Loss of protein homeostasis is a hallmark of cellular senescence, and ribosome pausing plays a crucial role in the collapse of proteostasis. However, our understanding of ribosome pausing in senescent cells remains limited. In this study, we utilized ribosome profiling and G-quadruplex RNA immunoprecipitation sequencing techniques to explore the impact of RNA G-quadruplex (rG4) on the translation efficiency in senescent cells. Our results revealed a reduction in the translation efficiency of rG4-rich genes in senescent cells and demonstrated that rG4 structures within coding sequence can impede translation both in vivo and in vitro. Moreover, we observed a significant increase in the abundance of rG4 structures in senescent cells, and the stabilization of the rG4 structures further exacerbated cellular senescence. Mechanistically, the RNA helicase DHX9 functions as a key regulator of rG4 abundance, and its reduced expression in senescent cells contributing to increased ribosome pausing. Additionally, we also observed an increased abundance of rG4, an imbalance in protein homeostasis, and reduced DHX9 expression in aged mice. In summary, our findings reveal a novel biological role for rG4 and DHX9 in the regulation of translation and proteostasis, which may have implications for delaying cellular senescence and the aging process.
G-Quadruplexes ; Cellular Senescence ; Ribosomes/genetics* ; Humans ; Animals ; Mice ; DEAD-box RNA Helicases/genetics* ; Protein Biosynthesis ; RNA/chemistry* ; Neoplasm Proteins

As patients undergoing orthopedic surgery are a high-risk group for venous thromboembolism (VTE), clinical guidelines suggest anticoagulant drugs for VTE prophylaxis during perioperative period. Global antithrombotic guidelines vary in recommendations for anticoagulant drugs, but there is a general consensus in favor of using low-molecular-weight heparin (LMWH) as the first choice for prophylaxis, followed by unfractionated heparin, fondaparinux, warfarin, aspirin, and other direct oral anticoagulants (DOACs). Of them, aspirin is an inexpensive, widely used antiplatelet drug with limited complications and clear efficacy in prevention of myocardial infarction, stroke, and certain specific cancers. It was also used early for venous thromboembolism prophylaxis in orthopedic patients after surgery. Clinical experience of orthopedic physicians in North America has shown the effectiveness of aspirin in VTE prevention over several decades so that aspirin continues to be used to this day, but its use for VTE prophylaxis is less common in Europe and Asia. Historically, the role and efficacy of aspirin in VTE prevention have been the subjects of considerable controversy, for the early and recent research findings contradict each other, and recommendations conflict in different guidelines. This review focuses on the advancements in clinical evidence and guideline recommendations regarding the use of aspirin for VTE prophylaxis in major orthopedic surgeries.

Objective To evaluate the economic value of using glucagon-like peptide-1 receptor agonist(GLP-1RA)in combination with metformin for the treatment of type 2 diabetes mellitus(T2DM).Methods Based on 7 randomized controlled clinical trials(RCTs),Markov model was built to simulate the dynamic changes of metformin alone or combined with GLP-1RA in the treatment of T2DM patients without or with complications and death from the perspective of China's health system.Quality-adjusted life years(QALYs)was used as a health output indicator and 3 times China's per capita gross domestic product(GDP)in 2023 was set as the willingness-to-pay(WTP)threshold.The cycle was at the rate of 1 year and a total of 20 years cohort simulation in Markov model was applied to obtain long-term cost and effect of each treatment strategy.The incremental cost-utility ratio(ICUR)was analyzed as the primary evaluation indicator and the sensitivity of cost,utility and discount was performed to test the stability of the results.Results Compared with metformin alone,the ICUR of GLP-1RA including liraglutide,dulaglutide,exenatide,loxenatide,semaglutide combined with metformin were all below the WTP threshold,and the increased cost was acceptable.Extending the simulation time to 30 years or 50 years had no effect on results.The results of probability sensitivity analysis showed that the cost effect of semaglutide 0.5 mg combined with metformin had the highest probability of a cost-utility advantage of 99.7％among all the treatment strategies when WTP threshold was 3 times China's per capita GDP in 2023(268 074 yuan).Conclusion GLP-1RA,including liraglutide,dulaglutide,exenatide,lixisenatide,and semaglutide,at the regular recommended dose combined with metformin,would present higher cost-utility compared to metformin monotherapy.

Objective To evaluate the efficacy and safety of glucagon-like peptide 1 receptor agonists(GLP-1RA)in type 2 diabetes mellitus(T2DM)patients with overweight or obese.Methods PubMed,Embase,Cochrane Library,Ovid,ClinicalTrial.gov,SinoMed,CNKI,WanFang Data and VIP databases were electronically searched to collect randomized controlled trials(RCTs)on the efficacy of GLP-1RA in the treatment of T2DM patients with overweight or obese from January 1,2005 to November 1,2023.Two researchers independently screened the literature,extracted data and evaluated the risk of bias of the included studies.R software was then used for meta-analysis.The level of evidence was assessed by using the GRADE system.Results A total of 71 RCTs were included,including 29 476 patients.The results of Meta-analysis showed that compared with other hypoglycemic drugs,GLP-1RA showed superior effects in improving HbAlc status(WMD=-0.55,95％CI-0.65 to-0.45,P＜0.001)and weight loss(WMD=-2.61,95％CI-3.25 to-1.97,P＜0.001),while the effect on fasting plasm glucose was time-dependent(within 16 weeks:WMD=0.25,95％CI-0.17 to 0.66,P=0.250;16 to 52 weeks:WMD=-0.06,95％CI-0.32 to 0.20,P=0.650;over 52 to 104 weeks:WMD=-1.67,95％CI-1.91 to-1.43,P＜0.001).In terms of safety,the incidence of GLP-1RA's adverse reactions was higher than other hypoglycemic drugs(RR=1.11,95％CI 1.07 to 1.15,P＜0.001);the incidence of hypoglycemia was lower with GLP-1RA than with insulin(RR=0.58,95％CI 0.48 to 0.71,P＜0.001)and similar to oral hypoglycemic drugs(RR=0.83,95％CI 0.58 to 1.19,P=0.310).According to the GRADE assessment,only the certainty of the evidence for the results of the incidence of hypoglycemia was moderate,and the certainty of the evidence for the other results was low.Conclusion Current evidence shows that for T2DM patients with overweight or obese,GLP-1RA especially semaglutide,was more effective in lowering blood glucose,controlling body weight and reducing the occurrence of hypoglycemia than placebo,insulin and oral hypoglycemic drugs.

Objective:To evaluate the preventive effect of indwelling pancreatic duct guide wire through nasobiliary drainage catheter for post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP) in cholelithiasis patients with small-caliber pancreatic duct.Methods:The clinical data of 127 patients with gall bladder and common bile duct stones undergoing ERCP and elective laparoscopic cholecystectomy in the Cholelithiasis Center of Shanghai East Hospital Affiliated to Tongji University from January 2019 to June 2023 were analyzed retrospectively, including 55 males and 72 females, aged (56.95±10.86) years old. According to the preventive methods of PEP, patients were divided into the guide wire group (indwelling pancreatic duct guide wire through nasobiliary drainage catheter), stenting group (nasobiliary catheter with 5Fr 5 cm single pigtail pancreatic duct stent) and conventional group (nasobiliary catheter). The incidence of post-ERCP hyperamylasemia (PEH) and PEP were compared.Results:The incidence of PEH in the guide wire group was lower than that in the conventional group [17.8% (8/45) vs. 43.5% (10/23), P=0.023], and also lower than that in the stenting group [17.8% (8/45) vs. 32.2% (19/59)], despite no statistical significance ( P=0.337). The incidences of PEH were comparable in the stenting group and conventional group [32.2% (19/59) vs. 43.5% (10/23), P=0.096)]. The incidence of PEP in the guide wire group was lower than that in both the stenting group [6.7% (3/45) vs. 23.7% (14/59), P=0.030]. and conventional group [6.7% (3/45) vs. 30.4% (7/23), P=0.025]. The incidences of PEP were comparable in the stenting and conventional group [23.7% (14/59) vs. 30.4% (7/23), P=0.532]. Conclusion:Compared to the preventive pancreatic duct stenting, indwelling pancreatic duct guide wire through nasobiliary drainage catheter can effectively prevent the PEH and PEP in high-risk patients with a small-caliber pancreatic duct.

LIN28 is an RNA binding protein with important roles in early embryo development, stem cell differentiation/reprogramming, tumorigenesis and metabolism. Previous studies have focused mainly on its role in the cytosol where it interacts with Let-7 microRNA precursors or mRNAs, and few have addressed LIN28's role within the nucleus. Here, we show that LIN28 displays dynamic temporal and spatial expression during murine embryo development. Maternal LIN28 expression drops upon exit from the 2-cell stage, and zygotic LIN28 protein is induced at the forming nucleolus during 4-cell to blastocyst stage development, to become dominantly expressed in the cytosol after implantation. In cultured pluripotent stem cells (PSCs), loss of LIN28 led to nucleolar stress and activation of a 2-cell/4-cell-like transcriptional program characterized by the expression of endogenous retrovirus genes. Mechanistically, LIN28 binds to small nucleolar RNAs and rRNA to maintain nucleolar integrity, and its loss leads to nucleolar phase separation defects, ribosomal stress and activation of P53 which in turn binds to and activates 2C transcription factor Dux. LIN28 also resides in a complex containing the nucleolar factor Nucleolin (NCL) and the transcriptional repressor TRIM28, and LIN28 loss leads to reduced occupancy of the NCL/TRIM28 complex on the Dux and rDNA loci, and thus de-repressed Dux and reduced rRNA expression. Lin28 knockout cells with nucleolar stress are more likely to assume a slowly cycling, translationally inert and anabolically inactive state, which is a part of previously unappreciated 2C-like transcriptional program. These findings elucidate novel roles for nucleolar LIN28 in PSCs, and a new mechanism linking 2C program and nucleolar functions in PSCs and early embryo development.
Animals ; Cell Differentiation ; Embryo, Mammalian/metabolism* ; Embryonic Development ; Mice ; Pluripotent Stem Cells/metabolism* ; RNA, Messenger/genetics* ; RNA, Ribosomal ; RNA-Binding Proteins/metabolism* ; Transcription Factors/metabolism* ; Zygote/metabolism*

Objective:To investigate the influence of preoperative thyroid dysfunction on the 30-day postoperative mortality and complications in elderly patients with hip fracture.Methods:A retrospective analysis was conducted of the 349 elderly patients with hip fracture who had been admitted to Department of Orthopedic Trauma, Beijing Luhe Hospital Affiliated to Capital Medical University from January 2018 to December 2019. They were 108 males and 241 females, with an average age of 76.3 years (from 60 to 104 years). There were 190 femoral intertrochanteric fractures and 159 femoral neck fractures. By the preoperative level of thyroid function, the patients were divided into a normal function group of 290 cases and a dysfunction group of 59 cases. The 2 groups were compared in terms of hospital stay, mortality and incidence of complications within 30 days postoperation.Results:In this cohort, the rate of 30-day postoperative mortality was 3.4%(12/349) and the incidence of 30-day postoperative complications 14.6%(51/349). The 2 groups were comparable because there was no significant difference between them in the preoperative general data except for the preoperative comorbidity of coronary heart disease ( P>0.05). In the dysfunction group, the hospital stay averaged (10.2±6.9) d, the rate of 30-d postoperative mortality 1.7%(1/59) and the incidence of 30-day postoperative complications 16.9%(10/59), which were insignificantly different from those in the normal function group [(10.7±7.5) d, 3.8%(11/290) and 14.1%(41/290), respectively] ( P> 0.05). Conclusion:Since preoperative thyroid dysfunction does not affect the 30-day postoperative mortality and postoperative complications in the elderly patients with hip fracture but no definite thyroid disease, routine thyroid function screening is not recommended for them.

Objective To investigate the usefulness of three-dimensional reconstruction in the preoperative evaluation of the texture of pituitary tumors. Methods Seventy patients with pituitary tumors admitted to our hospital between January 2015 and July 2018 were enrolled in the study. All patients underwent enhanced MRI scanning before surgery. They were classified into the soft group, medium group, and tough group according to the tumor texture. The patient's clinical data, MRI images, and surgery conditions were collected.The Mimics software was used to reconstruct the three-dimensional models of pituitary adenomas. The volume and surface area of different tumor signal groups were calculated and analyzed. In addition, the relationships between tumor size, tumor resection, and postoperative complications were analyzed. Results The three-dimensionally reconstructed model of the pituitary adenoma had a clear outline and was consistent with the tumor area in the MRI images. The calculated average threshold accurately segmented the images. Grouped by the classification of texture, the differences of the proportions of each part were statistically significant (P ＜ 0.01). According to the ordinal polytomous logistics regression analysis, the proportion of the volume of the higher part positively correlated with the tumor texture (P ＜0.05), and the ratio of the surface area of the medium part to the overall surface area positively correlated with the tumor texture (P ＜ 0.05).Conclusion The use of Mimics software for 3 D reconstruction of preoperative MRI images can accurately predict the tumor texture in pituitary tumors and can provide a basis for the choice of surgical methods.

Objective:To investigate the current situation and trend of the utilization of antihypertensive drugs in Wuhan city. Methods:The utilization data including varieties,consumption sum and DDDs of antihypertensive drugs in 34 hospitals in Wuhan city from 2013 to 2015 were analyzed.Results:The annual consumption sum of antihypertensive drugs increased year by year,and the val-ue was 20 896.67,23 527.19 and 24 033.44 million yuan, respectively. The calcium-channel blockers (CCB), angiotensin Ⅱ re-ceptor antagonist (ARB),adrenergic receptor blockers and angiotensin converting enzyme inhibitors (ACEIs) ranked the top four in consumption sum of antihypertensive drugs. Their constituent ratio was not changed during 2013 and 2015. The consumption amount and DDDs of new compound preparations increased. Top two drugs in terms of consumption amount and DDDs were amlodipine and le-vamlodipine. Conclusion:CCB,ARB,ACEI,adrenergic receptor blockers and diuretics occupy the predominant places among all the antihypertensive drugs in Wuhan city,which is accordance with the current treatment guideline of antihypertensive drugs.

Objective To understand the status of awareness of hand hygiene(HH)knowledge and compliance among health care workers (HCWs)in China,and provide scientific basis for further improvement of HH practice. Methods A multi-centre retrospective survey on awareness of HH knowledge and compliance was conducted in 200 nationwide hospitals in 2015.Results The awareness rates of HH methods and HH indications among HCWs were 86.5% and 82.5% respectively;cleaning staff had the lowest awareness rate of HH indications(69.9%),followed by the other interns and advanced-study students (70.2%),as well as medical technicians (79.8%);attendants had the lowest awareness rate of HH methods(76.9%),followed by advanced-study students and interns(81.0%),and cleaning staff (82.4%);HH knowledge awareness rate among HCWs in secondary hospitals was lower than tertia-ry hospitals,and the district-level hospitals had the lowest awareness rate of HH.HH compliance rate and correct rate were 70.1% and 74.9% respectively;the interns and advanced-study students were at a low level of compliance and correct rates (61.4% and 60.9% respectively);the municipal hospitals had the lowest compliance and correct rates,non-teaching hospitals were lower than teaching hospitals.Conclusion HH in primary hospitals is weak,HH of interns,advanced-study students,as well as attendants and cleaning staffs are not enough,HH management should be strengthened,awareness and compliance of HH should be improved.