Search

Abstract Retinoblastoma (RB) poses significant challenges in clinical management due to the emergence of resistance to conventional chemotherapeutic agents, particularly carboplatin (CBP). In this study, we investigated the molecular mechanisms underlying CBP resistance in RB, with a focus on the role of autophagy and the influence of ubiquitin‐specific peptidase 49 (USP49). We observed upregulation of USP49 in RB tissues and cell lines, correlating with disease progression. Functional assays revealed that USP49 promoted aggressive proliferation and conferred CBP resistance in RB cells. Furthermore, USP49 accelerated tumor growth and induced CBP resistance in vivo. Mechanistically, we found that USP49 facilitated CBP resistance by promoting autophagy activation. In addition, we identified insulin‐like growth factor 2 mRNA‐binding protein 3 (IGF2BP3)‐mediated N6‐methyladenosine (m6A) modification of USP49 as a regulatory mechanism, wherein IGF2BP3 upregulated USP49 expression in an m6A‐dependent manner. Moreover, USP49 stabilized SIRT1, a protein associated with CBP resistance and autophagy, by inhibiting its ubiquitination and degradation. Rescue experiments confirmed the pivotal role of SIRT1 in USP49‐mediated CBP resistance. Our findings delineate a novel molecular network involving USP49‐mediated autophagy in promoting CBP resistance in RB, offering potential targets for therapeutic intervention to enhance treatment efficacy and improve outcomes for RB patients.

Abstract Background Adolescents exhibit a high prevalence of mental health disorders, with more than half of all cases emerging before the age of 14 years. Since the advent of the COVID-19 pandemic, there has been a marked upsurge in anxiety and depression among adolescents across several nations. Emotional disorders often lead to severe outcomes, including school absenteeism, self-harm, and suicidal tendencies. The suboptimal efficacy of pharmacotherapy, compounded by limited availability and substantial costs associated with individual psychotherapy, underscores the critical need for identifying simple yet efficacious psychotherapeutic interventions suitable for both individual and group settings. Tension and Trauma Release Exercise (TRE) is a mind-body therapeutic approach that efficiently alleviates symptoms of anxiety and depression. This randomized controlled trial (RCT) aims to evaluate the effectiveness of a mother-child intervention model using TRE in enhancing the clinical management of adolescent patients diagnosed with emotional disorders. Methods This study recruits 140 dyads of adolescents with emotional disorders and their mothers, randomly assigned to intervention or control groups. The intervention arm combines eight weeks of standard pharmacotherapy with an eight-week TRE group therapy, assessing at baseline, post-8-week treatment, and three-month follow-up. Initially, controls receive eight weeks of standard medication with parallel assessments, later transitioning to the same TRE intervention while maintaining continuous evaluation. The study further examines the influence of maternal emotional health on adolescent treatment response and investigates associated neurophysiological and psychological mechanisms. Discussion This research endeavors to identify a straightforward and potent body-oriented psychological intervention that could improve the clinical outcomes for adolescent patients with emotional disorders. Such findings would carry profound implications not only for the healthy development of teenagers but also for potentially mitigating the burden on families, educational institutions, and society as a whole. Trial registration ChiCTR2100044553, Registered March 24, 2021.

Abstract Accumulating evidence has shown that adipose-derived stem cells (ADSCs) have the potential to differentiate into hepatic lineages, which are ideal engraftments for tissue-engineered repair. In this study, we investigated the potential of transplanted induced hepatocyte-like cells (iHEPs) in treating hepatic alveolar echinococcosis and describe an efficient three-step protocol for the generation of iHEPs in vitro from ADSCs. The expression of hepatocyte lineage markers was assessed and iHEPs function was evaluated by Periodic acid-Schiff staining. iHEPs were intravenously transplanted into mice infected with Echinococcus multilocularis. Histopathological analysis and liver function tests were used to assess therapeutic effects. The iHEPs exhibit morphological features and a glycogen storage function similar to those of mature hepatocytes and demonstrate an upregulation in hepatic gene programs with increasing induction time. Following transplantation, iHEPs were observed surrounding the metacestode lesions in the liver parenchyma of E. multilocularis-infected mice. iHEPs transplantation effectively restored liver function and improved liver injury in the infected mice. Additionally, we observed significant activation of the Wnt/β-catenin signaling pathway in the livers of infected mice transplanted with iHEPs. Our results provide evidence that iHEPs transplantation can alleviate E. multilocularis-induced liver injury, potentially creating new avenues for treating liver injury in end-stage hepatic alveolar echinococcosis.

Background and objective Pembrolizumab (PEM) has been shown to be effective in clinical trials for the treatment of advanced non-small cell lung cancer (NSCLC), but clinical trials were based on cohorts of patients selected on specific criteria, and whether the findings are consistent with real-world patients is debatable. The aim of this study is to evaluate the efficacy and safety of PEM in the treatment of advanced NSCLC based on real-world data. Methods A retrospective collection of real-world data from patients with advanced NSCLC receiving PEM was conducted. Propensity score matching was used to eliminate inter-group differences and assess the efficacy and safety of PEM compared to chemotherapy. Results Among 450 matched patients, the incidence rates of any-grade adverse events were 79.87% in the PEM group and 86.71% in the chemotherapy group, while the incidence rates of grade ≥3 adverse events were 4.03% and 7.31%, respectively. The objective response rates were 48.63% for PEM and 36.00% for chemotherapy (P=0.011). The median progression-free survival was 15.5 months for PEM and 8.8 months for chemotherapy (P

The initial section of the Arctic Northeast Passage is located in the Yellow Sea and Bohai Sea of China. The severe weather types that may threaten the safety of shipping in this area are mainly strong winds and heavy precipitation. Among them the cold air gale accompanied by the cold wave process, as well as the disastrous weather such as strong wind and heavy precipitation caused by weather systems such as tropical cyclones and extratropical cyclones, have a great impact on shipping safety in this area. Based on the National Centers for Environmental Prediction (NCEP) global daily reanalysis data from 1991 to 2020, we analyze the energy propagation characteristics of the Rossby wave along the upper-level jet stream during the seaworthiness period (July to October) of the Arctic Northeast Passage and its impact on the weather in the initial section of the Arctic Northeast Passage, especially on heavy precipitation. The results are as follows. (1) The meridional wind along the 250 hPa westerly jet axis in the subtropical region of the Northern Hemisphere shows a zonal three-wave quasi-stationary Rossby wave pattern. (2) The atmospheric quasi-stationary Rossby wave source at 250 hPa is located in the Mediterranean region. The wave is excited here and propagates eastward along the jet stream. Although the wave energy is dissipated during the propagation process, continuous input of energy from the Mediterranean region maintains and strengthens the wave. (3) The absolute value of the correlation coefficient between the key area of the wave action flux divergence and the precipitation and wind speed in the initial section of the Arctic Northeast Passage is greater than 0.5. While the absolute value of the correlation coefficient between the key area wave action flux index and the precipitation and wind speed is close to 0.9, indicating a strong correlation, it shows that the energy of the Rossby wave is concentrated and strengthened when it propagates along the upper jet stream, significantly influencing the precipitation and wind speed in the initial section of the Northeast Passage of the Arctic, thus triggering disastrous weather such as heavy precipitation and strong winds. (4) When the Rossby wave disturbance is stronger, the downstream propagation energy is also stronger. The westerly jet is then strengthened, and the vertical upward motion is enhanced. This results in an abnormal increase in precipitation in the initial section of the Arctic Northeast Passage.

Abstract Diabetic retinopathy (DR) is a common complication of diabetes, with its prevalence increasing globally. While previous research has linked obesity indices such as body mass index (BMI) to DR, the association with weight-adjusted-waist index (WWI) remains unclear. Additionally, the relationship between WWI and DR has not been fully elucidated. This cross-sectional study analyzed data from the National Health and Nutrition Examination Survey (2005–2008) to investigate these associations in Americans aged 40 and above. The study included 5436 participants (2705 men and 2731 women). Weighted logistic regression analysis revealed a significant increase in DR prevalence with higher WWI and BMI values. Smooth curve analysis demonstrated a linear correlation between WWI and DR. The findings suggest that both WWI and BMI are independently associated with DR risk among older US adults, highlighting the importance of considering central obesity measures in assessing diabetic complications.

Abstract Aims To examine longitudinal and dose-d ependent associations between dietary fiber intake and various clinical outcomes over 48 weeks of pharmacological treatment in T2DM patients. Methods In this secondary analysis, we used data from the MARCH trial, which was designed to compare the efficacy of acarbose or metformin monotherapy as the initial therapy in Chinese patients newly diagnosed with T2DM. Dietary data were obtained using a 24-h dietary recall method to evaluate the intakes of dietary fiber from different sources as well as the carbohydrate-to-fiber ratio. Results A total of 551 newly-diagnosed patients with T2DM complete dietary records (286 in the acarbose group and 265 in the metformin group) were included. Higher intake of total fiber and whole grain fiber was positively associated with better β‐cell function, insulin sensitivity and postprandial glycemic control under acarbose treatment. Higher intake of legume fiber was associated with better glycemic control under both acarbose and metformin treatment but with better weight loss only under metformin treatment. A high-carbohydrate–low-fiber diet was associated with worse glycemic control and lower HDL-C under acarbose treatment but with higher insulin sensitivity and better weight loss under metformin treatment. Conclusions The notable effects of various dietary fibers when combined with different oral glucose-lowering medications should be considered to maximize therapeutic benefit.

Excessive inflammation caused by bacterial infection is the primary cause of implant failure. Antibiotic treatment often fails to prevent peri-implant infection and may induce unexpected drug resistance. Herein, a non-antibiotic strategy based on the synergy of silver ion release and macrophage reprogramming is proposed for preventing infection and bacteria-induced inflammation suppression by the organic-inorganic hybridization of silver nanoparticle (AgNP) and quercetin (Que) into a polydopamine (PDA)-based coating on the 3D framework of porous titanium (SQPdFT). Once the planktonic bacteria (e.g., Escherichia coli, Staphylococcus aureus) reach the surface of SQPdFT, released Que disrupts the bacterial membrane. Then, AgNP can penetrate the invading bacterium and kill them, which further inhibits the biofilm formation. Simultaneously, released Que can regulate macrophage polarization homeostasis via the peroxisome proliferators-activated receptors gamma (PPARγ)-mediated nuclear factor kappa-B (NF-κB) pathway, thereby terminating excessive inflammatory responses. These advantages facilitate the adhesion and osteogenic differentiation of bone marrow-derived mesenchymal stem cells (BMSCs), concomitantly suppressing osteoclast maturation, and eventually conferring superior mechanical stability to SQPdFT within the medullary cavity. In summary, owing to its excellent antibacterial effect, immune remodeling function, and pro-osteointegration ability, SQPdFT is a promising protective coating for titanium-based implants used in orthopedic replacement surgery.

Abstract Objective This retrospective cohort identified the association of human serum albumin (HSA) with adverse outcomes (septic shock, in-hospital and out-of-hospital mortality) in elderly hospitalized patients who have community-acquired pneumonia (CAP) and specific body mass index (BMI). Materials and methods This research included hospitalized CAP individuals (≥ 60 years) and was conducted at a teaching hospital in western China. All the patients were categorized into three populations based on two BMI cutoff values (18.5 kg/m2 and 24 kg/m2). The data was acquired from medical records, local government mortality databases, and telephone interviews. Binomial logistic regression analysis was used to explore the associations between low HSA and septic shock and in-hospital mortality, and Cox regression analysis was used to explore the association between low HSA and out-of-hospital mortality. Results A total of 627 patients were included in the analysis of in-hospital death and septic shock, and 431 patients were included in the analysis of out-of-hospital death. The study showed that 120 elderly patients with CAP (19.14%) died in the hospital, while 141 patients (32.71%) died out of the hospital, and 93 patients (14.83%) developed septic shock. No differences in in-hospital and out-of-hospital mortality were observed for BMI values

Abstract Background Feed efficiency is a crucial economic trait in poultry industry. Both host genetics and gut microbiota influence feed efficiency. However, the associations between gut microbiota and host genetics, as well as their combined contributions to feed efficiency in laying hens during the late laying period, remain largely unclear. Methods In total, 686 laying hens were used for whole-genome resequencing and liver transcriptome sequencing. 16S rRNA gene sequencing was conducted on gut chyme (duodenum, jejunum, ileum, and cecum) and fecal samples from 705 individuals. Bioinformatic analysis was performed by integrating the genome, transcriptome, and microbiome to screen for key genetic variations, genes, and gut microbiota associated with feed efficiency. Results The heritability of feed conversion ratio (FCR) and residual feed intake (RFI) was determined to be 0.28 and 0.48, respectively. The ileal and fecal microbiota accounted for 15% and 10% of the FCR variance, while the jejunal, cecal, and fecal microbiota accounted for 20%, 11%, and 10% of the RFI variance. Through SMR analysis based on summary data from liver eQTL mapping and GWAS, we further identified four protein-coding genes, SUCLA2, TNFSF13B, SERTM1, and MARVELD3, that influence feed efficiency in laying hens. The SUCLA2 and TNFSF13B genes were significantly associated with SNP 1:25664581 and SNP rs312433097, respectively. SERTM1 showed significant associations with rs730958360 and 1:33542680 and is a potential causal gene associated with the abundance of Corynebacteriaceae in feces. MARVELD3 was significantly associated with the 1:135348198 and was significantly correlated with the abundance of Enterococcus in ileum. Specifically, a lower abundance of Enterococcus in ileum and a higher abundance of Corynebacteriaceae in feces were associated with better feed efficiency. Conclusions This study confirms that both host genetics and gut microbiota can drive variations in feed efficiency. A small portion of the gut microbiota often interacts with host genes, collectively enhancing feed efficiency. Therefore, targeting both the gut microbiota and host genetic variation by supporting more efficient taxa and selective breeding could improve feed efficiency in laying hens during the late laying period.

Abstract Background Targeted protein degradation of neosubstrates plays a crucial role in hematological cancer treatment involving immunomodulatory imide drugs (IMiDs) therapy. Nevertheless, the persistence of inevitable drug resistance and hematological toxicities represents a significant obstacle to their clinical effectiveness. Methods Phenotypic profiling of a small molecule compounds library in multiple hematological cancer cell lines was conducted to screen for hit degraders. Molecular dynamic-based rational design and cell-based functional assays were conducted to develop more potent degraders. Multiple myeloma (MM) tumor xenograft models were employed to investigate the antitumor efficacy of the degraders as single or combined agents with standard of care agents. Unbiased proteomics was employed to identify multiple therapeutically relevant neosubstrates targeted by the degraders. MM patient-derived cell lines (PDCs) and a panel of solid cancer cell lines were utilized to investigate the effects of candidate degrader on different stage of MM cells and solid malignancies. Unbiased proteomics of IMiDs-resistant MM cells, cell-based functional assays and RT-PCR analysis of clinical MM specimens were utilized to explore the role of BRD9 associated with IMiDs resistance and MM progression. Results We identified a novel cereblon (CRBN)-dependent lead degrader with phthalazinone scaffold, MGD-4, which induced the degradation of Ikaros proteins. We further developed a novel potent candidate, MGD-28, significantly inhibited the growth of hematological cancer cells and induced the degradation of IKZF1/2/3 and CK1α with nanomolar potency via a Cullin-CRBN dependent pathway. Oral administration of MGD-4 and MGD-28 effectively inhibited MM tumor growth and exhibited significant synergistic effects with standard of care agents. MGD-28 exhibited preferentially profound cytotoxicity towards MM PDCs at different disease stages and broad antiproliferative activity in multiple solid malignancies. BRD9 modulated IMiDs resistance, and the expression of BRD9 was significant positively correlated with IKZF1/2/3 and CK1α in MM specimens at different stages. We also observed pronounced synergetic efficacy between the BRD9 inhibitor and MGD-28 for MM treatment. Conclusions Our findings present a strategy for the multi-targeted degradation of Ikaros proteins and CK1α against hematological cancers, which may be expanded to additional targets and indications. This strategy may enhance efficacy treatment against multiple hematological cancers and solid tumors.

Abstract Background Intestinal obstruction represents a severe intestinal disease associated with higher mortality rates. However, the determinants of mortality in patients with intestinal obstruction remain inadequately understood. This study sought to elucidate the potential risk factors associated with mortality in the context of intestinal obstruction during the COVID-19 pandemic. Methods A retrospective analysis was performed on a cohort of 227 patients diagnosed with intestinal obstruction at the First Hospital of Hebei Medical University, spanning the period from September 7, 2022, to January 7, 2023. The primary endpoint of the study was mortality within four weeks following discharge. Univariate and multivariable logistic regression models were utilized to evaluate the risk factors associated with mortality outcomes. Results A cohort of 227 patients diagnosed with intestinal obstruction (median age, 59.02 years [IQR, 48.95–70.85 years]) was included in our study. Malignant bowel obstruction (MBO) and COVID-19 were identified as independent risk factors for mortality among these patients. Notably, the mortality rate increased significantly to 38.46% when MBO was concomitant with COVID-19. Furthermore, postoperative pulmonary complications (PPC) (OR, 54.21 [death]; 95% CI, 3.17-926.31), gastric cancer (OR, 9.71 [death]; 95% CI, 1.38–68.18), VTE (Caprini Score ≥ 5) (OR, 7.64 [death]; 95% CI, 1.37–42.51), and COVID-19 (OR, 5.72 [death]; 95% CI, 1.01–32.29) were all determined to be independent risk factors for postoperative mortality. Additionally, gastric cancer could have emerged as one of the most severe risk factors for mortality in individuals with intestinal obstruction within the cohort of cancer patients, of which gastric cancer exhibited higher mortality rates compared to individuals with other forms of cancer. Conclusion The study identifies MBO, gastric cancer, COVID-19, PPC, and VTE as potential risk factors for mortality in cases of intestinal obstruction. These findings highlight the necessity for continuous monitoring of indicators related to these mortality risk factors and their associated complications, thereby offering valuable insights for the management and treatment of intestinal obstruction.

Abstract To achieve high power conversion efficiency in perovskite/silicon tandem solar cells, it is necessary to develop a promising wide-bandgap perovskite absorber and processing techniques in relevance. To date, the performance of devices based on wide-bandgap perovskite is still limited mainly by carrier recombination at their electron extraction interface. Here, we demonstrate assembling a binary two-dimensional perovskite by both alternating-cation-interlayer phase and Ruddlesden−Popper phase to passivate perovskite/C60 interface. The binary two-dimensional strategy takes effects not only at the interface but also in the bulk, which enables efficient charge transport in a wide-bandgap perovskite solar cell with a stabilized efficiency of 20.79% (1 cm2). Based on this absorber, a monolithic perovskite/silicon tandem solar cell is fabricated with a steady-state efficiency of 30.65% assessed by a third party. Moreover, the tandem devices retain 96% of their initial efficiency after 527 h of operation under full spectral continuous illumination, and 98% after 1000 h of damp-heat testing (85 °C with 85% relative humidity).

Abstract Aims Heart failure with reduced ejection fraction (HFrEF) significantly impacts health‐related quality of life (HR‐QoL). Existing HR‐QoL questionnaires can show inconsistencies, potentially misrepresenting patient self‐reports. This study examines the variation in HR‐QoL measurement tools for HFrEF patients, identifying related determinants. Methods and results We retrospectively analysed 134 hospitalized patients with acute decompensated HFrEF at a Taiwanese tertiary centre's Heart Failure Post‐Acute‐Care (HF‐PAC) programme. Participants completed the EuroQol‐5 dimension (EQ‐5D) questionnaire, the EQ‐5D visual analogue scale (VAS), and the Minnesota Living with Heart Failure Questionnaire (MLHFQ). Utility values were obtained from the EQ‐5D questionnaire. Demographic features were depicted using descriptive statistics, while multivariate regression was used to ascertain relationships between HR‐QoL measurements and determinants. Average scores for EQ‐5D, MLHFQ, EQ‐5D utility, and VAS were 6.1 ± 1.6, 21.8 ± 21.3, 81.7 ± 27.0, and 59.5 ± 14.6, respectively. Significant correlations were observed among the three tools. The New York Heart Association functional class showed a notable association with all tool scores. Other associations encompassed EQ‐5D with coronary artery disease, mineralocorticoid receptor antagonists, and the 6 min walk test; EQ‐5D VAS with chronic kidney disease; and MLHFQ with age. Conclusions This study illuminates the variance in HR‐QoL measurement tools for Taiwanese HFrEF patients. Using a range of these tools is beneficial in unveiling diverse determinants and approaching comprehensive patient‐centred care. However, for a more precise HR‐QoL assessment in Taiwanese HFrEF patients, recalibrating the EQ‐5D‐derived utility scores might be necessary, emphasizing the importance of patient‐specific considerations within the HF‐PAC programme.

Abstract. Mycoplasma hominis is an opportunistic microorganism that colonizes the genitourinary tract and causes genitourinary infections. However, pulmonary infections caused by M. hominis have rarely been reported in immunocompetent individuals. Herein, we report a rare case of an immunocompetent adult male with M. hominis pneumonia who presented with multiple pulmonary nodules that progressed to a cavitary mass with a halo sign. The presence of M. hominis infection was confirmed using multiplex polymerase chain reaction (mPCR) of the bronchoalveolar lavage fluid. The patient demonstrated no response to the initial levofloxacin therapy; however, the symptoms subsequently improved after the administration of moxifloxacin. M. hominis may be an underestimated causative agent of community-acquired pneumonia of unknown etiology in immunocompetent adults, and the involvement of the organism should be especially suspected in sexually active patients. Molecular diagnostic methods, such as mPCR, can be used to identify the etiology of atypical pneumonia. Appropriate antibiotics are crucial for effective treatment.

In this study, the effects of adding mixtures of mono- and di-fatty acid glycerides and Tween 80 with different hydrophilic-lipophilic balance (HLB) values on the stability and whipping characteristics of cream were studied, and the hardness, whipping rate, apparent viscosity, stability, and microstructure of the cream samples were detected. The results showed that with the increase in HLB value, the apparent viscosity of the emulsion decreased, and shear thinning occurred in all cream samples. The centrifugal creaming rate and turbiscan stability index (TSI) decreased first and then increased, and so did the absolute value of zeta potential. The results of whipping characteristics analysis showed that with the increase in HLB value, the whipping time and whipping rate of cream decreased, and the hardness after whipping increased first and then decreased, reaching a maximum of 1 150.1 g when the HLB value was 9. At HLB values in the range of 9–11, cream exhibited a shorter whipping time, higher whipping hardness, appropriate whipping rate, and good mounting performance with no collapse or deformation. Meanwhile, the microstructure showed that the size of the cream bubbles was relatively uniform after whipping, and the fat globules around the bubbles were dense and close to each other, thus forming a better network structure to protect the bubbles and make the foam more stable. Therefore, the HLB value of mixed emulsifiers should be controlled in the range of 9–11 to obtain cream with good stability and whipping characteristics.

Abstract Quasi-two-dimensional (Q-2D) perovskite exhibits exceptional photoelectric properties and demonstrates reduced ion migration compared to 3D perovskite, making it a promising material for the fabrication of highly sensitive and stable X-ray detectors. However, achieving high-quality perovskite films with sufficient thickness for efficient X-ray absorption remains challenging. Herein, we present a novel approach to regulate the growth of Q-2D perovskite crystals in a mixed atmosphere comprising methylamine (CH3NH2, MA) and ammonia (NH3), resulting in the successful fabrication of high-quality films with a thickness of hundreds of micrometers. Subsequently, we build a heterojunction X-ray detector by incorporating the perovskite layer with titanium dioxide (TiO2). The precise regulation of perovskite crystal growth and the meticulous design of the device structure synergistically enhance the resistivity and carrier transport properties of the X-ray detector, resulting in an ultrahigh sensitivity (29721.4 μC Gyair −1 cm−2) for low-dimensional perovskite X-ray detectors and a low detection limit of 20.9 nGyair s−1. We have further demonstrated a flat panel X-ray imager (FPXI) showing a high spatial resolution of 3.6 lp mm−1 and outstanding X-ray imaging capability under low X-ray doses. This work presents an effective methodology for achieving high-performance Q-2D perovskite FPXIs that holds great promise for various applications in imaging technology.

Abstract Background Broilers stand out as one of the fastest-growing livestock globally, making a substantial contribution to animal meat production. However, the molecular and epigenetic mechanisms underlying the rapid growth and development of broiler chickens are still unclear. This study aims to explore muscle development patterns and regulatory networks during the postnatal rapid growth phase of fast-growing broilers. We measured the growth performance of Cornish (CC) and White Plymouth Rock (RR) over a 42-d period. Pectoral muscle samples from both CC and RR were randomly collected at day 21 after hatching (D21) and D42 for RNA-seq and ATAC-seq library construction. Results The consistent increase in body weight and pectoral muscle weight across both breeds was observed as they matured, with CC outpacing RR in terms of weight at each stage of development. Differential expression analysis identified 398 and 1,129 genes in the two dimensions of breeds and ages, respectively. A total of 75,149 ATAC-seq peaks were annotated in promoter, exon, intron and intergenic regions, with a higher number of peaks in the promoter and intronic regions. The age-biased genes and breed-biased genes of RNA-seq were combined with the ATAC-seq data for subsequent analysis. The results spotlighted the upregulation of ACTC1 and FDPS at D21, which were primarily associated with muscle structure development by gene cluster enrichment. Additionally, a noteworthy upregulation of MUSTN1, FOS and TGFB3 was spotted in broiler chickens at D42, which were involved in cell differentiation and muscle regeneration after injury, suggesting a regulatory role of muscle growth and repair. Conclusions This work provided a regulatory network of postnatal broiler chickens and revealed ACTC1 and MUSTN1 as the key responsible for muscle development and regeneration. Our findings highlight that rapid growth in broiler chickens triggers ongoing muscle damage and subsequent regeneration. These findings provide a foundation for future research to investigate the functional aspects of muscle development.

Background/purpose: Periodontitis is associated with various systemic diseases, potentially facilitated by the passage of Porphyromonas gingivalis outer membrane vesicles (Pg-OMVs). Several recent studies have suggested a connection between Pg-OMVs and neuroinflammation and neurodegeneration, but the precise causal relationship remains unclear. This study aimed to investigate the mechanisms underlying these associations using in vitro models. Materials and methods: Isolated Pg-OMVs were characterized by morphology, size, and gingipain activity. We exposed SH-SY5Y neuroblastoma cells and BV-2 microglial cells to various concentrations of Pg-OMVs. Cell morphology, a 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, an enzyme-linked immunosorbent assay, and Western blot analysis were used to evaluate the cellular mechanism underlying Pg-OMV-induced neurotoxicity in neuronal cells and inflammatory responses in microglial cells. Results: Exposure to Pg-OMVs induced neurotoxicity in SH-SY5Y cells, as evidenced by cellular shrinkage, reduced viability, activation of apoptotic pathways, and diminished neuronal differentiation markers. Gingipain inhibition mitigated these effects, suggesting that gingipain mediates Pg-OMVs-induced neurotoxicity in SH-SY5Y cells. Our research on neuroinflammation suggests that upon endocytosis of Pg-OMVs by BV-2 cells, lipopolysaccharide (LPS) can modulate the production of inducible nitric oxide synthase and tumor necrosis factor-alpha by activating pathways that involve phosphorylated AKT and the phosphorylated JNK pathway. Conclusion: Our study demonstrated that following the endocytosis of Pg-OMVs, gingipain can induce neurotoxicity in SH-SY5Y cells. Furthermore, the Pg-OMVs-associated LPS can trigger neuroinflammation via AKT and JNK signaling pathways in BV-2 cells.

ABSTRACT: A reliable pedigree serves as the backbone of genetic evolution in domesticated animals, providing guidance for daily management and breeding strategies. However, in commercial chicken breeding, pedigree errors and omissions are common. The large-scale application of genomic selection provides an opportunity to reconstruct chicken pedigrees using SNP markers. Here, to reconstruct pedigrees in chickens, we detected high-quality SNPs from 2866 parent–offspring pairs and calculated their genomic relationship and identity by descent (IBD). The results showed that the IBD values for parent–offspring pairs ranged from 0.48 to 0.58, clearly distinguishing them from nonparent–offspring pairs and demonstrating robustness in parentage assignment. In contrast, the genomic relatedness coefficients varied from 0.32 to 0.65. The accuracy of pedigree reconstruction significantly improved as the SNP number and minor allele frequency (MAF) increased. When the number of SNPs exceeded 200, better inference power was exhibited with IBD than with genomic relatedness. Upon reaching an effective SNP quantity of 350, despite a MAF of 0.01, the accuracy of the pedigrees inferred reached a remarkable level of 99%. Furthermore, with a doubled SNP quantity of 700 and a MAF of 0.05, the accuracy increased to a perfect 100%. This study demonstrated the feasibility of accurately constructing pedigrees in chickens using low-density SNP markers and emphasized the importance of considering the number and MAFs of these markers to achieve optimal outcomes. The adoption of the IBD as a suitable metric for pedigree inference is promising for improving the efficiency and accuracy of genetic breeding programs. These findings are paramount for the development of cost-effective yet accurate parentage verification systems.

The durability of post-tensioned concrete (PTC) bridge structures has been greatly threatened by the corrosion of steel strands, especially in the case of insufficient grouting. In this paper, the effect of grouting quality on flexural behavior of corroded post-tensioned concrete (CPTC) beams is experimentally investigated with two groups of T-beams, i.e., five fully grouted beams in Group A and five partially grouted beams in Group B. Results indicate that when the mass loss of steel strands in Group A ranges from 0 % to 10.47 %, the cracking load decreases by 5.8821.57 %, and the ultimate bearing capacity decreases by 5.45–30.45 %. While for Group B, when the mass loss of steel strands ranges from 0 % to 14.26 %, the cracking load decreases by 3.75–25.00 %, and the ultimate bearing capacity decreases by 7.41–44.91 %. It is observed that as the degree of corrosion increases, both cracking load and ultimate bearing capacity of the beam gradually deteriorate, with the flexural capacity of partially grouted beams deteriorating faster. Built on this and with the model of bond reduction coefficient, an analytical method is proposed to predict the flexural capacity of CPTC beams under different grouting conditions. The developed method provides good predictions compared with experimental results of current study and from literature, paving the way for accurate assessment of the flexural bearing capacity of PTC beams with different grouting qualities in corrosive environments.

Background At present, the discovery of new biomarkers is of great significance for the early diagnosis, treatment and prognosis assessment of ovarian cancer. Previous findings indicated that aberrant G-protein-coupled receptor 176 (GPR176) expression might contribute to tumorigenesis and subsequent progression. However, the expression of GPR176 and the molecular mechanisms in ovarian cancer had not been investigated.Methods GPR176 expression was compared with clinicopathological features of ovarian cancer using immunohistochemical and bioinformatics analyses. GPR176-related genes and pathways were analysed using bioinformatics analysis. Additionally, the effects of GPR176 on ovarian cancer cell phenotypes were investigated.Results GPR176 expression positively correlated with elder age, clinicopathological staging, tumour residual status, and unfavourable survival of ovarian cancer, but negatively with purity loss, infiltration of B cells, and CD8+ T cells. Gene Set Enrichment Analysis showed that differential expression of GPR176 was involved in focal adhesion, ECM-receptor interaction, cell adhesion molecules and so on. STRING and Cytoscape were used to determine the top 10 nodes. Kyoto Encyclopaedia of Genes and Genomes analysis indicated that GPR176-related genes were involved in the ECM structural constituent and organisation and so on. GPR176 overexpression promoted the proliferation, anti-apoptosis, anti-pyroptosis, migration and invasion of ovarian cancer cells with overexpression of N-cadherin, Zeb1, Snail, Twist1, and under-expression of gasdermin D, caspase 1, and E-cadherin.Conclusion GPR176 might be involved in the progression of ovarian cancer. It might be used as a biomarker to indicate the aggressive behaviour and poor prognosis of ovarian cancer and a target of genetic therapy.

AbstractStress is a series of physical and psychological responses to external and internal environmental stimuli. Growing studies have demonstrated the detrimental impacts of acute restraint stress (ARS) and chronic restraint stress (CRS) on animal behavior. However, the related pathogenesis and therapeutic mechanisms remain unclear. Hence, the present study aimed to examine whether unfolded protein response (UPR) and Kelch-like ECH-associated protein 1 (Keap1)-nuclear factor erythroid 2 related factor 2 (Nrf2) pathway are associated with ARS- and CRS- induced abnormal behaviors of pain sensitivity and cognitive function. We here used four behavioral tests to evaluate pain sensitivity and cognitive function in ARS and CRS mice. CRS markedly decreased Paw Withdrawal Mechanical Threshold (PWMT) and Tail-flick Latency (TFL) scores, whereas ARS altered TFL but had no effect on PWMT scores. Additionally, CRS, but not ARS, significantly changed behaviors in nest building behavior and MWMT. Intriguingly, the expression of Keap1 and Nrf2 protein were decreased in the spinal cord and hippocampus in CRS mice, but not in ARS mice. Moreover, neither the ARS nor the CRS groups significantly differed from the control group in terms of endoplasmic reticulum stress (ERS). Taken together, this study demonstrated that CRS could induce abnormal pain sensitivity and cognitive function probably via Keap1/Nrf2 pathway in spinal cord and hippocampus. It is therefore likely that effective intervention of Keap1/Nrf2 pathway may contribute to preventing and treating hyperalgesia and cognitive dysfunction in CRS.

ABSTRACT: Marek's disease (MD), an immunosuppression disease induced by Marek's disease virus (MDV), is one of the significant diseases affecting the health and productive performance of poultry. The roles of circular RNAs (circRNAs) in MD development were poorly understood. In this study, we found a circRNA derived from exon 6 of RUNX family transcription factor 2 (RUNX2) gene, named circRUNX2.2, was highly expressed in chicken tumorous spleens (TS) induced by MDV. Through fluorescence in situ hybridization and nuclear-cytoplasmic separation assay, we determined circRUNX2.2 was mainly located in the nucleus. Knockout experiments confirmed that the flanking complementary sequences (RCMs) mediated its circularization. Gain of function assay and dual luciferase reporter gene assay revealed that circRUNX2.2 could promote the expression of RUNX2 via binding with its promoter region. RNA antisense purification assay and mass spectrometry assay showed circRUNX2.2 could recruit proteins such as CHD9 protein. Knocking down CHD9 expression decreased the expression of RUNX2 gene, which confirmed the positive regulation that circRUNX2.2 on RUNX2 expression was probably facilitated via recruiting CHD9 protein. Functional experiments showed that circRUNX2.2 promoted the proliferation of the MD lymphoma-derived chicken cell line, MDCC-MSB1, which confirmed the potential oncogenic role of circRNX2.2 in tumor development. In conclusion, we found that the RUNX2-derived circRUNX2.2 can positively regulate the transcription of the parental gene RUNX2 in a cis-acting manner. The high expression of circRUNX2.2 in MD tumor tissues indicated that it might mediate MD lymphoma progression.

ABSTRACT: Eggshell is predominantly composed of calcium carbonate, making up about 95% of its composition. Eggshell quality is closely related to the amount of calcium deposition in the shell, which requires chickens to maintain a robust state of calcium metabolism. In this study, we introduced a novel parameter, Total Eggshell Weight (TESW), which measures the total weight of eggshells produced by chickens over a period of 10 consecutive d, providing valuable information on the intensity of calcium metabolism in chickens. Genome-wide association study (GWAS) was conducted to explore the genetic determinants of eggshell calcification in a population of 570 Rhode Island Red laying hens at 90 wk of age. This study revealed a significant association between a specific SNP (rs14249431) and TESW. Additionally, using random forest modeling and 2-tailed testing, we identified 3 genera, Lactobacillus in the jejunum, Lactobacillus, and Fournierella in the cecum, that exhibited a significant association with TESW. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) analysis of claudin-1 and occludin genes in individuals with low TESW and high abundance of jejunal Lactobacillus confirmed that the inhibitory effect of jejunal Lactobacillus on calcium uptake was achieved through the up-regulation of tight junctions in intestinal epithelial cells. Notably, both host and microbial factors influence TESW, displaying a mutually influential relationship between them. The microbiome-wide Genome-Wide Association Study (mb-GWAS) identified significant associations between these 3 genera and specific genomic variants, such as rs316115020 and rs316420452 on chromosome 5, rs313198529 on chromosome 11, linked to Lactobacillus in the cecum. Moreover, rs312552529 on chromosome 1 exhibited potential association with Fournierella in the cecum. This study highlights the influence of host genetics and gut microbiota on calcium deposition in eggshells during the late laying phase, providing a foundational reference for studying calcium metabolism in hens.

Abstract Objectives We hope to offer a comprehensive understanding of the advancements and patterns in research on PND. Methods: We performed a thorough search on the Web of Science Core Collection to locate relevant studies published from 1969 to 2022 and utilized four distinct tools, namely VOSviewer (J Data Inf Sci, 2017, 2, 1; J Am Soc Inf Sci, 1973, 24, 265; Amer Doc, 1963, 14, 10 and Scientometrics, 2010, 82, 581), CiteSpace (Scientometrics, 2010, 84, 523), Scimago Graphica, and R‐bibliometrix which allowed us to examine various aspects. Results: We included a total of 6787 articles and reviews for analysis which described PND research, the sources, and the subfields; highlighted the significant developments in this field; identified three main directions in PND.Conclusion: This study highlights the rapid growth of research on PND in recent years and provided an overview of previous studies in the field of PND, thereby establishing the overall landscape of PND research and identifying potential avenues for future investigations. Methods We performed a thorough search on the Web of Science Core Collection to locate relevant studies published from 1969 to 2022. To perform bibliometric analysis and network visualization, we utilized four distinct tools, namely VOSviewer (J Data Inf Sci, 2017, 2, 1; J Am Soc Inf Sci, 1973, 24, 265; Amer Doc, 1963, 14, 10 and Scientometrics, 2010, 82, 581), CiteSpace (Scientometrics, 2010, 84, 523), Scimago Graphica, and R‐bibliometrix. These tools allowed us to examine various aspects, including the yearly publication output, the contribution of different countries or regions, the involvement of active journals, co‐citation analysis, publication status, keywords, and terms, as well as scientific categories. We hope to offer a comprehensive understanding of the advancements and patterns in research on PND. The insights gained from this study can assist researchers and clinicians in enhancing the management and implementation of their work in this field. Results In this study, we included a total of 6787 articles and reviews for analysis. First, publication trends and contribution by country analysis described PND research. Second, a historical analysis described PND research, the sources, and the subfields. Third, an analysis of keywords highlighted the significant developments in this field. Fourth, an analysis of research themes identified three main directions in PND. Conclusion In summary, the research volume exhibits exponential growth over time. Furthermore, the majority of contributions originate from Western countries and China. The interdisciplinary nature of the field is evident, with its roots in biology and medicine and further branching into psychology and social sciences. POCD, delirium‐predominant associated clinical management were major research themes about PND.

Abstract Background Acute thrombotic events play a major role in various cardiovascular diseases. Therefore, direct thrombus imaging can be proved beneficial for early diagnosis and prompt therapy of thrombosis. Our study investigated targeted dual‐modality cyclic arginine‐glycine‐aspartic micro bubbles (cRGD‐MBs) for direct imaging of thrombi by fluorescence and ultrasound. Methods cRGD‐MBs were prepared by mechanical vibration and chemical chelation methods. Results Coulter counter analysis demonstrated that the cRGD‐MBs were well dispersed, with diameters ranging from 1 to 3 μm. They emitted bright red fluorescence under an excitation wavelength of 660 nm. In vivo fluorescence and ultrasound imaging revealed that cRGD‐MBs accumulated at the site of thrombus in the carotid artery with significant fluorescence and ultrasonic signal. Conclusions This study showed that novel microbubble cRGD‐MBs were successfully synthesized, and that these could potentially be used as contrast agents for immediate diagnosis of acute thrombus in vivo.

Abstract Background The breeding of layers emphasizes the continual selection of egg-related traits, such as egg production, egg quality and eggshell, which enhance their productivity and meet the demand of market. As the breeding process continued, the genomic homozygosity of layers gradually increased, resulting in the emergence of runs of homozygosity (ROH). Therefore, ROH analysis can be used in conjunction with other methods to detect selection signatures and identify candidate genes associated with various important traits in layer breeding. Results In this study, we generated whole-genome sequencing data from 686 hens in a Rhode Island Red population that had undergone fifteen consecutive generations of intensive artificial selection. We performed a genome-wide ROH analysis and utilized multiple methods to detect signatures of selection. A total of 141,720 ROH segments were discovered in whole population, and most of them (97.35%) were less than 3 Mb in length. Twenty-three ROH islands were identified, and they overlapped with some regions bearing selection signatures, which were detected by the De-correlated composite of multiple signals methods (DCMS). Sixty genes were discovered and functional annotation analysis revealed the possible roles of them in growth, development, immunity and signaling in layers. Additionally, two-tailed analyses including DCMS and ROH for 44 phenotypes of layers were conducted to find out the genomic differences between subgroups of top and bottom 10% phenotype of individuals. Combining the results of GWAS, we observed that regions significantly associated with traits also exhibited selection signatures between the high and low subgroups. We identified a region significantly associated with egg weight near the 25 Mb region of GGA 1, which exhibited selection signatures and has higher genomic homozygosity in the low egg weight subpopulation. This suggests that the region may be play a role in the decline in egg weight. Conclusions In summary, through the combined analysis of ROH, selection signatures, and GWAS, we identified several genomic regions that associated with the production traits of layers, providing reference for the study of layer genome.

Abstract Synthetic hexaploid wheats (SHWs) are effective genetic resources for transferring agronomically important genes from wild relatives to common wheat (Triticum aestivum L.). Dozens of reference-quality pseudomolecule assemblies of hexaploid wheat have been generated, but none is reported for SHW-derived cultivars. Here, we generated a chromosome-scale assembly for the SHW-derived cultivar ‘Chuanmai 104’ based on PacBio HiFi reads and chromosome conformation capture sequencing. The total assembly size was 14.81 Gb with a contig N50 length of 58.25 Mb. A BUSCO analysis yielded a completeness score of 99.30%. In total, repetitive elements comprised 81.36% of the genome and 122,554 high-confidence protein-coding gene models were predicted. In summary, the first chromosome-level assembly for a SHW-derived cultivar presents a promising outlook for the study and utilization of SHWs in wheat improvement, which is essential to meet the global food demand.

Objective To study the changes in related parameters after secondary preparation of blood components, in order to further improve the quality of blood components. Methods Different centrifugation conditions were selected for the preparation of primary blood component red blood cells in additive solution leukocytes reduced, and the quality was tested. Then, using the red blood cells in additive solution leukocytes reduced as the initial blood for secondary preparation, and the red blood cells were washed through the Haemonetics ACP 215 device, and the quality was tested. The preparation parameters of blood components were observed, compared and optimized. Results Under comparable centrifugation effects of different centrifugation conditions, the quality control items, which of primary blood components of red blood cells in additive solution leukocytes reduced and frozen plasma prepared by the separation, such as volume, hemoglobin, hematocrit and residual white blood cells met the relevant national standards. And the quality control items of secondary blood components of washed red blood cells such as the hemoglobin and superalbumin content both met the relevant national standards, while volume exceeded the standard by 7-14 mL, which can be operated to the standard range. In addition, the recovery rate of red blood cells and the clearance rate of plasma protein could reach 75% and 99% respectively. Conclusion There is a certain correlation between primary and secondary preparation of blood components, but the relevant parameters of secondary preparation of blood components can be flexibly adjusted according to the actual situation to ensure that the quality of prepared blood component products meet the national standards, thus ensuring clinical treatment effect and safety.

Abstract Advances in modern medicine have extended human life expectancy, leading to a world with a gradually aging society. Aging refers to a natural decline in the physiological functions of a species over time, such as reduced pain sensitivity and reaction speed. Healthy-level physiological pain serves as a warning signal to the body, helping to avoid noxious stimuli. Physiological pain sensitivity gradually decreases in the elderly, increasing the risk of injury. Therefore, geriatric health care receives growing attention, potentially improving the health status and life quality of the elderly, further reducing medical burden. Health food is a geriatric healthcare choice for the elderly with Ganoderma tsuage (GT), a Reishi type, as the main product in the market. GT contains polysaccharides, triterpenoids, adenosine, immunoregulatory proteins, and other components, including anticancer, blood sugar regulating, antioxidation, antibacterial, antivirus, and liver and stomach damage protective agents. However, its pain perception-related effects remain elusive. This study thus aimed at addressing whether GT could prevent pain sensitivity reduction in the elderly. We used a galactose-induced animal model for aging to evaluate whether GT could maintain pain sensitivity in aging mice undergoing formalin pain test, hot water test, and tail flexes. Our results demonstrated that GT significantly improved the sensitivity and reaction speed to pain in the hot water, hot plate, and formalin tests compared with the control. Therefore, our animal study positions GT as a promising compound for pain sensitivity maintenance during aging.

Abstract Drug screening based on in-vitro primary tumor cell culture has demonstrated potential in personalized cancer diagnosis. However, the limited number of tumor cells, especially from patients with early stage cancer, has hindered the widespread application of this technique. Hence, we developed a digital microfluidic system for drug screening using primary tumor cells and established a working protocol for precision medicine. Smart control logic was developed to increase the throughput of the system and decrease its footprint to parallelly screen three drugs on a 4 × 4 cm2 chip in a device measuring 23 × 16 × 3.5 cm3. We validated this method in an MDA-MB-231 breast cancer xenograft mouse model and liver cancer specimens from patients, demonstrating tumor suppression in mice/patients treated with drugs that were screened to be effective on individual primary tumor cells. Mice treated with drugs screened on-chip as ineffective exhibited similar results to those in the control groups. The effective drug identified through on-chip screening demonstrated consistency with the absence of mutations in their related genes determined via exome sequencing of individual tumors, further validating this protocol. Therefore, this technique and system may promote advances in precision medicine for cancer treatment and, eventually, for any disease.