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Cellular senescence is characterized by a decrease in protein synthesis, although the underlying processes are mostly unclear. Chemical modifications to transfer RNAs (tRNAs) frequently influence tRNA activity, which is crucial for translation. We describe how tRNA N7-methylguanosine (m7G46) methylation, catalyzed by METTL1-WDR4, regulates translation and influences senescence phenotypes. Mettl1/Wdr4 and m7G gradually diminish with senescence and aging. A decrease in METTL1 causes a reduction in tRNAs, especially those with the m7G modification, via the rapid tRNA degradation (RTD) pathway. The decreases cause ribosomes to stall at certain codons, impeding the translation of mRNA that is essential in pathways such as Wnt signaling and ribosome biogenesis. Furthermore, chronic ribosome stalling stimulates the ribotoxic and integrative stress responses, which induce senescence-associated secretory phenotype. Moreover, restoring eEF1A protein mitigates senescence phenotypes caused by METTL1 deficiency by reducing RTD. Our findings demonstrate that tRNA m7G modification is essential for preventing premature senescence and aging by enabling efficient mRNA translation. The heterodimer of METTL1-WDR4 is responsible for adding methylation group to the N7 atom of guanine (m7G) in tRNA molecules. Here the authors show how the tRNA m7G modification mediates tRNA stability to control proteostasis by maintaining efficient protein synthesis, which is important for preventing premature senescence and aging. [ABSTRACT FROM AUTHOR]

Background: Adjuvant therapy may improve survival of patients with hepatocellular carcinoma (HCC) after curative resection. This study compared safety and efficacy outcomes between patients at high risk of recurrence who received different types of adjuvant therapy or no such therapy after hepatic resection for HCC. Methods: Recurrence-free survival (RFS), overall survival, and adverse events were compared among patients who received adjuvant immune checkpoint inhibitors (ICIs) alone, ICIs with tyrosine kinase inhibitors (TKIs), or no adjuvant therapy between 13 March 2019 and 19 March 2022. This study was registered on ClinicalTrials.gov (NCT05221398). Results: Of the 517 patients in final analysis, 432 (83.6%) received no adjuvant therapy, 53 (10.2%) received ICIs alone, and 32 (6.2%) received adjuvant ICIs and TKIs. During median follow-up of 34.0 months (IQR 27.8 to 41.6 months), RFS was significantly longer among patients who received either type of adjuvant therapy (25.2 months, 95%CI 16.4–34.0) than among those who received none (16.1 months, 95%CI 12.9–19.4), and this difference remained significant after propensity score matching (HR 0.52, 95%CI 0.35–0.76, P = 0.004). Overall survival was unaffected by either type of adjuvant therapy, while significant difference was observed between patients who received adjuvant therapy or not after propensity score matching (HR 0.31, 95%CI 0.17–0.59, P = 0.005). The rate of grade 3 or 4 adverse events was similar between the two types of adjuvant therapy. Conclusions: ICIs alone or with TKIs may improve RFS of patients at high risk of HCC recurrence after curative resection. [ABSTRACT FROM AUTHOR]

Copyright of Rare Metals is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Rare Metals is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

An equiatomic refractory high-entropy alloy (RHEA) NbMoTaWRe is prepared by mechanical alloying (MA) and spark plasma sintering (SPS). The effects of mechanical alloying and sintering behaviors on the microstructure and properties of the RHEA are investigated. After ball-milling for 30 h, the metastable and supersaturated MA powders with the body-centered cubic (BCC) structure are obtained. Then, the MA powders are sintered using the SPS method under the sintering temperature range of 1700–1900 °C, and the C atoms and WC introduced by the MA process reacts with the metastable and supersaturated Ta/Nb phase of the MA powers to form the face-centered cubic (FCC) structure (Nb, Ta)C particles along the BCC matrix boundaries during the SPS process. The NbMoTaWRe alloy sintered at 1800 °C consisted of BCC matrix and FCC-type (Nb, Ta)C particles has high compactness (porosity fraction is 0.32%), fracture strength (2630 MPa), plastic strain (6.82%), and hardness (992 ± 20 HV). These excellent properties of this RHEA are mainly attributed to the combination of multi-effects, including sintering densification, grain refinement strengthening from the refined sizes (3.80 μm) BCC matrix, precipitation strengthening from the (Nb, Ta)C particles, solid solution strengthening from multi-principal elements and interstitial solid solution strengthening from C atoms dissolving into BCC matrix. [ABSTRACT FROM AUTHOR]

Copyright of Rare Metals is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Background: Lenvatinib is regarded as the first-line therapy for patients with unresectable hepatocellular carcinoma (HCC). This study assessed the efficacy and safety of lenvatinib with or without immune checkpoint inhibitors (ICIs) in patients with unresectable HCC. Methods: In this multicentric retrospective study, patients with unresectable HCC who treated with lenvatinib with or without ICIs would be enrolled. Overall survival, progression-free survival, objective response rate, and disease control rate were calculated to assess the antitumor response. Results: Between January 2019 and August 2020, 65 patients received lenvatinib plus ICIs while other 45 patients received lenvatinib. The baseline characteristics were comparable between the two groups. Lenvatinib plus ICIs provided significantly higher overall survival (hazard ratio = 0.47, 95% CI 0.26–0.85; p = 0.013) and progression-free survival (hazard ratio = 0.35, 95% CI 0.20–0.63; p < 0.001) than lenvatinib monotherapy. Moreover, patients with lenvatinib plus ICIs had significantly higher objective response rate (41.5% vs 20.0%, p = 0.023) and disease control rate (72.3% vs 46.7%, p = 0.009) per RECIST v1.1 than those with lenvatinib. No treatment-related deaths were observed. Grade 3 or greater adverse events occurring in 10% or more of patients in either treatment group were hypertension [13 (20.0%) of 65 patients treated with lenvatinib plus ICIs vs 8 (17.8%) of 45 patients treated with lenvatinib], and palmar–plantar erythrodysesthesia [seven (10.8%) vs two (4.4%)]. Conclusions: In this real-world study, lenvatinib combined with ICIs showed significantly promising efficacy and manageable safety than lenvatinib alone in patients with unresectable HCC. [ABSTRACT FROM AUTHOR]

The online version of the original article can be found at https://doi.org/10.1007/s10067-021-06003-z B Correction to: Clinical Rheumatology b https://doi.org/10.1007/s10067-021-06003-z In the original published version of the above article contained the following errors and should have been corrected. 4 Pooled estimates of relative risk of major cardiovascular events in rheumatoid arthritis patients, stratifed by JAK inhibitor treatment The original article has been corrected. [Extracted from the article]

Objectives: Janus kinase (JAK) inhibitors are a new class of medication for treatment of rheumatoid arthritis (RA), and such inhibitors alter levels of high-density lipoprotein (HDL) and low-density lipoprotein (LDL) in RA patients. However, the extent of such changes has not been systematically reviewed. Method: A systematic review and network meta-analysis was performed on randomized trials in RA patients in response to JAKi identified from Pubmed, Medline, Embase, and Cochrane Controlled Trials Register. The primary outcome was mean change of HDL-C and LDL-C from baseline. Mean treatment differences and the rank of the effect of various JAKi on HDL-C and LDL-C were estimated. Results: Based on data from 18 unique studies involving five approved JAK inhibitors and 6697 RA patients (JAKi = 3341, placebo = 3356), such inhibitors led to a mean increase of 8.11 mg/dl (95% CI 6.65–9.58, I2 = 82%) in HDL levels from baseline, and a mean increase of 11.37 mg/dl (95% CI 7.84–14.91, I2 = 88%) in LDL levels from baseline. Cardiovascular disease risk did not differ significantly between patients who received JAK inhibitors or those who received placebo or active agents. Conclusions: Our analysis suggests that, at their recommended doses, all five JAK inhibitors lead to an increase in HDL and LDL levels in RA patients. Further long-term research is required to extend these results and understand whether changes in lipid levels in RA patients can affect cardiovascular risk. Key Points • This is the first systematic review and NMA examining the effect of all five clinically approved JAK inhibitors on lipid levels in RA patients. • Recommended doses of JAK inhibitors used for the treatment of RA patients can induce a significant increase in HDL and LDL levels. • Indirect pairwise comparisons suggest that only upadacitinib and peficitinib have significantly different ability to induce LDL change in RA patients. [ABSTRACT FROM AUTHOR]

Although the recent treatment in melanoma through the use of anti-PD-1 immunotherapy is successful, the efficacy of this approach remains to be improved. Here, we explore the feasibility of combination strategy with the armed oncolytic adenovirus ZD55-IL-24 and PD-1 blockade. We find that combination therapy with localized ZD55-IL-24 and systemic PD-1 blockade leads to synergistic inhibition of both local and distant established tumors in B16-bearing immunocompetent mouse model. Our further mechanism investigation reveals that synergistic therapeutic effect is associated with marked promotion of tumor immune infiltration and recognition in both local and distant tumors as well as spleens. PD-1 blockade has no obvious effect on promotion of tumor immune infiltration and recognition. Localized therapy with ZD55-IL-24, however, can help PD-1 blockade to overcome the limitation of relatively low tumor immune infiltration and recognition. This study provides a rationale for investigation of such combination therapy in the clinic. [ABSTRACT FROM AUTHOR]

MiR-200a acts as a key role in tumor malignant progression. This work purposed to assess the function of miR-200a in Wilm's tumor. Based on bioinformatics analysis, the expression, prognostic value and related pathways of miR-200a and CDC7 (a potential downstream molecule of miR-200a) in Wilm's tumor were analyzed. qRT-PCR was conducted to confirm the miR-200a level in Wilm's tumor cells. The luciferase reporter assay was carried out to verify the binding of miR-200a to 3′-UTR of CDC7. Then, the impacts of miR-200a and CDC7 on cell viability and apoptosis were measured using CCK-8 and flow cytometry assays. Also, western blot was applied to measure the expression of CDC7 as well as Wnt/β-catenin signaling pathway-related proteins and apoptosis proteins. Herein, we revealed that miR-200a was lowly expressed in Wilm's tumor tissues and cells and the low miR-200a expression is closely bound up with death and poor outcomes. Moreover, miR-200a directly targeted and inhibited CDC7 in Wilm's tumor cells. Biological function experiments illustrated that overexpression of miR-200a reduced the viability and elevated the apoptosis of Wilm's tumor cells, while overexpression of CDC7 reversed the inhibitory impact of miR-200a on cell viability and the promoting impact of miR-200a on cell apoptosis. Besides, we revealed that miR-200a/CDC7 axis can decrease the expression of β-Catenin, Cyclin D1 and C-Myc as well as the phosphorylation of GSK-3β, thus inhibiting the Wnt/β-catenin signaling pathway. Furthermore, blocking the Wnt/β-catenin signaling pathway caused an increase on cell apoptosis, while overexpression of CDC7 can reverse these impacts. Collectively, miR-200a/CDC7 axis involved in regulating the malignant phenotype of Wilm's tumor through Wnt/β-catenin signaling pathway, which provides a theoretical basis for targeted molecular therapy of Wilm's tumor. [ABSTRACT FROM AUTHOR]

The sensing of bioactive molecules based on photochemical techniques has become one of the fastest-growing scientific fields. Surface-enhanced Raman scattering (SERS) is a highly sensitive technique for the detection of low-concentration molecules, including DNA, microRNA, proteins, blood, and bacteria; single-cell detection and identification; bioimaging; and disease diagnosis, providing abundant structural information for biological analytes. One rapidly developing field of SERS biosensor design is the use of carbon-based nanomaterials as substrate materials, such as zero-dimensional carbon quantum dots, one-dimensional carbon nanotubes, two-dimensional graphene, and graphene oxide (GO) and three-dimensional spatial carbon nanomaterials or carbon-based core-shell nanostructures. In this review, we describe the recent developments in SERS biosensors, in particular carbon-based SERS, for the detection of bioactive molecules. We systematically survey recent developments in carbon nanomaterial-based SERS biosensors, focusing on fundamental principles for carbon-based materials for SERS biosensor design, fabrication, and operation, and provide insights into their rapidly growing future potential in the fields of biomedical and biological engineering, in situ analysis, quantitative analysis, and flexible photoelectric functional materials. As such, this review can play the role of a roadmap to guide researchers toward concepts that can be used in the design of next-generation SERS biosensors while also highlighting current advancements in this field. Biosensors: Photochemical detection using carbon-based nanomaterials The various sheets, tubes, and dot-like nanostructures formed by carbon atoms can make a molecular sensing technology safer and more effective. In surface-enhanced Raman spectroscopy (SERS), detection of single molecules is achieved by attaching biological targets to signal-boosting substrates, typically metal nanoparticles. Biao Kong from Fudan University in Shanghai, China, and colleagues review how metal SERS substrates are being replaced by carbon-based nanostructures engineered to produce localized 'hotspots' where electric fields are enhanced. These substrates offer improved biocompatibility and customizable device structures. For example, graphene can easily host tumor cells for cancer sensing, while carbon dots can attach to DNA strands to act as ultra-small barcodes. The favorable mechanical properties of carbon also enable production of innovative materials including drug-sensing nanosheets that adhere to the surfaces of banknotes and coins. In this review, recent developments of carbon nanomaterial-based SERS biosensors are systematically summarized, which focus on fundamental principles for carbon-based materials for SERS biosensor design, fabrication methods and operation mechanisms, providing insight into their rapidly growing future potential in the fields of biomedical and biological engineering, in-situ analysis, quantitative analysis and flexible photoelectric functional materials. [ABSTRACT FROM AUTHOR]

Objective: Levetiracetam (LEV) is an antiepileptic drug with a novel pharmacological mechanism. Advances in functional magnetic resonance imaging (fMRI) enable researchers to explore the cognitive effects of antiepileptic drugs on the living brain. This study aimed to explore how the functional connectivity patterns of the cognitive networks changed in association with LEV treatment. Methods: Patients with temporal lobe epilepsy (TLE), including both users and nonusers of LEV, were included in this study along with healthy controls. Core cognitive networks were extracted using an independent component analysis approach. Functional connectivity patterns within and between networks were investigated. The relationships between functional connectivity patterns and clinical characteristics were also examined. Results: The patterns of intranetwork connectivity in the default mode network (DMN), left executive control network (lECN), and dorsal attention network (DAN) differed among the three groups. The internetwork interactions did not show intergroup differences once corrected for multiple comparisons. No correlation between functional connectivity and clinical characteristics was found in patients with TLE. Conclusions: Changes in intranetwork connectivity are a key effect of LEV administration. Significance: Alterations in intranetwork connectivity patterns may underlie the cognitive effects of LEV administration; this finding improves our understanding of the neural mechanisms of LEV therapy. [ABSTRACT FROM AUTHOR]

Objective: A randomized-controlled trial comparing study of the changes in brain sensitive-weighted imaging (SWI) of Wilson disease (WD) patients during the treatment with metal chelator was done. Methods: 100 untreated WD patients (80 cases of cerebral type, 20 cases of hepatic type, age 20.13 ± 9.12 years old) and 20 normal controls were selected. Neurological symptoms were scored using the modified Young scale. Liver function tests and copper indices were collected. All study objects received SWI test of the brain. The values of corrected phase (CP) were calculated on SWI. Cerebral-type WD patients were treated with D-penicillamine (DPA) (group 1) or Dimercaptopropane Sulfonate (DMPS) + Dimercaptosuccinic Acid (DMSA) (group 2). Hepatic-type WD patients were treated with DPA (group 3). All patients received annual neurological symptom score, liver function, copper indices, and SWI examination. Results: At the first year of treatment, score of the modified Young scale in group 2 was lower than that in group 1 (P = 0.023) and lower than that before treatment (P = 0.040). After 2 years of treatment, the score of the modified Young scale in group 1 was lower than that before treatment (P = 0.012). At the second year after treatment, the urinary copper in group 2 was higher than that in group 1 (P = 0.014). Urinary copper was maintained at 200 µg/day in group 1 and 300 µg/day in group 2 after 3 years of treatment. At the first year of treatment, serum copper in group 1 was lower than that in group 2 (P = 0.032). At the first year of treatment, CP values of the pallidum and substantia nigra in group 2 were higher than those in group 1 (P = 0.026, 0.040). At the second year of treatment, CP value of substantia nigra in group 2 was higher than that in group 1 (P = 0.037). After 3 years of treatment, there was no difference in CP values between WD patients and normal controls. Conclusions: Therapy with DMPS and DMSA improves neurological symptoms of WD patients more quickly and leads to less aggravation, compared with therapy with DPA. The metal content in the brain of WD patients was at a low level after 3 years of treatment. DMPS and DMSA can remove metal from brain tissue faster than DPA. [ABSTRACT FROM AUTHOR]

Based on the analysis of the factors influencing the dynamic control of reservoir normal elevation in flood season (RNEFS), the evaluation index system on optimizing dynamic RNEFS schemes is established firstly. The flood disaster losses evaluation model of reservoir downstream is established with MIKE software manufactured by the DHI Company, Denmark. Then, the Biliuhe Reservoir is taken as an example, and the flood disaster risk losses of Chengzitan town in its downstream area is calculated and linked with the flood control risk, the mean annual generated energy, the utilization rate of water resources and the reliability of water-supply guaranteed rate after running up the RNEFS. Lastly, the RNEFS schemes are optimized by variable fuzzy optimization model. And the satisfying scheme obtained will provide an important reference and basis for dynamically controlling RNEFS during real-time operation of a reservoir. [ABSTRACT FROM AUTHOR]

To obtain more accurate hydrogeological parameters of an aquifer, multi-methods are applied in this paper. Taking the Longkeng water source in Songyuan City as an example, a pumping test, as well as the groundwater dynamical, spring discharge inverse, and groundwater hydrochemical kinetics method are first applied to determine the hydrogeological parameters of the aquifer in this area. Groundwater numerical simulating models are then built using Groundwater Modeling System software to identify and certify the parameters. According to the all-time water-level fitting curve of long-term observation wells, the relative error of simulated water level is less than 6 %. According to these methods, the parameters for the whole region are obtained, and these parameters are more accurate than those obtained by using pumping tests alone. [ABSTRACT FROM AUTHOR]

AbstractAim:To evaluate the effects of the fibrinolytic enzyme FIIa from Agkistrodon acutus venom on acute pulmonary thromboembolism (APT) in animal models.Methods:Both rabbit and dog APT models were used. For the rabbit APT model, the thrombi weight before and after administration was measured. Central venous pressure (CVP) and mean arterial pressure (MAP) were measured before and 15, 30, 60, and 120 min after the injection of the blood clot. Partial thromboplastin time (APTT), prothrombin time (PT), platelet count, and fibrinogen concentration were measured using auto analyzers. Plasminogen activity was measured based on chromogenic substrates. In the dog APT model, pulmonary blood flow was recorded using pulmonary angiography.Results:Intravenous administration of FIIa (0.1-5.0 mg/kg) improved the APT-induced hemodynamic derangements and reduced thrombi weight. The angiography evidence also showed that the pulmonary emboli had almost disappeared after FIIa infusion. FIIa (0.1, 0.5, or 1.0 mg/kg) did not impair the coagulation pathways, although very high doses of FIIa (5.0 mg/kg) could stimulate the production of plasminogen and result in impairment of the pathways.Conclusion:FIIa could effectively protect against APT via degradation of thrombi with less activation of plasminogen, and may provide a novel fibrinolytic enzyme for targeting the main pathological processes of the disease. [ABSTRACT FROM AUTHOR]

In real sea states, damage incidents on offshore floating structures are not due to the whole time series of wave elevation characterized as statistical one but due to few extreme waves or wave groups in irregular wave train. So, using CFD tools to precisely simulate predetermined irregular wave train will lay sound basis for understanding the local characteristic of the flow field and impact loads on offshore floating structures when damage incidents occur. In this article, the generation of single extreme wave is investigated in a numerical wave tank. First, experimental irregular wave train is decomposed into certain number of smallamplitude waves. The Fourier series expansion is performed to determine the amplitude and initial phase angle of each wave component. A hydrodynamic transfer function is used to calculate the amplitude of wave-maker motion associated with each wave component. Then superposition is carried out on all of the wave-maker motion components to get the final wave-maker motion. With the wave-maker motion as input, simulation of the single extreme irregular wave train is modeled successfully. Then the method is applied to simulating a much more complicated irregular wave train. Once again main features of the complicated irregular wave train are reproduced compared with experiment carried out in the new deepwater experimental basin at Shanghai Jiao Tong University. In the simulation, dynamic mesh method is enabled to model the piston-type wave-maker, the Volume Of Fluid (VOF) method is employed to capture the free surface and a dissipation zone is introduced to deal with wave reflection. [ABSTRACT FROM AUTHOR]