Abstract Background Cutaneous squamous cell carcinoma (CSCC) is one of the most common types of skin cancer worldwide. Therefore, the identification of biomarkers associated with CSCC progression could aid in the early detection of high-risk squamous cell carcinoma and the development of novel therapeutic strategies. Objective This study aimed to investigate the expression patterns of silent mating type Information Regulation 2 homolog 6 (SIRT6) in CSCC and its clinical significance. Methods The protein expression level of SIRT6 in tissues was detected by immunohistochemistry, and the correlation between SIRT6 expression and clinicopathological parameters in CSCC patients was analyzed. The relative expression of SIRT6 in CSCC cell lineage and tissue specimens was determined by western blotting and PCR. The effect of SIRT6 silencing on cell proliferation was evaluated using cell counting kit 8. Wound healing, transwell method, and flow cytometry were used to investigate the migration, invasion, and cell cycle distribution/apoptosis of CSCC cells after SIRT6 silencing, respectively. Western blot was used to detect the expression of EMT (Epithelial-Mesenchymal Transition), cycle, apoptosis, and other related proteins. Results The high expression of SIRT6 was correlated with the location of cancer tissue and Broder staging in CSCC patients. Knockdown of SIRT6 inhibited the proliferation, migration, invasion and EMT of CSCC cells, and promoted their apoptosis, with cells blocked in G1 phase. Study limitations No animal experiments were conducted to further verify the results. Conclusion Decreased expression of SIRT6 can inhibit the occurrence and development of CSCC. (CSCC worldwide Therefore highrisk risk strategies SIRT (SIRT6 significance immunohistochemistry analyzed PCR 8 healing method migration distributionapoptosis distribution apoptosis respectively EpithelialMesenchymal Epithelial Mesenchymal Transition, Transition , Transition) proteins G phase results (SIRT

Abstract Background In a recent genome-wide association study, novel genetic variations of WNT9A were reported to be involved in the etiopathogenesis of thumb osteoarthritis (TOA) in Caucasians. Our purposes were to replicate the association of WNT9A with the development of TOA in the Chinese population and to further unveil the functional role of the risk variants. Methods SNP rs11588850 of WNT9A were genotyped in 953 TOA patients and 1124 healthy controls. The differences of genotype and allele distributions between the patients and healthy controls were evaluated using the Chi-square test. Luciferase Reporter Assay was performed to investigate the influence of variant on the gene expression. Results There was significantly lower frequency of genotype AA in TOA patients than in the controls 74.9% vs. 81.9%, p < 0.001). The frequency of allele A was remarkably lower in the patients than in the controls (86.3% vs. 90.5%, p < 0.001), with an odds ratio of 0.66 (95% CI = 0.54–0.80). Luciferase Reporter Assay showed that the construct containing mutant allele G of rs11588850 displayed 29.1% higher enhancer activity than the wild allele A construct (p < 0.05). Conclusions Allele G of rs11588850 was associated with the increased risk of TOA possibly via up-regulation of WNT9A expression. Further functional analysis into the regulatory role of rs11588850 in WNT9A expression can shed new light on the genetic architecture of TOA. Key Points Genetic variants of WNT9A were associated with the incidence and severity of TOA. Allele G of rs11588850 was associated with an increased transcriptional activity of WNT9A promoter. Allele G of rs11588850 may add to the risk of TOA possibly via up-regulation of WNT9A expression. Further functional analysis into the regulatory role of rs11588850 in WNT9A expression can shed new light on the genetic architecture of TOA. genomewide genome wide study WNTA WNT (TOA Caucasians rs rs1158885 95 112 Chisquare Chi square test 749 74 9 74.9 vs 819 81 81.9% 0.001. 0001 0.001 . 0 001 0.001) 86.3% 863 86 3 (86.3 905 90 5 90.5% 0.001, , 066 66 0.6 95% (95 0.54–0.80. 054080 0.54–0.80 54 80 0.54–0.80) 291 29 1 29.1 0.05. 005 0.05 05 0.05) upregulation up regulation promoter rs115888 11 7 74. 8 81.9 000 0.00 00 86.3 (86. 90.5 06 6 0. (9 05408 0.54–0.8 2 29. 0.0 rs11588 81. 86. (86 90. ( 0540 0.54–0. rs1158 (8 054 0.54–0 rs115 0.54– rs11 0.54 rs1 0.5

Abstract Background Talaromyces Marneffei (TM) is a rare opportunistic pathogen that mostly infects patients with low immunity compared to those with normal immunity. It may be related to immune deficiency or genetic factors. Objective To evaluate the gene mutation of a patient infected with TM in an endemic area with negative anti-interferon-γ autoantibodies, and negative human immunodeficiency virus (HIV) infection. Methods Extract deoxyribonucleic acid (DNA) samples from the patient's peripheral blood, detect the mutation gene by whole exome sequencing (WES), and carry out Sanger sequencing verification for the detected mutation gene. Results The authors detected a mutation in the IFNGR1 gene (NM_001363526.1) and validated the detected gene mutation using Sanger sequencing. The results showed a heterozygous mutation c.4C&gt;T (p.L2F) located in the IFNGR1 gene (NM_001363526.1). Study limitations The mechanism of the IFNGR1 gene has not been further investigated in this study. Conclusions The IFNGR1 gene mutation may be a potential risk factor for TM infection, and the presence of anti-interferon-γ autoantibodies can aggravate disease symptoms. (TM factors antiinterferonγ anti interferon γ HIV (HIV infection DNA (DNA s blood WES, WES , (WES) IFNGR NM_001363526.1 NM0013635261 NM 001363526 1 (NM_001363526.1 c.4C&gtT c4CgtT cCgtT c.4C&gt T c 4C gt C p.L2F pL2F pLF p L2F L F (p.L2F NM_001363526.1. . study symptoms (WES NM_001363526. NM001363526 00136352 (NM_001363526. gtT CgtT c4Cgt cCgt pL LF NM_001363526 NM00136352 0013635 (NM_001363526 Cgt NM_00136352 NM0013635 001363 (NM_00136352 NM_0013635 NM001363 00136 (NM_0013635 NM_001363 NM00136 0013 (NM_001363 NM_00136 NM0013 001 (NM_00136 NM_0013 NM001 00 (NM_0013 NM_001 NM00 0 (NM_001 NM_00 NM0 (NM_00 NM_0 (NM_0 NM_ (NM_ (NM

Abstract The flexibility matrix finds extensive application in detecting damage in civil and mechanical engineering structures, a focus explored in-depth within this paper. This study meticulously examines distinct components of the flexibility matrix, namely the proposed Diagonal of the Flexibility Matrix Vector (DFV) and a singular row/column of the flexibility matrix (RFV). Both DFV and RFV can be represented uniquely as a specialized form-a weighted combination of the Hadamard product of two mode shapes. Sensitivity analysis reveals that DFV undergoes a sharp change in proximity to damage, establishing it as a dependable indicator for pinpointing damage locations. Conversely, this characteristic is not consistently observed with RFV. The results of numerical simulations conducted on a 16-story frame structure corroborate the outcomes of the sensitivity analysis, underscoring the efficacy of DFV not only in localizing damage but also in gauging its severity. To illustrate the potential and limitations of DFV/RFV in practical scenarios, damage localization for the I-40 Bridge is provided. structures indepth depth paper (DFV rowcolumn row column . (RFV) forma form shapes locations Conversely 16story story 16 severity DFVRFV scenarios I40 I 40 I-4 provided (RFV 1 I4 4 I-

ABSTRACT Through a long-term micro-area positioning experiment (2006-2017), the precise fertilization locations of spring maize (Zea mays L.) in Jilin, China, were investigated using an embedded cement bucket pot. The effects of different fertilization placements and additional application of organic manure on maize yield, biomass, grain nutrient uptake, and soil fertility were examined. Six treatments were designed: base fertilizer + topdressing shallow application (BF1TD1); base fertilizer deep + topdressing shallow application (BF2TD1); base fertilizer + topdressing deep application (BF1TD2); base fertilizer deep + topdressing deep application (BF2TD2); base fertilizer + topdressing + organic manure shallow application (BF1TD1 + OS); and base fertilizer + topdressing shallow application + organic manure deep application (BF1TD1 + OD). After 12 years of continuous experimentation, the findings revealed that BF2TD2, BF1TD1 + OS, and BF1TD1 + OD exhibited 10.59 %, 25.17 %, and 29.34 % higher average yields than BF1TD1, respectively. Deep topdressing was more beneficial in increasing maize yield and nutrient accumulation, and additionally, increasing the use of organic fertilizer enhanced plant biomass and nutrient uptake. Over the 12 years considered, the soil organic matter in the 0-20 cm and 20-40 cm layers increased by 45.96 % and 80.61 %, respectively, and the soil pH increased from 0.38 to 0.48. In general, the deep application of organic manure was more beneficial for soil retention as it can increase soil fertility in the 0-40 cm layer. Considering the high yield and nutrient absorption and utilization of maize, technical advancement for soil fertilizer in whole-field tillage layers was crucial. longterm long term microarea micro area 20062017, 20062017 2006 2017 , (2006-2017) Zea L. L Jilin China pot uptake examined designed BFTD BF TD (BF1TD1) BF2TD1 (BF2TD1) BF1TD2 (BF1TD2) BF2TD2 (BF2TD2) (BF1TD OS OS) OD. . OD) 1 experimentation BF1TD 1059 10 59 10.5 2517 25 17 25.1 2934 29 34 29.3 respectively accumulation additionally considered 020 0 20 0-2 2040 40 20-4 4596 45 96 45.9 8061 80 61 80.6 038 38 0.3 048 48 0.48 general 040 0-4 layer wholefield whole field crucial 2006201 200 201 (2006-2017 BF2TD (BF2TD1 (BF1TD2 (BF2TD2 105 5 10. 251 2 25. 293 3 29. 02 0- 204 4 20- 459 9 45. 806 8 6 80. 03 0. 04 0.4 200620 (2006-201 (BF2TD 20062 (2006-20 (2006-2 (2006- (2006 (200 (20 (2 (

Tuberculosis (TB), caused by Mycobacterium tuberculosis, remains the leading cause of mortality by a single infectious agent in the world. M. tuberculosis infection could also result in clinical chronic infection, known as latent TB infection (LTBI). Compared to the current limited treatment, several subunit vaccines showed immunotherapeutic effects and were included in clinical trials. In this study, a subunit vaccine of Ag85B with a novel mucosal adjuvant c-di-AMP (Ag85B:c-di-AMP) was delivered intranasally to a persistent M. tuberculosis H37Ra infection mouse model, which also presented the asymptomatic characteristics of LTBI. Compared with Ag85B immunization, Ag85B:c-di-AMP vaccination induced stronger humoral immune responses, significantly higher CD4+ T cells recruitment, enhanced Th1/Th2/Th17 profile response in the lung, decreased pathological lesions of the lung, and reduced M. tuberculosis load in mice. Taken together, Ag85B:c-di-AMP mucosal route immunization provided an immunotherapeutic effect on persistent M. tuberculosis H37Ra infection, and c-di-AMP, as a promising potential mucosal adjuvant, could be further used in therapeutic or prophylactic vaccine strategies for persistent M. tuberculosis infection as well as LTBI. TB, , (TB) world M LTBI . (LTBI) treatment trials study AgB Ag B cdiAMP c di AMP Ag85BcdiAMP AgBcdiAMP (Ag85B:c-di-AMP HRa H Ra model responses CD4 CD recruitment Th1Th2Th17 ThThTh Th1 Th2 Th17 Th Th1/Th2/Th1 lung mice together cdiAMP, AMP, (TB (LTBI BcdiAMP Th1Th2Th1 Th1/Th2/Th Th1Th2Th

RESUMO Objetivo: As fraturas do planalto tibial são fraturas intra-articulares comuns de classificação e tratamento desafiadores aos cirurgiões ortopédicos. Objetivo: Este estudo investiga o uso de impressão 3D para classificar e planejar a cirurgia de fraturas complexas do planalto tibial. Métodos: 54 fraturas complexas do planalto tibial tratadas em nosso hospital de janeiro de 2017 a janeiro de 2019 foram revisadas. Os pacientes foram submetidos a tomografias computadorizadas em espiral pré-operatórias, com dados DICOM processados usando o software Mimics. A tecnologia de impressão 3D gerou modelos precisos em escala 1:1 das fraturas. Estes modelos ajudaram a subdividir as fraturas em sete tipos com base nos planos geométricos do planalto tibial. As abordagens cirúrgicas e as operações simuladas, incluindo a redução da fratura e a colocação de placa, foram planejadas utilizando estes modelos. Resultados: Os modelos 3D representaram com precisão a direção e a extensão da deslocação da fratura e do colapso do planalto. Os modelos facilitaram o planejamento pré-operatório, viabilizando estratégias de reconstrução precisas e a correspondência dos detalhes intraoperatórios com os modelos pré-impressos. Após a cirurgia, a estrutura anatômica do planalto tibial melhorou significativamente em todos os 54 casos. Conclusão: A impressão 3D ajuda na classificação e no planejamento pré-operatório de fraturas complexas do planalto tibial, melhorando os resultados cirúrgicos e a restauração anatômica. Nível de Evidência IV, Estudo Prospectivo. Objetivo intraarticulares intra articulares ortopédicos D Métodos 5 201 revisadas préoperatórias, préoperatórias pré operatórias, operatórias pré-operatórias Mimics 11 1 1: simuladas placa Resultados préoperatório, préoperatório operatório, operatório préimpressos. préimpressos impressos. impressos pré-impressos casos Conclusão IV Prospectivo 20 2

ABSTRACT Objective: Tibial plateau fractures are common intra-articular fractures that pose classification and treatment challenges for orthopedic surgeons. Objective: This study examines the value of 3D printing for classifying and planning surgery for complex tibial plateau fractures. Methods: We reviewed 54 complex tibial plateau fractures treated at our hospital from January 2017 to January 2019. Patients underwent preoperative spiral CT scans, with DICOM data processed using Mimics software. 3D printing technology created accurate 1:1 scale models of the fractures. These models helped subdivide the fractures into seven types based on the tibial plateau's geometric planes. Surgical approaches and simulated operations, including fracture reduction and plate placement, were planned using these models. Results: The 3D models accurately depicted the direction and extent of fracture displacement and plateau collapse. They facilitated the preoperative planning, allowing for precise reconstruction strategies and matching intraoperative details with the pre-printed models. Post-surgery, the anatomical structure of the tibial plateau was significantly improved in all 54 cases. Conclusion: 3D printing effectively aids in the classification and preoperative planning of complex tibial plateau fractures, enhancing surgical outcomes and anatomical restoration. Level of Evidence IV, Prospective Study. Objective intraarticular intra articular surgeons D Methods 5 201 2019 scans software 11 1 1: plateaus s planes operations placement Results collapse preprinted pre printed Postsurgery, Postsurgery Post surgery, Post-surgery cases Conclusion restoration IV Study 20 2

ABSTRACT The mechanical properties of magnesium alloy in different molding stages are very important factors to determine its application approaches in engineering. In order to ensure the prediction accuracy of mechanical properties, a TCMSSA-ELM model, which is a hybrid of the sparrow search algorithm (SSA) optimized by the tent chaotic mapping (TCM) algorithm and the extreme learning machine (ELM), is proposed in this study, and the stresses of AZ80 magnesium alloy are predicted by the model through a 812-record dataset. The predicting results indicate that TCMSSA improves the accuracy of ELM model. Compared with ELM model, the data points formed by experimental values of stress and the predicted ones by TCMSSA-ELM model are closer to the ideal 45° line, the average determination coefficient rises by 1.43%, and the average root mean squared error (RMSE) decreases by nearly 61.96%, implying that TCMSSA-ELM model accurately reflects the influence rule of thermodynamic parameters on stress. The novelty of this study is that TCM is used to optimize the population initialization of SSA, which enables SSA to have a higher global search ability, and thus optimizes the weight and threshold selection of ELM, then making TCMSSA-ELM have higher prediction accuracy than other improved ELM models. engineering TCMSSAELM (SSA (TCM , (ELM) AZ AZ8 812record record 812 dataset 45 line 143 1 43 1.43% RMSE (RMSE 6196 61 96 61.96% ability models (ELM 81 4 14 1.43 619 6 9 61.96 8 1.4 61.9 1. 61.

Abstract Melon (Cucumis melo L.) is an economically important horticultural crop. Spotted rind at maturity is an important appearance quality trait in melons. However, the gene controlling this trait remains unknown. In this study, the inheritance pattern of this trait was explored, and the candidate gene underlying this trait was also successfully identified. Genetic analysis showed that a single dominant gene, Cucumis melo Spotted Rind (CmSR), regulates the spotted rind trait. A preliminary genetic mapping analysis was conducted based on a BSA-seq approach. The CmAPRR2 gene was identified to be linked with the spotted rind trait and was located on the short arm of chromosome 4. It harbored two single-nucleotide mutations (chr4: 687014 G/A and chr4: 687244 C/A) in the non-spotted line ‘Yellow 2’, which may result in the alternative splicing of the transcript and an amino acid change in the respective protein, from proline to glutamine, respectively. Moreover, marker SNP687014-G/A was developed and co-segregated with the spotted rind trait. Therefore, it is speculated that the CmAPRR2 gene may be involved in the regulation of the spotted rind trait in melon. This study provides a theoretical foundation for further research on the gene regulatory mechanism of the rind color in melon. L. L crop melons However unknown explored CmSR, CmSR , (CmSR) BSAseq BSA seq approach CmAPRR 4 singlenucleotide nucleotide chr4 chr (chr4 68701 GA G 68724 C/A CA C nonspotted non Yellow 2, 2 2’ protein glutamine respectively Moreover SNP687014G/A SNP687014GA SNPGA SNP687014 SNP cosegregated co segregated Therefore melon (CmSR (chr 6870 6872 SNP687014G SNP68701 687 SNPG SNP6870 68 SNP687 6 SNP68 SNP6

ABSTRACT Objective: This study aimed to identify differentially expressed microRNAs (miRNAs) in exosomes derived from the blood plasma of Rheumatoid Arthritis (RA) patients and explore their clinical significance and biological roles. Methods: Illumina high-throughput sequencing was employed to measure miRNA expression levels in plasma exosomes, followed by validation using qRT-PCR. The correlation between exosomal miRNAs and disease activity was systematically analyzed. Additionally, the pathogenic effects of RA exosomes were investigated through bioinformatics analysis and in vitro experiments. Results: Significantly reduced levels of exosomal miR-144-3p and miR-30b-5p were observed in RA patients, which were negatively correlated with DAS28 scores and anti-CCP antibody levels. ROC curve analysis showed that miR-144-3p and miR-30b-5p in plasma exosomes could effectively distinguish RA patients from healthy controls, with AUC values of 0.725 and 0.773, respectively. Combining bioinformatics analysis and in vitro experiments, it was demonstrated that plasma exosomes contribute to ongoing autoantibody production in RA by promoting B-cell differentiation and antibody production. Conclusion: The present study indicates that plasma exosomes from RA patients may be potentially pathogenic. Exosomal miR-144-3p and miR-30b-5p exhibit significant decreases in RA patients and are associated with disease activity, suggesting their potential as valuable biomarkers for RA. Objective (miRNAs (RA roles Methods highthroughput high throughput qRTPCR. qRTPCR qRT PCR. PCR qRT-PCR analyzed Additionally experiments Results miR1443p miRp miR 144 3p p miR30b5p miRbp 30b 5p b DAS DAS2 antiCCP anti CCP controls 0725 0 725 0.72 0773 773 0.773 respectively Bcell B cell Conclusion 14 072 72 0.7 077 77 0.77 1 07 7 0.

SUMMARY: We investigated Tweety Family Member 3 (TTYH3) level in lung adenocarcinoma (LUAD) and its relationship with immune infiltration in tumors by bioinformatics. Differential expressions of TTYH3 in lung cancer were analyzed with Oncomine, TIMER, GEO, UALCAN and HPA. Relationship of TTYH3 mRNA/protein levels with clinical parameters was analyzed by UALCAN. Co-expressed genes of TTYH3 in LUAD were analyzed using Cbioportal. Its relationship with LUAD prognosis was analyzed by Kaplan-Meier plotter. GO and KEGG analysis were performed. Correlation between TTYH3 and tumor immune infiltration were tested by TIMER, TISIDB and GEPIA. We found that TTYH3 was significantly increased in LUAD tissues. TTYH3 high expression was closely related to poor overall survival, post progression survival and first progression in LUAD patients. TTYH3 mRNA/protein levels were significantly associated with multiple pathways. Specifically, TTYH3 up-regulation was mostly related to biological regulation, metabolic process, protein blinding, extracellular matrix organization and pathways in cancer. Moreover, TTYH3 was positively associated with immune cell infiltration in LUAD. Finally, TTYH3 was highly expressed in LUAD as revealed by meta-analysis. TTYH3 is closely related to the prognosis of LUAD and immune cell infiltration, and it can be used as a prognostic biomarker for LUAD and immune infiltration.

RESUMEN: Investigamos por bioinformática el nivel de Tweety Family Member 3 (TTYH3) con adenocarcinoma de pulmón (LUAD) y su relación con la infiltración inmune en tumores. Las expresiones diferenciales de TTYH3 en cáncer de pulmón se analizaron con Oncomine, TIMER, GEO, UALCAN y HPA. Con UALCAN se analizó la relación de los niveles de ARNm/proteína de TTYH3 con los parámetros clínicos. Los genes coexpresados de TTYH3 en LUAD se analizaron utilizando Cbioportal. Su relación con el pronóstico LUAD se analizó mediante plotter de Kaplan- Meier. Se realizaron análisis GO y KEGG. TIMER, TISIDB y GEPIA probaron la correlación entre TTYH3 y la infiltración inmune tumoral. Encontramos que TTYH3 aumentó significativamente en los tejidos LUAD. La alta expresión de TTYH3 estuvo estrechamente relacionada con una supervivencia general deficiente, supervivencia posterior a la progresión y primera progresión en pacientes con LUAD. Los niveles de ARNm/ proteína de TTYH3 se asociaron significativamente con múltiples vías. Específicamente, la regulación positiva de TTYH3 se relacionó principalmente con la regulación biológica, el proceso metabólico, el cegamiento de proteínas, la organización de la matriz extracelular y las vías en el cáncer. Además, TTYH3 se asoció positivamente con la infiltración de células inmunitarias en LUAD. Finalmente, TTYH3 se expresó altamente en LUAD como lo reveló el metanálisis. TTYH3 está estrechamente relacionado con el pronóstico de LUAD y la infiltración de células inmunitarias, y se puede utilizar como biomarcador pronóstico para LUAD y la infiltración de células inmunitarias.

ABSTRACT Introduction: A giant left atrium may cause respiratory dysfunction and hemodynamic disturbance postoperatively. This retrospective study aimed to evaluate clinical effects of surgical left atrial reduction in concomitant cardiac valves operations. Methods: One hundred and thirty-five patients with heart valve diseases and giant left atriums from January 2004 to July 2021 were enrolled into this research. They were divided into the folded group (n=63) and the unfolded group (n=72). Patients in the folded group had undergone cardiac valve operations concomitantly with left atrial reductions. The perioperative characteristics were compared between both groups, and subgroup analysis was performed. Results: There were five deaths in the folded group and 25 deaths in the unfolded group (P<0.001). Complications including pneumonia, sepsis, multiple organs dysfunction syndrome, low cardiac output syndrome, and the use of continuous renal replacement therapy were significantly fewer in the folded group. The receiver operating characteristic curve of left atrial max. diameter predicting mortality was significant (area under the curve=0.878, P=0.005), and the cutoff point was 96.5 mm. The stratified analysis for sex showed that more female patients died in the unfolded group. Logistic regression for mortality showed that the left atrium unfolded, left atrial max. diameter, cardiopulmonary bypass time, and mechanical ventilation time increased the risk of death. Conclusion: Surgical left atrial reduction concomitantly with valves replacement could decrease mortality and was safe and effective in giant left atrium patients. Introduction postoperatively Methods thirtyfive thirty 200 202 research n=63 n63 n 63 (n=63 n=72. n72 n=72 . 72 (n=72) reductions groups performed Results 2 P<0.001. P0001 P P<0.001 0 001 (P<0.001) pneumonia sepsis syndrome max area curve0878 878 curve=0.878 P=0.005, P0005 P=0.005 , 005 P=0.005) 965 96 5 96. mm death Conclusion 20 n=6 n6 6 (n=6 n7 n=7 7 (n=72 P000 P<0.00 00 (P<0.001 curve087 87 curve=0.87 P=0.00 9 n= (n= (n=7 P00 P<0.0 (P<0.00 curve08 8 curve=0.8 P=0.0 (n P0 P<0. (P<0.0 curve0 curve=0. P=0. P<0 (P<0. curve=0 P=0 P< (P<0 curve= P= (P< (P

Abstract Objective Osteoarthritis is a condition characterized by articular cartilage degradation. The increased expression of β1,4-Galactosyltransferase-I (β1,4-GalT-I) in the articular cartilage of osteoarthritis patients was related to an inflammatory response. The aim of this study was to elucidate the role of β1,4-GalT-I in osteoarthritis. This study aimed to determine the function of 1,4-GalT-I in osteoarthritis. Methods The osteoarthritis mouse model with the destabilization of the medial meniscus was established by microsurgical technique. Pathological changes in articular cartilage were observed by hematoxylin and eosin staining and safranin O-fast green staining. Quantitative real-time polymerase chain reaction, western blot, and enzyme-linked immunosorbent assays were used to observe mRNA and protein expression, respectively. RNA interactions were verified by a luciferase reporter assay. SA-β-Gal staining was used to assess chondrocyte senescence. Immunofluorescence staining was conducted to observe the localization of Nuclear Factor-kappaB (NF-κB). Results β1,4-GalT-I and microRNA-15a (miR-15a) show high and low expression in the articular cartilage of osteoarthritis, respectively. MiR-15a inhibits the mRNA translation of β1,4-GalT-I. β1,4-GalT-I promotes extracellular matrix degradation, senescence, and NF-κB activation in IL-1β-stimulated chondrocytes, which can be reversed by overexpression of miR-15a. Intra-articular injection of microRNA-15a ameliorates cartilage degeneration by inhibiting β1,4-GalT-I and phosphorylation of NF-κB in vivo. Conclusion The authors clarified that the miR-15a/β1,4-GalT-I axis inhibits the phosphorylation of NF-κB thereby inhibiting extracellular matrix degradation and senescence in chondrocytes to alleviate cartilage degeneration in osteoarthritis. MiR-15a and β1,4-GalT-I may serve as potentially effective targets for the future treatment of osteoarthritis. β1,4GalactosyltransferaseI β14GalactosyltransferaseI βGalactosyltransferaseI β1,4 Galactosyltransferase I β1 4 β β1,4GalTI β14GalTI βGalTI GalT (β1,4-GalT-I response 1,4GalTI 14GalTI GalTI 1,4 1 technique Ofast O fast realtime real time reaction blot enzymelinked enzyme linked respectively assay SAβGal SA Gal FactorkappaB Factor kappaB NFκB. NFκB NF κB . (NF-κB) microRNA15a microRNAa microRNA 15a miR15a miRa miR (miR-15a MiR15a MiRa MiR β1,4GalTI. I. IL1βstimulated ILβstimulated IL 1β stimulated miR15a. 15a. miR-15a Intraarticular Intra vivo miR15a/β1,4GalTI miR15aβ14GalTI miRaβGalTI 15a/β1,4 4GalactosyltransferaseI GalactosyltransferaseI β14 β1, 4GalTI 14 1, (NF-κB βstimulated aβ 15aβ14 15a/β1, 15aβ1 15a/β1 15aβ 15a/β

Abstract Objectives The pathological mechanisms of patients with Renal Cell Carcinoma (RCC) remain defined. This study aimed to evaluate relationships between the landscape of gene mutations and their clinical significance in RCC patients. Methods Tissue and peripheral blood samples of 42 patients with RCC were collected and performed for the Next Generation Sequencing (NGS) with Geneseeq PrimeTM 425-gene panel probes. Their landscapes of gene mutation were analyzed. We also carried out an evaluation of Tumor-Node-Metastasis (TNM) staging, RENAL nephelometry score, surgery, and targeted drug treatment of patients. Then we compared the correlations of landscape in gene mutations and the prognosis. Results The most common gene alternations, including BAP1, PBRM1, SETD2, CSF1R, NPM1, EGFR, POLE, RB1, and VHL genes, were identified in tissue and blood samples of 75% of patients. EGFR, POLE, and RB1 gene mutations frequently occurred in relapsed and metastatic patients. BAP1, CCND2, KRAS, PTPN11, ERBB2/3, JAK2, and POLE were presented in the patients with > 9 RENAL nephelometry score. Univariable analysis indicated that SETD2, BAP1, and PBRM1 genes were key factors for Disease-Free Survival (DFS). Multivariable analysis confirmed that mutated SETD1, NPM1, and CSF1R were critical factors for the Progression Free Survival (PFS) of RCC patients with target therapy. Conclusions Wild-type PBRM1 and mutated BAP1 in patients with RCC were strongly associated with the outcomes of the patient. The PFS of the patients with SETD2, NPM1, and CSF1R mutations were significantly shorter than those patients without variants. (RCC defined 4 NGS (NGS 425gene 425 probes analyzed TumorNodeMetastasis Tumor Node Metastasis TNM (TNM staging score surgery prognosis alternations BAP PBRM SETD2 SETD CSFR CSF R NPM1 NPM EGFR RB 75 CCND2 CCND KRAS PTPN11 PTPN ERBB23 ERBB ERBB2 3 ERBB2/3 JAK2 JAK DiseaseFree Disease DFS. DFS . (DFS) SETD1 (PFS therapy Wildtype Wild type patient variants 7 PTPN1 ERBB2/ (DFS