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Abstract Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is highly transmissible and has caused a pandemic named coronavirus disease 2019 (COVID-19), which has quickly spread worldwide. Although several therapeutic agents have been evaluated or approved for the treatment of COVID-19 patients, efficacious antiviral agents are still lacking. An attractive therapeutic target for SARS-CoV-2 is the main protease (Mpro), as this highly conserved enzyme plays a key role in viral polyprotein processing and genomic RNA replication. Therefore, the identification of efficacious antiviral agents against SARS-CoV-2 Mpro using a rapid, miniaturized and economical high-throughput screening (HTS) assay is of the highest importance at the present. Results In this study, we first combined the fluorescence polarization (FP) technique with biotin-avidin system (BAS) to develop a novel and step-by-step sandwich-like FP screening assay to quickly identify SARS-CoV-2 Mpro inhibitors from a natural product library. Using this screening assay, dieckol, a natural phlorotannin component extracted from a Chinese traditional medicine Ecklonia cava, was identified as a novel competitive inhibitor against SARS-CoV-2 Mpro in vitro with an IC50 value of 4.5 ± 0.4 µM. Additionally, dieckol exhibited a high affinity with SARS-CoV-2 Mpro using surface plasmon resonance (SPR) analysis and could bind to the catalytic sites of Mpro through hydrogen-bond interactions in the predicted docking model. Conclusions This innovative sandwich-like FP screening assay enables the rapid discovery of antiviral agents targeting viral proteases, and dieckol will be an excellent lead compound for generating more potent and selective antiviral agents targeting SARS-CoV-2 Mpro.

The Yonaguni Knoll IV is an active seafloor hydrothermal system associated with submarine silicic volcanism located in the “cross back-arc volcanic trail” (CBVT) in the southwestern Okinawa Trough. However, the behavior of volatiles during magmatic differentiation in the shallow silicic magma chamber is unclear. Here, the volatile contents of apatite inclusions trapped in different phenocrysts (orthopyroxene and amphibole) and microphenocrysts in the rhyolite from the Yonaguni Knoll IV hydrothermal field were analyzed by using electron microprobe analysis, which aims to track the behavior of volatiles in the shallow magma chamber. Notably, the ‘texturally constrained’ apatites showed a decreasing trend of XCl/XOH and XF/XCl ratios. Based on the geochemical analyses in combination with thermodynamic modeling, we found that the studied apatites were consistent with the mode of volatile-undersaturated crystallization. Therefore, volatiles were not saturated in the early stage of magmatic differentiation in the shallow rhyolitic magma chamber, and consequently, the metal elements were retained in the rhyolitic melt and partitioned into crystalline magmatic sulfides. Additionally, previous studies suggested that the shallow rhyolitic magma chamber was long-lived and periodically replenished by mafic magma. The injection of volatile-rich and oxidized subduction-related mafic magmas can supply abundant volatiles and dissolve magmatic sulfide in the shallow magma chamber. These processes are important for the later-stage of volatile exsolution, while the forming metal-rich magmatic fluids contribute to the overlying Yonaguni Knoll IV hydrothermal system.

Strontium (Sr), hydrogen (H) and oxygen (O) in vent fluids are important for understanding the water–rock interaction and hydrothermal flux in hydrothermal systems. We have analyzed the Sr, H and O isotopic compositions of seawater, vent fluid and hydrothermal plume samples in the Kueishantao hydrothermal field, as well as their calcium (Ca), total sulfur (S), Sr, arsenic (As), stibium (Sb), chlorine (Cl) and manganese (Mn) concentrations for understanding the origin and processes of fluids. The results suggest that most As, Sb and Mn are leached from andesitic rocks into the fluids, and most Ca and Cl remained in the deep reaction zone during the fluid–andesitic rock interaction. The ranges of 87Sr/86Sr, δDV-SMOW and δ18OV-SMOW values in the yellow spring, white spring and plumes are small. The 87Sr/86Sr, δDV-SMOW and δ18OV-SMOW values of fluids and plumes are like those of ambient seawater, indicating that the Sr, H and O of vent fluids and hydrothermal plumes are derived primarily from seawater. This suggests that the interaction of andesite and subseafloor fluid is of short duration and results in the majority of As, Sb and Mn being released into fluids, while most Ca and Cl remained in the deep reaction zone. In addition, there was no significant variation of Sr, H and O isotopic compositions in the upwelling fluid, keeping the similar isotopic compositions of seawater. There are obvious correlations among the pH values, As and Sb concentrations, and H isotopic compositions of the vent fluids and hydrothermal plumes, implying that the As and Sb concentrations and H isotopic compositions can trace the dispersion of plumes in the ambient seawater. According to the Sr concentrations and 87Sr/86Sr values, the water/rock ratios are 3076~8124, which is consistent with the idea that the interaction between fluid and andesite at the subseafloor is of short duration. The hydrothermal flux of Sr discharged from the yellow spring into the seawater is between 2.06 × 104 and 2.26 × 104 mol/yr, and the white spring discharges 1.18 × 104~1.26 × 104 mol/yr Sr if just andesites appear in the reaction zone.

Studies of the element contents and isotopic characteristics of sulfide minerals from seafloor hydrothermal sulfide deposits are a significant method of investigating seawater-fluid mixing and fluid-rock and/or sediment interactions in hydrothermal systems. The seafloor hydrothermal sulfide ores from the Noho hydrothermal field (NHF) in the Okinawa Trough (OT) consist of pyrrhotite, isocubanite, sphalerite, galena, and amorphous silica. The Rh, Ag, Sb, and Tl contents mostly increase in galena as the fluid temperature decreases in the late ore-forming stage. In the sulfide minerals, the rare earth elements are mainly derived from the hydrothermal fluids, while the volcanic rocks and/or sediments are the sources of the sulfur and lead in the sulfide minerals. After the precipitation of galena, the redox state becomes oxidizing, and the pH value of the fluid increases, which is accompanied by the formation of amorphous silica. Finally, neither pyrite nor marcasite has been observed in association with pyrrhotite in the NHF sulfides, likely indicating that the amount of sulfur was limited in this hydrothermal system, and most of the residual Fe was incorporated into the sphalerite. This suggests that the later pyrite and/or marcasite precipitation in the seafloor hydrothermal sulfide deposit is controlled by the sulfur content of the fluid. Furthermore, it is possible to use hydrothermal sulfides and their inclusions to trace subseafloor fluid circulation processes.

In our study, a unique ratiometric fluorescent sensor for the rapid detection of arginine (Arg) and acetaminophen (AP) was constructed by the integration of blue fluorescent N-CDs and yellowish-green fluorescent calcein. The N-CD/calcein ratiometric fluorescent sensor exhibited dual emission at 435 and 519 nm under the same excitation wavelength of 370 nm, and caused potential Förster resonance energy transfer (FRET) from N-CDs to calcein. When detecting Arg, the blue fluorescence from the N-CDs of the N-CD/calcein sensor was quenched by the interaction of N-CDs and Arg. Then, the fluorescence of our sensor was recovered with the addition of AP, possibly due to the stronger association between AP and Arg, leading to the dissociation of Arg from N-CDs. Meanwhile, we observed an obvious fluorescence change from blue to green, then back to blue, when Arg and AP were added, exhibiting the “on–off–on” pattern. Next, we determined the detection limits of the N-CD/calcein sensor to Arg and AP, which were as low as 0.08 μM and 0.02 μM, respectively. Furthermore, we discovered that the fluorescence changes of the N-CD/calcein sensor were only responsible for Arg and AP. These results suggested its high sensitivity and specificity for Arg and AP detection. In addition, we have successfully achieved its application in bovine serum samples, indicating its practicality. Lastly, the logic gate was generated by the N-CD/calcein sensor and presented its good reversibility. Overall, we have demonstrated that our N-CD/calcein sensor is a powerful sensor to detect Arg and AP and that it has potential applications in biological analysis and imaging.

Renal ischemia–reperfusion injury (IRI) is a major cause of acute kidney injury (AKI) and has no effective treatment. Exploring the molecular mechanisms of renal IRI is critical for the prevention of AKI and its evolution to chronic kidney disease and end-stage renal disease. The aim of the present study was to determine the biological function and molecular mechanism of action of miR-92a-3p in tubular epithelial cell (TEC) pyroptosis. We investigated the relationship between nuclear factor-erythroid 2-related factor 1 (Nrf1) and TEC pyroptosis induced by ischemia–reperfusion in vivo and oxygen–glucose deprivation/reoxygenation (OGD/R) in vitro. MicroRNAs (miRNAs) are regulators of gene expression and play a role in the progression of renal IRI. Nrf1 was confirmed as a potential target for miRNA miR-92a-3p. In addition, the inhibition of miR-92a-3p alleviated oxidative stress in vitro and decreased the expression levels of NLRP3, caspase-1, GSDMD-N, IL-1β, and IL-18 in vitro and in vivo. Moreover, Zn-protoporphyrin-IX, an inhibitor of heme oxygenase-1, reduced the protective effect of Nrf1 overexpression on OGD/R-induced TEC oxidative stress and pyroptosis. The results of this study suggest that the inhibition of miR-92a-3p can alleviate TEC oxidative stress and pyroptosis by targeting Nrf1 in renal IRI.

Abnormal expressions of long noncoding RNAs (lncRNAs) and protein-encoding messenger RNAs (mRNAs) are important for the development of childhood acute lymphoblastic leukemia (ALL). This study developed an lncRNA-mRNA integrated classifier for the prediction of recurrence and prognosis in relapsed childhood ALL by using several transcriptome data. Weighted gene coexpression network analysis revealed that green, turquoise, yellow, and brown modules were preserved across the TARGET, GSE60926, GSE28460, and GSE17703 datasets, and they were associated with clinical relapse and death status. A total of 184 genes in these four modules were differentially expressed between recurrence and nonrecurrence samples. Least absolute shrinkage and selection operator analysis showed that seven genes constructed a prognostic signature (including one lncRNA: LINC00652 and six mRNAs: INSL3, NIPAL2, REN, RIMS2, RPRM, and SNAP91). Kaplan-Meier curve analysis observed that patients in the high-risk group had a significantly shorter overall survival than those of the low-risk group. Receiver operating characteristic curve analysis demonstrated that this signature had high accuracy in predicting the 5-year overall survival and recurrence outcomes, respectively. LINC00652 may function by coexpressing with the above prognostic genes (INSL3, SNAP91, and REN) and lipid metabolism-related genes (MIA2, APOA1). Accordingly, this lncRNA-mRNA-based classifier may be clinically useful to predict the recurrence and prognosis for childhood ALL. These genes represent new targets to explain the mechanisms for ALL.

Nitrogen-doped carbon dots exhibiting excitation-dependent full-color emissions (F-NCDs) were prepared via the one-step hydrothermal method with citric acid and phenylenediamine. Specifically, the emission wavelength of the F-NCDs tuned from 452 nm to 602 nm due to the introduction of new energy levels by C=O and C=N functional groups. We exploited its stability in illumination, ionic strength, and pH, as well as its specificity, sensitivity, especially in ascorbic acid (AA) detection. F-NCDs could measure the AA concentration in the linear ranges of 0~0.1 and 0.1~1 mmol/L with the detection limit (LOD, S/N = 3) as low as 2.6 nmol/L. Additionally, we successfully detected AA in bovine serum with our F-NCDs and obtained the result within 1 min. Because of full-color emission features, we believe our F-NCDs have a great potential in fluorescent sensor detection.

The in situ element concentrations and the sulfur (S), and lead (Pb) isotopic compositions in anglesite were investigated for samples from seafloor hydrothermal fields in the Okinawa Trough (OT), Western Pacific. The anglesite grains are of two kinds: (1) low Pb/high S primary hydrothermal anglesite (PHA), which is formed by mixing of fluid and seawater, and (2) high Pb/low S secondary supergene anglesite (SSA), which is the product of low-temperature (

Determining the influence of subduction input on back-arc basin magmatism is important for understanding material transfer and circulation in subduction zones. Although the mantle source of Okinawa Trough (OT) magmas is widely accepted to be modified by subducted components, the role of slab-derived fluids is poorly defined. Here, major element, trace element, and Li, O and Mg isotopic compositions of volcanic lavas from the middle OT (MOT) and southern OT (SOT) were analyzed. Compared with the MOT volcanic lavas, the T9-1 basaltic andesite from the SOT exhibited positive Pb anomalies, significantly lower Nd/Pb and Ce/Pb ratios, and higher Ba/La ratios, indicating that subducted sedimentary components affected SOT magma compositions. The δ7Li, δ18O, and δ26Mg values of the SOT basaltic andesite (−5.05‰ to 4.98‰, 4.83‰ to 5.80‰ and −0.16‰ to −0.09‰, respectively) differed from those of MOT volcanic lavas. Hence, the effect of the Philippine Sea Plate subduction component, (low δ7Li and δ18O and high δ26Mg) on magmas in the SOT was clearer than that in the MOT. This contrast likely appears because the amounts of fluids and/or melts derived from altered oceanic crust (AOC, lower δ18O) and/or subducted sediment (lower δ7Li, higher δ18O and δ26Mg) injected into magmas in the SOT are larger than those in the MOT and because the injection ratio between subducted AOC and sediment is always >1 in the OT. The distance between the subducting slab and overlying magma may play a significant role in controlling the differences in subduction components injected into magmas between the MOT and SOT.

The composition of hydrothermal plumes reflects the physical and chemical characteristics of seafloor hydrothermal fluids, which in turn reflects the host rock and subseafloor reaction conditions as well as the water column processes that act to alter the plumes as they disperse and age. Here, we show that the turbidity, current, pH value, dissolved Fe (dFe), and dissolved Mn (dMn) compositions of hydrothermal plumes can be used to understand the spatial distribution and source of hydrothermal systems in the submarine geological environment. Data were obtained from 18 hydrocast stations, among which the water column samples were collected at 8 stations during the MANUS cruise of R/V KEXUE in 2015. The results showed that the Satanic Mills plume and Fenway plume rose approximately 140 m and 220 m above the seafloor, respectively. In the Satanic Mills plume, dFe remained longer than dMn during lateral plume dispersal. There was a clear intersection of the Satanic Mills plume and Fenway plume between 1625 m and 1550 m in the PACMANUS hydrothermal field, and the varied dispersion trends of the mixed plumes were affected by current velocities at different depths. The physical and chemical properties of the seawater columns in the Manus Basin were affected by the input of high-Mn, high-Fe, and low-Mg vent fluids. The turbidity and dFe, dMn, and dissolved Mg concentrations in the sections of the plumes proximal to the Satanic Mills, Fenway, and Desmos vent sites were generally higher (turbidity, Mn, and Fe) and lower (Mg) than those in the sections of the plumes that were more distal from the vent sites. This implied that the plumes proximal to their vent fluid sources, which were interpreted to have relatively young ages, dispersed chemically over time, and their concentrations became more similar to those of the plumes that were more distal from their vent fluid sources.

Luminescent Ln-MOFs (Eu0.075Tb0.925-MOF) were successfully synthesised through the solvothermal reaction of Tb(NO3)3·6H2O, Eu(NO3)3·6H2O, and the ligand pyromellitic acid. The product was characterised by X-ray diffraction (XRD), TG analysis, EM, X-ray photoelectron spectroscopy (XPS), and luminescence properties, and results show that the synthesised material Eu0.075Tb0.925-MOF has a selective ratio-based fluorescence response to Fe3+ or Cr2O72−. On the basis of the internal filtering effect, the fluorescence detection experiment shows that as the concentration of Fe3+ or Cr2O72− increases, the intensity of the characteristic emission peak at 544 nm of Tb3+ decreases, and the intensity of the characteristic emission peak at 653 nm of Eu3+ increases in Eu0.075Tb0.925-MOF. The fluorescence intensity ratio (I653/I544) has a good linear relationship with the target concentration. The detection linear range for Fe3+ or Cr2O72− is 10–100 μM/L, and the detection limits are 2.71 × 10−7 and 8.72 × 10−7 M, respectively. Compared with the sensor material with a single fluorescence emission, the synthesised material has a higher anti-interference ability. The synthesised Eu0.075Tb0.925-MOF can be used as a highly selective and recyclable sensing material for Fe3+ or Cr2O72−. This material should be an excellent candidate for multifunctional sensors.

Detrital apatite is a promising accessory mineral for reliable fingerprinting of the protolith composition of detrital sediment. Here, we present the geochemical compositions of detrital apatites from four sections of a high-resolution (~140 cm/kyr) sedimentary archive from the southern Okinawa Trough (SOT) for constraining sediment source rock types and establishing changes in provenance. A series of diagrams based on the geochemical data show that apatites in Section 1 derived mainly from mafic/intermediate rocks, while apatites in the three younger sections largely originated from mafic/intermediate rocks and acid rocks. Further, the four sections included a few contributions of apatites from alkaline rocks and metamorphic rocks. Through a comprehensive analysis of controlling factors and regional stratigraphy in the study area, we concluded that sediments in the SOT are the weathering/erosion products of sedimentary and meta-sedimentary rocks in the western and northeastern Taiwan Island, with ultimate sources containing a wide variety of rock types. The sediment from rivers in eastern Taiwan did not significantly contribute to deposition in the SOT. Apatites in Sections 2−4 showed strong geochemical similarity but differed from those in Section 1, indicating that the types of weathered/eroded sedimentary rocks in the weathering profile of river drainage basins of Taiwan Island changed in Section 2 (2010−1940 cal. yr BP) and have remained stable since then.

Ethyl carbamate (EC), a potential carcinogen, can be formed during the fermentation and storage of alcoholic beverages. In this work, quantitative detection of EC in alcoholic beverages by using surface-enhanced Raman spectroscopy (SERS) is reported. Flower-shaped silver nanostructure substrates and silver nanocube substrates were prepared and employed as SERS platform. Flower-like silver substrates had better Raman enhancement effect on EC and were selected for further EC detection. In EC SERS spectra based on flower-shaped silver substrates, the strongest and reproducible characteristic band at 857 cm−1 was chosen for establishing a linear regression model in the concentrations ranging from 10−5 to 10−9 M, which effectively extended the application scope of the quantitative model for determination EC. Furthermore, a real alcoholic beverage was tested to verify the feasibility and reliability of the method.

Studies of the major components of hydrothermal plumes in seafloor hydrothermal fields are critical for an improved understanding of biogeochemical cycles and the large-scale distribution of elements in the submarine environment. The composition of major components in hydrothermal plume water column samples from 25 stations has been investigated in the middle and southern Okinawa Trough. The physical and chemical properties of hydrothermal plume water in the Okinawa Trough have been affected by input of the Kuroshio current, and its influence on hydrothermal plume water from the southern Okinawa Trough to the middle Okinawa Trough is reduced. The anomalous layers of seawater in the hydrothermal plume water columns have higher K+, Ca2+, Mn2+, B3+, Ca2+/SO42-, and Mn2+/Mg2+ ratios and higher optical anomalies than other layers. The Mg2+, SO42-, Mg2+/Ca2+, and SO42-/Mn2+ ratios of the anomalous layers are lower than other layers in the hydrothermal plume water columns and are consistent with concentrations in hydrothermal vent fluids in the Okinawa Trough. This suggests that the chemical variations of hydrothermal plumes in the Tangyin hydrothermal field, like other hydrothermal fields, result in the discharge of high K+, Ca2+, and B3+ and low Mg2+ and SO42- fluid. Furthermore, element ratios (e.g., Sr2+/Ca2+, Ca2+/Cl−) in hydrothermal plume water columns were found to be similar to those in average seawater, indicating that Sr2+/Ca2+ and Ca2+/Cl− ratios of hydrothermal plumes might be useful proxies for chemical properties of seawater. The hydrothermal K+, Ca2+, Mn2+, and B3+ flux to seawater in the Okinawa Trough is about 2.62–873, 1.04–326, 1.30–76.4, and 0.293–34.7 × 106 kg per year, respectively. The heat flux is about 0.159–1,973 × 105 W, which means that roughly 0.0006% of ocean heat is supplied by seafloor hydrothermal plumes in the Okinawa Trough.

Studies on the concentrations of arsenic (As) and antimony (Sb) in seawater columns are very important for tracing hydrothermal plumes and understanding fluid characteristics of seafloor hydrothermal systems. The total As, Sb, Mn, and Cl− concentrations of three hydrothermal plume seawater column samples have been studied at Stations 18G, 18K, and 18B in the eastern Manus back-arc basin, Bismarck Sea, Papua New Guinea. At Stations 18G and 18K, the plumes above North Su and near the Suzette site in the SuSu Knolls hydrothermal field are both enriched in As, Sb, and Mn and depleted in Cl, as a result of contribution of As-Sb-Mn-enriched and Cl-depleted vent fluid outputs to the hydrothermal plume, which is most likely generated in the subseafloor by fluid-rock interaction, magma degassing, or phase separation (boiling of hydrothermal fluid). The plume at Station 18B is enriched in As, Sb, Mn, and Cl, suggesting that As-Sb-Mn-Cl-enriched fluid discharges from vents, which have been generated by fluid-rock interaction. The concentrations of As and Sb anomalous layers, like manganese (Mn), are higher than those of the other layers in the three hydrothermal plume seawater columns. As and Sb with Mn showed a positive correlation (R2>0.8, p

Background and objective It remains disputed whether doublets are more effective than single-agent chemotherapy for elderly patients with advanced non-small cell lung cancer (NSCLC). The aim of this study is to evaluate the efficacy and safety of doublets and single-agent chemotherapy for elderly patients with NSCLC. Methods Data from all published, randomized trials that compared doublets and single-agent chemotherapy in elderly patients were collected from electronic databases (PubMed, EMBASE, Cochrane Library, CNKI and the CBMdice). Meta-analysis was completed using software Stata 11.0. Results The results of the meta-analysis, including 12 eligible trials (2,306 patients), showed that the doublets significantly increased the overall response rate (OR=1.80, 95%CI:1.50-2.17, P

BACKGROUND: Emerging evidence showed that common functional -31G>C polymorphism (rs9904341 G>C) in the promoter region of the survivin gene is involved in the regulation of survivin expression, thus increasing an individual's susceptibility to gastrointestinal tract (GIT) cancer; but individually published results are inconclusive. The aim of this systematic review and meta-analysis was to derive a more precise estimation of the association between survivin -31G>C polymorphism and GIT cancer risk. METHODS: A literature search of PubMed, Embase, Web of Science and CBM databases was conducted from inception through July 1st, 2012. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of association. RESULTS: Nine case-control studies were included with a total of 2,231 GIT cancer cases and 2,287 healthy controls. The results indicated that survivin -31G>C polymorphism was associated with increased risk of GIT cancer. In the stratified analysis by cancer types, significant associations were observed between survivin -31G>C polymorphism and increased risk of colorectal and gastric cancers. However, the lack of association of survivin -31G>C polymorphism with esophageal cancer risk may be due to a lack of a sufficient number of eligible studies and the influence of different genetic and environmental factors. CONCLUSION: Results from the current meta-analysis suggests that survivin -31G>C polymorphism might increase the risk of GIT cancer, especially among gastric and colorectal cancers.

HIV-1 prevalence in Guangxi, China, has been growing since 1996, when the first case was reported. Over half of HIV-1 positive patients in Guangxi Province were injecting drug users (IDUs), possibly because of the province's location near drug-trafficking routes. Since a phase II HIV vaccine trial is ongoing there, a current characterization of the subtypes of HIV-1 among IDUs in Guangxi would provide critical information for future HIV vaccine trials, as well as further control and prevention of HIV-1 transmission. Thus, we conducted a molecular epidemiological investigation of HIV-1 samples from 2008-2010 among IDUs in multiple cities in Guangxi Province. Our results, based on the gag/pol fragment, indicated a very high proportion (78.47%) of HIV-1 CRF08_BC recombinants, some CRF01_AE (15.38%) recombinants, and a low proportion of CRF07_BC (6.15%) recombinants among the IDUs. The high proportion of CRF08 HIV-1 strains among recent IDUs matches the vaccine candidate constructs. However, future vaccine development should also incorporate CRF01-targeted vaccine candidates. Distinct Env sequence evolution patterns were observed for CRF08_BC and CRF01_AE, indicating that different local selection pressures have been exerted on these two HIV-1 subtypes. Unique drug-resistant mutations were also detected, and our data indicate that HIV treatment programs should consider pre-existing drug-resistant mutations.

DNA damage such as double-stranded DNA breaks (DSBs) has been reported to stimulate mitochondrial biogenesis. However, the underlying mechanism is poorly understood. The major player in response to DSBs is ATM (ataxia telangiectasia mutated). Upon sensing DSBs, ATM is activated through autophosphorylation and phosphorylates a number of substrates for DNA repair, cell cycle regulation and apoptosis. ATM has been reported to phosphorylate the alpha subunit of AMP-activated protein kinase (AMPK), which senses AMP/ATP ratio in cells, and can be activated by upstream kinases. Here we provide evidence for a novel role of ATM in mitochondrial biogenesis through AMPK activation in response to etoposide-induced DNA damage.Three pairs of human ATM+ and ATM- cells were employed. Cells treated with etoposide exhibited an ATM-dependent increase in mitochondrial mass as measured by 10-N-Nonyl-Acridine Orange and MitoTracker Green FM staining, as well as an increase in mitochondrial DNA content. In addition, the expression of several known mitochondrial biogenesis regulators such as the major mitochondrial transcription factor NRF-1, PGC-1alpha and TFAM was also elevated in response to etoposide treatment as monitored by RT-PCR. Three pieces of evidence suggest that etoposide-induced mitochondrial biogenesis is due to ATM-dependent activation of AMPK. First, etoposide induced ATM-dependent phosphorylation of AMPK alpha subunit at Thr172, indicative of AMPK activation. Second, inhibition of AMPK blocked etoposide-induced mitochondrial biogenesis. Third, activation of AMPK by AICAR (an AMP analogue) stimulated mitochondrial biogenesis in an ATM-dependent manner, suggesting that ATM may be an upstream kinase of AMPK in the mitochondrial biogenesis pathway.These results suggest that activation of ATM by etoposide can lead to mitochondrial biogenesis through AMPK activation. We propose that ATM-dependent mitochondrial biogenesis may play a role in DNA damage response and ROS regulation, and that defect in ATM-dependent mitochondrial biogenesis could contribute to the manifestations of A-T disease.

Telomere dysfunction is known to induce growth arrest (senescence) and cell death. However, the regulation of the senescence-death process is poorly understood. Here using a yeast dysfunctional telomere model cdc13-1, which carries a temperature sensitive-mutant telomere binding protein Cdc13p, we demonstrate that inhibition of TOR (Target of Rapamycin), a central regulator of nutrient pathways for cell growth, prevents cell death, but not growth arrest, induced by inactivation of Cdc13-1p. This function of TOR is novel and separable from its G1 inhibition function, and not associated with alterations in the telomere length, the amount of G-tails, and the telomere position effect (TPE) in cdc13-1 cells. Furthermore, antioxidants were also shown to prevent cell death initiated by inactivation of cdc13-1. Moreover, inhibition of TOR was also shown to prevent cell death induced by inactivation of telomerase in an est1 mutant. Interestingly, rapamycin did not prevent cell death induced by DNA damaging agents such as etoposide and UV. In the aggregate, our results suggest that the TOR signaling pathway is specifically involved in the regulation of cell death initiated by telomere dysfunction.

Abstract Background The role of circular RNAs (circRNAs) as biomarkers of coronary artery disease (CAD) remains poorly explored. This study aimed to identify and validate potential circulating circRNAs as biomarkers for the diagnosis of CAD. Methods The expression profile of circRNAs associated with CAD was obtained from Gene Expression Omnibus (GEO) database. Differential expression analysis, weighted gene co-expression network analysis (WGCNA) and least absolute shrinkage and selection operation (LASSO) were employed to identify CAD-related hub circRNAs. The expression levels of these hub circRNAs were validated using qRT-PCR in blood samples from 100 CAD patients and 100 controls. The diagnostic performance of these circRNAs was evaluated through logistic regression analysis, receiver operator characteristic (ROC) analysis, integrated discrimination improvement (IDI), and net reclassification improvement (NRI). Functional enrichment analyses were performed to predict the possible mechanisms of circRNAs in CAD. Results A total of ten CAD-related hub circRNAs were identified through WGCNA and LASSO analysis. Among them, hsa_circ_0069972 and hsa_circ_0021509 were highly expressed in blood samples of CAD patients, and they were identified as independent predictors after adjustment for relevant confounders. The area under the ROC curve for hsa_circ_0069972 and hsa_circ_0021509 was 0.760 and 0.717, respectively. The classification of patients was improved with the incorporation of circRNAs into the clinical model composed of conventional cardiovascular risk factors, showing an IDI of 0.131 and NRI of 0.170 for hsa_circ_0069972, and an IDI of 0.111 and NRI of 0.150 for hsa_circ_0021509. Functional enrichment analyses revealed that the hsa_circ_0069972-miRNA-mRNA network was enriched in TGF-β、FoxO and Hippo signaling pathways, while the hsa_circ_0021509-miRNA-mRNA network was enriched in PI3K/Akt and MAPK signaling pathways. Conclusion Hsa_circ_0069972 and hsa_circ_0021509 were identified by integrated analysis, and they are highly expressed in CAD patients. They may serve as novel biomarkers for CAD.

Abstract Background Ethyl acetate extracts from Tetrastigma hemsleyanum (Sanyeqing) (EFT), a member of the Vitaceae plant family, have been shown to exhibit efficacy against a variety of cancers. In this light, our current study seeks to examine the mechanism of efficacy between EFT extracts and human pancreatic cancer PANC-1 cells. Methods The chemical components of EFT were analyzed by gas chromatography–mass spectrometry. The cytotoxicity of EFT on PANC-1 cells was measured using an MTT assay. In order to investigate EFT induction of cell cycle arrest, changes in cell-cycle distribution were monitored by flow cytometry. Wound healing and transwell assays were employed to investigate whether migration and invasion of PANC-1 cells were inhibited by EFT. Relative protein expression was detected using Western blot. Results GC-MS analysis of the chemical composition of EFT revealed that the majority of constituents were organic acids and their corresponding esters. EFT exhibits measurable cytotoxicity and inhibition of PANC-1 invasion. Growth inhibition was primarily attributed to downregulation of CDK2 which induces cell cycle arrest in the S-phase. Inhibition of metastasis is achieved through downregulation of mesenchymal-associated genes/activators, including ZEB1, N-cadherin, Vimentin, and Fibronectin. Meanwhile, the expression of E-cadherin was significantly increased by EFT treatment. Furthermore, downregulation of MMP-2 and MMP-9 were observed. Conclusion Treatment of PANC-1 with EFT demonstrated measurable cytotoxic effects. Furthermore, EFT evoked S phase arrest while inhibiting the migration and invasion of PANC-1 cells. Additionally, EFT inhibited the epithelial to mesenchymal transition and MMPs expression in PANC-1 cells. This study serves to confirm the strong therapeutic potential of EFT while identifying the mechanisms of action.

Abstract Background Kawasaki disease (KD) is a systemic vasculitis accompanied by many systemic physiological and biochemical changes. Elucidating its molecular mechanisms is crucial for diagnosing and developing effective treatments. NLR Family CARD Domain Containing 4 (NLRC4) encodes the key components of inflammasomes that function as pattern recognition receptors. The purpose of this study was to investigate the potential of NLRC4 methylation as a biomarker for KD. Methods In this study, pyrosequencing was utilized to analyze NLRC4 promoter methylation in blood samples from 44 children with initial complete KD and 51 matched healthy controls. Methylation at five CpG sites within the NLRC4 promoter region was evaluated. Results Compared to controls, NLRC4 methylation significantly decreased in KD patients (CpG1: p = 2.93E-06; CpG2: p = 2.35E-05; CpG3: p = 6.46E-06; CpG4: p = 2.47E-06; CpG5: p = 1.26E-05; average methylation: p = 5.42E-06). These changes were significantly reversed after intravenous immunoglobulin (IVIG) treatment. ROC curve analysis demonstrated remarkable diagnostic capability of mean NLRC4 gene methylation for KD (areas under ROC curve = 0.844, sensitivity = 0.75, p = 9.61E-06, 95% confidence intervals were 0.762–0.926 for mean NLRC4 methylation). In addition, NLRC4 promoter methylation was shown to be significantly negatively correlated with the levels of central granulocyte percentage, age, mean haemoglobin quantity and mean erythrocyte volume. Besides, NLRC4 promoter methylation was positively correlated with lymphocyte percentage, lymphocyte absolute value. Conclusions Our work revealed the role of peripheral NLRC4 hypomethylation in KD pathogenesis and IVIG treatment response, could potentially serve as a treatment monitoring biomarker, although its precise functions remain to be elucidated.

Background: Gastric cancer (GC) is a typical malignant tumor and the main cause of cancer-related deaths. Its pathogenesis involves multiple steps, including pyroptosis, although these steps are still uncertain. Pyroptosis, also known as gasdermin-mediated programmed necrosis, participates in various pathological processes in tumors, including GC. ELANE, which encodes neutrophil elastase, is closely associated with GC. Additionally, ELANE has been implicated in GC cell pyroptosis, but this has not been confirmed. Therefore, investigating the link between ELANE and pyroptosis in GC is warranted. This research uses bioinformatics and experiments to examine the relationship between ELANE, pyroptosis, and GC prognosis. Methods: The GEO and TCGA databases, along with pyroptosis-related genes, were applied to identify pyroptosis-related differentially expressed genes (DEGs). ELANE was selected via primary screening. Using the median expression level of ELANE as the threshold, pyroptosis-related DEGs were divided into low- and high-ELANE groups. Based on the DEGs in these two groups, GO, KEGG and GSEA analyses were conducted to elucidate the mechanisms of ELANE in GC. Furthermore, we plotted ROC and Kaplan–Meier curves to analyze the clinical and pathological features of ELANE expression. The Nomograms tool was applied to calculate the predictive value of ELANE for the clinical outcomes of GC cases. Immunohistochemical analysis was performed to detect the level of ELANE in GC tissues and to validate whether ELANE was involved in pyroptosis in GC cells through cell experiments. Finally, the immune infiltration of ELANE was investigated, and interaction networks (proteins-ELANE, microRNA-ELANE, and small-molecule drug-ELANE) were constructed. Results: We aimed to investigate the expression of the ELANE gene in GC and study the relationship among ELANE, pyroptosis, and the prognosis of patients with GC. Differential expression analysis of gene-expression datasets from TCGA-STAD and GSE49051 revealed that the expression of the ELANE gene was significantly up-regulated in GC. Using STRING network analysis, we identified multiple proteins involved in the occurrence and development of GC, including interactions between ELANE and GSDMC, a member of the gasdermin protein family. Survival analysis showed that ELANE expression levels significantly affected overall survival (OS), disease-free survival (DFS), and progression-free survival (PFS) in patients with GC. Additionally, ROC analysis demonstrated that ELANE was effective in distinguishing GC patients from normal controls (AUC = 0.812). Immunohistochemical analysis showed that ELANE was highly expressed in gastric cancer tissues and was closely related to age, tumor grade, and stage. The cell experiments further confirmed that the high expression of ELANE in gastric cancer cells was associated with pyroptosis. Comprehensive analysis indicated that ELANE could be used as a potential prognostic marker for GC and plays an important role in pyroptosis. Conclusion: High ELANE expression is related to poor survival and prognosis of patients with GC. It participates in pyroptosis and immune infiltration in GC. Therefore, ELANE is a promising prognostic biomarker for pyroptosis in GC.

Consider a simple undirected connected graph G, with D(G) and A(G) representing its degree and adjacency matrices, respectively. Furthermore, L(G)=D(G)−A(G) is the Laplacian matrix of G, and Ht=exp⁡(−tL(G)) is the heat kernel (HK) of G, with t>0 denoting the time variable. For a vertex u∈V(G), the uth element of the diagonal of the HK is defined as Ht(u,u)=(exp⁡(−tL(G)))uu=∑k=0∞((−tL(G))k)uuk!, and HE(G)=∑i=1ne−tλi=∑u=1nHt(u,u) is the HK trace of G, where λ1,λ2,⋯,λn denote the eigenvalues of L(G). This study provides new computational formulas for the HK diagonal entries of graphs using an almost equitable partition and the Schur complement technique. We also provide bounds for the HK trace of the graphs.

Purpose: Transforaminal lumbar interbody fusion (TLIF) is a classic surgical procedure for posterior lumbar fusion. This study aims to analyze the TLIF field by bibliometric method and comprehensively summarize the research status and trends. Methods: All TLIF-related articles were retrieved from the Web of Science. The data were analyzed using R software and SPSS to calculate corresponding indicators. Visualizations were drawn using VOSviewer and Scimago Graphica, including country, institution, journal, author, and keywords. Results: A total of 919 articles were included. The annual publication volume of TLIF-related articles presented an exponential growth. North America, Europe, and Asia were the main sources of articles, with the USA and China being the main contributors and the USA being the global research center for TLIF. The level of the national economy was an important factor affecting TLIF-related research. The highest number of contributions in this field was made by Kern Singh among authors and by Rush University among institutions. The European Spine Journal was the most influential journal. The research focus has gradually shifted from perfecting the TLIF technique toward emphasizing the patient level. The improvement of minimally invasive techniques and how to improve clinical outcomes as well as accelerate postoperative rehabilitation of patients may be the hot spot of future research. Conclusions: With the advancement of medical technology and the popularization of minimally invasive concepts in recent years, TLIF and its derivative technologies have attracted increasing attention. Patient-centered minimally invasive surgery is a hot research topic in the field of TLIF currently and will continue to be so into the future