Genomic structural variation contributes to evolved changes in gene expression in high-altitude Tibetan sheep.

Tibetan sheep were introduced to the Qinghai Tibet plateau roughly 3,000 B.P., making this species a good model for investigating genetic mechanisms of high-altitude adaptation over a relatively short timescale. Here, we characterize genomic structural variants (SVs) that distinguish Tibetan sheep from closely related, low-altitude Hu sheep, and we examine associated changes in tissue-specific gene expression. We document differentiation between the two sheep breeds in frequencies of SVs associated with genes involved in cardiac function and circulation. In Tibetan sheep, we identified high-frequency SVs in a total of 462 genes, including EPAS1, PAPSS2, and PTPRD. Single-cell RNA-Seq data and luciferase reporter assays revealed that the SVs had cis-acting effects on the expression levels of these three genes in specific tissues and cell types. In Tibetan sheep, we identified a high-frequency chromosomal inversion that exhibited modified chromatin architectures relative to the noninverted allele that predominates in Hu sheep. The inversion harbors several genes with altered expression patterns related to heart protection, brown adipocyte proliferation, angiogenesis, and DNA repair. These findings indicate that SVs represent an important source of genetic variation in gene expression and may have contributed to high-altitude adaptation in Tibetan sheep.

Sympatric speciation of the spiny mouse from Evolution Canyon in Israel substantiated genomically and methylomically.

SignificanceWhether sympatric speciation (SS) is rare or common is still debated. Two populations of the spiny mouse, Acomys cahirinus, from Evolution Canyon I (EC I) in Israel have been depicted earlier as speciating sympatrically by molecular markers and transcriptome. Here, we investigated SS both genomically and methylomically, demonstrating that the opposite populations of spiny mice are sister taxa and split from the common ancestor around 20,000 years ago without an allopatric history. Mate choice, olfactory receptors, and speciation genes contributed to prezygotic/postzygotic reproductive isolation. The two populations showed different methylation patterns, facilitating adaptation to their local environment. They cope with abiotic and biotic stresses, due to high solar interslope radiation differences. We conclude that our new genomic and methylomic data substantiated SS.

Genomic insights into zokors' phylogeny and speciation in China.

The phylogeny and speciation of subterranean zokors in China are unclear, as previous studies on morphology and limited molecular markers have generated conflicting results. This study unraveled the complex evolutionary history of eight zokor species in China based on de novo assembly at chromosome level and whole-genome sequencing of 23 populations. We found extensive phylogenetic discordances between nuclear and mitochondrial phylogenies, and different coalescent phylogenies, which could be explained by introgression and incomplete lineage sorting (ILS). The recent Qinghai-Tibet Plateau uplift (∼3.60 million y ago; Mya) drove Eospalax to speciate into clade A and clade B (∼3.22 Mya), and discordant phylogenies in this node were mainly attributed to introgression rather than ILS. Clade A rapidly diverged into three lineages due to geographical isolation and glaciation, while glaciation and C4 plant expansion contributed to the speciation of clade B. ILS contributed to the discordances of two rapidly radiated nodes rather than introgression. The effective population sizes (Ne's) of all the species of Eospalax were affected by three glaciations. Ancient polymorphisms and divergence hitchhiking contribute to genomic islands of all the species pairs. Positively selected genes putatively related to specific inhabitation adaptations were identified, such as heart development, neurogenesis, DNA repair, and immune response. Climate, geological tectonism, and C4 vegetation shaped the adaptation and speciation of zokors in China.

Magnetic-optical dual-modality imaging monitoring chemotherapy efficacy of pancreatic ductal adenocarcinoma with a low-dose fibronectin-targeting Gd-based contrast agent.

PURPOSE: Pancreatic ductal adenocarcinoma (PDAC) is a lethal hypovascular tumor surrounded by dense fibrosis. Albumin-bound paclitaxel and gemcitabine (AG) chemotherapy is the mainstay of PDAC treatment through depleting peritumoral fibrosis and killing tumor cells; however, it remains challenging due to the lack of a noninvasive imaging method evaluating fibrotic changes during AG chemotherapy. In this study, we developed a dual-modality imaging platform that enables noninvasive, dynamic, and quantitative assessment of chemotherapy-induced fibrotic changes through near-infrared fluorescence molecular imaging (FMI) and magnetic resonance imaging (MRI) using an extradomain B fibronectin (EDB-FN)-targeted imaging probe (ZD2-Gd-DOTA-Cy7). METHODS: The ZD2-Gd-DOTA-Cy7 probe was constructed by conjugating a peptide (Cys-TVRTSAD) to Gd-DOTA and the near-infrared dye Cy7. PDAC murine xenograft models were intravenously injected with ZD2-Gd-DOTA-Cy7 at a Gd concentration of 0.05 mmol/kg or free Cy7 and Gd-DOTA as control. The normalized tumor background ratio (TBR) on FMI and the T1 reduction ratio on MRI were quantitatively analyzed. For models receiving AG chemotherapy or saline, MRI/FMI was performed before and after treatment. Histological analyses were performed for validation. RESULTS: The ZD2-Gd-DOTA-Cy7 concentration showed a linear correlation with the fluorescence intensity and T1 relaxation time in vitro. The optimal imaging time was 30 min after injection of the ZD2-Gd-DOTA-Cy7 (0.05 mmol/kg), only half of the clinic dosage of gadolinium. Additionally, ZD2-Gd-DOTA-Cy7 generated a 1.44-fold and 1.90-fold robust contrast enhancement compared with Cy7 (P < 0.05) and Gd-DOTA (P < 0.05), respectively. For AG chemotherapy monitoring, the T1 reduction ratio and normalized TBR in the fibrotic tumor areas were significantly increased by 1.99-fold (P < 0.05) and 1.78-fold (P < 0.05), respectively, in the control group compared with those in the AG group. CONCLUSION: MRI/FMI with a low dose of ZD2-Gd-DOTA-Cy7 enables sensitive imaging of PDAC and the quantitative assessment of fibrotic changes during AG chemotherapy, which shows potential clinical applications for precise diagnosis, post-treatment monitoring, and disease management.

A Retrospective Cohort Study of vNOTES Extraperitoneal Versus Laparoscopic Sacral Hysteropexy With Uterine Preserving Regarding Surgical Outcomes and Two-Year Follow-Up Results.

STUDY OBJECTIVE: To explore the effectiveness of transvaginal natural orifice transluminal endoscopic surgery extraperitoneal sacral hysteropexy (vNOTES-ESH) in women with symptomatic uterine prolapse over a 2 year follow-up. DESIGN: Retrospective cohort study. SETTING: Gynecological minimally invasive center. PATIENTS: Women undergoing sacral hysteropexy either by vNOTES (n = 25) or laparoscopic (n = 74) between November 2016 and December 2020. INTERVENTIONS: Both vNOTES-ESH and laparoscopic sacral hysteropexy (LAP-SH) were used for uterine prolapse. Demographic data, operative characteristics, perioperative outcomes, and follow-up information 2 years postsurgery in the 2 groups were retrospectively evaluated. RESULTS: Both procedures showed similar operation time, estimated blood loss, hospital stays, and pain scores (p >0.05). During a median follow-up of 59 (24-72) months, the surgical success rate was 96% for vNOTES-ESH and 97.3% for LAP-SH (p >0.05), with no differences in anatomical position or pelvic organ function after the operation. Women in the LAP-SH group experienced more bothersome symptoms of constipation compared to those in the vNOTES-ESH group (5.41% vs 0, p <0.05). Lastly, 1 case in the vNOTES-ESH group had a mesh exposed area of less than 1 cm2, and 1 patient in the LAP-SH group experienced stress incontinence. CONCLUSIONS: In this retrospective study, vNOTES-ESH met our patients' preference for uterine preservation and was a successful and effective treatment for uterine prolapse, providing good functional improvement in our follow-up. This procedure should be considered as an option for patients with pelvic organ prolapse.

Construction and testing of a risk prediction classifier for cardia carcinoma.

OBJECTIVES: This research aimed to construct a prediction model for stages II and III cardia carcinoma (CC), and provide an effective preoperative evaluation tool for clinicians. METHODS: CC mRNA expression matrix was obtained from Gene Expression Omnibus and The Cancer Genome Atlas databases. Non-negative matrix factorization was used to cluster data to obtain subgroup information, and weighted gene co-expression network analysis was used to uncover key modules linked to different subgroups. Gene-set enrichment analysis analyzed biological pathways of different subgroups. The related pathways of multiple modules were scrutinized with Kyoto Encyclopedia of Genes and Genomes. Key modules were manually annotated to screen CC-related genes. Subsequently, quantitative real-time polymerase chain reaction assessed CC-related gene expression in fresh tissues and paraffin samples, and Pearson correlation analysis was performed. A classification model was constructed and the predictive ability was evaluated by the receiver operating characteristic curve. RESULTS: CC patients had four subgroups that were associated with brown, turquoise, red, and black modules, respectively. The CC-related modules were mainly associated with abnormal cell metabolism and inflammatory immune pathways. Then, 76 CC-elated genes were identified. Pearson correlation analysis presented that THBS4, COL14A1, DPYSL3, FGF7, and SVIL levels were relatively stable in fresh and paraffin tissues. The area under the curve of 5-gene combined prediction for staging was 0.8571, indicating good prediction ability. CONCLUSIONS: The staging classifier for CC based on THBS4, COL14A1, DPYSL3, FGF7, and SVIL has a good predictive effect, which may provide effective guidance for whether CC patients need emergency surgery.

Characteristics of vaginal microbiota in various cervical intraepithelial neoplasia: a cross-sectional study.

BACKGROUND: Precancerous lesions of cervical cancer exhibit characteristics indicative of natural progression. To prevent overtreatment of patients whose cervical intraepithelial neoplasia (CIN) in regression and to predict the onset of invasive cervical cancer at an early stage, we've identified the vaginal microbiome as a potential key factor, which is associated with both HPV infection and the various cervical intraepithelial neoplasia. This study aims to investigate the microbiome characteristics of patients with various cervical intraepithelial neoplasia. METHODS: Utilizing high-throughput 16S ribosomal RNA (16S rRNA) sequencing technology, a description of the characteristics and community composition of Vaginal Microbiota (VMB) was conducted among 692 Chinese women infected with the High-risk Human Papillomavirus (HR-HPV). RESULTS: As the grade of the lesions increased, the proportions of Lactobacillus and Pseudomonas demonstrated a significant declining trend, while the proportions of Gardnerella, Dialister, and Prevotella significantly increased. The diversity of the VMB was more significant in high-grade CIN. Furthermore, KEGG pathway enrichment analysis indicates that high-grade cervical intraepithelial neoplasia can inhibit various pathways, including those of phosphotransferase system, transcription factors, Fructose and mannose metabolism, amino sugar and nucleotide sugar metabolism, and galactose metabolism, which may contribute to the development of early cervical cancer symptoms. CONCLUSION: Patients with CIN exhibit a distinct vaginal microbial profile characterized by a decrease in Lactobacillus and Pseudomonas, and an increase in Gardnerella, Prevotella, and Dialister. The proliferation and diminution of these two types of microbial communities are interrelated, suggesting a mutual restraint and balance among them. Disruption of this regulatory balance could potentially lead to the onset of cervical lesions and carcinogenesis. Retrospectively registered: This study was approved by the Ethics Committee of the Beijing Chaoyang Hospital affiliated with the Capital Medical University (NO.2023-S-415).

Sensitive and quantitative in vivo analysis of PD-L1 using magnetic particle imaging and imaging-guided immunotherapy.

PURPOSE: The programmed cell death protein-1 (PD-1) and programmed cell death ligand-1 (PD-L1) expression correlate with the immunotherapeutic response rate. The sensitive and non-invasive imaging of immune checkpoint biomarkers is favorable for the accurate detection and characterization, image-guided immunotherapy in cancer precision medicine. Magnetic particle imaging (MPI), as a novel and emerging imaging modality, possesses the advantages of high sensitivity, no image depth limitation, positive contrast, and absence of radiation. Hence, in this study, we performed the pioneer investigation of monitoring PD-L1 expression using MPI and the MPI-guided immunotherapy. METHODS: We developed anti-PD-L1 antibody (aPDL1)-conjugated magnetic fluorescent hybrid nanoparticles (MFNPs-aPDL1) and utilized MPI in combination with fluorescence imaging (FMI) to dynamically monitor and quantify PD-L1 expression in various tumors with different PD-L1 expression levels. The ex vivo real-time polymerase chain reaction (qPCR), western blotting, and immunofluorescence staining analysis were further performed to validate the in vivo imaging observation. Moreover, the MPI was further performed for the guidance of immunotherapy. RESULTS: Our data showed that PD-L1 expression can be specifically and sensitively monitored and quantified using MPI and FMI imaging methods, which were validated by ex vivo qPCR and western blotting analysis. In addition, MPI-guided PD-L1 immunotherapy can enhance the effectiveness of cancer immunotherapy. CONCLUSION: To our best knowledge, this is the pioneer study to utilize MPI in combination with a newly developed MFNPs-aPDL1 imaging probe to dynamically visualize and quantify PD-L1 expression in tumor microenvironment. This imaging strategy may facilitate the clinical optimization of immunotherapy management.

Association Between Daily Internet Use and Incidence of Chronic Diseases Among Older Adults: Prospective Cohort Study.

BACKGROUND: Chronic disease incidence among the elderly is increasing, which is correlated with the acceleration of population aging. Evolving internet technologies may help prevent and provide interventions for chronic diseases in an accelerating aging process. However, the impact of daily internet use on the incidence of chronic diseases is not well understood. OBJECTIVE: This study aims to investigate whether daily internet use by middle-aged and older adults may inhibit or promote the occurrence of chronic diseases. METHODS: We included participants from the China Health and Retirement Longitudinal Study (CHARLS), a longitudinal survey of Chinese residents aged ≥45 years. We assessed 8-year data from wave 1 (June 2011-March 2012) to wave 4 (July-September 2018) in CHARLS. Data from wave 4 were used for a cross-sectional study, and data from all 4 waves were used for a longitudinal study. Self-reported data were used to track variables, including internet use, use frequency, and the incidence of different chronic diseases. Cox proportional hazards modeling was applied in the longitudinal study to examine the relationship between daily internet use and chronic diseases among middle-aged and older adults, while adjusting for sociodemographic characteristics and health behaviors. In addition, longitudinal data were used to analyze internet usage trends, and cross-sectional data were used to analyze the factors influencing internet use. RESULTS: Among the 20,113 participants included in the longitudinal analyses, internet use increased significantly, from 2% to 12.3%, between 2011 and 2018. The adjusted model found statistically significant relationships between daily internet use and a lower incidence of the following chronic diseases: hypertension (hazard ratio [HR] 0.78, 95% CI 0.65-0.95, P=.01), chronic lung disease (HR 0.74, 95% CI 0.57-0.97, P=.03), stroke (HR 0.69, 95% CI 0.50-0.94, P=.02), digestive disease (HR 0.73, 95% CI 0.58-0.91, P=.005), memory-related disorders (HR 0.58, 95% CI 0.37-0.91, P=.02), arthritis or rheumatism (HR 0.60, 95% CI 0.48-0.76, P<.001), asthma (HR 0.52, 95% CI 0.33-0.84, P=.007), depression (HR 0.80, 95% CI 0.71-0.89, P<.001), and vision impairment (HR 0.83, 95% CI 0.74-0.93, P=.004). Moreover, our study also showed that with increasing frequency of internet use, the risk of some chronic diseases decreases. CONCLUSIONS: This study found that middle-aged and older adults who use the internet have a reduced risk of developing chronic diseases versus those who do not use the internet. The increasing prevalence of daily internet use among middle-aged and older adults may stimulate contemplation of the potential role of internet platforms in future research on chronic disease prevention.

Identification of Asymptomatic COVID-19 Patients on Chest CT Images Using Transformer-Based or Convolutional Neural Network-Based Deep Learning Models.

Novel coronavirus disease 2019 (COVID-19) has rapidly spread throughout the world; however, it is difficult for clinicians to make early diagnoses. This study is to evaluate the feasibility of using deep learning (DL) models to identify asymptomatic COVID-19 patients based on chest CT images. In this retrospective study, six DL models (Xception, NASNet, ResNet, EfficientNet, ViT, and Swin), based on convolutional neural networks (CNNs) or transformer architectures, were trained to identify asymptomatic patients with COVID-19 on chest CT images. Data from Yangzhou were randomly split into a training set (n = 2140) and an internal-validation set (n = 360). Data from Suzhou was the external-test set (n = 200). Model performance was assessed by the metrics accuracy, recall, and specificity and was compared with the assessments of two radiologists. A total of 2700 chest CT images were collected in this study. In the validation dataset, the Swin model achieved the highest accuracy of 0.994, followed by the EfficientNet model (0.954). The recall and the precision of the Swin model were 0.989 and 1.000, respectively. In the test dataset, the Swin model was still the best and achieved the highest accuracy (0.980). All the DL models performed remarkably better than the two experts. Last, the time on the test set diagnosis spent by two experts-42 min, 17 s (junior); and 29 min, 43 s (senior)-was significantly higher than those of the DL models (all below 2 min). This study evaluated the feasibility of multiple DL models in distinguishing asymptomatic patients with COVID-19 from healthy subjects on chest CT images. It found that a transformer-based model, the Swin model, performed best.

Growth, Biochemical Characteristics, Flesh Quality, and Gut Microbiota of the Pacific White Shrimp (Penaeus vannamei) Fed a Defatted Superworm (Zophobas atratus) Larvae Meal.

This study evaluated the effects of defatted superworm (Zophobas atratus) larvae meal (DBWLM) as an alternative protein ingredient for juvenile Pacific white shrimp (Penaeus vannamei). Six isonitrogenous and isolipidic experimental diets were characterized by replacing 0%, 15%, 30%, 45%, 60%, and 75% fish meal (DBWLM0, DBWLM15, DBWLM30, DBWLM45, DBWLM60, and DBWLM75, respectively) with DBWLM on a w/w basis and feeding them to juvenile shrimp (0.34 ± 0.04 g) for 56 days. The results showed that the replacement of up to 75% fish meal by DBWLM had no negative effect on the growth performance of P. vannamei. The survival of shrimp in the DBWLM30 group was the highest, and the weight gain, specific growth rate, feed conversion ratio, condition factor, and apparent digestibility coefficients of dry matter in the DBWLM15 group were the highest. The substitution of DBWLM for fish meal significantly increased the elasticity of flesh, improved the total content of umami amino acids in flesh (aspartic acid, glutamic acid, glycine, and alanine), promoted lipid metabolism in shrimp, and reduced serum lipid levels. With the increase in DBWLM level, serum acid phosphatase, alkaline phosphatase activity, and intestinal inflammatory gene expression (IGF-1 and IL-6) were inhibited, malondialdehyde content decreased, and total antioxidant capacity level and superoxide dismutase activity increased significantly. Histological sections of the hepatopancreas showed that when 60% or more fish meal was replaced, the hepatopancreas atrophied and had irregular lumen distortion, but the cell membrane was not damaged. Microbiome analysis showed that the abundance of Bacteroidetes and Firmicutes increased and the abundance of Proteobacteria decreased in the DBWLM replacement group, and it was rich in "metabolism"-related functional pathways. It is worth mentioning that the expression of amino-acid-related enzymes was upregulated in the DBWLM15 and DBWLM30 groups, and the DBWLM75 group inhibited the biosynthesis of steroids and hormones. To conclude, the replacement of 15%-45% fish meal with DBWLM can result in better growth and immune status, improved meat elasticity, and reduced inflammation in P. vannamei. However, it is recommended that the replacement level should not exceed 60%, otherwise it will cause atrophy of hepatopancreas cells.

[Clinicopathological Features of Primary Small Cell Neuroendocrine Carcinoma of the Bladder].

Objective To investigate the clinicopathological features,immunohistochemical features,diagnosis,and relationship with sporadic prostate cancer in primary small cell neuroendocrine carcinoma of the bladder. Methods We retrospectively analyzed the clinical characteristics of 12 patients with primary small cell neuroendocrine carcinoma of the bladder diagnosed at Beijing Chao-Yang Hospital affiliated to Capital Medical University from January 2013 to September 2022.The histological features of primary small cell neuroendocrine carcinoma of the bladder were re-evaluated by two pathologists according to the 2022 revision of the World Health Organization Classification of Tumors of the Urinary System and Male Genital Organs.Electronic medical records were retrieved,and telephone follow-up was conducted from the time of histopathological diagnosis to the death or the end of the last follow-up until January 31,2023. Results The 12 patients include 7 patients in pT3 stage and 1 patient in pT4 stage.Eight patients were complicated with other types of tumors,such as high-grade urothelial carcinoma of the bladder and squamous cell carcinoma.Five patients had sporadic prostate cancer.Immunohistochemical staining showed that 12 (100.0%),10 (83.3%),and 8 (66.7%) patients were tested positive for CD56,Syn,and CgA,respectively.The Ki67 proliferation index ranged from 80% to 90%.Five patients with urothelial carcinoma were tested positive for CK20,GATA3,and CK7.P504S was positive in all the 5 patients with prostate cancer,while P63 and 34ßE12 were negative.The follow-up of the 12 patients lasted for 3-60 months.Eight of these patients died during follow-up,with the median survival of 15.5 months.Four patients survived. Conclusions Primary small cell neuroendocrine carcinoma of the bladder is a rare urological tumor with high aggressiveness and poor prognosis.In male patients with bladder prostatectomy,all prostate tissue should be sampled.If prostate cancer is detected,the prostate-specific antigen level should be monitored.

Dual-targeting nanozyme for tumor activatable photo-chemodynamic theranostics.

Tumor phototheranostics holds a great promise on account of its high spatiotemporal resolution, tumor-specificity, and noninvasiveness. However, physical limitation of light penetration and "always on" properties of conventional photothermal-conversion agents usually cause difficulty in accurate diagnosis and completely elimination of tumor. Meanwhile, nanozymes mediated Fenton reactions can well utilize the tumor microenvironment (TME) to generate hydroxyl radicals for chemodynamic therapy (CDT), but limited by the concentration of H2O2 in TME and the delivery efficiency of nanozymes. To overcome these problems, a dual-targeting nanozyme (FTRNPs) is developed for tumor-specific in situ theranostics, based upon the assembling of ultrasmall Fe3O4 nanoparticles, 3,3',5,5'-tetrameth-ylbenzidine (TMB) and the RGD peptide. The FTRNPs after H2O2 treatment exhibits superior photothermal stability and high photothermal conversion efficiency (η = 50.9%). FTRNPs shows extraordinary accumulation and retention in the tumor site by biological/physical dual-targeting, which is 3.54-fold higher than that without active targeting. Cascade-dual-response to TME for nanozymes mediated Fenton reactions and TMB oxidation further improves the accuracy of both photoacoustic imaging and photothermal therapy (PTT). The tumor inhibition rate of photo-chemodynamic therapy is ~ 97.76%, which is ~ 4-fold higher than that of PTT or CDT only. Thus, the combination of CDT and PTT to construct "turn on" nanoplatform is of great significance to overcome their respective limitations. Considering its optimized "all-in-one" performance, this new nanoplatform is expected to provide an advanced theranostic strategy for the future treatment of cancers.

NOX4 blockade suppresses titanium nanoparticle-induced bone destruction via activation of the Nrf2 signaling pathway.

Periprosthetic osteolysis (PPO) triggered by wear particles is the most severe complication of total joint replacement (TJR) surgeries, representing the major cause of implant failure, which is public health concern worldwide. Previous studies have confirmed the specialized role of osteoclast-induced progressive bone destruction in the progression of PPO. Additionally, the reactive oxygen species (ROS) induced by wear particles can promote excessive osteoclastogenesis and bone resorption. Nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4), a cellular enzyme, is considered to be responsible for the production of ROS and the formation of mature osteoclasts. However, NOX4 involvement in PPO has not yet been elucidated. Therefore, we investigated the mechanism by which NOX4 regulates osteoclast differentiation and the therapeutic effects on titanium nanoparticle-induced bone destruction. We found that NOX4 blockade suppressed osteoclastogenesis and enhanced the scavenging of intracellular ROS. Our rescue experiment revealed that nuclear factor-erythroid 2-related factor 2 (Nrf2) silencing reversed the effects of NOX4 blockade on ROS production and osteoclast differentiation. In addition, we found increased expression levels of NOX4 in PPO tissues, while NOX4 inhibition in vivo exerted protective effects on titanium nanoparticle-induced osteolysis through antiosteoclastic and antioxidant effects. Collectively, these findings suggested that NOX4 blockade suppresses titanium nanoparticle-induced bone destruction via activation of the Nrf2 signaling pathway and that NOX4 blockade may be an attractive therapeutic approach for preventing PPO.

GSK-3ß suppression upregulates Gli1 to alleviate osteogenesis inhibition in titanium nanoparticle-induced osteolysis.

Wear particle-induced periprosthetic osteolysis (PPO) have become a major reason of joint arthroplasty failure and secondary surgery following joint arthroplasty and thus pose a severe threat to global public health. Therefore, determining how to effectively suppress particle-induced PPO has become an urgent problem. The pathological mechanism involved in the PPO signaling cascade is still unclear. Recently, the interaction between osteogenic inhibition and wear particles at the implant biological interface, which has received increasing attention, has been revealed as an important factor in pathological process. Additionally, Hedgehog (Hh)-Gli1 is a crucial signaling cascade which was regulated by multiple factors in numerous physiological and pathological process. It was revealed to exert a crucial part during embryonic bone development and metabolism. However, whether Hh-Gli1 is involved in wear particle-induced osteogenic inhibition in PPO remains unknown. Our present study explored the mechanism by which the Hh-Gli1 signaling cascade regulates titanium (Ti) nanoparticle-induced osteolysis. We found that Hh-Gli1 signaling was dramatically downregulated upon Ti particle treatment. Mechanistically, glycogen synthesis kinase 3ß (GSK-3ß) activation was significantly increased in Ti particle-induced osteogenic inhibition via changes in GSK-3ß phosphorylation level and was found to participate in the posttranslational modification and degradation of the key transcription factor Gli1, thus decreasing the accumulation of Gli1 and its translocation from the cytoplasm to the nucleus. Collectively, these findings suggest that the Hh-Gli1 signaling cascade utilizes a GSK3ß-mediated mechanism and may serve as a rational new therapeutic target against nanoparticle-induced PPO.

Trusted Data Storage Architecture for National Infrastructure.

National infrastructure is a material engineering facility that provides public services for social production and residents' lives, and a large-scale complex device or system is used to ensure normal social and economic activities. Due to the problems of difficult data collection, long project period, complex data, poor security, difficult traceability and data intercommunication, the archives management of most national infrastructure is still in the pre-information era. To solve these problems, this paper proposes a trusted data storage architecture for national infrastructure based on blockchain. This consists of real-time collection of national infrastructure construction data through sensors and other Internet of Things devices, conversion of heterogeneous data source data into a unified format according to specific business flows, and timely storage of data in the blockchain to ensure data security and persistence. Knowledge extraction of data stored in the chain and the data of multiple regions or fields are jointly modeled through federal learning. The parameters and results are stored in the chain, and the information of each node is shared to solve the problem of data intercommunication.

Bacillus aryabhattai LAD impacts rhizosphere bacterial community structure and promotes maize plant growth.

BACKGROUND: Plant growth-promoting rhizobacteria may significantly impact the soil microbial community and the growth of plant roots and have critical roles in soil ecosystem functioning. However, the interactions between rhizobacteria and plants are extremely complicated and remain understudied. RESULTS: In this study, a Bacillus strain was isolated from a long-term maize colonization soil and identified as Bacillus aryabhattai strain LAD. Laboratory tests showed that B. aryabhattai LAD had phosphate-solubilizing and nitrogen-fixing functions that benefit plant growth. The effects of LAD cultures on the root system development of corn seedlings and the structure of rhizosphere bacterial communities were studied. The most significant stimulations of LAD culture on plant growth were observed at a cell density of 102 CFU mL-1 . Treatment with LAD culture in hydroponics caused an increase of 107%, 197%, and 25% in the shoot length, total root length, and main root thickness respectively. The LAD treatment also significantly affected the rhizosphere microbial abundance and community structure. The rhizobacterial abundance and species richness in the corn seedlings treated with LAD culture were significantly lower than those in the control group. However, the LAD-treated samples had higher relative abundances of plant growth-promoting rhizobacteria like Bacillus and Burkholderia than the control samples did, suggesting that LAD treatment may facilitate the mutualistic relation between the rhizosphere microbiome and the plant. CONCLUSION: These results collectively demonstrated that LAD is capable of shaping the rhizosphere microbial community structure and functions as a plant growth-promoting agent, which makes it a strong candidate for application as bio-fertilizer in agricultural systems. © 2022 Society of Chemical Industry.

Urolithin A suppresses RANKL-induced osteoclastogenesis and postmenopausal osteoporosis by, suppresses inflammation and downstream NF-κB activated pyroptosis pathways.

Osteoporosis (OP) is characterized by decreased trabecular bone volume and microarchitectural deterioration in the medullary cavity. Urolithin A (UA) is a biologically active metabolite generated by the gut microbiota. UA is the measurable product considered the most relevant urolithin as the final metabolic product of polyphenolic compounds. Considering that catabolic effects mediated by the intestinal microbiota are highly involved in pathological bone disorders, exploring the biological influence and molecular mechanisms by which UA alleviates OP is crucial. Our study aimed to investigate the effect of UA administration on OP progression in the context of estrogen deficiency-induced bone loss. The in vivo results indicated that UA effectively reduced ovariectomy-induced systemic bone loss. In vitro, UA suppressed Receptor Activator for Nuclear Factor-κB Ligand (RANKL)-triggered osteoclastogenesis in a concentration-dependent manner. Signal transduction studies and sequencing analysis showed that UA significantly decreased the expression of inflammatory cytokines (e.g., IL-6 and TNF-α) in osteoclasts. Additionally, attenuation of inflammatory signaling cascades inhibited the NF-κB-activated NOD-like receptor signaling pathway, which eventually led to decreased cytoplasmic secretion of IL-1ß and IL-18 and reduced expression of pyroptosis markers (NLRP3, GSDMD, and caspase-1). Consistent with this finding, an NLRP3 inflammasome inhibitor (MCC950) was employed to treat OP, and modulation of pyroptosis was found to ameliorate osteoclastogenesis and bone loss in ovariectomized (OVX) mice, suggesting that UA suppressed osteoclast formation by regulating the inflammatory signal-dependent pyroptosis pathway. Conceivably, UA administration may be a safe and promising therapeutic strategy for osteoclast-related bone diseases such as OP.

Study on the effect and mechanism of NFKBIA on cervical cancer progress in vitro and in vivo.

AIM: NFKBIA is frequently encountered. However, its expression and relevance of the proliferation, invasion, and migration in human cervical cancer (CC) remain unclear. The role and novel mechanism of NFKBIA in CC progression were investigated in this study. METHODS: We analyzed the expression of NFKBIA in CC and adjacent normal tissues and explored the proliferation, migration, and invasion of HeLa cells by treating with either wild-type NFKBIA plasmid or NFKBIA siRNA. Effect of NFKBIA on the epithelial-mesenchymal transition (EMT) and the ß-catenin-mediated transcription of target genes were evaluated subsequently. RESULTS: NFKBIA expression was lower in CC tissues than that of adjacent tissues. An obvious dysregulation of NFKBIA overexpression was revealed in CC cell proliferation, invasion, and migration, which differed from the effect of knockdown NFKBIA. NFKBIA overexpression facilitated the expression of both phosphorylated ß-catenin and E-cadherin protein. It inhibited the expression of vimentin, TWIST, as well as downstream targets of ß-catenin including c-MYC, TCF-4 and MMP14. Conversely, NFKBIA silencing elevated the expression of c-MYC, TCF-4, and MMP14, and promoted the EMT in HeLa cells. Both endogenous and exogenous NFKBIA interacted with ß-catenin. Moreover, ß-catenin overexpression stemmed effects of NFKBIA on the proliferation, migration, and invasion of HeLa cells. By overexpressing NFKBIA in vivo, the volume and size of tumors were notably decreased, while no obvious alteration was found in mice body weight. CONCLUSION: By inhibiting ß-catenin-mediated transcription, NFKBIA functioning as a tumor suppressor might be introduced as a novel anti-metastatic agent for the treatment of targeted CC.

Whole-genome sequencing reveals distinct genetic bases for insulinomas and non-functional pancreatic neuroendocrine tumours: leading to a new classification system.

OBJECTIVE: Insulinomas and non-functional pancreatic neuroendocrine tumours (NF-PanNETs) have distinctive clinical presentations but share similar pathological features. Their genetic bases have not been comprehensively compared. Herein, we used whole-genome/whole-exome sequencing (WGS/WES) to identify genetic differences between insulinomas and NF-PanNETs. DESIGN: The mutational profiles and copy-number variation (CNV) patterns of 211 PanNETs, including 84 insulinomas and 127 NF-PanNETs, were obtained from WGS/WES data provided by Peking Union Medical College Hospital and the International Cancer Genome Consortium. Insulinoma RNA sequencing and immunohistochemistry data were assayed. RESULTS: PanNETs were categorised based on CNV patterns: amplification, copy neutral and deletion. Insulinomas had CNV amplifications and copy neutral and lacked CNV deletions. CNV-neutral insulinomas exhibited an elevated rate of YY1 mutations. In contrast, NF-PanNETs had all three CNV patterns, and NF-PanNETs with CNV deletions had a high rate of loss-of-function mutations of tumour suppressor genes. NF-PanNETs with CNV alterations (amplification and deletion) had an elevated risk of relapse, and additional DAXX/ATRX mutations could predict an increased relapse risk in the first 2-year period. CONCLUSION: These WGS/WES data allowed a comprehensive assessment of genetic differences between insulinomas and NF-PanNETs, reclassifying these tumours into novel molecular subtypes. We also proposed a novel relapse risk stratification system using CNV patterns and DAXX/ATRX mutations.