Comparative morphology of the cruciate ligaments: A radiological study.

Background: The anterior cruciate ligament (ACL) and posterior cruciate ligament (PCL) are important structures to maintain knee stability. The present study aimed to further enrich understandings of the morphology of the cruciate ligaments and explore the relationship between the diameter of ACL and PCL. Method: This study collected valid MRI samples of 50 male and 50 female normal right knee joints and measured the diameter of each point of the ACL and PCL through the 3D Slicer. Results: The diameter of the ACL in the sagittal MRI of the normal right knee joint was significantly different from the diameter of each point of the PCL. The average diameter of each point of the ACL was larger than the diameter of the corresponding point of the PCL. Males and females had statistical differences in their PCL origin point, PCL midpoint, ACL origin point, ACL midpoint, and ACL insertion point diameters under sagittal MRI examination. The average diameter of males was greater than the average diameter of females at the above corresponding sites. In sagittal MRI scans of the normal right knee joint, we observed that only the origin point of the PCL exhibited a moderate correlation with the midpoint and insertion point of the ACL in terms of their respective diameters. Conclusion: The correlation between diameters of normal ACL and PCL in knee joint MRI was moderate and may help clinicians determine appropriate graft for cruciate ligament reconstruction surgery quickly for severe cruciate ligament injuries.

Low-Triggering-Potential and Narrow-Potential-Window Electrochemiluminescence of Silver Nanoclusters for Gene Assay.

A low-triggering potential and a narrow-potential window are anticipated to decrease the electrochemical interference and cross talk of electrochemiluminescence (ECL). Herein, by exploiting the low oxidative potential (0.82 V vs Ag/AgCl) of dihydrolipoic acid-capped sliver nanoclusters (DHLA-AgNCs), a coreactant ECL system of DHLA-AgNCs/hydrazine (N2H4) is proposed to achieve efficient and oxidative-reduction ECL with a low-triggering potential of 0.82 V (vs Ag/AgCl) and a narrow-potential window of 0.22 V. The low-triggering-potential and narrow-potential-window nature of ECL can be primarily preserved upon labeling DHLA-AgNCs to probe DNA and immobilizing DHLA-AgNCs onto the Au surface via sandwiched hybridization, which eventually enables a selective ECL strategy for the gene assay at +0.82 V. This gene assay strategy can sensitively determine the gene of human papillomavirus from 10 to 1000 pM with a low limit of detection of 5 pM (S/N = 3) and would open a way to improve the applied ECL bioassay.

Clinical Manifestation, Risk Factors, and Immune Checkpoint Inhibitor Rechallenge of Checkpoint Inhibitor-Associated Pneumonitis in Patients With Lung Cancer.

SUMMARY: Immune-related adverse effects can lead to damage to various systems of the body, checkpoint inhibitor-associated pneumonitis (CIP) is one of the potentially lethal immune-related adverse effects. However, evidence regarding the risk factors associated with CIP is limited. To timely and accurate identification and prompt treatment of CIP, understanding the risk factors for multimorbidity among diverse study populations becomes crucial. We retrospectively analyzed the clinical data of 1131 patients with lung cancer receiving immunotherapy to identify 110 patients with CIP, the clinical characteristics and radiographic features of patients with CIP were analyzed. A case-control study was subsequently performed to identify the risk factors of CIP. The median treatment cycle was 5 cycles and the median time to onset of CIP was 4.2 months. CIP was mainly grade I or II. Most cases improved after discontinuation of immune checkpoint inhibitors (ICIs) or hormone therapy. Severe CIP tended to occur earlier in comparison to mild to moderate cases. The recurrence rate was 20.6% in ICI-rechallenged patients, and patients with relapsed CIP were usually accompanied by higher-grade adverse events than at first onset. Among the 7 patients with relapse, ICI-associated deaths occurred in 2 patients (28.6%). For rechallenging with ICIs after recovery from CIP, caution should be practiced. Male [odds ratio (OR): 2.067; 95% CI: 1.194-3.579; P = 0.009], history of chest radiation (OR: 1.642; 95% CI: 1.002-2.689; P = 0.049) and underlying lung disease (OR: 2.347; 95% CI: 1.008-5.464; P =0.048) was associated with a higher risk of CIP.

Genkwanin alleviates intervertebral disc degeneration via regulating ITGA2/PI3K/AKT pathway and inhibiting apoptosis and senescence.

Intervertebral disc degeneration (IVDD) is a progressive degenerative disease influenced by various factors. Genkwanin, a known anti-inflammatory flavonoid, has not been explored for its potential in IVDD management. This study aims to investigate the effects and mechanisms of genkwanin on IVDD. In vitro, cell experiments revealed that genkwanin dose-dependently inhibited Interleukin-1ß-induced expression levels of inflammatory factors (Interleukin-6, inducible nitric oxide synthase, cyclooxygenase-2) and degradation metabolic protein (matrix metalloproteinase-13). Concurrently, genkwanin upregulated the expression of synthetic metabolism genes (type II collagen, aggrecan). Moreover, genkwanin effectively reduced the phosphorylation of phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin, mitogen-activated protein kinase (MAPK), and nuclear factor-κB (NF-κB) pathways. Transcriptome sequencing analysis identified integrin α2 (ITGA2) as a potential target of genkwanin, and silencing ITGA2 reversed the activation of PI3K/AKT pathway induced by Interleukin-1ß. Furthermore, genkwanin alleviated Interleukin-1ß-induced senescence and apoptosis in nucleus pulposus cells. In vivo animal experiments demonstrated that genkwanin mitigated the progression of IVDD in the rat model through imaging and histological examinations. In conclusion, This study suggest that genkwanin inhibits inflammation in nucleus pulposus cells, promotes extracellular matrix remodeling, suppresses cellular senescence and apoptosis, through the ITGA2/PI3K/AKT, NF-κB and MAPK signaling pathways. These findings indicate that genkwanin may be a promising therapeutic candidate for IVDD.

Tyrosine hydroxylase inhibits HCC progression by downregulating TGFß/Smad signaling.

The alteration of metabolic processes has been found to have significant impacts on the development of hepatocellular carcinoma (HCC). Nevertheless, the effects of dysfunction of tyrosine metabolism on the development of HCC remains to be discovered. This research demonstrated that tyrosine hydroxylase (TH), which responsible for the initial and limiting step in the bio-generation of the neuro-transmitters dopamine and adrenaline, et al. was shown to be reduced in HCC. Increased expression of TH was found facilitates the survival of HCC patients. In addition, decreased TH indicated larger tumor size, much more numbers of tumor, higher level of AFP, and the presence of cirrhosis. TH effectively impairs the growth and metastasis of HCC cells, a process dependent on the phosphorylation of serine residues (S19/S40). TH directly binds to Smad2 and hinders the cascade activation of TGFß/Smad signaling with the treatment of TGFß1. In summary, our study uncovered the non-metabolic functions of TH in the development of HCC and proposes that TH might be a promising biomarker for diagnosis as well as an innovative target for metastatic HCC.

Deterministic reprogramming of neutrophils within tumors.

Neutrophils are increasingly recognized as key players in the tumor immune response and are associated with poor clinical outcomes. Despite recent advances characterizing the diversity of neutrophil states in cancer, common trajectories and mechanisms governing the ontogeny and relationship between these neutrophil states remain undefined. Here, we demonstrate that immature and mature neutrophils that enter tumors undergo irreversible epigenetic, transcriptional, and proteomic modifications to converge into a distinct, terminally differentiated dcTRAIL-R1+ state. Reprogrammed dcTRAIL-R1+ neutrophils predominantly localize to a glycolytic and hypoxic niche at the tumor core and exert pro-angiogenic function that favors tumor growth. We found similar trajectories in neutrophils across multiple tumor types and in humans, suggesting that targeting this program may provide a means of enhancing certain cancer immunotherapies.

Sakuranetin reduces inflammation and chondrocyte dysfunction in osteoarthritis by inhibiting the PI3K/AKT/NF-κB pathway.

Osteoarthritis (OA) is a prevalent degenerative disease that impairs limb function, and its pathogenesis is closely related to inflammation. Sakuranetin (SK) is a cherry flavonoid phytoalexin with potent anti-inflammatory, anti-oxidant, and ant-ifungal properties. In recent studies, flavonoid and phytoalexin-related medicines have shown promise in the treatment of OA. However, the effects of SK on chondrocyte inflammation and the chondrogenesis process have remained unexplored, as have its functions in OA treatment. This study sought to confirm the therapeutic effects of SK in the OA rat model and reveal the potential mechanisms for protecting chondrocytes. The relevant mechanisms of SK were analyzed by network pharmacology analysis. Chondrocytes were subjected to IL-1ß intervention to simulate an inflammatory environment and received SK treatment. Then, anabolism, catabolism, and inflammatory markers were detected by western blot, qPCR, elisa, and immunofluorescence. Chondrogenic ability was evaluated by micromass and 3D culture assays. The rats were treated with destabilization of the medial meniscus (DMM) surgery to establish an OA model and SK intra-articular injections subsequently. Histological staining, immunohistochemistry, and micro-CT were performed to analyze the structural and morphological changes of cartilage and subchondral bone. In chondrocytes, IL-1ß treatment reduced chondrogenic ability, promoted catabolism, and exacerbated inflammation by triggering the PI3K/AKT/NF-κB pathway, whereas SK treatment partially rescued these negative effects. In vivo, SK treatment effectively alleviated the degeneration of cartilage and subchondral bone, thereby delaying the progression of OA. In summary, SK alleviates chondrocyte inflammation and promotes chondrogenesis by inhibiting the PI3K/AKT/NF-κB pathway, thereby improving OA progression.

Outcomes of Filtering Surgery Versus Clear Lens Extraction in Young Patients With Angle-Closure Glaucoma.

PURPOSE: To compare the effect of filtering surgery versus clear lens extraction in young patients with medically uncontrolled angle-closure glaucoma (ACG). DESIGN: Retrospective, nonrandomized, comparative, interventional study. METHODS: We reviewed the medical charts of patients with the following scenarios: (1) age ≤40 years; (2) diagnosis of ACG without cataract, including primary angle-closure glaucoma (PACG), nanophthalmic ACG, and ACG combined with retinal dystrophies; and (3) ACG undergoing filtering surgery or clear lens extraction. The main outcomes including intraocular pressure (IOP), number of medications, best-corrected visual acuity, and severe complications were extracted at the postoperative early (within 1 week) and late stage (>3 months) follow-up. RESULTS: Data from 160 eyes of 130 young patients with ACG were available. Eyes with 76 PACG, 12 nanophthalmic ACG, and 26 ACG with retinal diseases underwent filtering surgery, whereas eyes with 22 PACG, 12 nanophthalmic ACG, and 12 ACG with retinal diseases received clear lens extraction. Overall, filtering surgery and clear lens extraction resulted in significant but comparable IOP and drug reductions at the postoperative late stage in each ACG subgroup, with similar complete success rates between 2 treatments (all P > .05). Regarding the safety, filtering surgery and patients with retinal diseases were independent factors associated with postoperative malignant glaucoma (P < .05 in both multivariable logistic regression models). CONCLUSIONS: This study highlights that the efficacy of clear lens extraction is comparable to that of filtering surgery in medically uncontrolled ACG in young patients, but clear lens extraction is safer, especially for young patients with ACG comorbid with retinal diseases.

Rutaecarpine ameliorates osteoarthritis by inhibiting PI3K/AKT/NF­κB and MAPK signalling transduction through integrin αVß3.

Osteoarthritis (OA) is a chronic progressive articular illness which commonly affects older­aged adults, presenting with cartilage inflammation and degradation. Rutaecarpine (RUT) has been shown to exert promising anti­inflammatory effects; however, the efficacy of RUT in the treatment of OA is debatable. The present study investigated the potential of RUT in alleviating OA in a mouse model. Treatment with RUT inhibited the inflammatory response and extracellular matrix degradation by suppressing process regulators in interleukin (IL)­1ß­stimulated chondrocytes. Moreover, treatment with RUT in vitro upregulated the gene expression of anabolic agents, such as collagen type II, aggrecan and SRY­box transcription factor 9, indicating that RUT contributed to cartilage repair. Additionally, flow cytometric assays, and the measurement of ß­galactosidase levels, autophagic flux and related protein expression revealed that RUT effectively attenuated IL­1ß­induced chondrocyte apoptosis, senescence and autophagy impairment. In addition, bioinformatics analysis and in vitro experiments demonstrated that RUT protected cartilage by mediating the phosphoinositide­3­kinase (PI3K)/Akt/nuclear factor­κB (NF­κB) and mitogen­activated protein kinase (MAPK) pathways. The ameliorative effects of RUT on IL­1ß­stimulated chondrocytes were abrogated when siRNA was used to knock down integrin αVß3. Furthermore, the results of immunohistochemical analysis and microcomputed tomography confirmed the in vivo therapeutic effects of RUT in mice with OA. On the whole, the present study demonstrates that RUT attenuates the inflammatory response and cartilage degradation in mice with OA by suppressing the activation of the PI3K/AKT/NF­κB and MAPK pathways. Integrin αVß3 may play a pivotal role in these effects.

Phosphorylation of PPDPF via IL6-JAK2 activates the Wnt/ß-catenin pathway in colorectal cancer.

Inflammation plays an important role in the initiation and progression of colorectal cancer (CRC) and leads to ß-catenin accumulation in colitis-related CRC. However, the mechanism remains largely unknown. Here, pancreatic progenitor cell differentiation and proliferation factor (PPDPF) is found to be upregulated in CRC and significantly correlated with tumor-node-metastasis (TNM) stages and survival time. Knockout of PPDPF in the intestinal epithelium shortens crypts, decreases the number of stem cells, and inhibits the growth of organoids and the occurrence of azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced CRC. Mechanistically, PPDPF is found to interact with Casein kinase 1α (CK1α), thereby disrupting its binding to Axin, disassociating the ß-catenin destruction complex, decreasing the phosphorylation of ß-catenin, and activating the Wnt/ß-catenin pathway. Furthermore, interleukin 6 (IL6)/Janus kinase 2 (JAK2)-mediated inflammatory signals lead to phosphorylation of PPDPF at Tyr16 and Tyr17, stabilizing the protein. In summary, this study demonstrates that PPDPF is a key molecule in CRC carcinogenesis and progression that connects inflammatory signals to the Wnt/ß-catenin signaling pathway, providing a potential novel therapeutic target.

Nicotinamide adenine dinucleotide kinase promotes lymph node metastasis of NSCLC via activating ID1 expression through BMP pathway.

Metastasis is a significant cause of high mortality in lung cancer. Lymph node (LN) metastasis is the most common metastatic pathway in non-small cell lung cancer and the most crucial factor affecting the prognosis of NSCLC. Nevertheless, the molecular mechanism underlying metastasis is unknown. We demonstrated that higher NADK expression suggests worsened survival prognosis, and NADK expression positively correlates with the lymph node metastasis rate and TNM and AJCC stages in NSCLC patients. Moreover, patients with LN metastasis show higher NADK expression than those without LN metastasis. NADK can promote NSCLC progression by enhancing the migration, invasion, lymph node metastasis and growth of NSCLC cells. Mechanistically, NADK inhibits the ubiquitination and degradation of BMPR1A by interacting with Smurf1, further activating the BMPs signalling pathway and promoting ID1 transcription. In conclusion, NADK may be a potential diagnostic indicator and a novel therapeutic target for metastatic NSCLC.

Establishing a human bone marrow single cell reference atlas to study ageing and diseases.

Introduction: Ageing in the human bone marrow is associated with immune function decline that results in the elderly being vulnerable to illnesses. A comprehensive healthy bone marrow consensus atlas can serve as a reference to study the immunological changes associated with ageing, and to identify and study abnormal cell states. Methods: We collected publicly available single cell transcriptomic data of 145 healthy samples encompassing a wide spectrum of ages ranging from 2 to 84 years old to construct our human bone marrow atlas. The final atlas has 673,750 cells and 54 annotated cell types. Results: We first characterised the changes in cell population sizes with respect to age and the corresponding changes in gene expression and pathways. Overall, we found significant age-associated changes in the lymphoid lineage cells. The naïve CD8+ T cell population showed significant shrinkage with ageing while the effector/memory CD4+ T cells increased in proportion. We also found an age-correlated decline in the common lymphoid progenitor population, in line with the commonly observed myeloid skew in haematopoiesis among the elderly. We then employed our cell type-specific ageing gene signatures to develop a machine learning model that predicts the biological age of bone marrow samples, which we then applied to healthy individuals and those with blood diseases. Finally, we demonstrated how to identify abnormal cell states by mapping disease samples onto the atlas. We accurately identified abnormal plasma cells and erythroblasts in multiple myeloma samples, and abnormal cells in acute myeloid leukaemia samples. Discussion: The bone marrow is the site of haematopoiesis, a highly important bodily process. We believe that our healthy bone marrow atlas is a valuable reference for studying bone marrow processes and bone marrow-related diseases. It can be mined for novel discoveries, as well as serve as a reference scaffold for mapping samples to identify and investigate abnormal cells.

Spatially informed clustering, integration, and deconvolution of spatial transcriptomics with GraphST.

Spatial transcriptomics technologies generate gene expression profiles with spatial context, requiring spatially informed analysis tools for three key tasks, spatial clustering, multisample integration, and cell-type deconvolution. We present GraphST, a graph self-supervised contrastive learning method that fully exploits spatial transcriptomics data to outperform existing methods. It combines graph neural networks with self-supervised contrastive learning to learn informative and discriminative spot representations by minimizing the embedding distance between spatially adjacent spots and vice versa. We demonstrated GraphST on multiple tissue types and technology platforms. GraphST achieved 10% higher clustering accuracy and better delineated fine-grained tissue structures in brain and embryo tissues. GraphST is also the only method that can jointly analyze multiple tissue slices in vertical or horizontal integration while correcting batch effects. Lastly, GraphST demonstrated superior cell-type deconvolution to capture spatial niches like lymph node germinal centers and exhausted tumor infiltrating T cells in breast tumor tissue.

Effects of Sodium Nitrate and Coated Methionine on Lactation Performance, Rumen Fermentation Characteristics, Amino Acid Metabolism, and Microbial Communities in Lactating Buffaloes.

Sodium nitrate is used as a non-protein nitrogen supplement while methionine is considered as a common methionine additive for ruminants. This study investigated the effects of sodium nitrate and coated methionine supplementation on milk yield, milk composition, rumen fermentation parameters, amino acid composition, and rumen microbial communities in lactating buffaloes. Forty mid-lactation multiparous Murrah buffaloes within the initial days in milk (DIM) = 180.83 ± 56.78 d, milk yield = 7.63 ± 0.19 kg, body weight = 645 ± 25 kg were selected and randomly allocated into four groups (N = 10). All of animals received the same total mixed ratio (TMR) diet. Furthermore, the groups were divided into the control group (CON), 70 g/d sodium nitrate group (SN), 15 g/d palmitate coated L-methionine group (MET), and 70 g/d sodium nitrate +15 g/d palmitate coated L-methionine group (SN+MET). The experiment lasted for six weeks, including two weeks of adaption. The results showed that most rumen-free amino acids, total essential amino acids, and total amino acids in Group SN increased (p < 0.05), while the dry matter intake (DMI) and rumen acetate, propionate, valerate, and total volatile fatty acids (TVFA) in Group MET decreased (p < 0.05). However, there was no significant difference in milk yield, milk protein, milk fat, lactose, total solid content, and sodium nitrate residue in milk among groups (p > 0.05). Group SN+MET had a decreased rumen propionate and valerate (p < 0.05), while increasing the Ace, Chao, and Simpson indices of alpha diversity of rumen bacteria. Proteobacteria and Actinobacteriota were significantly increased (p < 0.05) in Group SN+MET, but Bacteroidota, and Spirochaetota were decreased (p < 0.05). In addition, Group SN+MET also increased the relative abundance of Acinetobacter, Lactococcus, Microbacterium, Chryseobacterium, and Klebsiella, which were positively correlated with cysteine and negatively correlated with rumen acetate, propionate, valerate, and TVFA. Rikenellaceae_RC9_gut_group was identified as a biomarker in Group SN. Norank_f__UCG-011 was identified as a biomarker in Group MET. Acinetobacter, Kurthia, Bacillus, and Corynebacterium were identified as biomarkers in Group SN+MET. In conclusion, sodium nitrate increased rumen free amino acids, while methionine decreased dry matter intake (DMI) and rumen volatile fatty acids. The combined use of sodium nitrate and methionine enriched the species abundance of microorganisms in the rumen and affected the composition of microorganisms in the rumen. However, sodium nitrate, methionine, and their combination had no significant effect on the milk yield and milk composition. It was suggested that the combined use of sodium nitrate and methionine in buffalo production was more beneficial.

Cervical Cell Image Classification-Based Knowledge Distillation.

Current deep-learning-based cervical cell classification methods suffer from parameter redundancy and poor model generalization performance, which creates challenges for the intelligent classification of cervical cytology smear images. In this paper, we establish a method for such classification that combines transfer learning and knowledge distillation. This new method not only transfers common features between different source domain data, but also realizes model-to-model knowledge transfer using the unnormalized probability output between models as knowledge. A multi-exit classification network is then introduced as the student network, where a global context module is embedded in each exit branch. A self-distillation method is then proposed to fuse contextual information; deep classifiers in the student network guide shallow classifiers to learn, and multiple classifier outputs are fused using an average integration strategy to form a classifier with strong generalization performance. The experimental results show that the developed method achieves good results using the SIPaKMeD dataset. The accuracy, sensitivity, specificity, and F-measure of the five classifications are 98.52%, 98.53%, 98.68%, 98.59%, respectively. The effectiveness of the method is further verified on a natural image dataset.

Effect of Sodium Nitrate and Cysteamine on In Vitro Ruminal Fermentation, Amino Acid Metabolism and Microbiota in Buffalo.

Nitrate is used as a methane inhibitor while cysteamine is considered as a growth promoter in ruminants. The present study evaluated the effect of sodium nitrate and cysteamine on methane (CH4) production, rumen fermentation, amino acid (AA) metabolism, and rumen microbiota in a low protein diet. Four treatments containing a 0.5 g of substrate were supplemented with 1 mg/mL sodium nitrate (SN), 100 ppm cysteamine hydrochloride (CS), and a combination of SN 1 mg/mL and CS 100 ppm (CS+SN), and a control (no additive) were applied in a completely randomized design. Each treatment group had five replicates. Two experimental runs using in vitro batch culture technique were performed for two consecutive weeks. Total gas and CH4 production were measured in each fermentation bottle at 3, 6, 9, 12, 24, 48, and 72 h of incubation. The results showed that SN and CS+SN reduced the production of total gas and CH4, increased the rumen pH, acetate, acetate to propionate ratio (A/P), and microbial protein (MCP) contents (p < 0.05), but decreased other volatile fatty acids (VFA) and total VFA (p = 0.001). The CS had no effect on CH4 production and rumen fermentation parameters except for increasing A/P. The CSN increased the populations of total bacteria, fungi, and methanogens but decreased the diversity and richness of rumen microorganisms. In conclusion, CS+SN exhibited a positive effect on rumen fermentation by increasing the number of fiber degrading and hydrogen-utilizing bacteria, with a desirable impact on rumen fermentation while reducing total gas and CH4 production.

Cervical Cell/Clumps Detection in Cytology Images Using Transfer Learning.

Cervical cancer is one of the most common and deadliest cancers among women and poses a serious health risk. Automated screening and diagnosis of cervical cancer will help improve the accuracy of cervical cell screening. In recent years, there have been many studies conducted using deep learning methods for automatic cervical cancer screening and diagnosis. Deep-learning-based Convolutional Neural Network (CNN) models require large amounts of data for training, but large cervical cell datasets with annotations are difficult to obtain. Some studies have used transfer learning approaches to handle this problem. However, such studies used the same transfer learning method that is the backbone network initialization by the ImageNet pre-trained model in two different types of tasks, the detection and classification of cervical cell/clumps. Considering the differences between detection and classification tasks, this study proposes the use of COCO pre-trained models when using deep learning methods for cervical cell/clumps detection tasks to better handle limited data set problem at training time. To further improve the model detection performance, based on transfer learning, we conducted multi-scale training according to the actual situation of the dataset. Considering the effect of bounding box loss on the precision of cervical cell/clumps detection, we analyzed the effects of different bounding box losses on the detection performance of the model and demonstrated that using a loss function consistent with the type of pre-trained model can help improve the model performance. We analyzed the effect of mean and std of different datasets on the performance of the model. It was demonstrated that the detection performance was optimal when using the mean and std of the cervical cell dataset used in the current study. Ultimately, based on backbone Resnet50, the mean Average Precision (mAP) of the network model is 61.6% and Average Recall (AR) is 87.7%. Compared to the current values of 48.8% and 64.0% in the used dataset, the model detection performance is significantly improved by 12.8% and 23.7%, respectively.

Micropeptide MIAC inhibits the tumor progression by interacting with AQP2 and inhibiting EREG/EGFR signaling in renal cell carcinoma.

BACKGROUND: Although, micropeptides encoded by non-coding RNA have been shown to have an important role in a variety of tumors processes, there have been no reports on micropeptide in renal cell carcinoma (RCC). Based on the micropeptide MIAC (micropeptide inhibiting actin cytoskeleton) discovered and named in the previous work, this study screened its tumor spectrum, and explored its mechanism of action and potential diagnosis and treatment value in the occurrence and development of renal carcinoma. METHODS: The clinical significance of MIAC in RCC was explored by bioinformatics analysis through high-throughput RNA-seq data from 530 patients with kidney renal clear cell carcinoma (KIRC) in the TCGA database, and the detection of clinical samples of 70 cases of kidney cancer. In vitro and in vivo experiments to determine the role of MIAC in renal carcinoma cell growth and metastasis; High-throughput transcriptomics, western blotting, immunoprecipitation, molecular docking, affinity experiments, and Streptavidin pulldown experiments identify MIAC direct binding protein and key regulatory pathways. RESULTS: The analysis of 600 renal carcinoma samples from different sources revealed that the expression level of MIAC is significantly decreased, and corelated with the prognosis and clinical stage of tumors in patients with renal carcinoma. Overexpression of MIAC in renal carcinoma cells can significantly inhibit the proliferation and migration ability, promote apoptosis of renal carcinoma cells, and affect the distribution of cells at various stages. After knocking down MIAC, the trend is reversed. In vivo experiments have found that MIAC overexpression inhibit the growth and metastasis of RCC, while the synthetized MIAC peptides can significantly inhibit the occurrence and development of RCC in vitro and in vivo. Further mechanistic studies have demonstrated that MIAC directly bind to AQP2 protein, inhibit EREG/EGFR expression and activate downstream pathways PI3K/AKT and MAPK to achieve anti-tumor effects. CONCLUSIONS: This study revealed for the first time the tumor suppressor potential of the lncRNA-encoded micropeptide MIAC in RCC, which inhibits the activation of the EREG/EGFR signaling pathway by direct binding to AQP2 protein, thereby inhibiting renal carcinoma progression and metastasis. This result emphasizes that the micropeptide MIAC can provide a new strategy for the diagnosis and treatment of RCC.

Bone Marrow Mesenchymal Stem Cell-Derived Extracellular Vesicles Carrying circ_0050205 Attenuate Intervertebral Disc Degeneration.

Objective: It has been reported that bone marrow mesenchymal stem cells (BMSCs) are a potential source of autologous stem cells to support the nucleus pulposus (NP) regeneration in intervertebral disc degeneration (IDD). Herein, we aim to study the mechanism underlying the effects of BMSC-derived extracellular vesicles (BMSC-EVs) on nucleus pulposus cells (NPCs) in IDD. Methods: EVs were isolated from BMSCs. An IDD model was surgically established in C57BL/6J mice. NPCs were exposed to tBHP to establish an IDD cell model. RNA sequencing was performed to identify differentially expressed circRNAs in NP tissues harvested from mice with IDD. Interactions among circ_0050205, miR-665, and GPX4 were validated, and different interventions were used to study the roles of these molecules in NPC biological functions. Results: BMSC-EVs promoted NPC survival and inhibited NPC apoptosis and extracellular matrix (ECM) degradation. circ_0050205 expression was downregulated in the NP tissues of IDD mice, and BMSC-EVs facilitated NPC survival and suppressed ECM degradation in NPCs by transferring circ_0050205. circ_0050205 sponged miR-665 and upregulated GPX4 expression. BMSC-EVs expressing circ_0050205 promoted NPC survival-inhibited ECM degradation in NPCs and alleviated IDD in mice via the miR-665/GPX4 axis. Conclusion: In conclusion, BMSC-EVs promoted NPC survival-inhibited ECM degradation in NPCs and attenuated IDD progression via the circ_0050205/miR-665/GPX4 axis.

Trends in insulin resistance: insights into mechanisms and therapeutic strategy.

The centenary of insulin discovery represents an important opportunity to transform diabetes from a fatal diagnosis into a medically manageable chronic condition. Insulin is a key peptide hormone and mediates the systemic glucose metabolism in different tissues. Insulin resistance (IR) is a disordered biological response for insulin stimulation through the disruption of different molecular pathways in target tissues. Acquired conditions and genetic factors have been implicated in IR. Recent genetic and biochemical studies suggest that the dysregulated metabolic mediators released by adipose tissue including adipokines, cytokines, chemokines, excess lipids and toxic lipid metabolites promote IR in other tissues. IR is associated with several groups of abnormal syndromes that include obesity, diabetes, metabolic dysfunction-associated fatty liver disease (MAFLD), cardiovascular disease, polycystic ovary syndrome (PCOS), and other abnormalities. Although no medication is specifically approved to treat IR, we summarized the lifestyle changes and pharmacological medications that have been used as efficient intervention to improve insulin sensitivity. Ultimately, the systematic discussion of complex mechanism will help to identify potential new targets and treat the closely associated metabolic syndrome of IR.