Transcription factor EGR2 alleviates autoimmune uveitis via activation of GDF15 to modulate the retinal microglial phenotype.

Uveitis is a vision-threatening disease primarily driven by a dysregulated immune response, with retinal microglia playing a pivotal role in its progression. Although the transcription factor EGR2 is known to be closely associated with uveitis, including Vogt-Koyanagi-Harada disease and Behcet's disease, and is essential for maintaining the dynamic homeostasis of autoimmunity, its exact role in uveitis remains unclear. In this study, diminished EGR2 expression was observed in both retinal microglia from experimental autoimmune uveitis (EAU) mice and inflammation-induced human microglia cell line (HMC3). We constructed a mice model with conditional knockout of EGR2 in microglia and found that EGR2 deficiency resulted in increased intraocular inflammation. Meanwhile, EGR2 overexpression downregulated the expression of inflammatory cytokines as well as cell migration and proliferation in HMC3 cells. Next, RNA sequencing and ChIP-PCR results indicated that EGR2 directly bound to its downstream target growth differentiation factor 15 (GDF15) and further regulated GDF15 transcription. Furthermore, intravitreal injection of GDF15 recombinant protein was shown to ameliorate EAU progression in vivo. Meanwhile, knockdown of GDF15 reversed the phenotype of EGR2 overexpression-induced microglial inflammation in vitro. In summary, this study highlighted the protective role of the transcription factor EGR2 in AU by modulating the microglial phenotype. GFD15 was identified as a downstream target of EGR2, providing a unique target for uveitis treatment.

A postmeiotically bifurcated roadmap of honeybee spermatogenesis marked by phylogenetically restricted genes.

Haploid males of hymenopteran species produce gametes through an abortive meiosis I followed by meiosis II that can either be symmetric or asymmetric in different species. Thus, one spermatocyte could give rise to two spermatids with either equal or unequal amounts of cytoplasm. It is currently unknown what molecular features accompany these postmeiotic sperm cells especially in species with asymmetric meiosis II such as bees. Here we present testis single-cell RNA sequencing datasets from the honeybee (Apis mellifera) drones of 3 and 14 days after emergence (3d and 14d). We show that, while 3d testes exhibit active, ongoing spermatogenesis, 14d testes only have late-stage spermatids. We identify a postmeiotic bifurcation in the transcriptional roadmap during spermatogenesis, with cells progressing toward the annotated spermatids (SPT) and small spermatids (sSPT), respectively. Despite an overall similarity in their transcriptomic profiles, sSPTs express the fewest genes and the least RNA content among all the sperm cell types. Intriguingly, sSPTs exhibit a relatively high expression level for Hymenoptera-restricted genes and a high mutation load, suggesting that the special meiosis II during spermatogenesis in the honeybee is accompanied by phylogenetically young gene activities.

Accurate segmentation of intracellular organelle networks using low-level features and topological self-similarity.

MOTIVATION: Intracellular organelle networks (IONs) such as the endoplasmic reticulum (ER) network and the mitochondrial (MITO) network serve crucial physiological functions. The morphology of these networks plays a critical role in mediating their functions. Accurate image segmentation is required for analyzing the morphology and topology of these networks for applications such as molecular mechanism analysis and drug target screening. So far, however, progress has been hindered by their structural complexity and density. RESULTS: In this study, we first establish a rigorous performance baseline for accurate segmentation of these organelle networks from fluorescence microscopy images by optimizing a baseline U-Net model. We then develop the multi-resolution encoder (MRE) and the hierarchical fusion loss (Lhf) based on two inductive components, namely low-level features and topological self-similarity, to assist the model in better adapting to the task of segmenting IONs. Empowered by MRE and Lhf, both U-Net and Pyramid Vision Transformer (PVT) outperform competing state-of-the-art models such as U-Net++, HR-Net, nnU-Net, and TransUNet on custom datasets of the ER network and the MITO network, as well as on public datasets of another biological network, the retinal blood vessel network. In addition, integrating MRE and Lhf with models such as HR-Net and TransUNet also enhances their segmentation performance. These experimental results confirm the generalization capability and potential of our approach. Furthermore, accurate segmentation of the ER network enables analysis that provides novel insights into its dynamic morphological and topological properties. AVAILABILITY AND IMPLEMENTATION: Code and data are openly accessible at https://github.com/cbmi-group/MRE.

Enhancing Spns2/S1P in macrophages alleviates hyperinflammation and prevents immunosuppression in sepsis.

Sepsis is a leading cause of in-hospital mortality resulting from a dysregulated response to infection. Novel immunomodulatory therapies targeting macrophage metabolism have emerged as an important focus for current sepsis research. However, understanding the mechanisms underlying macrophage metabolic reprogramming and how they impact immune response requires further investigation. Here, we identify macrophage-expressed Spinster homolog 2 (Spns2), a major transporter of sphingosine-1-phosphate (S1P), as a crucial metabolic mediator that regulates inflammation through the lactate-reactive oxygen species (ROS) axis. Spns2 deficiency in macrophages significantly enhances glycolysis, thereby increasing intracellular lactate production. As a key effector, intracellular lactate promotes pro-inflammatory response by increasing ROS generation. The overactivity of the lactate-ROS axis drives lethal hyperinflammation during the early phase of sepsis. Furthermore, diminished Spns2/S1P signaling impairs the ability of macrophages to sustain an antibacterial response, leading to significant innate immunosuppression in the late stage of infection. Notably, reinforcing Spns2/S1P signaling contributes to balancing the immune response during sepsis, preventing both early hyperinflammation and later immunosuppression, making it a promising therapeutic target for sepsis.

Icariin alleviates oxygen-induced retinopathy by targeting microglia hexokinase 2.

Retinopathy of prematurity (ROP) is a retinal disease-causing retinal neovascularization that can lead to blindness. Oxygen-induced retinopathy (OIR) is a widely used ROP animal model. Icariin (ICA) has anti-oxidative and anti-inflammation properties; however, whether ICA has a regulatory effect on OIR remains unclear. In this study, ICA alleviated pathological neovascularization, microglial activation and blood-retina barrier (BRB) damage in vivo. Further results indicated that endothelial cell tube formation, migration and proliferation were restored by ICA treatment in vitro. Proteomic microarrays and molecular mimicry revealed that ICA can directly bind to hexokinase 2 (HK2) and decrease HK2 protein expression in vivo and in vitro. In addition, ICA inhibited the AKT/mTOR/HIF1α pathway activation. The effects of ICA on pathological neovascularization, microglial activation and BRB damage disappeared after HK2 overexpression in vivo. Similarly, the endothelial cell function was revised after HK2 overexpression. HK2 overexpression reversed ICA-induced AKT/mTOR/HIF1α pathway inhibition in vivo and in vitro. Therefore, ICA prevented pathological angiogenesis in OIR in an HK2-dependent manner, implicating ICA as a potential therapeutic agent for ROP.

Metabolic perturbation and oxidative damage induced by tris(1,3-dichloro-2-propyl) phosphate (TDCIPP) and tris(2-ethylhexyl) phosphate (TEHP) on Escherichia coli through integrative analyses of metabolome.

Organophosphate esters (OPEs) are one of the emerging environmental threats, causing the hazard to ecosystem safety and human health. Yet, the toxic effects and metabolic response mechanism after Escherichia coli (E.coli) exposed to TDCIPP and TEHP is inconclusive. Herein, the levels of SOD and CAT were elevated in a concentration-dependent manner, accompanied with the increase of MDA contents, signifying the activation of antioxidant response and occurrence of lipid peroxidation. Oxidative damage mediated by excessive accumulation of ROS decreased membrane potential and inhibited membrane protein synthesis, causing membrane protein dysfunction. Integrative analyses of GC-MS and LC-MS based metabolomics evinced that significant perturbation to the carbohydrate metabolism, nucleotide metabolism, lipids metabolism, amino acid metabolism, organic acids metabolism were induced following exposure to TDCIPP and TEHP in E.coli, resulting in metabolic reprogramming. Additionally, metabolites including PE(16:1(5Z)/15:0), PA(17:0/15:1(9Z)), PC(20:2(11Z,14Z)/12:0), LysoPC(18:3(6Z,9Z,12Z)/0:0) were significantly upregulated, manifesting that cell membrane protective molecule was afforded by these differential metabolites to improve permeability and fluidity. Overall, current findings generate new insights into the molecular toxicity mechanism by which E.coli respond to TDCIPP and TEHP stress and supply valuable information for potential ecological risks of OPEs on aquatic ecosystems.

A three-dimensional (3D) printed simulator as a feasible assessment tool for evaluating hip arthroscopy skills.

PURPOSE: The aims of this study were (1) to develop a three-dimensional (3D) printed simulator that facilitates the simulation of surgical skills for portal placement, intra-articular identification of anatomical structures and arthroscope navigation for hip arthroscopy and (2) to concurrently examine the feasibility of using this simulator as an assessment tool to evaluate trainees' surgical competencies. METHODS: A simulator was developed using a combination of medical imaging, computer-aided design, and 3D printing. A cross-sectional study was conducted with 29 participants divided into 3 subgroups (novice, intermediate and experienced). All participants performed related skills on the simulator, and their performance was evaluated using different assessment parameters. The participants' qualitative feedback regarding the simulator was also collected. The data collated from each group of participants were subsequently compared. RESULTS: Significant differences were observed between the three subgroups of participants with regard to the total checklist score (F2,26 = 11.3), total Arthroscopic Surgical Skill Evaluation score (F2,26 = 92.1), overall final global rating scale score (F2,26 = 49), number of times the participants used fluoroscopy (F2,26 = 7.4), and task completion times (F2,26 = 23.5). The participants' performance in the simulated operation was correlated with their prior clinical experience. There was mainly positive feedback with regard to the fidelity and utility of the simulator in relation to the surgeons' prior clinical experience. CONCLUSIONS: This study demonstrated that a reliable hip arthroscopic simulator can be developed for use by orthopedic surgeons to evaluate their hip arthroscopic skills before performing actual surgical operations. LEVEL OF EVIDENCE: Level III.

Pueraria thomsonii Radix Water Extract Alleviate Type 2 Diabetes Mellitus in db/db Mice through Comprehensive Regulation of Metabolism and Gut Microbiota.

Type 2 diabetes mellitus (T2DM) is an increasingly prevalent and serious health problem. Its onset is typically associated with metabolic disorders and disturbances in the gut microbiota. Previous studies have reported the anti-T2DM effects of Pueraria thomsonii Radix as a functional food. However, the mechanism of action is still unknown. In this study, rich polyphenols and polysaccharides from Pueraria Thomsonii Radix water extract (PTR) were quantitatively determined, and then the effects of PTR on db/db mice were evaluated by pharmacology, metabolomics, and 16S rRNA gene sequencing. The results showed that PTR could alleviate pancreatic tissue damage, significantly decrease fasting blood glucose (FBG), fasting serum insulin (FINS), homeostasis model assessment insulin resistance (HOMA-IR), urinary glucose (UGLU), and urinary albumin/creatinine ratio (UACR). Metabolomics showed that the Diabetes Control (DM) group produced 109 differential metabolites, of which 74 could be regulated by PTR. In addition, 16S rRNA sequencing was performed in fecal samples and results showed that PTR could reduce the Firmicutes/Bacteroidetes(F/B) ratio and regulate three beneficial bacteria and one harmful bacterium. In conclusion, the results showed that PTR could ameliorate the T2DM symptoms, metabolic disorder, and gut microbiota imbalance of db/db mice, and it was superior to metformin in some aspects. We suggested for the first time that γ-aminobutyric acid (GABA) may be involved in the regulation of the microbiota-gut-brain axis (MGB) and thus affects the metabolic disorders associated with T2DM. This study will provide a scientific basis for the development of functional food with PTR.

Genus-Wide Characterization of Bumblebee Genomes Provides Insights into Their Evolution and Variation in Ecological and Behavioral Traits.

Bumblebees are a diverse group of globally important pollinators in natural ecosystems and for agricultural food production. With both eusocial and solitary life-cycle phases, and some social parasite species, they are especially interesting models to understand social evolution, behavior, and ecology. Reports of many species in decline point to pathogen transmission, habitat loss, pesticide usage, and global climate change, as interconnected causes. These threats to bumblebee diversity make our reliance on a handful of well-studied species for agricultural pollination particularly precarious. To broadly sample bumblebee genomic and phenotypic diversity, we de novo sequenced and assembled the genomes of 17 species, representing all 15 subgenera, producing the first genus-wide quantification of genetic and genomic variation potentially underlying key ecological and behavioral traits. The species phylogeny resolves subgenera relationships, whereas incomplete lineage sorting likely drives high levels of gene tree discordance. Five chromosome-level assemblies show a stable 18-chromosome karyotype, with major rearrangements creating 25 chromosomes in social parasites. Differential transposable element activity drives changes in genome sizes, with putative domestications of repetitive sequences influencing gene coding and regulatory potential. Dynamically evolving gene families and signatures of positive selection point to genus-wide variation in processes linked to foraging, diet and metabolism, immunity and detoxification, as well as adaptations for life at high altitudes. Our study reveals how bumblebee genes and genomes have evolved across the Bombus phylogeny and identifies variations potentially linked to key ecological and behavioral traits of these important pollinators.

Genome-wide analysis of the NAAT, DMAS, TOM, and ENA gene families in maize suggests their roles in mediating iron homeostasis.

BACKGROUND: Nicotianamine (NA), 2'-deoxymugineic acid (DMA), and mugineic acid (MA) are chelators required for iron uptake and transport in plants. Nicotianamine aminotransferase (NAAT), 2'-deoxymugineic acid synthase (DMAS), transporter of MAs (TOM), and efflux transporter of NA (ENA) are involved in iron uptake and transport in rice (Oryza sativa), wheat (Triticum aestivum), and barley (Hordeum vulgare); however, these families have not been fully identified and comprehensively analyzed in maize (Zea mays L.). RESULTS: Here, we identified 5 ZmNAAT, 9 ZmDMAS, 11 ZmTOM, and 2 ZmENA genes by genome mining. RNA-sequencing and quantitative real-time PCR analysis revealed that these genes are expressed in various tissues and respond differently to high and low iron conditions. In particular, iron deficiency stimulated the expression of ZmDMAS1, ZmTOM1, ZmTOM3, and ZmENA1. Furthermore, we determined protein subcellular localization by transient expression of green fluorescent protein fusions in maize mesophyll protoplasts. ZmNAAT1, ZmNAAT-L4, ZmDMAS1, and ZmDMAS-L1 localized in the cytoplasm, whereas ZmTOMs and ZmENAs targeted to plasma and tonoplast membranes, endomembranes, and vesicles. CONCLUSIONS: Our results suggest that the different gene expression profiles and subcellular localizations of ZmNAAT, ZmDMAS, ZmTOM, and ZmENA family members may enable specific regulation of phytosiderophore metabolism in different tissues and under different external conditions, shedding light on iron homeostasis in maize and providing candidate genes for breeding iron-rich maize varieties.

The role of non-apoptotic cell death in the treatment and drug-resistance of digestive tumors.

Tumor cell apoptosis evasion is one of the main reasons for easy metastasis occurrence, chemotherapy resistance, and the low five-year survival rate of digestive system tumors. Current research has shown that non-apoptotic cell death plays an important role in tumors of the digestive system. Therefore, increasing the proportion of non-apoptotic tumor cells is one of the effective methods of improving therapeutic efficacies for digestive system tumors. Non-apoptotic cell death modes mainly include autophagic cell death, pyroptosis, ferroptosis, in addition to other cell death modes. This review covers a systematic review relating to the research progress made into autophagic cell death, pyroptosis, ferroptosis, and other cell death modes in the treatment of digestive system tumors. It also highlights how treatment is a reasonable prospect based on clinical experience and provides reliable guidance for the further development of digestive system tumor treatments.

Ultrasound shear wave elastography-derived tissue stiffness is positively correlated with rotator cuff tear size and muscular degeneration.

PURPOSE: The purpose of this study is to describe rotator cuff muscle stiffness in patients with different degrees of rotator cuff tear (RCT) severity and to assess its predictive ability for RCT reparability. METHODS: One hundred and thirty-three consecutive patients who were scheduled to undergo arthroscopic shoulder surgery were prospectively enrolled. Tendon retraction, fatty infiltration, and muscle atrophy were evaluated using magnetic resonance imaging. Shear modulus of supraspinatus (SSP) and infraspinatus (ISP) muscles were measured by ultrasound shear wave elastography (SWE). The tear size and reparability were determined intraoperatively. RESULTS: There were 97 patients in RCT group and 36 patients in control group. Bilateral shear modulus discrepancy (Δshear modulus) was used to represent rotator cuff stiffness. Severely fatty-infiltrated rotator cuff muscles possessed a significantly higher stiffness compared with their counterparts (SSP: CI 27.8-31.8 vs. 13.5-15.6 kPa, ISP: CI 33.2-38.1 vs. 8.8-11.2 kPa, p < 0.001). The same trend applied to muscles with distinct tendon retraction (SSP: CI 27.7-32.3 vs. 10.9-14.9 kPa, ISP: CI 33.2-38.6 vs. 6.5-11.0 kPa, p < 0.001) and obvious muscle atrophy (SSP: CI 27.9-32.1 vs. 13.6-15.8 kPa, ISP: CI 32.9-38.2 vs. 9.0-11.7 kPa, p < 0.001). Irreparable massive RCT (MRCT) patients had significantly stiffer SSP (CI 27.7-31.9 vs. 13.5-16.5 kPa, p < 0.001) and ISP (CI 33.5-37.8 vs. 10.3-14.8 kPa, p < 0.001) than reparable MRCT. The Δshear modulus of the ISP was a highly accurate predictor of RCT reparability. A cutoff value of 18.0 kPa had a sensitivity of 100% and specificity of 98.8% for irreparable MRCT. CONCLUSION: Ultrasound SWE-derived rotator cuff muscle stiffness is closely correlated with RCT size and severity. LEVEL OF EVIDENCE: I.

Bulk Nanostructured Metal from Multiply-Twinned Nanowires.

Using chemically synthesized silver nanowires with 5-fold twinning planes as a model system, a bottom-up process to generate a bulk nanostructured metal has been demonstrated. Although the nanowires would be shortened and deformed during densification, they are chosen as a model system because they are currently the most scalable and convenient way to obtain Ag particles with high twinning densities. Direct cold pressing of a silver nanowire filter cake did not generate a sufficiently cohesive sample, while hot pressing at 190 °C for 8 h resulted in extensive sintering, eliminating the nanowire morphology. Copper was then electroplated on the silver nanowires as a binder and filler to increase the densification upon hot pressing; despite nonuniform plating across the thickness of the filter cake, the thermal stability of the nanowires was increased, allowing hot pressing at 390 °C. Finally, a uniform copper coating on silver nanowires was achieved by electroless plating, leading to cohesive bulk metal after hot pressing.

Mechanical property and heavy metal leaching behavior enhancement of municipal solid waste incineration fly ash during the pressure-assisted sintering treatment.

The conventional sintering process of municipal solid waste incineration (MSWI) fly ash is always energy intensive. The process forms a cracked structure because of the difficulty in forming the liquid phase to enhance the mass transfer process. Therefore, exploring a new disposal method to simultaneously decrease the sintering temperature and improve the mechanical and heavy metal leaching properties of sintered samples is necessary. In this study, a pressure-assisted sintering treatment was introduced to dispose fly ash by varying the chemical composition and mechanical pressure at relatively low temperatures (300-500 °C). The results revealed that the compressive strength of treated samples increased with the CaO/SiO2 molar ratio increasing from 0.5 to 1.0, and a maximum value of 238.28 ± 8.50 MPa was obtained. The heavy metal leaching concentration results demonstrated a low risk of contamination in the treated samples. Microstructure analyses suggested that the densification process was enhanced with increased mechanical pressure, and the formed calcium silicates and aluminosilicates positively affected the compressive strength. Moreover, smaller crystal lattices were observed during aggregation formation, suggesting the restraint of anomalous crystal growth, which accelerated the densification process and increased the compressive strength. Moreover, the mass transfer process during the pressure-assisted sintering process was enhanced compared with the conventional thermal process, which was reflected by the transformation of elements from homogeneous to heterogeneous distribution. Therefore, the improved mechanical properties and leaching behavior of heavy metals were attributed to the densified microstructure, formation of new minerals, and enhanced driving force during the pressure-assisted sintering process. These findings suggest that pressure-assisted sintering is a promising method for maximizing the reutilization and minimizing the energy consumption simultaneously to dispose fly ash.

M2b macrophages stimulate lymphangiogenesis to reduce myocardial fibrosis after myocardial ischaemia/reperfusion injury.

CONTEXT: Therapeutic lymphangiogenesis is a new treatment for cardiovascular diseases. Our previous study showed M2b macrophages can alleviate myocardial ischaemia/reperfusion injury (MI/RI). However, the relation between M2b macrophages and lymphangiogenesis is not clear. OBJECTIVE: To investigate the effects of M2b macrophages on lymphangiogenesis after MI/RI. MATERIALS AND METHODS: Forty male Sprague-Dawley (SD) rats were randomized into Sham operation group (control, n = 8), MI/RI group (n = 16) and M2b macrophage transplantation group (n = 16). M2b macrophages (1 × 106) in 100 µL of normal saline or the same volume of vehicle was injected into the cardiac ischaemic zone. Two weeks later, echocardiography and lymphatic counts were performed, and the extent of myocardial fibrosis and the expression of vascular endothelial growth factor C (VEGFC) and VEGF receptor 3 (VEGFR3) were determined. In vitro, lymphatic endothelial cells (LECs) were cultured with M2b macrophages for 6-24 h, and the proliferation, migration and tube formation of the LECs were assessed. RESULTS: In vivo, M2b macrophage transplantation increased the level of lymphangiogenesis 2.11-fold, reduced 4.42% fibrosis, improved 18.65% left ventricular ejection fraction (LVEF) and upregulated the expressions of VEGFC and VEGFR3. In vitro, M2b macrophage increased the proliferation, migration, tube formation and VEGFC expression of LECs. M2b macrophage supernatant upregulated VEGFR3 expression of LECs. DISCUSSION AND CONCLUSIONS: Our study shows that M2b macrophages can promote lymphangiogenesis to reduce myocardial fibrosis and improve heart function, suggesting the possible use of M2b macrophage for myocardial protection therapy.

The typically developing pediatric foot - The data of the 1744 children in China.

BACKGROUND: The medial longitudinal arch (MLA) improves with age in childhood. However, it still causes parents to worry that children have flat feet. Due to the lack of a standard to quantitatively assess the arch development in kids at certain age, the pediatricians judge the flat feet by experience, causing many cases to be overtreated. The aim of this study was to plot the distribution of MLA parameters in children. METHODS: Children without lower limb deformity and lower limb pain were recruited from 12 primary schools and kindergartens in Chongqing province-level city. Foot length (FL) and navicular height (NH) was measured manually, arch index (AI) and arch volume (AV) were measured with the Foot Plantar Scanner. Each parameter was measured in both weight-bearing and non-weight-bearing positions. Significant differences were also compared between the measurements of consecutive years. RESULTS: This study was the first to use a three-dimensional laser surface scanner to measure the MLA parameters of children aged 3-12 years in China. 1744 children (871 girls, 873 boys) participated in this study. FL, NH, AI and AV varied significantly with age in both the weight-bearing and non-weight-bearing positions. These parameters have significant differences between the weighted and non-weighted positions (p < 0.05). CONCLUSIONS: The age distribution characteristics of these parameters indicated that the MLA improves with age. The establishment of a developmental scale for the children's MLA is necessary.

Astragalus polysaccharide attenuates LPS-related inflammatory osteolysis by suppressing osteoclastogenesis by reducing the MAPK signalling pathway.

Bacterial products can stimulate inflammatory reaction and activate immune cells to enhance the production of inflammatory cytokines, and finally promote osteoclasts recruitment and activity, leading to bone destruction. Unfortunately, effective preventive and treatment measures for inflammatory osteolysis are limited and usually confuse the orthopedist. Astragalus polysaccharide (APS), the main extractive of Astragali Radix, has been widely used for treating inflammatory diseases. In the current study, in vitro and in vivo experimental results demonstrated that APS notably inhibited osteoclast formation and differentiation dose-dependently. Moreover, we found that APS down-regulated RANKL-related osteoclastogenesis and levels of osteoclast marker genes, such as NFATC1, TRAP, c-FOS and cathepsin K. Further underlying mechanism investigation revealed that APS attenuated activity of MAPK signalling pathways (eg ERK, JNK and p38) and ROS production induced by RANKL. Additionally, APS was also found to suppress LPS-related inflammatory osteolysis by decreasing inflammatory factors' production in vivo. Overall, our findings demonstrate that APS effectively down-regulates inflammatory osteolysis due to osteoclast differentiation and has the potential to become an effective treatment of the disorders associated with osteoclast.

Comprehensive analysis of EMT-related genes and lncRNAs in the prognosis, immunity, and drug treatment of colorectal cancer.

BACKGROUND: EMT is an important biological process in the mechanism of tumor invasion and metastasis. However, there are still many unknowns about the specific mechanism of EMT in tumor. At present, a comprehensive analysis of EMT-related genes in colorectal cancer (CRC) is still lacking. METHODS: All the data were downloaded from public databases including TCGA database (488 tumor samples and 52 normal samples) as the training set and the GEO database (GSE40967 including 566 tumor samples and 19 normal samples, GSE12945 including 62 tumor samples, GSE17536 including 177 tumor samples, GSE17537 including 55 tumor samples) as the validation sets. One hundred and sixty-six EMT-related genes (EMT-RDGs) were selected from the Molecular Signatures Database. Bioinformatics methods were used to analyze the correlation between EMT-RDGs and CRC prognosis, metastasis, drug efficacy, and immunity. RESULTS: We finally obtained nine prognostic-related EMT-RDGs (FGF8, NOG, PHLDB2, SIX2, SNAI1, TBX5, TIAM1, TWIST1, TCF15) through differential expression analysis, Unicox and Lasso regression analysis, and then constructed a risk prognosis model. There were significant differences in clinical characteristics, 22 immune cells, and immune functions between the high-risk and low-risk groups and the different states of the nine prognostic-related EMT-RDGs. The methylation level and mutation status of nine prognostic-related EMT-RDGs all affect their regulation of EMT. The Cox proportional hazards regression model was also constructed by the methylation sites of nine prognostic-related EMT-RDGs. In addition, the expression of FGF8, PHLDB2, SIX2, and SNAIL was higher and the expression level of NOG and TWIST1 was lower in the non-metastasis CRC group. Nine prognostic-related EMT-RDGs also affected the drug treatment response of CRC. CONCLUSIONS: Targeting these nine prognostic-related EMT-RDGs can regulate CRC metastasis and immune, which is beneficial for the prognosis of CRC patients, improve drug sensitivity in CRC patients.

Irisin, an exercise myokine, potently suppresses tumor proliferation, invasion, and growth in glioma.

Glioblastoma multiforme is the most common and aggressive glial tumor with poor prognosis. Importantly, effective treatment options for glioblastoma are unmet needs. Obesity and low physical activity have been linked with a high risk of cancer, and exercise is related to delayed cancer development and progression. Epidemiological studies have revealed a correlation between exercise and the survival rate of patients with glioblastoma. Nevertheless, the mechanisms by which exercise exerts its anticancer effects in glioblastoma remain unclear. Here, we found that irisin, an exercise-induced myokine, induced G2 /M cell cycle arrest and increased p21 levels in glioblastoma cells, leading to the inhibition of cell proliferation. In addition, irisin inhibited glioblastoma cell invasion by upregulating TFPI-2 and even reversed the aggressive tumor phenotype promoted by co-cultivation with cancer-associated adipocytes. Furthermore, irisin retarded xenograft glioblastoma tumor growth, and radiolabeled irisin demonstrated specific tumor-targeting capability in vivo. Therefore, this study identified one potential molecular mechanism by which exercise prevents cancer progression via irisin. Intriguingly, irisin has the potential to be developed as a molecular imaging and therapeutic anticancer agent.

Global allele polymorphism indicates a high rate of allele genesis at a locus under balancing selection.

When selection favours rare alleles over common ones (balancing selection in the form of negative frequency-dependent selection), a locus may maintain a large number of alleles, each at similar frequency. To better understand how allelic richness is generated and maintained at such loci, we assessed 201 sequences of the complementary sex determiner (csd) of the Asian honeybee (Apis cerana), sampled from across its range. Honeybees are haplodiploid; hemizygotes at csd develop as males and heterozygotes as females, while homozygosity is lethal. Thus, csd is under strong negative frequency-dependent selection because rare alleles are less likely to end up in the lethal homozygous form. We find that in A. cerana, as in other Apis, just a few amino acid differences between csd alleles in the hypervariable region are sufficient to trigger female development. We then show that while allelic lineages are spread across geographical regions, allelic differentiation is high between populations, with most csd alleles (86.3%) detected in only one sample location. Furthermore, nucleotide diversity in the hypervariable region indicates an excess of recently arisen alleles, possibly associated with population expansion across Asia since the last glacial maximum. Only the newly invasive populations of the Austral-Pacific share most of their csd alleles. In all, the geographic patterns of csd diversity in A. cerana indicate that high mutation rates and balancing selection act together to produce high rates of allele genesis and turnover at the honeybee sex locus, which in turn leads to its exceptionally high local and global polymorphism.