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Abstract Cells regulate gene expression through various RNA regulatory mechanisms, and this regulation often becomes less efficient with age, contributing to accelerated aging and various age-related diseases. Nonsense-mediated mRNA decay (NMD), a well-characterized RNA surveillance mechanism, degrades aberrant mRNAs with premature termination codons (PTCs) to prevent the synthesis of truncated proteins. While the role of NMD in cancer and developmental and genetic diseases is well documented, its implications in human aging remain largely unexplored. This study reveals a significant decline in the levels of the protein UPF1, a key player in NMD, during cellular senescence. Additionally, NMD substrates accumulate in senescent cells, along with decreased levels of cap-binding protein 80/20 (CBP80/20)-dependent translation (CT) factors and reduced binding to active polysomes, indicating reduced efficiency of NMD. Moreover, knockdown of UPF1 in proliferating WI-38 cells induces senescence, as evidenced by increased senescence-associated β-galactosidase activity, alterations in senescence-associated molecular markers, increased endogenous γ-H2AX levels, and reduced cell proliferation. These findings suggest that the decline in UPF1 levels during cellular senescence accelerates the senescent phenotype by impairing NMD activity and the consequent accumulation of abnormal mRNA.

Abstract Background Prophylactic parenteral administration of antibiotics is strongly recommended to prevent surgical site infection (SSI). Cefoxitin is mainly administered intravenously in colorectal surgery. The current standard method for administering prophylactic antibiotics in adults is to administer a fixed dose quickly before skin incision. The percentage of time that the unbound concentration is maintained above the minimum inhibitory concentration (fT > MIC) during surgery is used as a surrogate measure for the effectiveness of prophylactic antibiotics. Target-controlled infusion (TCI) is a method of administration that changes the infusion rate to maintain a constant target concentration set by the user in consideration of the patient’s physical characteristics. When cefoxitin is administered using the TCI method, it is possible that fT > MIC can be well maintained while reflecting the patient’s physical characteristics compared to the standard method. Methods This prospective, single-centre, parallel-arm, single-blinded, randomised controlled trial with a 1:1 allocation was designed to compare the effectiveness of the TCI method with that of the standard cefoxitin administration method. We shall enrol 2494 patients scheduled to undergo colon or rectal surgery. Prior to the procedure, we shall randomise each patient to the control group (standard administration method) or study group (TCI method). In the control group, 2 g of cefoxitin was dissolved in 100 ml of normal saline and administered for approximately 10 min. Redosing was performed every 2 h from the start of the first dose of cefoxitin. In the study group, 2 g of cefoxitin was dissolved in 50 ml of normal saline and administered using a commercialised TCI syringe pump until the end of surgery. It was administered at a target concentration of 80 μg/ml using the total concentration pharmacokinetic model of cefoxitin. In all groups, 2 g of cefoxitin was administered using the standard administration method 12 h after the end of surgery. The primary outcome will be the incidence of SSI. The secondary outcome will be the administered dose of cefoxitin. Preoperative, intraoperative, and postoperative data were collected. Discussion This study will provide evidence for the effectiveness of administering cefoxitin using the TCI method compared to the standard method. Trial registration ClinicalTrials.gov, NCT05253339 , Registered on February 23, 2022 {2a, 2b}.

IntroductionAn effective vaccination policy must be implemented to prevent foot-and-mouth disease (FMD). However, the currently used vaccines for FMD have several limitations, including induction of humoral rather than cellular immune responses.MethodsTo overcome these shortcomings, we assessed the efficacy of levamisole, a small-molecule immunomodulator, as an adjuvant for the FMD vaccine. We conducted in vitro studies using murine peritoneal exudate cells (PECs) and porcine peripheral blood mononuclear cells (PBMCs) and in vivo studies using mice (experimental animals) and pigs (target animals). We evaluated levamisole-mediated modulation of the innate and adaptive immune responses; early, mid-term, and long-term immune-inducing effects; modes of action; and host defense against viral infection.ResultsLevamisole treatment promoted IFNγ secretion in murine PECs and porcine PBMCs. Additionally, it induced robust and long-lasting immune responses by eliciting high antibody titers and high virus-neutralizing antibody titers. By activating downstream signaling pathways of various pattern-recognition receptors, levamisole stimulated the expression of multiple cytokines and costimulatory molecules. Owing to these immunostimulatory effects, levamisole elicited host defense against viral infections in pigs. Our findings demonstrate the potential of levamisole as an immunostimulatory agent.DiscussionThe results also indicate that levamisole, as an adjuvant for animal vaccines, can elicit robust innate and adaptive immune responses, thereby enhancing host defense against viral infections. This study provides a promising approach for the development of improved FMD vaccine strategies in the future.

As animal welfare becomes more active in livestock industry, research is being conducted on ways to improve poor housing environments, reduce stress, and meet welfare standards. Among these, environmental enrichment methods are effective in reducing stress and creating a welfare-friendly rearing environment, but there are few cases of actual application to farms. Therefore, we aimed to investigate the effect of providing pecking materials (grain blocks), known as one of the environmental enrichment methods, to commercial broiler farms. This study used two facilities that could accommodate 32,000 one-day-old broilers (Arbor acres) per building, and two groups (control and treatment groups) were designed after creating two identical areas within each building (total two treatments, two replicates, 16,000 birds per replicate). Two identical zones within the house were created by installing a partition in the center; one side was provided with grain blocks (one grain block per 1000 birds), and the other side was not. Analysis items included productivity (body weight, uniformity), environmental variables (litter and air), welfare indicators (leg, gait score, feather cleanliness score), and serum corticosterone levels. Analysis of all items was conducted twice, on the 19th and 27th, taking into account the farm’s feed change date and slaughter schedule. Other environmental conditions (density, lighting, ventilation, temperature, humidity, feed, and water) were the same. As a result, no difference in productivity was observed according to enrichment, and the quality of litter and air was similar. Also, there was no significant difference in welfare indicators. Interestingly, however, provision of the environment enrichment lowered serum corticosterone levels (p < 0.05). The implications of our study are that grain blocks as a pecking material are an effective way to reduce stress without adversely affecting broiler performance and rearing environment. However, it is still necessary to explore optimal enrichment materials that can help not only the welfare level but also the broiler performance.

The aim of this study was to identify the feather section, among the whole feather, rachis, and vane, with the highest reliability for corticosterone measurement in 10 Pekin ducks aged 42 days. In total, 60 samples (i.e., 20 per section) were collected and each section was analyzed in duplicate. Corticosterone levels were measured using ELISA and statistical analyses were performed using ANOVA in SAS 9.2, and the intra-class correlation coefficient (ICC) was tested using IBM SPSS. The level in the whole feather (12.55 ± 4.41 pg/mg) was significantly lower (p < 0.001) than that in the rachis (18.12 ± 5.70 pg/mg). No significant differences were observed between the rachis and the vane (20.40 ± 3.04 pg/mg). ANOVA results confirmed substantial hormonal variability depending on the feather part analyzed. The ICCs for the whole feather, rachis, and vane were 0.923, 0.876, and 0.004, respectively. The vane section exhibited the highest concentration and lowest variance, whereas the whole feather exhibited the highest ICC. Although the whole feather had the lowest concentration, it exhibited greater consistency. Further research is necessary to improve the feather corticosterone analysis method for more accurate analysis. In conclusion, the whole feather provides the most reliable measure of corticosterone concentration among the three parts.

Context.--New-generation antiseizure medications (ASMs) are increasingly prescribed, and therapeutic drug monitoring (TDM) has been proposed to improve clinical outcome. However, clinical TDM data on new-generation ASMs are scarce. Objective.--To develop and validate a liquid chromatography- tandem mass spectrometry (LC-MS/MS) method for therapeutic drug monitoring (TDM) of 6 new-generation ASMs in serum and analyze the clinical TDM data from a large cohort of Korean patients with epilepsy. Design.--Stable isotope-labeled internal standards were added to protein precipitations of serum. One microliter of sample was separated on an Agilent Poroshell EC-C18 column, and lacosamide, perampanel, gabapentin, pregabalin, vigabatrin, and rufinamide were simultaneously quantified by Agilent 6460 triple-quad mass spectrometer in multiplereaction monitoring mode. Linearity, sensitivity, precision, accuracy, specificity, carryover, extraction recovery, and matrix effect were evaluated. TDM data of 458 samples from 363 Korean epilepsy patients were analyzed. Results.--The method was linear with limit of detection less than 0.05 lg/mL in all analytes. Intraassay and interassay imprecisions were less than 5% coefficient of variation. Accuracy was within 615% bias. Extraction recovery ranged from 85.9% to 98.8%. A total of 88% (403 of 458) were on polypharmacy, with 29% (118 of 403) using concomitant enzyme inducers. Only 38% (175 of 458) of the concentrations were therapeutic, with 53%(244 of 458) being subtherapeutic. Drug concentration and concentration-to-dose ratio were highly variable among individuals for all 6 ASMs. Conclusions.--A simple and rapid LC-MS/MS method for TDM of 6 ASMs was developed and successfully applied to clinical practice. These large-scale TDM data could help establish an effective monitoring strategy for these drugs. [ABSTRACT FROM AUTHOR]

Kirsten rat sarcoma viral oncogene homolog (KRAS) is the most frequently mutated oncogene in lung adenocarcinoma, with G12C and G12V being the most predominant forms. Recent breakthroughs in KRASG12C inhibitors have transformed the clinical management of patients with the G12C mutation and advanced our understanding of the function of this mutation. However, little is known about the targeted disruption of KRASG12V, partly due to a lack of specific inhibitors. Here, we leverage the degradation tag (dTAG) system to develop a KRASG12V-transgenic mouse model. We explored the therapeutic potential of KRASG12V degradation and characterized its effect on the tumor microenvironment (TME). Our study reveals that degradation of KRASG12V abolished lung and pancreatic tumors in mice and caused a robust inhibition of KRAS-regulated cancer-intrinsic signaling. Importantly, targeted degradation of KRASG12V reprogrammed the TME toward a stimulatory milieu and drove antitumor immunity, elicited mainly by effector and cytotoxic CD8+ T cells. Our work provides insights into the effect of KRASG12V degradation on both tumor progression and the immune response, highlighting degraders as a powerful strategy for targeting KRAS-mutant cancers. [ABSTRACT FROM AUTHOR]