The role of oxidative stress in intervertebral disc degeneration: Mechanisms and therapeutic implications.

Oxidative stress is one of the main driving mechanisms of intervertebral disc degeneration(IDD). Oxidative stress has been associated with inflammation in the intervertebral disc, cellular senescence, autophagy, and epigenetics of intervertebral disc cells. It and the above pathological mechanisms are closely linked through the common hub reactive oxygen species(ROS), and promote each other in the process of disc degeneration and promote the development of the disease. This reveals the important role of oxidative stress in the process of IDD, and the importance and great potential of IDD therapy targeting oxidative stress. The efficacy of traditional therapy is unstable or cannot be maintained. In recent years, due to the rise of materials science, many bioactive functional materials have been applied in the treatment of IDD, and through the combination with traditional drugs, satisfactory efficacy has been achieved. At present, the research review of antioxidant bioactive materials in the treatment of IDD is not complete. Based on the existing studies, the mechanism of oxidative stress in IDD and the common antioxidant therapy were summarized in this paper, and the strategies based on emerging bioactive materials were reviewed.

Highly sensitive photoelectrochemical biosensing detection of early cardiac injury enabled by novel self-assembled Bi2O3/MgIn2S4 photoelectrode coupled with ZnSnO3 quencher.

The development of photoelectrochemical (PEC) biosensors plays a critical role in enabling timely intervention and personalized treatment for cardiac injury. Herein, a novel approach is presented for the fabrication of highly sensitive PEC biosensor employing Bi2O3/MgIn2S4 heterojunction for the ultrasensitive detection of heart fatty acid binding protein (H-FABP). The Bi2O3/MgIn2S4 heterojunction, synthesized through in-situ growth of MgIn2S4 on Bi2O3 nanoplates, offers superior attributes including a larger specific surface area and more homogeneous distribution, leading to enhanced sensing sensitivity. The well-matched valence and conduction bands of Bi2O3 and MgIn2S4 effectively suppress the recombination of photogenerated carriers and facilitate electron transfer, resulting in a significantly improved photocurrent signal response. And the presence of the secondary antibody marker (ZnSnO3) introduces steric hindrance that hinders electron transfer between ascorbic acid and the photoelectrode, leading to a reduction in photocurrent signal. Additionally, the competition between the ZnSnO3 marker and the Bi2O3/MgIn2S4 heterojunction material for the excitation light source further diminishes the photocurrent signal response. After rigorous repeatability and selectivity tests, the PEC biosensor exhibited excellent performance, and the linear detection range of the biosensor was determined to be 0.05 pg/mL to 100 ng/mL with a remarkable detection limit of 0.029 pg/mL (S/N = 3).

Ionic liquid post-modified carboxylate-rich MOFs for efficient catalytic CO2 cycloaddition under solvent-free conditions.

The synthesis of cyclic carbonates through cycloaddition reactions between epoxides and carbon dioxide (CO2) is an important industrial process. Metal-Organic Frameworks (MOFs) have functional and ordered pore structures, making them attractive catalysts for converting gas molecules into valuable products. One approach to enhance the catalytic activity of MOFs in CO2 cycloaddition reactions is to create open metal sites within MOFs. In this study, the amino-functionalized rare earth Gd-MOF (Gd-TPTC-NH2) and its ionic liquid composite catalysts (Gd-TPTC-NH-[BMIM]Br) were synthesized using 2'-amino-[1,1':4',1''-terphenyl]-3,3'',5,5''-tetracarboxylic acid (H4TPTC-NH2) as the ligand. The catalytic performance of these two catalysts was observed in the cycloaddition reaction of CO2 and epoxides. Under the optimized reaction conditions, Gd-TPTC-NH-[BMIM]Br can effectively catalyze the cycloaddition reaction of a variety of epoxide substrates with good to excellent yields of cyclic carbonate products. Comparatively, epichlorohydrin and epibromohydrin, which possess halogen substituents, promote higher yields of cyclic carbonates due to the electron-withdrawing nature of Cl and Br substituents. Additionally, the Gd-TPTC-NH-[BMIM]Br catalyst demonstrated good recyclability and reproducibility, maintaining its catalytic activity without any changes in its structure or properties after five reuse cycles.

T790M mutation upconversion fluorescence biosensor via mild ATRP strategy and site-specific DNA cleavage of restriction endonuclease.

A unique combination of a specific nucleic acid restriction endonuclease (REase) and atom transfer radical polymerization (ATRP) signal amplification strategy was employed for the detection of T790M mutations prevalent in the adjuvant diagnosis of lung cancer. REase selectively recognizes and cleaves T790M mutation sites on double-stranded DNA formed by hybridization of a capture sequence and a target sequence. At the same time, the ATRP strategy resulted in the massive aggregation of upconverted nanoparticles (UCNPs), which significantly improved the sensitivity of the biosensor. In addition, the UCNPs have excellent optical properties and can eliminate the interference of autofluorescence in the samples, thus further improving the detection sensitivity. The proposed upconversion fluorescent biosensor is characterized by high specificity, high sensitivity, mild reaction conditions, fast response time, and a detection limit as low as 0.14 fM. The performance of the proposed biosensor is comparable to that of clinical PCR methods when applied to clinical samples. This work presents a new perspective for assisted diagnosis in the pre-intervention stage of tumor diagnostics in the early stage of precision oncology treatments.

Long-term all-cause death prediction by coronary, aortic, and valvular calcification in patients with acute ST-segment elevation myocardial infarction.

BACKGROUND: To determine the prognostic value of cumulative calcification score of coronary artery calcification (CAC), thoracic aortic calcification (TAC) and aortic valve calcification (AVC) in acute ST segment elevation myocardial infarction (STEMI) patients. METHODS: This was a retrospective, single-center cohort study. A total of 332 STEMI patients who received primary percutaneous coronary intervention (PPCI) were enrolled in this study between January 2010 to October 2018. We assessed the calcification in the left anterior descending branch (LAD), left circumflex branch (LCX), right coronary artery (RCA), thoracic aorta, and aortic valve. Calcification of each part was counted as 1 point, and the cumulative calcification score was calculated as the sum of all points. The primary endpoint was all-cause mortality. Multivariate Cox proportional hazards models were used to determine association of cumulative calcification score with end points. The performance of the score was evaluated by receiver operating characteristic (ROC) curve analysis and absolute net reclassification improvement (NRI), compared with the Global Registry of Acute Coronary Events (GRACE) risk score. RESULTS: The overall population's calcification score was 2.0 ± 1.6. During a mean follow-up time of 69.8 ± 29.3 months, the all-cause mortality rate was 12.1%. Kaplan-Meier curve showed that the score was significantly associated with mortality (log-rank p < 0.001). The multivariable Cox proportional hazard analyses showed that a calcification score of 4-5 was independently associated with all-cause death in STEMI patients [hazard ratio (HR) = 2.32, 95% confidence interval (CI): 1.01-5.31, p = 0.046]. The area under the ROC curve (AUC) of the calcification score was 0.67 (95% CI: 0.61-0.72), and the AUC of the GRACE score was 0.80 (95% CI: 0.75-0.84). There was no statistical difference in the predictive value between both scores for 3-year mortality in STEMI patients after PPCI (p = 0.06). Based on the NRI analysis, the calcification score showed better risk classification compared with the GRACE score (absolute NRI = 6.63%, P = 0.027). CONCLUSION: The cumulative calcification score is independently associated with the long-term prognosis of STEMI patients after PPCI.

Recent Advances in Synthesis of Non-Alternating Polyketone Generated by Copolymerization of Carbon Monoxide and Ethylene.

The copolymers of carbon monoxide (CO) and ethylene, namely aliphatic polyketones (PKs), have attracted considerable attention due to their unique property and degradation. Based on the arrangement of the ethylene and carbonyl groups in the polymer chain, PKs can be divided into perfect alternating and non-perfect alternating copolymers. Perfect alternating PKs have been previously reviewed, we herein focus on recent advances in the synthesis of PKs without a perfect alternating structure including non-perfect alternating PKs and PE with in-chain ketones. The chain structure of PKs, catalytic copolymerization mechanism, and non-alternating polymerization catalysts including phosphine-sulfonate Pd, diphosphazane monoxide (PNPO) Pd/Ni, and phosphinophenolate Ni catalysts are comprehensively summarized. This review aims to enlighten the design of ethylene/CO non-alternating polymerization catalysts for the development of new polyketone materials.

Sunlight-Activated Hour-Long Afterglow from Transparent and Flexible Polymers.

Afterglow materials featuring long emission durations ranging from milliseconds to hours have garnered increasing interest owing to their potential applications in sensing, bioimaging, and anti-counterfeiting. Unfortunately, polymeric materials rarely exhibit afterglow properties under ambient conditions because of the rapid nonradiative decay rate of triplet excitons. In this study, hour-long afterglow (HLA) polymer films are fabricated using a facile molecular doping strategy. Flexible and transparent polymer films emitted a bright afterglow lasting over 11 h at room temperature in air, which is one of the best performances among the organic afterglow materials reported to date. Intriguingly, HLA polymer films can be activated by sunlight, and their cyan afterglow in air can be readily observed by the naked eye. Moreover, the HLA color of the polymer films could be tuned from cyan to red through the Förster resonance energy transfer mechanism. Their application in flexible displays and information storage has also been demonstrated. With remarkable advantages, including an hour-long and bright afterglow, tunable afterglow colors, superior flexibility and transparency, and ease of fabrication, the HLA polymer paves the way for the practical application of afterglow materials in the engineering sector.

Experimental and theoretical insights into palladium-mediated polymerization of para-N,N-disubstituted aminostyrene.

Experimental and theoretical insights into polymerization of para-N,N-disubstituted aminostyrene monomers (St-4-NR2, R = Me, Et, Ph) using cationic α-diimine palladium complexes have been initially reported. The effects of the catalyst structure and monomer substituent were studied systematically. Polymerization turnover frequency (TOF) was shown to decrease in the order of monomer substituents Me > Et > Ph, whereas the molecular weight of the produced polymers showed an opposite trend (Me < Et < Ph). Methanol-mediated polymerization of para-N,N-dimethylaminostyrene (DMAS), along with polymer chain-end analysis, and palladium intermediate isolation proved that palladium-initiated DMAS polymerization obeyed a cationic mechanism. Comprehensive theoretical calculations further revealed that the carbocation was generated from the insertion of DMAS into the palladium center rather than the polarization of the methyl palladium intermediate with a coordinated DMAS. The produced amine-functionalized amorphous polystyrenes have low stereoregularity and exhibit good hydrophilic properties. The poly(para-N,N-disphenylaminostyrene) is a luminescent polymer and shows fluorescence properties, rendering this material a promising candidate for versatile potential applications.

Synthesis and Thermoreversible Gelation of Coil-Rod Copolymers with a Dendritic Polyethylene Core and Multiple Helical Poly(γ-benzyl-L-glutamate) Arms.

Coil-rod copolymers with a dendritic polyethylene (DPE) core and multiple helical poly(γ-benzyl-L-glutamate) (PBLG) arms (DPE-(PBLG)n) were prepared by palladium-catalyzed copolymerization in tandem with ring-opening polymerization (ROP). Macroinitiator (DPE-(NH2)11) was firstly prepared by the group transformation of DPE-(OH)11 generated from palladium-catalyzed copolymerization of ethylene and acrylate comonomer. Coil-helical DPE-(PBLG)11 copolymers were prepared by ROP of γ-benzyl-L-glutamate-N-carboxyanhydride (BLG-NCA). These DPE-(PBLG)11 copolymers could form thermoreversible gels in toluene solvent, and the dendritic topology of the DPE core increased the critical gelation concentrations. The self-assembled nanostructure of gels was fully characterized by transmission electron microscopy (TEM), atomic force microscopy (AFM), small-angle X-ray scattering (SAXS), and wide-angle X-ray diffraction (WAXD), and the morphology of the fibrous structure was a twisted flat ribbon through a self-assembled nanoribbon mechanism. The self-assembled fibers formed by DPE-(PBLG45)11 are more heterogeneous and ramified than previously observed fibers formed by PBLG homopolymer and block copolymers.

A theoretical study on hydrated sodium ion-phenylalanine clusters Na+(Phe)(H2O)n (n = 0-6; Phe = phenylalanine).

The cation-π interaction is of importance in many chemical and biological processes such as those involving protein geometries and functionals and ion channels. In this study, to understand the cation-π interaction between essential ions and protein in the water-aqueous environment, geometries, electronic structures, bonding properties, and dynamic stabilities of hydrated Na+-phenylalanine clusters Na+(Phe)(H2O)n (n = 0-6) were studied using density functional theory calculations and ab initio molecular dynamics simulations. After the addition of water molecules, Na+(Phe)(H2O)n structures change from a tridentate complex to quadridentate or pentadentate complexes while the cation-π interaction always exists. The fluctuation between quadridentate and pentadentate complexes results from the competition between cation-O bonding and hydrogen bonding. The charge analysis reveals that the positive charge is mainly located on the Na ion, whereas the further addition of water reduces the binding energy of water, electron affinity, and ionization potential. As the number of water molecules increases, the bonding interactions between the sodium ion and the remaining phenylalanine-water complex increase and correlate with the coordination number, in which the electrostatic interaction contributes more than the orbital interaction. The important orbital interaction terms come from the donation of the carboxyl and amino groups and water to the Na+ ion. Molecular dynamic simulations revealed that Na+(Phe)(H2O)6 is stable at 300 K.

Therapeutic targeting of FUBP3 phase separation by GATA2-AS1 inhibits malate-aspartate shuttle and neuroblastoma progression via modulating SUZ12 activity.

Malate-aspartate shuttle (MAS) is essential for maintaining glycolysis and energy metabolism in tumors, while its regulatory mechanisms in neuroblastoma (NB), the commonest extracranial malignancy during childhood, still remain to be elucidated. Herein, by analyzing multi-omics data, GATA binding protein 2 (GATA2) and its antisense RNA 1 (GATA2-AS1) were identified to suppress MAS during NB progression. Mechanistic studies revealed that GATA2 inhibited the transcription of glutamic-oxaloacetic transaminase 2 (GOT2) and malate dehydrogenase 2 (MDH2). As a long non-coding RNA destabilized by RNA binding motif protein 15-mediated N6-methyladenosine methylation, GATA2-AS1 bound with far upstream element binding protein 3 (FUBP3) to repress its liquid-liquid phase separation and interaction with suppressor of zest 12 (SUZ12), resulting in decrease of SUZ12 activity and epigenetic up-regulation of GATA2 and other tumor suppressors. Rescue experiments revealed that GATA2-AS1 inhibited MAS and NB progression via repressing interaction between FUBP3 and SUZ12. Pre-clinically, administration of lentivirus carrying GATA2-AS1 suppressed MAS, aerobic glycolysis, and aggressive behaviors of NB xenografts. Notably, low GATA2-AS1 or GATA2 expression and high FUBP3, SUZ12, GOT2 or MDH2 levels were linked with unfavorable outcome of NB patients. These findings suggest that GATA2-AS1 inhibits FUBP3 phase separation to repress MAS and NB progression via modulating SUZ12 activity.

Oridonin promotes endoplasmic reticulum stress via TP53-repressed TCF4 transactivation in colorectal cancer.

BACKGROUND: The incidence of colorectal cancer and cancer death rate are increasing every year, and the affected population is becoming younger. Traditional Chinese medicine therapy has a unique effect in prolonging survival time and improving the prognosis of patients with colorectal cancer. Oridonin has been reported to have anti-cancer effects in a variety of tumors, but the exact mechanism remains to be investigated. METHODS: Cell Counting Kit-8 assay (CCK8) and 5-Ethynyl-2'-deoxyuridine (EdU) staining assay, Tranwell, and Wound healing assays were performed to measure cell proliferation, invasion, and migration capacities, respectively. The protein and mRNA expression levels of various molecules were reflected by Western blot and Reverse Transcription quantitative Polymerase Chain Reaction (qRT-PCR). Transcription Factor 4 (TCF4) and its target genes were analyzed by Position Weight Matrices (PWMs) software and the Gene Expression Omnibus (GEO) database. Immunofluorescence (IF) was performed to visualize the expression and position of Endoplasmic Reticulum (ER) stress biomarkers. The morphology of the ER was demonstrated by the ER tracker-red. Reactive Oxygen Species (ROS) levels were measured using a flow cytometer (FCM) or fluorescent staining. Calcium ion (Ca2+) concentration was quantified by Fluo-3 AM staining. Athymic nude mice were modeled with subcutaneous xenografts. RESULTS: Oridonin inhibited the proliferation, invasion, and migration of colorectal cancer, and this effect was weakened in a concentration-dependent manner by ER stress inhibitors. In addition, oridonin-induced colorectal tumor cells showed increased expression of ER stress biomarkers, loose morphology of ER, increased vesicles, and irregular shape. TCF4 was identified as a regulator of ER stress by PWMs software and GEO survival analysis. In vitro and in vivo experiments confirmed that TCF4 inhibited ER stress, reduced ROS production, and maintained Ca2+ homeostasis. In addition, oridonin also activated TP53 and inhibited TCF4 transactivation, further exacerbating the elevated ROS levels and calcium ion release in tumor cells and inhibiting tumorigenesis in colorectal cancer cells in vivo. CONCLUSIONS: Oridonin upregulated TP53, inhibited TCF4 transactivation, and induced ER stress dysregulation in tumor cells, promoting colorectal cancer cell death. Therefore, TCF4 may be one of the important nodes for tumor cells to regulate ER stress and maintain protein synthesis homeostasis. And the inhibition of the TP53/TCF4 axis plays a key role in the anti-cancer effects of oridonin.

Therapeutic targeting of CNBP phase separation inhibits ribosome biogenesis and neuroblastoma progression via modulating SWI/SNF complex activity.

BACKGROUND: Neuroblastoma (NB) is the most common extracranial malignancy in childhood; however, the mechanisms underlying its aggressive characteristics still remain elusive. METHODS: Integrative data analysis was performed to reveal tumour-driving transcriptional regulators. Co-immunoprecipitation and mass spectrometry assays were applied for protein interaction studies. Real-time reverse transcription-polymerase chain reaction, western blotting, sequential chromatin immunoprecipitation and dual-luciferase reporter assays were carried out to explore gene expression regulation. The biological characteristics of NB cell lines were examined via gain- and loss-of-function assays. For survival analysis, the Cox regression model and log-rank tests were used. RESULTS: Cellular nucleic acid-binding protein (CNBP) was found to be an independent factor affecting NB outcome, which exerted oncogenic roles in ribosome biogenesis, tumourigenesis and aggressiveness. Mechanistically, karyopherin subunit beta 1 (KPNB1) was responsible for nuclear transport of CNBP, whereas liquid condensates of CNBP repressed the activity of switch/sucrose-nonfermentable (SWI/SNF) core subunits (SMARCC2/SMARCC1/SMARCA4) via interaction with SMARCC2, leading to alternatively increased activity of SMARCC1/SMARCA4 binary complex in facilitating gene expression essential for 18S ribosomal RNA (rRNA) processing in tumour cells, extracellular vesicle-mediated delivery of 18S rRNA and subsequent M2 macrophage polarisation. A cell-penetrating peptide blocking phase separation and interaction of CNBP with SMARCC2 inhibited ribosome biogenesis and NB progression. High KPNB1, CNBP, SMARCC1 or SMARCA4 expression or low SMARCC2 levels were associated with poor survival of NB patients. CONCLUSIONS: These findings suggest that CNBP phase separation is a target for inhibiting ribosome biogenesis and tumour progression in NB via modulating SWI/SNF complex activity.

Amphiphilic Polyethylene-b-poly(L-lysine) Block Copolymer: Synthesis, Self-Assembly, and Responsivity.

Polyethylene-b-polypeptide copolymers are biologically interesting, but studies of their synthesis and properties are very few. This paper reports synthesis and characterization of well-defined amphiphilic polyethylene-block-poly(L-lysine) (PE-b-PLL) block copolymers by combining nickel-catalyzed living ethylene polymerization with controlled ring-opening polymerization (ROP) of ε-benzyloxycarbonyl-L-lysine-N-carboxyanhydride (Z-Lys-NCA) and sequential post-functionalization. Amphiphilic PE-b-PLL block copolymers self-assembled into spherical micelles with a hydrophobic PE core in aqueous solution. The pH and ionic responsivities of PE-b-PLL polymeric micelles were investigated by means of fluorescence spectroscopy, dynamic light scattering, UV-circular dichroism, and transmission electron microscopy. The variation of pH values led to the conformational alteration of PLL from α-helix to coil, thereby changing the micelle dimensions.

E2F1 inhibits cellular senescence and promotes oxaliplatin resistance in colorectal cancer.

Background: Doctors have always been overwhelmed by tumor drug resistance because it is a major challenge in the clinical treatment of tumors. Cellular senescence has a strong relationship with the development of tumor drug resistance. Herein, we aimed to explore new regulatory factors involved in the aging process of colorectal cancer (CRC) cells and assess the effect of cellular senescence on CRC drug resistance. Methods: Genes associated with cellular senescence for anticipating regulatory factors were first used, and the regulatory molecules of survival significance were then identified based on the results of public database analysis. The effects of E2F translation factor 1 (E2F1) on CRC cell viability, invasion, migration, and cellular senescence processes were assessed through 3-(4,5)-dimethylthiahiazo(-z-y1)-3,5-di-phenytetrazoliumromide (MTT), 5-Ethynyl-2'-deoxyuridine (EdU), Transwell, scar repairining, ß-galactosidase staining, and cell immunofluorescence assays, respectively. Overexpression or silencing plasmids were used for transfecting HCT116 or OXA-HCT116 to assess the effect of E2F1 on the senescence process and drug resistance in CRC cells. Results: On combining the database analysis results with those of our studies, we found that E2F1 was a critical regulator of cellular senescence in CRC. In the in vitro experiments, the E2F1 overexpression significantly stimulated the proliferation, invasion, and migration of CRC cells and even reduced oxaliplatin-induced senescence, further enhancing their resistance to oxaliplatin. Conversely, the tumorigenesis of colorectal cancer was repressed after the suppression of E2F1. Furthermore, CRC cells, which were otherwise resistant to oxaliplatin, also showed senescent phenotypes. Conclusions: Our results suggest that E2F1 suppresses the aging of CRC cells and tumor cells develop resistance to oxaliplatin through high E2F1 expression. Moreover, E2F1 may act as a possible target for oxaliplatin resistance studies.

Long-Term Survival of Neuroblastoma Patients Receiving Surgery, Chemotherapy, and Radiotherapy: A Propensity Score Matching Study.

Neuroblastoma is the most common extracranial solid malignancy in children. This study was undertaken to determine the long-term survival of neuroblastoma patients receiving conventional therapeutics (surgery, chemotherapy, and radiotherapy). The neuroblastoma patients examined were registered in the Surveillance, Epidemiology and End Results (SEER) database (1975-2016). Using propensity score matching analysis, the patients were paired by record depending on whether they received surgery, chemotherapy, or radiotherapy. Univariate and multivariate analyses of the disease-specific survival of the paired patients were performed by the log-rank test and Cox regression assay. A total of 4568 neuroblastoma patients were included in this study. During 1975-2016, the proportion of histopathological grade III/IV cases receiving surgery gradually increased, while the number of patients with tumors of grade I to IV undergoing chemotherapy or radiotherapy was stable or even decreased. After propensity score analysis, for Grade I + II and Grade III tumors, surgery obviously improved the disease-specific survival of patients, while chemotherapy was unfavorable for patient prognosis, and radiotherapy exerted no obvious effect on the patients. However, no matter what treatment was chosen, the patients with advanced-histopathological-grade tumors had a poor prognosis. Meanwhile, for all histopathological grades, the patients receiving surgery and subsequent chemotherapy or radiotherapy suffered from worsen disease-specific survival than those simply undergoing surgery. Fortunately, the negative effects of surgery, chemotherapy, or radiotherapy improved gradually over time. Surgery improved the long-term survival of the neuroblastoma patients, while chemotherapy and radiotherapy exerted an unfavorable impact on patient outcome. These results provide an important reference for the clinical treatment of neuroblastoma.

Nitrogen and titanium-codoped porous carbon nanocomposites derived from metal-organic framework as cathode to address polysulfides shuttle effects by Ti-assisted N-inhibiting strategy.

To address the problem of shutting effect of Li-S batteries, we used Ti-based MOF as precursor to obtain a conductive matrix with dual inhibitors. The target material, namely NTiPC, shown remarkable discharge capacity with 1178 mA h g-1, and maintained at 732 mA h g-1 after 100 cycles. The results indicated the N- and Ti-active sites synergistic acted with conductive framework can facilitate binding reaction between matrix and polysulfides.

Local chronicles reveal the effect of anthropogenic and climatic impacts on local extinctions of Chinese pangolins (Manis pentadactyla) in mainland China.

Anthropogenic and climatic factors affect the survival of animal species. Chinese pangolin is a critically endangered species, and identifying which variables lead to local extinction events is essential for conservation management. Local chronicles in China serve as long-term monitoring data, providing a perspective to disentangle the roles of human impacts and climate changes in local extinctions. Therefore, we established generalized additive models to identify factors leading to local extinction with historical data from 1700-2000 AD in mainland China. Then we decreased the time scale and constructed extinction risk models using MaxEnt in a 30-year transect (1970-2000 AD) to further assess extinction probability of extant Chinese pangolin populations. Lastly, we used principal component analysis to assess variation of related anthropogenic and climatic variables. Our results showed that the extinction probability increased with global warming and human population growth. An extinction risk assessment indicated that the population and distribution range of Chinese pangolins had been persistently shrinking in response to highly intensive human activities (main cause) and climate change. PCA results indicated that variability of climatic variables is greater than anthropogenic variables. Overall, the factors causing local extinctions are intensive human interference and drastic climatic fluctuations which induced by the effect of global warming. Approximately 28.10% of extant Chinese pangolins populations are confronted with a notable extinction risk (0.37 ≤ extinction probability≤0.93), specifically those in Southeast China, including Guangdong, Jiangxi, Zhejiang, Hunan and Fujian Provinces. To rescue this critically endangered species, we suggest strengthening field investigations, identifying the exact distribution range and population density of Chinese pangolins and further optimizing the network of nature reserves to improve conservation coverage on the landscape scale and alleviate human interference. Conservation practices that concentrate on the viability assessment of scattered populations could help to improve restoration strategies of the Chinese pangolin.

HNF4A-AS1-encoded small peptide promotes self-renewal and aggressiveness of neuroblastoma stem cells via eEF1A1-repressed SMAD4 transactivation.

Cancer stem cells play crucial roles in tumorigenesis and aggressiveness, while regulatory mechanisms in neuroblastoma (NB), a pediatric extracranial malignancy with highest incidence, are still unknown. Herein, a small 51-amino acid peptide (sPEP1) encoded by hepatocyte nuclear factor 4 alpha antisense RNA 1 (HNF4A-AS1) was identified in tumor tissues and cells, which facilitated self-renewal and aggressiveness of NB stem cells. MiRNA-409-5p interacted with HNF4A-AS1 to facilitate sPEP1 translation via recruiting eukaryotic translation initiation factor 3 subunit G, while sPEP1 repressed serum deprivation-induced senescence and promoted sphere formation, growth, or metastasis of NB stem cells. Mechanistically, sPEP1 directly interacted with eukaryotic translation elongation factor 1 alpha 1 (eEF1A1) to facilitate its binding to SMAD family member 4 (SMAD4), resulting in repression of SMAD4 transactivation and transcriptional upregulation of stem cell genes associated with tumor progression. Rescue experiments revealed that sPEP1 exerted oncogenic roles via facilitating physical interaction between eEF1A1 and SMAD4. Notably, knockdown of sPEP1 significantly repressed the self-renewal and metastasis of NB stem cells in vivo. High sPEP1 or eEF1A1 levels in clinical NB tissues were linked to poor patients' survival. These findings suggest that HNF4A-AS1-encoded sPEP1 promotes self-renewal and aggressive features of NB stem cells by eEF1A1-repressed SMAD4 transactivation.

Influence of Pleistocene climate fluctuations on the demographic history and distribution of the critically endangered Chinese pangolin (Manis pentadactyla).

BACKGROUND: Pleistocene climate fluctuations have strongly modified species genetic diversity and distributions. The Chinese pangolin (Manis pentadactyla) has been recognized as a critically endangered animal due to heavy poaching and trafficking. However, the effect of Pleistocene climate fluctuations on the genetic diversity and spatial distribution of the Chinese pangolin remains largely unknown. Here, we combined whole genome sequencing data, analysis of complete mitochondrial genomes, and a large amount of occurrence data from field surveys to infer the ancestral demographic history and predict the past spatial dynamics of the Chinese pangolin in Guangdong Province, China. RESULTS: Our results indicated that there were two subpopulations, which showed similar trends of population size change in response to past climatic changes. We estimated a peak effective population size (Ne) during the last interglacial (LIG), followed by a marked decrease (~ 0.5 to fivefold change) until the last glacial maximum (LGM) and a rebound to a small peak population size during the Mid-Holocene (MH). The estimated time of the separation event between two subpopulations was approximately 3,000-2,500 years ago (ka). We estimated that the distribution of suitable areas shrank by 14.4% from the LIG to LGM, followed by an expansion of 31.4% from the LGM to MH and has been stable since then. In addition, we identified an elevational shift and suitable area decreased significantly during the LGM, but that the geographic extent of suitable areas in the western region increased from the LIG to present. The eastern region of Guangdong Province had the highest habitat suitability across all the climate scenarios. CONCLUSIONS: Our results suggested that Pleistocene climate fluctuations played an important role in shaping patterns of genetic diversity and spatial distribution, and that human stressors likely contributed to the recent divergence of two Chinese pangolin subpopulations sampled here. We argue that a key protected area should be established in the eastern region of Guangdong Province. As such, this study provides a more thorough understanding of the impacts of Pleistocene climate fluctuations impacts on a mammalian species in southern China and suggests more robust management and conservation plans for this Critically Endangered species of special interest.