Identification of Anticancer Enzymes and Biomarkers for Hepatocellular Carcinoma through Constraint-Based Modeling.

Hepatocellular carcinoma (HCC) results in the abnormal regulation of cellular metabolic pathways. Constraint-based modeling approaches can be utilized to dissect metabolic reprogramming, enabling the identification of biomarkers and anticancer targets for diagnosis and treatment. In this study, two genome-scale metabolic models (GSMMs) were reconstructed by employing RNA sequencing expression patterns of hepatocellular carcinoma (HCC) and their healthy counterparts. An anticancer target discovery (ACTD) framework was integrated with the two models to identify HCC targets for anticancer treatment. The ACTD framework encompassed four fuzzy objectives to assess both the suppression of cancer cell growth and the minimization of side effects during treatment. The composition of a nutrient may significantly affect target identification. Within the ACTD framework, ten distinct nutrient media were utilized to assess nutrient uptake for identifying potential anticancer enzymes. The findings revealed the successful identification of target enzymes within the cholesterol biosynthetic pathway using a cholesterol-free cell culture medium. Conversely, target enzymes in the cholesterol biosynthetic pathway were not identified when the nutrient uptake included a cholesterol component. Moreover, the enzymes PGS1 and CRL1 were detected in all ten nutrient media. Additionally, the ACTD framework comprises dual-group representations of target combinations, pairing a single-target enzyme with an additional nutrient uptake reaction. Additionally, the enzymes PGS1 and CRL1 were identified across the ten-nutrient media. Furthermore, the ACTD framework encompasses two-group representations of target combinations involving the pairing of a single-target enzyme with an additional nutrient uptake reaction. Computational analysis unveiled that cell viability for all dual-target combinations exceeded that of their respective single-target enzymes. Consequently, integrating a target enzyme while adjusting an additional exchange reaction could efficiently mitigate cell proliferation rates and ATP production in the treated cancer cells. Nevertheless, most dual-target combinations led to lower side effects in contrast to their single-target counterparts. Additionally, differential expression of metabolites between cancer cells and their healthy counterparts were assessed via parsimonious flux variability analysis employing the GSMMs to pinpoint potential biomarkers. The variabilities of the fluxes and metabolite flow rates in cancer and healthy cells were classified into seven categories. Accordingly, two secretions and thirteen uptakes (including eight essential amino acids and two conditionally essential amino acids) were identified as potential biomarkers. The findings of this study indicated that cancer cells exhibit a higher uptake of amino acids compared with their healthy counterparts.

Genetic characterization of the first Deltacoronavirus from wild birds around Qinghai Lake.

Deltacoronavirus, widely distributed among pigs and wild birds, pose a significant risk of cross-species transmission, including potential human epidemics. Metagenomic analysis of bird samples from Qinghai Lake, China in 2021 reported the presence of Deltacoronavirus. A specific gene fragment of Deltacoronavirus was detected in fecal samples from wild birds at a positive rate of 5.94% (6/101). Next-generation sequencing (NGS) identified a novel Deltacoronavirus strain, which was closely related to isolates from the United Arab Emirates (2018), China (2022), and Poland (2023). Subsequently the strain was named A/black-headed gull/Qinghai/2021(BHG-QH-2021) upon confirmation of the Cytochrome b gene of black-headed gull in the sample. All available genome sequences of avian Deltacoronavirus, including the newly identified BHG-QH-2021 and 5 representative strains of porcine Deltacoronavirus (PDCoV), were classified according to ICTV criteria. In contrast to Coronavirus HKU15, which infects both mammals and birds and shows the possibility of cross-species transmission from bird to mammal host, our analysis revealed that BHG-QH-2021 is classified as Putative species 4. Putative species 4 has been reported to infect 5 species of birds but not mammals, suggesting that cross-species transmission of Putative species 4 is more prevalent among birds. Recombination analysis traced BHG-QH-2021 origin to dut148cor1 and MW01_1o strains, with MW01_1o contributing the S gene. Surprisingly, SwissModle prediction showed that the optimal template for receptor-binding domain (RBD) of BHG-QH-2021 is derived from the human coronavirus 229E, a member of the Alphacoronavirus, rather than the anticipated RBD structure of PDCoV of Deltacoronavirus. Further molecular docking analysis revealed that substituting the loop 1-2 segments of HCoV-229E significantly enhanced the binding capability of BHG-QH-2021 with human Aminopeptidase N (hAPN), surpassing its native receptor-binding domain (RBD). Most importantly, this finding was further confirmed by co-immunoprecipitation experiment that loop 1-2 segments of HCoV-229E enable BHG-QH-2021 RBD binding to hAPN, indicating that the loop 1-2 segment of the RBD in Putative species 4 is a probable key determinant for the virus ability to spill over into humans. Our results summarize the phylogenetic relationships among known Deltacoronavirus, reveal an independent putative avian Deltacoronavirus species with inter-continental and inter-species transmission potential, and underscore the importance of continuous surveillance of wildlife Deltacoronavirus.

Multi-Group Polymer Coating on Zn Anode for High Overall Conversion Efficiency Photorechargeable Zinc-Ion Batteries.

The solar-driven photorechargeable zinc-ion batteries have emerged as a promising power solution for smart electronic devices and equipment. However, the subpar cyclic stability of the Zn anode remains a significant impediment to their practical application. Herein, poly(diethynylbenzene-1,3,5-triimine-2,4,6-trione) (PDPTT) was designed as a functional polymer coating of Zn. Theoretical calculations demonstrate that the PDPTT coating not only significantly homogenizes the electric field distribution on the Zn surface, but also promotes ion-accessible surface of Zn. With multiple N and C=O groups exhibiting strong adsorption energies, this polymer coating reduces the nucleation overpotential of Zn, alters the diffusion pathway of Zn2+ at the anode interface, and decreases the corrosion current and hydrogen evolution current. Leveraging these advantages, Zn-PDPTT//Zn-PDPTT exhibits an exceptionally long cycling time (≥4300 h, 1 mA cm-2). Zn-PDPTT//AC zinc-ion hybrid capacitors can withstand 50,000 cycles at 5 A/g. Zn-PDPTT//NVO zinc-ion battery exhibits a faster charge storage rate, higher capacity, and excellent cycling stability. Coupling Zn-PDPTT//NVO with high-performance perovskite solar cells results in a 13.12% overall conversion efficiency for the photorechargeable zinc-ion battery, showcasing significant value in advancing the efficiency and upgrading conversion of renewable energy utilization.

[Progress of allergic rhinitis research based on transcriptome sequencing].

Traditional studies on allergic rhinitis（AR） have mainly adopted animal models and biomolecular approaches. In addition, the advent of transcriptome sequencing technology is promoting the development of AR at the genetic level. Recently, many scholars have focused on the role of common RNA in the pathogenesis of AR, suggesting that breakthroughs have been made in the field of AR bioinformatics analysis. This review aims to summarize the research advances in AR, the development of transcriptome sequencing technology, and the application of transcriptome sequencing in AR, in order to explore potential drug targets for AR treatment and provide new insights into precision medicine.

Flexible Aqueous Supercapacitors for Long Cycle-Life Using Electrode with Multiple Active C═S Sites.

Even though a few organic materials have attracted considerable attention for energy storage applications, their dissolution in the electrolyte during the charging-discharging processes presents a formidable challenge to their long-term performance. In this work, according to the principle of like dissolves like, non-polar trithiocyanuric acid (TCA) can effectively inhibit dissolution in an aqueous electrolyte, hence prolonging the cycle life. Moreover, theoretical calculations suggest that TCA lowers lowest unoccupied molecular orbital (LUMO) energy level, thereby promoting reaction kinetics. The CV curves of TCA maintain a rectangular structure even at a high scan rate of 1000 mV s‒1 and exhibit a remarkable capacitance retention rate of 93.1% after 50,000 cycles. Asymmetric flexible supercapacitors utilizing the TCA exhibit an impressive energy density. Moreover, they maintain 94.2% of their capacitance after undergoing 80,000 cycles. Their integration with perovskite solar cells to facilitate the rapid storage of photogenerated charges enables efficient solar energy utilization, providing a practical solution for capturing and storing renewable energy.

Robust ultrahigh electromagnetic interference shielding effectiveness based on engineered structures of carbon nanotube films.

High-performance electromagnetic interference (EMI) shielding materials with ultrathin, flexible, and pliable mechanical properties are highly desired for high-end equipments, yet there remain large challenges in the manufacture of these materials. Here, carbon nanotube film (CNTF)/copper (Cu) nanoparticle (NP) composite films are fabricated via a facile electrodeposition method to achieve high electromagnetic shielding efficiency. Notably, a CNTF/Cu NP composite film with 15 µm thickness can achieve excellent EMI shielding efficiency of ∼248 dB and absolute EMI shielding effectiveness as high as 2.17 × 105 dB cm2 g-1, which are the best values for composite EMI shielding materials with similar or greater thicknesses. These engineered composite films exhibit excellent deformation tolerance, which ensures the robust reliability of EMI shielding efficiency after 20,000 cycles of repeated bending. Our results represent a critical breakthrough in the preparation of ultrathin, flexible, and pliable shielding films for applications in smart, portable and wearable electronic devices, and 5G communication.

A Practical and Modular Method for Direct C-H Functionalization of the BODIPY Core via Thianthrenium Salts.

Direct structural modification of small-molecule fluorophores represents a straightforward and appealing strategy for accessing new fluorescent dyes with desired functionalities. We report herein a general and efficient visible-light-mediated method for the direct C-H functionalization of BODIPY, an important fluorescent chromophore, using readily accessible and bench-stable aryl and alkenylthianthrenium salts. This practical approach operates at room temperature with extraordinary site-selectivity, providing a step-economical means to construct various valuable aryl- and alkenyl-substituted BODIPY dyes. Remarkably, this protocol encompasses a broad substrate scope and excellent functional-group tolerance, and allows for the modular synthesis of sophisticated symmetrical and asymmetrical disubstituted BODIPYs by simply employing different combinations of thianthrenium salts. Moreover, the late-stage BODIPY modification of complex drug molecules further highlights the potential of this novel methodology in the synthesis of fluorophore-drug conjugates.

Correlation Analysis Between Tumor Deposit and Clinicopathologic Characteristics and Prognosis of Gastric Cancer: A Multicenter Retrospective Study.

BACKGROUND: The mechanism underlying the formation of gastric tumor deposits (TDs) is unclear. We aimed to explore the risk factors for the formation and prognostic value of TDs. METHODS: This retrospective analysis included 781 locally advanced gastric cancer (LAGC) patients from four medical institutions in China, from June 2014 to June 2018. The risk factors for TD formation and prognostic value were determined through univariate and multivariate analyses. RESULTS: Univariate analysis revealed that TD positivity was closely related to tumor diameter, Borrmann classification, differentiation degree, pT stage, pN stage, pTNM stage, and nerve and vascular invasion (p < 0.05). Multivariate logistic regression revealed that tumor diameter ≥ 5 cm (odds ratio [OR] 1.836, 95% confidence interval [CI] 1.165-2.894, p = 0.009) and vascular invasion (OR 2.152, 95% CI 1.349-3.433, p = 0.001) were independent risk factors for TD positivity. Multivariate Cox analysis revealed that TD positivity (OR 1.533, 95% CI 1.101-2.134, p = 0.011), tumor diameter ≥ 5 cm (OR 1.831, 95% CI 1.319-2.541, p < 0.001), pT4a stage (OR 1.652, 95% CI 1.144-2.386, p = 0.007), and vascular invasion (OR 1.458, 95% CI 1.059-2.008, p = 0.021) were independent risk factors for GC prognosis. The 5-year overall and disease-free survival of the TD-positive group showed significant effects among patients in the pT4a and pN3b stages (p < 0.05). CONCLUSIONS: TDs are closely related to tumor diameter and vascular invasion in LAGC patients, and TD positivity is an independent prognostic factor for LAGC patients, especially those at pT4a and pN3b stages.

The safety, feasibility, and oncological outcomes of laparoscopic completion total gastrectomy for remnant gastric cancer: a prospective study with 3-year follow-up (FUGES-004 study).

BACKGROUND: The efficacy of laparoscopic completion total gastrectomy (LCTG) for remnant gastric cancer (RGC) remains controversial. METHODS: The primary outcome was postoperative morbidity within 30 days after surgery. Secondary outcomes included 3-year disease-free survival (DFS), 3-year overall survival (OS), and recurrence. Inverse probability treatment weighted (IPTW) was used to balance the baseline between LCTG and OCTG. RESULTS: Final analysis included 46 patients with RGC who underwent LCTG at the FJMUUH between June 2016 and June 2020. The historical control group comprised of 160 patients who underwent open completion total gastrectomy (OCTG) in the six tertiary teaching hospitals from CRGC-01 study. After IPTW, no significant difference was observed between the LCTG and OCTG groups in terms of incidence (LCTG vs. OCTG: 28.0 vs. 35.0%, P =0.379) or severity of complications within 30 days after surgery. Compared with OCTG, LCTG resulted in better short-term outcomes and faster postoperative recovery. However, the textbook outcome rate was comparable between the two groups (45.9 vs. 32.8%, P =0.107). Additionally, the 3-year DFS and 3-year OS of LCTG were comparable to those of OCTG (DFS: log-rank P =0.173; OS: log-rank P =0.319). No significant differences in recurrence type, mean recurrence time, or 3-year cumulative hazard of recurrence were observed between the two groups (all P >0.05). Subgroup analyses and concurrent comparisons demonstrated similar trends. CONCLUSIONS: This prospective study suggested that LCTG was noninferior to OCTG in both short-term and long-term outcomes. In experienced centers, LCTG may be considered as a viable treatment option for RGC.

Single dual-specific anti-PD-L1/TGF-ß antibody synergizes with chemotherapy as neoadjuvant treatment for pancreatic ductal adenocarcinoma: a preclinical experimental study.

AIMS: Chemotherapy resistance is an important cause of neoadjuvant therapy failure in pancreatic ductal adenocarcinoma (PDAC). BiTP (anti-PD-L1/TGF-ß bispecific antibody) is a single antibody that can simultaneously and dually target transforming growth factor-beta (TGF-ß) and programmed cell death ligand 1 (PD-L1). We attempted in this study to investigate the efficacy of BiTP in combination with first-line chemotherapy in PDAC. METHODS: Preclinical assessments of BiTP plus gemcitabine and nab-paclitaxel were completed through a resectable KPC mouse model (C57BL/6J). Spectral flow cytometry, tissue section staining, enzyme-linked immunosorbent assays, Counting Kit-8, transwell, and Western blot assays were used to investigate the synergistic effects. RESULTS: BiTP combinatorial chemotherapy in neoadjuvant settings significantly downstaged PDAC tumors, enhanced survival, and had a higher resectability for mice with PDAC. BiTP was high affinity binding to targets and reverse chemotherapy resistance of PDAC cells. The combination overcame immune evasion through reprogramming tumor microenvironment via increasing penetration and function of T cells, natural killer cells, and dendritic cells and decreasing the function of immunosuppression-related cells as regulatory T cells, M2 macrophages, myeloid-derived suppressor cells, and cancer-associated fibroblasts. CONCLUSION: Our results suggest that the BiTP combinatorial chemotherapy is a promising neoadjuvant therapy for PDAC.

An Accesss to 4,5,6-Trisubstituted Pyrimidines from 2H-Azirines and α-Isocyanoacetates or α-Isocyanoacetamides Enabled by 1,3-Dipolar [3 + 2] Cycloaddition/Ring-Expanding/Oxidative Aromatization Process.

The products containing pyrimidine scaffolds exhibit various important physiological and biological activities. To date, the strategies to generate 4,5,6-trisubstituted pyrimidines were not reported. Here, a copper-catalyzed reaction of 2H-azirines with α-isocyanoacetates or α-isocyanoacetamides has been developed, rapidly preparing 4,5,6-trisubstituted pyrimidines. The mechanistic results reveal that this strategy underwent a formal 1, 3-dipolar [3 + 2] cycloaddition/ring-expanding/oxidative aromatization procedure to construct the desired pyrimidines.

Accuracy of computer-assisted dynamic navigation when performing coronectomy of the mandibular third molar: A pilot study.

OBJECTIVES: The study represents a preliminary evaluation of the accuracy of the dynamic navigation system (DNS) in coronectomy of the mandibular third molar (M3M). METHODS: The study included participants with an impacted M3M near the inferior alveolar canal. The coronectomy planes were designed before the surgery using cone-beam computed tomography (CBCT) imaging data and then loaded into the DNS program. Intraoperatively, the navigation system was used to guide the complete removal of the target crown. Postoperative CBCT imaging was used to assess any three-dimensional deviations of the actual postoperative from the planned preoperative section planes for each patient. RESULTS: A total of 12 patients (13 teeth) were included. The root mean square (RMS) deviation of the preoperatively designed plane from the actual postoperative surface was 0.69 ± 0.21 mm, with a maximum of 1.45 ± 0.83/-1.87 ± 0.63 mm deviation. The areas with distance deviations < 1 mm, 1-2 mm, and 2-3 mm were 71.97 ± 5.72 %, 22.96 ± 6.57 %, and 4.52 ± 2.28 %, respectively. Most patients showed extremely high convexity of the surface area located in the mesial region adjacent to the base of the extraction socket. There was no observable evidence of scratching of the buccolingual bone plate at the base of the extraction socket by the handpiece drill. CONCLUSIONS: These results provide preliminary support for the use of DNS-based techniques when extracting M3M using a buccal approach. This would improve the accuracy of coronectomy and reduce the potiential damage to the surrounding tissue. CLINICAL SIGNIFICANCE: DNS is effective for guiding coronectomy.

DMSO-promoted direct δ-selective arylation of p-quinone methenylpiperidine bearinides to generate fuchsones under metal-free conditions by employing p-QMs themselves or substituted phenols as aryl sources.

Fuchsones have wide applications in modern society. Present methods for generating fuchsones have many disadvantages and there are significant limitations for further exploration of fuchsone applications. Herein, we describe a DMSO-promoted direct δ-selective arylation of p-QMs to synthesize symmetrical and unsymmetrical fuchsones under metal-free conditions by employing p-QMs themselves or substituted phenols as aryl sources. As unprecedented methods, these novel strategies present a great advantage and significance for further exploration of fuchsones and the development of new applications.

Diagnostic accuracy of updated risk assessment criteria and development of novel computational prediction models for patients with suspected choledocholithiasis.

BACKGROUND: There are risks of choledocholithiasis in symptomatic gallstones, and some surgeons have proposed the identification of choledocholithiasis before cholecystectomy. Our goal was to evaluate the diagnostic accuracy of the latest guidelines and create computational prediction models for the accurate prediction of choledocholithiasis. METHODS: We retrospectively reviewed symptomatic gallstone patients hospitalized with suspected choledocholithiasis. The diagnostic performance of 2019 and 2010 guidelines of the American Society for Gastrointestinal Endoscopy (ASGE) and 2019 guideline of the European Society of Gastrointestinal Endoscopy (ESGE) in different risks. Lastly, we developed novel prediction models based on the preoperative predictors. RESULTS: A total of 1199 patients were identified and 681 (56.8%) had concurrent choledocholithiasis and were included in the analysis. The specificity of the 2019 ASGE, 2010 ASGE, and 2019 ESGE high-risk criteria was 85.91%, 72.2%, and 88.42%, respectively, and their positive predictive values were 85.5%, 77.4%, and 87.3%, respectively. For Mid-risk patients who followed 2019 ASGE about 61.8% of them did not have CBD stones in our study. On the choice of surgical procedure, laparoscopic cholecystectomy + laparoscopic transcystic common bile duct exploration can be considered the optimal treatment choice for cholecysto-choledocholithiasis instead of Endoscopic Retrograde Cholangio-Pancreatography (ERCP). We build seven machine learning models and an AI diagnosis prediction model (ModelArts). The area under the receiver operating curve of the machine learning models was from 0.77 to 0.81. ModelArts AI model showed predictive accuracy of 0.97, recall of 0.97, precision of 0.971, and F1 score of 0.97, surpassing any other available methods. CONCLUSION: The 2019 ASGE guideline and 2019 ESGE guideline have demonstrated higher specificity and positive predictive value for high-risk criteria compared to the 2010 ASGE guideline. The excellent diagnostic performance of the new artificial intelligence prediction model may make it a better choice than traditional guidelines for managing patients with suspected choledocholithiasis in future.

High glucose-upregulated PD-L1 expression through RAS signaling-driven downregulation of PTRH1 leads to suppression of T cell cytotoxic function in tumor environment.

BACKGROUND: Nearly 80% of patients with pancreatic cancer suffer from glucose intolerance or diabetes. Pancreatic cancer complicated by diabetes has a more immunosuppressive tumor microenvironment (TME) and is associated with a worse prognosis. The relationship between glucose metabolism and programmed cell death-Ligand 1 (PD-L1) is close and complex. It is important to explore the regulation of high glucose on PD-L1 expression in pancreatic cancer and its effect on infiltrating immune effectors in the tumor microenvironment. METHODS: Diabetic murine models (C57BL/6) were used to reveal different immune landscape in euglycemic and hyperglycemic pancreatic tumor microenvironment. Bioinformatics, WB, iRIP [Improved RNA Binding Protein (RBP) Immunoprecipitation]-seq were used to confirm the potential regulating role of peptidyl-tRNA hydrolase 1 homolog (PTRH1) on the stability of the PD-L1 mRNA. Postoperative specimens were used to identify the expression of PD-L1 and PTRH1 in pancreatic cancer. Co-culturing T cells with pancreatic cancer cells to explore the immunosuppressive effect of pancreatic tumor cells. RESULTS: Our results revealed that a high dose of glucose enhanced the stability of the PD-L1 mRNA in pancreatic tumor cells by downregulating PTRH1 through RAS signaling pathway activation following epidermal growth factor receptor (EGFR) stimulation. PTRH1 overexpression significantly suppressed PD-L1 expression in pancreatic cells and improved the proportion and cytotoxic function of CD8+ T cells in the pancreatic TME of diabetic mice. CONCLUSIONS: PTRH1, an RBP, plays a key role in the regulation of PD-L1 by high glucose and is closely related to anti-tumor immunity in the pancreatic TME.

Highly stereoselective synthesis of trans-alkenes via electrochemical Ni-catalyzed hydroarylation of alkynes with aryl iodides.

An electrochemical nickel catalyzed hydroarylation reaction of various alkynes is herein described. In this reaction, alkynes were coupled with aryl iodides by electrochemical Ni catalysis to obtain highly selective trans-olefins. The outstanding features of this protocol include mild reaction conditions, operational simplicity, and excellent functional group tolerance.

Enhancing the thermostability of carboxypeptidase A by a multiple computer-aided rational design based on amino acids preferences at ß-turns.

Carboxypeptidase A (CPA) with efficient hydrolysis ability has shown vital potential in food and biological fields. In addition, it is also the earliest discovered enzyme with Ochratoxin A (OTA) degradation activity. Thermostability plays an imperative role to catalyze the reactions at high temperatures in industry, but the poor thermostability of CPA restricts its industrial application. In order to improve the thermostability of CPA, flexible loops were predicted through molecular dynamics (MD) simulation. Based on the amino acid preferences at ß-turns, three ΔΔG-based computational programs (Rosetta, FoldX and PoPMuSiC) were employed to screen three variants from plentiful candidates and MD simulations were then used to verify two potential variants with enhanced thermostability (R124K and S134P). Results showed that compared to the wild-type CPA, the variants S134P and R124K exhibited rise of 4.2 min and 7.4 min in half-life (t1/2) at 45 °C, 3 °C and 4.1 °C in the half inactivation temperature (T5010), in addition to increase by 1.9 °C and 1.2 °C in the melting temperature (Tm), respectively. The mechanism responsible for the enhanced thermostability was elucidated through the comprehensive analysis of molecular structure. This study shows that the thermostability of CPA can be improved by the multiple computer-aided rational design based on amino acid preferences at ß-turns, broadening its industrial applicability of OTA degradation and providing a valuable strategy for the protein engineering of mycotoxin degrading enzymes.

Associations between high-altitude adaptation and risk of cardiovascular diseases: a bidirectional Mendelian randomization study.

High-altitude adaptation (HAA) was reported to be significantly associated with reduced risks for multiple cardiovascular diseases (CVDs). However, the causality and direction of the associations are largely uncharacterized. We aimed to examine the potential causal relationships between HAA and six types of CVD, including coronary artery disease (CAD), cerebral aneurysm, ischemic stroke, peripheral artery disease, arrhythmia and atrial fibrillation. We obtained the summary data from largest available genome-wide association study of HAA and six types of CVD. Two-sample bidirectional Mendelian randomization (MR) analyses were performed to infer the causality between them. In the sensitivity analyses, MR-Egger regression analyses and MR-Pleiotropy RESidual Sum and Outlier (MR-PRESSO) global analyses were used to assess the pleiotropic effects; Cochran's Q tests were used to test the heterogeneity by inverse variance-weighted (IVW) and MR-Egger methods; and the leave-one-out analyses were used to examine whether some single nucleotide polymorphisms (SNPs) could influence the results independently. The MR main analyses showed that the genetically instrumented HAA was significantly causally associated with the reduced risks of CAD (odds ratio [OR] = 0.029; 95% confidence interval [CI] = 0.004-0.234; P = 8.64 × 10-4). In contrast, there was no statistically significant relationship between CVDs and HAA. Our findings provide evidence for the causal effects of HAA on the reduced risks of CAD. However, there is no causality of CVDs on HAA. These findings might be helpful in developing the prevention and intervention strategies for CAD.

METTL3 promotes pancreatic cancer proliferation and stemness by increasing stability of ID2 mRNA in a m6A-dependent manner.

In eukaryotes, N6-methyladenosine (m6A) is the most prevalent epigenetic alteration. Methyltransferase-like 3 (METTL3) is a key player in the control of m6A, although its function in pancreatic cancer is incompletely understood. In this study, we examined the role that METTL3 plays in pancreatic cancer cell proliferation and stemness. We discovered that in pancreatic cancer cells, METTL3-mediated m6A alterations regulate ID2 as a downstream target. The stability of ID2 mRNA was decreased and m6A modification was effectively eliminated by METTL3 knockdown in pancreatic cancer cells. We also demonstrate that m6a-YTHDF2 is necessary for the METTL3-mediated stabilization of ID2 mRNA. Additionally, we show that ID2 controls the stemness molecules NANOG and SOX2 via the PI3K-AKT pathway to support pancreatic cancer growth and stemness maintenance. Our data suggest that METTL3 may post-transcriptionally upregulate ID2 expression in an m6A-YTHDF2-dependent manner to further promote the stabilization of ID2 mRNA, which may be a new target for pancreatic cancer treatment.

Precise determination of major and trace elements in micrometer-scale ilmenite lamellae in titanomagnetite using LA-ICP-MS technique: application of regression analysis to time-resolved signals.

Laser ablation ICP-MS (LA-ICP-MS) is a powerful microbeam technique capable of rapid and precise determination for a large spectrum of trace elements at ppm or sub-ppm levels. Micrometer-scale minerals and inclusions are very common in geological materials, for which direct measurement is restricted by the spot size using LA-ICP-MS (generally 20-50 µm). In this study, ilmenite lamellae intergrown with magnetite were selected as an example to describe a practical algorithm that applies regression analysis to extract the chemical compositions of binary phases from mixed LA-ICP-MS signals. The method accuracy is confirmed by the agreement between the regressed value for various trace elements in ilmenite exsolutions and their reference values (direct analyses using EPMA and LA-ICP-MS). Results were obtained for most detectable components (Mg, Mn, V, Nb, Ta, Sc, Zr, Hf, Sn, et c.) and their relative deviations are within ±10%, even for those <10 ppm (such as Hf and W). Relative standard errors on the regressed value were calculated to evaluate the precision of the method, which is mostly within 10%, and the worst up to 25%. Therefore, the algorithm described in this contribution provides a solution for precise determination of trace element compositions for micrometer-scale ilmenite lamellae in titanomagnetite using LA-ICP-MS, and is potentially practical for other geological materials.