trend = 0.010) compared to the lowest DII quartile. The levels of DII were found to be positively correlated with BMI (ß = 0.258, p = 0.001), FPG (ß = 0.019, p = 0.049), TG (ß = 2.043, p = 0.013), waistline (ß = 0.580, p = 0.002), and negatively correlated with HDL-C (ß = -0.672, p = 0.003). (4) Conclusions: In middle-aged and elderly individuals in the United States, a high DII score has been linked to the presence of MetS, low HDL-C, and hyperglycemia. Therefore, dietary recommendations for the middle-aged and elderly should focus on reducing the DII by choosing foods rich in antioxidants, dietary fiber, and unsaturated fatty acids.

Borenium-Ion-Catalyzed C-H Borylation of Arenes.

Non-metal-catalyzed C-H borylation of arenes represents a sustainable and environment-friendly approach for the functionalization of arenes. Despite its promise as an alternative to traditional transition-metal systems, its substrate scope is generally limited to electron-rich arenes, thus hindering its application in organic synthesis. Herein, we report the development of a borenium-ion catalyst which can borylate unactivated arenes under ambient conditions with 4-chlorocatecholborane (HBcatCl) as borylation reagent. This metal-free catalytic system is suitable for the borylation of C-H bonds in sterically encumbered positions, which has been a challenging task for transition-metal systems. Additionally, this catalytic system allows para-selective one-pot borylation of phenols, which has not been achieved by using transition-metal systems. Our mechanistic investigations and computational studies support a synergistic activation of the H-BcatCl bond by the arene substrate and the borenium-ion catalyst. This generates a Wheland intermediate and a neutral hydroborane species and is followed by deprotonation of the Wheland intermediate with the hydroborane species. The latter step of C-H bond cleavage is likely the rate-limiting step.

Dynamic Nomogram Based on the Metastatic Number and Sites and Therapy Strategies Predicting the Prognosis of Patients with Metastatic Cervical Cancer.

Background: Individual survival prediction is of vital importance to optimize the individualized treatment of metastatic cervical cancer (mCC) patients. The goal of this study was to identify the potential risk factors for the survival of mCC patients and construct a nomogram for their prognosis. Methods: Medical records of patients with newly diagnosed mCC at the First Affiliated Hospital of Xi'an Jiaotong University were reviewed retrospectively. Risk factors were identified using Cox proportional hazards analysis and Kaplan-Meier curves. Random forest was used to identify factors associated with therapy strategy. Nomogram and dynamic nomogram were established using 'rms' and "DynNom" R package. Results: A total of 98 patients with mCC were finally identified. In Cox analyses, multiple metastases and concurrent chemoradiotherapy (CCRT) were identified as independent predictors for overall survival (OS). We further explored the prognostic value of metastatic number and sites and therapy strategies for mCC patients by Kaplan-Meier curves. A dynamic nomogram including metastases number and sites (multiple metastases, liver and lymph node (LN) above diaphragm metastases) and chemoradiotherapy strategies (CCRT, postradiotherapy chemotherapy, and radiotherapy to metastatic sites) was constructed for predicting the prognosis of mCC patients. For newly diagnosed patients, we strongly recommended the combination of chemotherapy and definitive pelvic radiotherapy and, if possible, radiation to metastatic site, but CCRT should be implemented with caution. We constructed a dynamic nomogram indicating that patients with younger age, shorter symptom duration, and better laboratory test results are suitable for CCRT. Conclusion: Survival analyses showed that the metastatic number and sites and therapy strategies are associated with the prognosis of mCC patients. The CCRT and prognostic nomograms may help clinicians to make better clinical decisions and effectively predict the prognosis for newly diagnosed mCC patients.

Frequency-Modulated Signal Measurement Using Closed-Loop Methodology.

Frequency-modulated (FM) signals are widely used in sensing, measurement, and signal detection due to their strong anti-interference and easy transmission characteristics. Although the high-precision measurement methods for static signals are quite complete, the high-precision measurement methods for dynamic FM signals still need to be studied, and the measurement accuracy in the high-sampling system still has room for improvement. Traditionally, the equal-precision measurement method is widely applied in most scenarios. However, its accuracy is limited by the quantization error of ±1 word and the sampling gate time, making it difficult to improve the frequency measurement accuracy while ensuring a high sampling rate at the same time. In this paper, a high-precision feedback frequency measurement system with the capability to eliminate the quantization error of ±1 word is proposed. The proposed system consists of two stages, the rough measurement stage based on the equal-precision measurement method and the precise measurement stage based on the negative feedback tracking architecture using the phase-frequency detector (PFD) and direct digital synthesizer (DDS). The effectiveness and feasibility of the system are verified by both simulation and experiment. At the sampling rate of 2 kHz, the frequency measurement accuracy is improved by more than 30 dB.

Recent advances in borenium catalysis.

Borenium ions are strong Lewis acids because of the positive charge on boron. While their high reactivity had long restricted their role in organic synthesis to stoichiometric reagents, in the past ten years the introduction of suitable supporting ligands, such as N-heterocyclic carbenes, has enabled them to function as competent catalysts for various organic transformations involving the activation of strong covalent bonds, such as H-H, Si-H, B-H, C-H and C-C bonds. This review provides an overview of the recent advances in borenium-catalysed reactions with emphasis on catalyst synthesis, methodology development and mechanistic insight.

Nano-selenium attenuates mitochondrial-associated apoptosis via the PI3K/AKT pathway in nickel-induced hepatotoxicity in vivo and in vitro.

The aim of this study was to investigate the protective effects of Nano-Se against nickel (Ni)-induced hepatotoxicity and the potential mechanism. Hence, we constructed in vivo and in vitro models of Ni-induced hepatotoxicity. Sprague-Dawley (SD) rats were exposed to nickel sulfate (NiSO4 , 5.0 mg/kg, i.p.) with or without Nano-Se (0.5, 1, and 2 mg/kg, oral gavage) co-administration for 14 days, and HepG2 cells were exposed to NiSO4 (1500 µM) with or without Nano-Se (20 µM) for 24 h. Nano-Se obviously prevented Ni-induced hepatotoxicity indicated by ameliorating pathological change and decreasing Ni accumulation in rat livers. Ni induced a significant increase in hepatic activities of superoxide dismutase (SOD), catalase (CAT), glutathione reductase (GSH-Px), and malondialdehyde (MDA) level, decreased the glutathione (GSH) content while compared to those in the control group. Nano-Se administration improved the hepatic antioxidant capacity through increase hepatic GSH contents and GSH-Px activity, decrease the activities of SOD, CAT, and MDA level. Nano-Se improved the cell viability, decreased active oxygen (ROS) generation and ameliorated morphological changes of nuclear structures in Ni-treated HepG2 cells. In addition, Nano-Se inhibited the Ni-induced increases of cytochrome c, caspase-9, cleaved caspase-3, increased PI3K and AKT phosphorylation both in vivo and in vitro. Besides, the PI3K inhibitor Y294002 could inhibit the protective effects of Nano-Se on apoptosis. Thus, Nano-Se significantly activates PI3K/AKT signaling to ameliorate apoptosis in Ni-induced hepatotoxicity.

Promethazine inhibits proliferation and promotes apoptosis in colorectal cancer cells by suppressing the PI3K/AKT pathway.

AIM: To elucidate the potential effect of promethazine on colorectal cancer (CRC) cells and the underlying mechanism. MATERIALS AND METHODS: Targets of the drug promethazine (PMTZ) were identified by DrugBank and comparative toxicogenomic databases (CTD), and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis was performed with STRING software. The effects of PMTZ were predicted to be associated with the PI3K/AKT pathway. Cell Counting Kit 8 (CCK-8) assays were used to evaluate the effects of different concentrations of PMTZ on the proliferation of various types of CRC cells. Flow cytometry and Western blotting analyses were used to detect the degree of CRC cell apoptosis and the expression of the apoptosis-related proteins Bcl-2, Bax and caspase-3 after PMTZ treatment. The expression levels of PI3K/AKT pathway-related proteins [PI3K, AKT, phosphorylated (P)-PI3K and p-AKT] in CRC cells treated with PMTZ were analyzed by Western blotting. RESULTS: PMTZ inhibited the proliferation and promoted the apoptosis of CRC cells and suppressed the activation of the PI3K/AKT signaling pathway in a dose-dependent manner. DISCUSSION AND CONCLUSIONS: PMTZ may suppress the proliferation and induce the apoptosis of CRC cells by inhibiting the PI3K/ AKT signaling pathway. This study reported, for the first time, the function of PMTZ in CRC cells and the underlying mechanism and further confirmed the potential antitumor effects of phenothiazine. The combination of bioinformatics analyses and experiments provides informative evidence for the reuse of drugs and the development of new drugs.

The SPOP-ITCH Signaling Axis Protects Against Prostate Cancer Metastasis.

Prostate cancer is one of the most common causes of cancer incidence and death in men, with the mortality caused primarily by the late-stage and metastatic forms of the disease. The mechanisms and molecular markers for prostate cancer metastasis are not fully understood. Speckle type Poz Protein (SPOP) is an E3 ubiquitin ligase adaptor that is often mutated in prostate cancer. In this study, we sequenced the SPOP gene in 198 prostate cancer patients and found 16 mutations in the cohort. Multivariate analysis revealed that SPOP mutations correlated with the clinical stage of the disease and strongly with metastasis. We identified ITCH as a candidate protein for SPOP-mediated degradation via mass spectrometry. We demonstrated the interaction between SPOP and ITCH, and found that the SPOP F133L mutation disrupted the SPOP-ITCH interaction, leading to a subsequent increase in the ITCH protein level. Further, we found that the SPOP knockdown led to higher levels of Epithelial- mesenchymal transition (EMT) proteins and increased cell invasion. Together, our results highlight the functional significance of the SPOP-ITCH pathway in prostate cancer metastasis.

Identification of significant genes and therapeutic agents for breast cancer by integrated genomics.

Breast cancer is the most commonly diagnosed malignancy in women; thus, more cancer prevention research is urgently needed. The aim of this study was to predict potential therapeutic agents for breast cancer and determine their molecular mechanisms using integrated bioinformatics. Summary data from a large genome-wide association study of breast cancer was derived from the UK Biobank. The gene expression profile of breast cancer was from the Oncomine database. We performed a network-wide association study and gene set enrichment analysis to identify the significant genes in breast cancer. Then, we performed Gene Ontology analysis using the STRING database and conducted Kyoto Encyclopedia of Genes and Genomes pathway analysis using Cytoscape software. We verified our results using the Gene Expression Profile Interactive Analysis, PROgeneV2, and Human Protein Atlas databases. Connectivity map analysis was used to identify small-molecule compounds that are potential therapeutic agents for breast cancer. We identified 10 significant genes in breast cancer based on the gene expression profile and genome-wide association study. A total of 65 small-molecule compounds were found to be potential therapeutic agents for breast cancer.

Closest Packing Polymorphism Interfaced Metastable Transition Metal for Efficient Hydrogen Evolution.

Metastable materials are promising because of their catalytic properties, high-energy structure, and unique electronic environment. However, the unstable nature inherited from the metastability hinders further performance improvement and practical applications of these materials. Herein, this limitation is successfully addressed by constructing an in situ polymorphism interface (inf) between the metastable hexagonal-close-packed (hcp) phase and its stable counterpart (face-centered cubic, fcc) in cobalt-nickel (CoNi) alloy. Calculations reveal that the interfacial synergism derived from the hcp and fcc phases lowers the formation energy and enhances stability. Consequently, the optimized CoNi-inf exhibits an exceptionally low potential of 72 mV at 10 mA cm-2 and a Tafel slope of 57 mV dec-1 for the hydrogen evolution reaction (HER) in 1.0 m KOH. Furthermore, it is superior to most state-of-the-art non-noble-metal-based HER catalysts. No noticeable activity decay or structural changes are observed even over 14 h of catalysis. The computational simulation further rationalizes that the interface of CoNi-inf with a suitable d-band center provides uniform sites for hydrogen adsorption, leading to a distinguished HER catalytic activity. This work, therefore, presents a new route for designing metastable catalysts for potential energy conversion.

Integrative, genome-wide association study identifies chemicals associated with common women's malignancies.

BACKGROUND: Breast cancer, cervical cancer, and ovarian cancer are three of the most commonly diagnosed malignancies in women, and more cancer prevention research is urgently needed. METHODS: Summary data of a large genome-wide association study of female cancers were derived from the UK biobank. We performed a transcriptome-wide association study and a gene set enrichment analysis to identify correlations between chemical exposure and aberrant expression, repression, or mutation of genes related to cancer using the Comparative Toxicogenomics Database. RESULTS: We identified five chemicals (NSC668394, glafenine, methylnitronitrosoguanidine, fenofibrate, and methylparaben) that were associated with the incidence of both breast cancer and cervical cancer. CONCLUSION: Using a transcriptome-wide association study and gene set enrichment analysis we identified environmental chemicals that are associated with an increased risk of breast cancer, cervical cancer, and ovarian cancer.

Tamoxifen induces fatty liver disease in breast cancer through the MAPK8/FoxO pathway.

BACKGROUND: Prevention of metabolic complications of long-term adjuvant endocrine therapy in breast cancers remained a challenge. We aimed to investigate the molecular mechanism in the development of tamoxifen (TAM)-induced fatty liver in both estrogen receptor (ER)-positive and ER-negative breast cancer. METHODS AND RESULTS: First, the direct protein targets (DPTs) of TAM were identified using DrugBank5.1.7. We found that mitogen-activated protein kinase 8 (MAPK8) was one DPT of TAM. We identified significant genes in breast cancer and fatty liver disease (FLD) using the MalaCards human disease database. Next, we analyzed the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways of those significant genes in breast cancer and FLD using the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING). We found that overlapping KEGG pathways in these two diseases were MAPK signaling pathway, Forkhead box O (FoxO) signaling pathway, HIF-1 signaling pathway, AGE-RAGE signaling pathway in diabetic complications, and PI3K-Akt signaling pathway. Furthermore, the KEGG Mapper showed that the MAPK signaling pathway was related to the FoxO signaling pathway. Finally, the functional relevance of breast cancer and TAM-induced FLD was validated by Western blot analysis. We verified that TAM may induce fatty liver in breast cancer through the MAPK8/FoxO signaling pathway. CONCLUSION: Bioinformatics analysis combined with conventional experiments may improve our understanding of the molecular mechanisms underlying side effects of cancer drugs, thereby making this method a new paradigm for guiding future studies on this issue.

Integrating Genome-Wide Association Studies and Gene Expression Profiles With Chemical-Genes Interaction Networks to Identify Chemicals Associated With Colorectal Cancer.

Colorectal cancer (CRC) is the third most common cancer and has the second highest mortality rate in global cancer. Exploring the associations between chemicals and CRC has great significance in prophylaxis and therapy of tumor diseases. This study aims to explore the relationships between CRC and environmental chemicals on genetic basis by bioinformatics analysis. The genome-wide association study (GWAS) datasets for CRC were obtained from the UK Biobank. The GWAS data for colon cancer (category C18) includes 2,581 individuals and 449,683 controls, while that of rectal cancer (category C20) includes 1,244 individuals and 451,020 controls. In addition, we derived CRC gene expression datasets from the NCBI-GEO (GSE106582). The chemicals related gene sets were acquired from the comparative toxicogenomics database (CTD). Transcriptome-wide association study (TWAS) analysis was applied to CRC GWAS summary data and calculated the expression association testing statistics by FUSION software. We performed chemicals related gene set enrichment analysis (GSEA) by integrating GWAS summary data, mRNA expression profiles of CRC and the CTD chemical-gene interaction networks to identify relationships between chemicals and genes of CRC. We observed several significant correlations between chemicals and CRC. Meanwhile, we also detected 5 common chemicals between colon and rectal cancer, including methylnitronitrosoguanidine, isoniazid, PD 0325901, sulindac sulfide, and importazole. Our study performed TWAS and GSEA analysis, linked prior knowledge to newly generated data and thereby helped identifying chemicals related to tumor genes, which provides new clues for revealing the associations between environmental chemicals and cancer.

Se-Incorporation Stabilizes and Activates Metastable MoS2 for Efficient and Cost-Effective Water Gas Shift Reaction.

Although the water gas shift (WGS) reaction has sparked intensive attention for the production of high-purity hydrogen, the design of cost-efficient catalysts with noble metal-like performance still remains a great challenge. Here, we successfully overcome this obstacle by using Se-incorporated MoS2 with a 1T phase. Combining the optimized electronic structure, additional active sites from edge sites, and a sulfur vacancy based on the 1T phase, as well as the high surface ratio from the highly open structure, the optimal MoS1.75Se0.25 exhibits superior activity and stability compared to the conventional 2H-phase MoS2, with poor activity, large sulfur loss, and rapid inactivation. The hydrogen production of MoS1.75Se0.25 is 942 µmol, which is 1.9 times higher than MoS2 (504 µmol) and 2.8 times higher than MoSe2 (337 µmol). Furthermore, due to the lattice stabilization via Se-incorporation, MoS1.75Se0.25 exhibited excellent long-term stability without obvious change in more than 10 reaction rounds. Our results demonstrate a pathway to design efficient and cost-efficient catalysts for WGS.

SPOP regulates the DNA damage response and lung adenocarcinoma cell response to radiation.

Speckle-type POZ protein (SPOP) plays an important role in maintaining genome stability. Disability or mutation of the SPOP gene has been reported to contribute to prostate cancer incidence and prognosis. However, the functions of SPOP in lung cancer remain poorly understood, especially in lung adenocarcinoma (LUAD). Here, we found that SPOP affects the LUAD cell response to radiation by regulating the DNA damage response (DDR) pathway. SPOP is widely expressed in lung cancer cell lines, and SPOP protein levels are upregulated when cells experience DNA damage. SPOP knockdown affects DDR repair kinetics, apoptosis and cell cycle checkpoints that are induced by IR (ionizing radiation). Furthermore, we found that SPOP positively regulates the expression of DDR factors Rad51 and Ku80. Taken together, these data indicate the essential roles of SPOP in the DDR signaling pathways and LUAD cell response to radiation.

Identification of a Five-CpG Signature with Diagnostic Value in Thyroid Cancer.

Thyroid cancer (TC) ranks as the most common endocrine malignancy, and its incidence and mortality rates continue to rise annually. Increasing evidence have shown that DNA methylation, a kind of stable epigenetic modification, is associated with carcinogenesis, suggesting its potential as biomarkers for the early detection of tumors. With the aim of exploring likely DNA methylation biomarkers for TC diagnosis, we conducted a synthetic analysis of DNA methylation profiles based on 789 samples from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases. In the discovery phase, we identified five CpG probes (cg11228682, cg01291854, cg06778183, cg01668008, and cg01702055) on the condition of DNA methylation data from GSE86961 (n = 82) and constructed a five-CpG signature-based diagnostic model for TC. In addition, we validated the diagnostic score formula in two independent training cohorts, GSE97466 (n = 141) and TCGA (n = 566), as well as the previous developing cohort GSE86961. Receiver operating characteristic analysis revealed that the five-CpG signature had a good diagnostic performance to distinguish TC samples from benign samples. In conclusion, our findings suggest that the five-CpG signature could provide a novel biomarker with useful applications in TC diagnosis.