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OBJECTIVE: This study aimed to distinguish tuberculous spondylodiscitis (TS) from pyogenic spondylodiscitis (PS) based on laboratory, magnetic resonance imaging (MRI) and computed tomography (CT) findings. Further, a novel diagnostic model for differential diagnosis was developed. METHODS: We obtained MRI, CT and laboratory data from TS and PS patients. Predictive models were built using binary logistic regression analysis. The receiver operating characteristic curve was analyzed. Both internal and external validation was performed. RESULTS: A total of 81 patients with PS (n = 46) or TS (n = 35) were enrolled. All patients had etiological evidence from the focal lesion. Disc signal or height preservation, skip lesion or multi segment (involved segments ≥ 3) involvement, paravertebral calcification, massive sequestra formation, subligamentous bone destruction, bone erosion with osteosclerotic margin, higher White Blood Cell Count (WBC) and positive result of tuberculosis infection T cell spot test (T-SPOT.TB) were more prevalent in the TS group. A diagnostic model was developed and included four predictors: WBC<7.265 * (10^9/L), skip lesion or involved segments ≥ 3, massive sequestra formation and subligamentous bone destruction. The model showed good sensitivity, specificity, and total accuracy (91.4%, 95.7%, and 93.8%, respectively); the area under the receiver operating characteristic curve (AUC) was 0.981, similar to the results of internal validation using bootstrap resampling (1000 replicates) and external validation set, indicating good clinical predictive ability. CONCLUSIONS: This study develop a good diagnostic model based on both CT and MRI, as well as laboratory findings, which may help clinicians distinguish between TS and PS.
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BACKGROUND: Heterotopic mesenteric ossification (HMO) is a clinically rare condition characterized by the formation of bone tissue in the mesentery. The worldwide reporting of such cases is limited to just over 70 instances in the medical literature. The etiology of HMO remains unclear, but the disease is possibly induced by mechanical trauma, ischemia, or intra-left lower quadrant abdominal infection, leading to the differentiation of mesenchymal stem cells into osteoblasts. Here, we present a rare case of HMO that occurred in a 34-year-old male, who presented with left lower quadrant abdominal pain. CASE SUMMARY: We report the case of a 34-year-old male patient who presented with left lower abdominal pain following trauma to the left lower abdomen. He subsequently underwent surgical treatment, and the postoperative pathological diagnosis was HMO. CONCLUSION: We believe that although there is limited literature and research on HMO, when patients with a history of trauma or surgery to the left lower abdomen present with corresponding imaging findings, clinicians should be vigilant in distinguishing this condition and promptly selecting appropriate diagnostic and therapeutic interventions.
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Background: Cancer stem cells (CSCs) are pivotal in tumor resistance to chemotherapy and gastric cancer's rapid proliferation and metastasis. We aimed to explore the CSCs-related genes in gastric cancer epithelial cells. Methods: The mRNA expression profile and single-cell sequencing data of gastric cancer were downloaded from the public database. Results: We identified WDR72 as a CSCs-related gene in gastric cancer epithelial cells. WDR72 was highly expressed in gastric cancer tissues, and high expression of WDR72 was associated with inferior prognosis of patients. WDR72 expression had a significant negative correlation with the infiltration of CD8 + T cells and activated memory CD4 + T cells. PD-L1 expression was significantly reduced in gastric cancer patients with high WDR72 expression. WDR72 was correlated with IC50 of multiple small-molecule drugs. Conclusion: We identified a novel CSCs-related gene in gastric cancer epithelial cells, WDR72, which was highly expressed in patients with high stemness scores.
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The final step in the de novo synthesis of cytidine 5'-triphosphate (CTP) is catalyzed by CTP synthase (CTPS), which can form cytoophidia in all three domains of life. Recently, we have discovered that CTPS binds to ribonucleotides (NTPs) to form filaments, and have successfully solved the structures of Drosophila melanogaster CTPS bound with NTPs. Previous biochemical studies have shown that CTPS can bind to deoxyribonucleotides (dNTPs) to produce 2'-deoxycytidine-5'-triphosphate (dCTP). However, the structural basis of CTPS binding to dNTPs is still unclear. In this study, we find that Drosophila CTPS can also form filaments with dNTPs. Using cryo-electron microscopy, we are able to solve the structure of Drosophila melanogaster CTPS bound to dNTPs with a resolution of up to 2.7 Å. By combining these structural findings with biochemical analysis, we compare the binding and reaction characteristics of NTPs and dNTPs with CTPS. Our results indicate that the same enzyme can act bifunctionally as CTP/dCTP synthase in vitro, and provide a structural basis for these activities.
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BACKGROUND: Peptide transporter 1 (PepT1) transports bacterial oligopeptide products and induces inflammation of the bowel. Nutritional peptides compete for the binding of intestinal bacterial products to PepT1. We investigated the mechanism of short-peptide-based enteral nutrition (SPEN) on the damage to the gut caused by the bacterial oligopeptide product muramyl dipeptide (MDP), which is transported by PepT1. The gut-lung axis is a shared mucosal immune system, and immune responses and disorders can affect the gut-respiratory relationship. METHODS AND RESULTS: Sprague-Dawley rats were gavaged with solutions containing MDP, MDP + SPEN, MDP + intact-protein-based enteral nutrition (IPEN), glucose as a control, or glucose with GSK669 (a NOD2 antagonist). Inflammation, mitochondrial damage, autophagy, and apoptosis were explored to determine the role of the PepT1-nucleotide-binding oligomerization domain-containing protein 2 (NOD2)-beclin-1 signaling pathway in the small intestinal mucosa. MDP and proinflammatory factors of lung tissue were explored to determine that MDP can migrate to lung tissue and cause inflammation. Induction of proinflammatory cell accumulation and intestinal damage in MDP gavage rats was associated with increased NOD2 and Beclin-1 mRNA expression. IL-6 and TNF-α expression and apoptosis were increased, and mitochondrial damage was severe, as indicated by increased mtDNA in the MDP group compared with controls. MDP levels and expression of proinflammatory factors in lung tissue increased in the MDP group compared with the control group. SPEN, but not IPEN, eliminated these impacts. CONCLUSIONS: Gavage of MDP to rats resulted in damage to the gut-lung axis. SPEN reverses the adverse effects of MDP. The PepT1-NOD2-beclin-1 pathway plays a role in small intestinal inflammation, mitochondrial damage, autophagy, and apoptosis.
Subject(s)
Acetylmuramyl-Alanyl-Isoglutamine , Beclin-1 , Enteral Nutrition , Lung Injury , Nod2 Signaling Adaptor Protein , Peptide Transporter 1 , Rats, Sprague-Dawley , Signal Transduction , Animals , Peptide Transporter 1/metabolism , Peptide Transporter 1/genetics , Rats , Beclin-1/metabolism , Beclin-1/genetics , Nod2 Signaling Adaptor Protein/metabolism , Nod2 Signaling Adaptor Protein/genetics , Signal Transduction/drug effects , Lung Injury/metabolism , Male , Acetylmuramyl-Alanyl-Isoglutamine/pharmacology , Enteral Nutrition/methods , Apoptosis/drug effects , Intestinal Mucosa/metabolism , Intestinal Mucosa/drug effects , Intestinal Mucosa/pathology , Autophagy/drug effects , Lung/metabolism , Lung/pathology , Lung/drug effects , Inflammation/metabolismABSTRACT
BACKGROUND: The index of microcirculatory resistance is a reliable measure for evaluating coronary microvasculature, but its prognostic value in patients with non-ST-segment elevation myocardial infarction (NSTEMI) remains unclear. OBJECTIVES: This study aimed to evaluate the prognostic impact of post-percutaneous coronary intervention (PCI) angiography-derived index of microcirculatory resistance (angio-IMR) in patients with NSTEMI. METHODS: The culprit vessel's angio-IMR was measured after PCI in 2,212 NSTEMI patients at 3 sites. The primary endpoint was 2-year major adverse cardiac events (MACEs), defined as a composite of cardiac death, readmission for heart failure, myocardial reinfarction, and target vessel revascularization. RESULTS: The mean post-PCI angio-IMR was 20.63 ± 4.17 in NSTEMI patients. Two hundred six patients were categorized as the high post-PCI angio-IMR group according to maximally selected log-rank statistics. Patients with angio-IMR >25 showed a higher rate of MACEs than those with angio-IMR ≤25 (32.52% vs 9.37%; P < 0.001). Post-PCI angio-IMR >25 was an independent predictor of MACEs (HR: 4.230; 95% CI: 3.151-5.679; P < 0.001) and showed incremental prognostic value compared with conventional risk factors (AUC: 0.774 vs 0.716; P < 0.001; net reclassification index: 0.317; P < 0.001; integrated discrimination improvement: 0.075; P < 0.001). CONCLUSIONS: In patients undergoing PCI for NSTEMI, an increased post-PCI angio-IMR is associated with a higher risk of MACEs. The addition of post-PCI angio-IMR into conventional risk factors significantly improves the ability to reclassify patients and estimate the risk of MACEs. (Angiograph-Derived Index of Microcirculatory Resistance in Patients With Acute Myocardial Infarction; NCT05696379).
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BACKGROUND: Uterine endometrial cancer (UEC) is a common gynecological estrogen-dependent carcinoma, usually accompanied by intermenstrual bleeding. Active heme metabolism frequently plays an increasingly important role in many diseases, especially in cancers. Tumor-associated macrophages (TAMs) are the major population in the immune microenvironment of UEC. However, the roles of heme metabolisms in the crosstalk between UEC cells (UECCs) and macrophages are unclear. MATERIALS AND METHODS: In our study, by using TCGA database analysis, integration analysis of the protein-protein interaction (PPI) network and sample RNA transcriptome sequencing were done. The expression level of both heme-associated molecules and iron metabolism-related molecules were measured by quantitative real-time polymerase chain reaction. Heme level detection was done through dehydrohorseradish peroxidase assay. In addition to immunohistochemistry, phagocytosis assay of macrophages, immunofluorescence staining, intracellular ferrous iron staining, as well as enzyme-linked immune sorbent assay were performed. RESULTS: In the study, we verified that heme accumulation in UECCs is apparently higher than in endometrial epithelium cells. Low expression of succinate dehydrogenase B under the regulation of estrogen contributes to over-production of succinate and heme accumulation in UECC. More importantly, excessive heme in UECCs impaired macrophage phagocytosis by regulation of CD36. Mechanistically, this process is dependent on toll-like receptor (TLR4)/type I interferons alpha (IFN Iα) regulatory axis in macrophage. CONCLUSION: Collectively, these findings elucidate that active heme metabolism of UECCs directly decreases phagocytosis by controlling the secretion of TLR4-mediated IFN Iα and the expression of CD36, and further contributing to the immune escape of UEC.
Subject(s)
CD36 Antigens , Endometrial Neoplasms , Heme , Interferon Type I , Phagocytosis , Signal Transduction , Toll-Like Receptor 4 , Female , Humans , Toll-Like Receptor 4/metabolism , Heme/metabolism , Endometrial Neoplasms/immunology , Endometrial Neoplasms/metabolism , Interferon Type I/metabolism , CD36 Antigens/metabolism , Macrophages/immunology , Macrophages/metabolism , Tumor Microenvironment/immunologyABSTRACT
The emergence of SARS-CoV-2 variants of concern (VOCs) with increased transmissibility and partial resistance to neutralization by antibodies has been observed globally. There is an urgent need for an effective vaccine to combat these variants. Our study demonstrated that the B.1.351 variant inactivated vaccine candidate (B.1.351V) generated strong binding and neutralizing antibody responses in BALB/c mice against the B.1.351 virus and other SARS-CoV-2 variants after two doses within 28 days. Immunized K18-hACE2 mice also exhibited elevated levels of live virus-neutralizing antibodies against various SARS-CoV-2 viruses. Following infection with these viruses, K18-hACE2 mice displayed a stable body weight, a high survival rate, minimal virus copies in lung tissue, and no lung damage compared to the control group. These findings indicate that B.1.351V offered protection against infection with multiple SARS-CoV-2 variants in mice, providing insights for the development of a vaccine targeting SARS-CoV-2 VOCs for human use.
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Chlorogenic acid (CGA) is a polyphenol substance contained in many plants, which has good antioxidant activity. This experiment aimed to explore the protective effects of CGA on hydrogen peroxide(H2O2)-induced inflammatory response, apoptosis, and antioxidant capacity of bovine intestinal epithelial cells (BIECs-21) under oxidative stress and its mechanism. The results showed that compared with cells treated with H2O2 alone, CGA pretreatment could improve the viability of BIECs-21. Importantly, Chlorogenic acid pretreatment significantly reduced the formation of malondialdehyde (MDA), lowered reactive oxygen species (ROS) levels, and enhanced the activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-PX) (P<0.05). In addition, CGA can also improve the intestinal barrier by increasing the abundance of tight junction proteins claudin-1 and occuludin. Meanwhile, CGA can reduce the gene expression levels of pro-inflammatory factors Interleukin-6 (IL-6) and Interleukin-8 (IL-8), increase the expression of anti-inflammatory factor Interleukin-10 (IL-10), promote the expression of the nuclear factor-related factor 2 (Nrf2) signaling pathway, enhance cell antioxidant capacity, and inhibit Nuclear Factor Kappa B (NF-κB) the activation of the signaling pathway reducing the inflammatory response, thereby alleviating inflammation and oxidative stress damage.
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Multiple studies have documented low human papillomavirus (HPV) vaccine uptake among Chinese girls. It remains crucial to determine the parental willingness to pay (WTP) HPV vaccine for girls. We conducted a cross-sectional study recruiting 3904 parents with girls aged 9-14 in Shanghai, China, employing an online questionnaire with a convenience sampling strategy. Parental WTP, both range of payment and estimated point value, were determined for themselves (or wives) and daughters. HPV vaccine uptake was 22.44% in mothers and 3.21% in daughters. Respondents favored WTP ≤ 1000 CNY/138 USD for themselves (or wives), whereas showed increasing WTP along with valency of HPV vaccine for daughters (2-valent: 68.62% ≤1000 CNY/138 USD; 4-valent: 56.27% 1001-2000 CNY/138-277 USD; 9-valent: 65.37% ≥2001 CNY/277 USD). Overall, respondents showed higher WTP for daughters (median 2000 CNY/277 USD; IQR 1000-3600 CNY/138-498 USD) than for themselves (2000 CNY/277 USD; 1000-3500 CNY/138-483 USD) or wives (2000 CNY/277 USD; 800-3000 CNY/110-414 USD) (each p < .05). Furthermore, parental WTP was higher for international vaccine and 9-valent vaccine (each p < 0.05). Between two assumed government subsidy scenarios, parental preference for 9-valent vaccine remained consistently high for daughters (approximately 24% in each scenario), whereas preference for themselves (or wives) was sensitive to payment change between the subsidy scenarios. Using a discrete choice experiment, we found domestic vaccine was commonly preferred; however, certain sociodemographic groups preferred multivalent HPV vaccines. In conclusion, the valency of HPV vaccine may influence parental decision-making for daughters, in addition to vaccine price. Our findings would facilitate tailoring the HPV immunization program in China.
Subject(s)
Papillomavirus Infections , Papillomavirus Vaccines , Parents , Humans , Papillomavirus Vaccines/administration & dosage , Papillomavirus Vaccines/economics , Papillomavirus Vaccines/immunology , Female , China , Cross-Sectional Studies , Child , Adolescent , Papillomavirus Infections/prevention & control , Adult , Parents/psychology , Surveys and Questionnaires , Patient Acceptance of Health Care/statistics & numerical data , Vaccination/economics , Vaccination/psychology , Vaccination/statistics & numerical data , Male , Middle AgedABSTRACT
BACKGROUND: Hypertrophic scar (HTS) is dermal fibroproliferative disorder, which may cause physiological and psychological problems. Currently, the potential mechanism of WuFuYin (WFY) in the treatment of HTS remained to be elucidated. AIM: To explore the potential mechanism of WFY in treating HTS. METHODS: Active components and corresponding targets were retrieved from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform. HTS-related genes were obtained from the GeneCards, DisGeNET, and National Center for Biotechnology Information. The function of targets was analyzed by performing Gene Ontology and Kyoto Encyclopaedia of Genes and Genome (KEGG) enrichment analysis. A protein + IBM-protein interaction (PPI) network was developed using STRING database and Cytoscape. To confirm the high affinity between compounds and targets, molecular docking was performed. RESULTS: A total of 65 core genes, which were both related to compounds and HTS, were selected from multiple databases. PPI analysis showed that CKD2, ABCC1, MMP2, MMP9, glycogen synthase kinase 3 beta (GSK3B), PRARG, MMP3, and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit gamma (PIK3CG) were the hub targets and MOL004941, MOL004935, MOL004866, MOL004993, and MOL004989 were the key compounds of WFY against HTS. The results of KEGG enrichment analysis demonstrated that the function of most genes were enriched in the PI3K-Akt pathway. Moreover, by performing molecular docking, we confirmed that GSK3B and 8-prenylated eriodictyol shared the highest affinity. CONCLUSION: The current findings showed that the GSK3B and cyclin dependent kinase 2 were the potential targets and MOL004941, MOL004989, and MOL004993 were the main compounds of WFY in HTS treatment.
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The aim of this systematic review is to report the normal cortical development of different fetal cerebral fissures on ultrasound, describe associated anomalies in fetuses with cortical malformations, and evaluate the quality of published charts of cortical fissures. The inclusion criteria were studies reporting development, anomalies, and reference charts of fetal cortical structures on ultrasound. The outcomes observed were the timing of the appearance of different cortical fissures according to different gestational age windows, associated central nervous system (CNS) and extra-CNS anomalies detected at ultrasound in fetuses with cortical malformation, and rate of fetuses with isolated anomaly. Furthermore, we performed a critical evaluation of the published reference charts for cortical development on ultrasound. Random-effect meta-analyses of proportions were used to combine the data. Twenty-seven studies (6875 fetuses) were included. Sylvian fissure was visualized on ultrasound in 97.69% (95% CI 92.0-100) of cases at 18-19, 98.17% (95% CI 94.8-99.8) at 20-21, 98.94% (95% CI 97.0-99.9) at 22-23, and in all cases from 24 weeks of gestation. Parieto-occipital fissure was visualized in 81.56% (95% CI 48.4-99.3) of cases at 18-19, 96.59% (95% CI 83.2-99.8) at 20-21, 96.85% (95% CI 88.8-100) at 22-23, and in all cases from 24 weeks of gestation, while the corresponding figures for calcarine fissure were 37.27% (95% CI 0.5-89.6), 80.42% (95% CI 50.2-98.2), 89.18% (95% CI 74.0-98.2), and 96.02% (95% CI 96.9-100). Malformations of cortical development were diagnosed as an isolated finding at ultrasound in 6.21% (95% CI 2.9-10.9) of cases, while they were associated with additional CNS anomalies in 93.79% (95% CI 89.1-97.2) of cases. These findings highlight the need for large studies specifically looking at the timing of the appearance of the different brain sulci. Standardized algorithms for prenatal assessment of fetuses at high risk of malformations of cortical development are also warranted.
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Furcate cord insertion refers to the separation of umbilical vessels before reaching the placenta, where the branching vessels normally attach at the edge of the placental parenchyma or near the placental membranes. This is an extremely rare abnormal umbilical cord insertion. This paper reported a case of a furcate cord insertion, where the rupture of exposed umbilical vessels led to intrauterine fetal death at full term. Through literature review, we analyzed the prenatal ultrasound characteristics and pregnancy outcomes of furcate cord insertions, with the aim to improve detection rates and reduce the risk of adverse pregnancy outcomes.
Subject(s)
Fetal Death , Ultrasonography, Prenatal , Umbilical Cord , Humans , Female , Pregnancy , Umbilical Cord/abnormalities , Fetal Death/etiology , Adult , Placenta/blood supply , Placenta/pathologyABSTRACT
BACKGROUND: Numerous studies indicate that natural polysaccharides have immune-enhancing effects as a host defense potentiator. Few reports are available on hormetic effects of natural polysaccharides, and the underlying mechanisms remain unclear. PURPOSE: AELP-B6 (arabinose- and galactose-rich pectin polysaccharide) from Aralia elata (Miq.) Seem was taken as a case study to clarify the potential mechanism of hormetic effects of natural polysaccharides. METHODS: The pharmacodynamic effect of AELP-B6 was verified by constructing the CTX-immunosuppressive mouse model. The hormetic effects were explored by TMT-labeled proteomics, energy metabolism analysis, flow cytometry and western blot. The core-affinity target of AELP-B6 was determined by pull down, nanoLC-nanoESI+-MS, CETSA, immunoblot and SPR assay. The RAW264.7Clec4G-RFP and RAW264.7Rab1A-RFP cell lines were simultaneously constructed to determine the affinity difference between AELP-B6 and targets by confocal laser scanning live-cell imaging. Antibody blocking assays were further used to verify the mechanism of hormetic effects. RESULTS: AELP-B6 at low and medium doses may maintain the structural integrity of thymus and spleen, increase the concentrations of TNF-α, IFN-γ, IL-3 and IL-8, and alleviate CTX-induced reduction of immune cell viability in vivo. Proteomics and energy metabolism analysis revealed that AELP-B6 regulate HIF-1α-mediated metabolic programming, causing Warburg effects in macrophages. AELP-B6 at low and medium doses promoted the release of intracellular immune factors, and driving M1-like polarization of macrophages. As a contrast, AELP-B6 at high dose enhanced the expression levels of apoptosis related proteins, indicating activation of the intrinsic apoptotic cascade. Two highly expressed transmembrane proteins in macrophages, Clec4G and Rab1A, were identified as the primary binding targets of AELP-B6 which co-localized with the cell membrane and directly impacted with immune cell activation and apoptosis. AELP-B6 exhibits affinity differences with Clec4G and Rab1A, which is the key to the hormetic effects. CONCLUSION: We observed hormesis of natural polysaccharide (AELP-B6) for the first time, and AELP-B6 mediates the hormetic effects through two dose-related targets. Low dose of AELP-B6 targets Clec4G, thereby driving the M1-like polarization via regulating NF-κB signaling pathway and HIF-1α-mediated metabolic programming, whereas high dose of AELP-B6 targets Rab1A, leading to mitochondria-dependent apoptosis.
Subject(s)
Pectins , Animals , Mice , Pectins/pharmacology , Lectins, C-Type/metabolism , RAW 264.7 Cells , Energy Metabolism/drug effects , Polysaccharides/pharmacologyABSTRACT
The aim of this study was to explore the neuroprotective effects of the P2X7 receptor antagonist A740003 on retinal ganglion cells (RGCs) in chronic intraocular hypertension (COH) experimental glaucoma mouse model. Bioinformatics was used to analyze the glaucoma-related genes. Western blot, real-time fluorescence quantitative PCR, and immunofluorescence staining techniques were employed to explore the mechanisms underlying the neuroprotective effects of A740003 on RGCs in COH retinas. Bioinformatic analysis revealed that oxidative stress, neuroinflammation, and cell apoptosis were highly related to the pathogenesis of glaucoma. In COH retinas, intraocular pressure elevation significantly increased the levels of translocator protein, a marker of microglial activation, which could be reversed by intravitreal preinjection of A740003. A740003 also suppressed the increased mRNA levels of proinflammatory cytokines interleukin (IL) 1ß and tumor necrosis factor α in COH retinas. In addition, although the mRNA levels of anti-inflammatory cytokine IL-4 and IL-10 were kept unchanged in COH retinas, administration of A740003 could increase their levels. The mRNA and protein levels of Bax and cleaved caspase-3 were increased in COH retinas, which could be partially reversed by A740003, while the levels of Bcl-2 kept unchanged in COH retinas with or without the injections of A740003. Furthermore, A740003 partially attenuated the reduction in the numbers of Brn-3a-positive RGCs in COH mice. A740003 could provide neuroprotective roles on RGCs by inhibiting the microglia activation, attenuating the retinal inflammatory response, reducing the apoptosis of RGCs, and enhancing the survival of RGCs in COH experimental glaucoma.
Subject(s)
Glaucoma , Mice, Inbred C57BL , Neuroprotective Agents , Purinergic P2X Receptor Antagonists , Retinal Ganglion Cells , Animals , Retinal Ganglion Cells/drug effects , Retinal Ganglion Cells/metabolism , Retinal Ganglion Cells/pathology , Glaucoma/drug therapy , Glaucoma/metabolism , Neuroprotective Agents/pharmacology , Mice , Purinergic P2X Receptor Antagonists/pharmacology , Disease Models, Animal , Male , Benzopyrans/pharmacology , Neuroprotection/drug effects , Apoptosis/drug effects , Receptors, Purinergic P2X7/metabolism , Receptors, Purinergic P2X7/drug effects , Ocular Hypertension/drug therapy , Ocular Hypertension/metabolism , Intraocular Pressure/drug effects , CarbazolesABSTRACT
Multi-factor screenings are commonly used in diverse applications in medicine and bioengineering, including optimizing combination drug treatments and microbiome engineering. Despite the advances in high-throughput technologies, large-scale experiments typically remain prohibitively expensive. Here we introduce a machine learning platform, structure-augmented regression (SAR), that exploits the intrinsic structure of each biological system to learn a high-accuracy model with minimal data requirement. Under different environmental perturbations, each biological system exhibits a unique, structured phenotypic response. This structure can be learned based on limited data and once learned, can constrain subsequent quantitative predictions. We demonstrate that SAR requires significantly fewer data comparing to other existing machine-learning methods to achieve a high prediction accuracy, first on simulated data, then on experimental data of various systems and input dimensions. We then show how a learned structure can guide effective design of new experiments. Our approach has implications for predictive control of biological systems and an integration of machine learning prediction and experimental design.
Subject(s)
Computational Biology , Machine Learning , Computational Biology/methods , Models, Biological , Computer Simulation , Algorithms , Humans , Regression AnalysisABSTRACT
As a terrestrial ecosystem, alpine grasslands feature diverse vegetation types and play key roles in regulating water resources and carbon storage, thus shaping global climate. The dynamics of soil nutrients in this ecosystem, responding to regional climate change, directly impact primary productivity. This review comprehensively explored the effects of climate change on soil nitrogen (N), phosphorus (P), and their balance in the alpine meadows, highlighting the significant roles these nutrients played in plant growth and species diversity. We also shed light on machine learning utilization in soil nutrient evaluation. As global warming continues, alongside shifting precipitation patterns, soil characteristics of grasslands, such as moisture and pH values vary significantly, further altering the availability and composition of soil nutrients. The rising air temperature in alpine regions substantially enhances the activity of soil organisms, accelerating nutrient mineralization and the decomposition of organic materials. Combined with varied nutrient input, such as increased N deposition, plant growth and species composition are changing. With the robust capacity to use and integrate diverse data sources, including satellite imagery, sensor-collected spectral data, camera-captured videos, and common knowledge-based text and audio, machine learning offers rapid and accurate assessments of the changes in soil nutrients and associated determinants, such as soil moisture. When combined with powerful large language models like ChatGPT, these tools provide invaluable insights and strategies for effective grassland management, aiming to foster a sustainable ecosystem that balances high productivity and advanced services with reduced environmental impacts.
Subject(s)
Climate Change , Environmental Monitoring , Grassland , Machine Learning , Nitrogen , Phosphorus , Soil , Soil/chemistry , Nitrogen/analysis , Phosphorus/analysis , Environmental Monitoring/methods , Nutrients/analysis , EcosystemABSTRACT
Bacteria in nature often form surface-attached communities that initially comprise distinct subpopulations, or patches. For pathogens, these patches can form at infection sites, persist during antibiotic treatment, and develop into mature biofilms. Evidence suggests that patches can emerge due to heterogeneity in the growth environment and bacterial seeding, as well as cell-cell signaling. However, it is unclear how these factors contribute to patch formation and how patch formation might affect bacterial survival and evolution. Here, we demonstrate that a 'rich-get-richer' mechanism drives patch formation in bacteria exhibiting collective survival (CS) during antibiotic treatment. Modeling predicts that the seeding heterogeneity of these bacteria is amplified by local CS and global resource competition, leading to patch formation. Increasing the dose of a non-eradicating antibiotic treatment increases the degree of patchiness. Experimentally, we first demonstrated the mechanism using engineered Escherichia coli and then demonstrated its applicability to a pathogen, Pseudomonas aeruginosa. We further showed that the formation of P. aeruginosa patches promoted the evolution of antibiotic resistance. Our work provides new insights into population dynamics and resistance evolution during surface-attached bacterial growth.
Subject(s)
Anti-Bacterial Agents , Biofilms , Drug Resistance, Bacterial , Escherichia coli , Pseudomonas aeruginosa , Pseudomonas aeruginosa/drug effects , Pseudomonas aeruginosa/genetics , Pseudomonas aeruginosa/growth & development , Anti-Bacterial Agents/pharmacology , Escherichia coli/drug effects , Escherichia coli/genetics , Escherichia coli/growth & development , Biofilms/drug effects , Biofilms/growth & development , Drug Resistance, Bacterial/genetics , Models, Biological , Biological EvolutionABSTRACT
The kinetics of type I interferon (IFN) induction versus the virus replication compete, and the result of the competition determines the outcome of the infection. Chaperone proteins that involved in promoting the activation kinetics of PRRs rapidly trigger antiviral innate immunity. We have previously shown that prior to the interaction with MAVS to induce type I IFN, 14-3-3η facilitates the oligomerization and intracellular redistribution of activated MDA5. Here we report that the cleavage of 14-3-3η upon MDA5 activation, and we identified Caspase-3 activated by MDA5-dependent signaling was essential to produce sub-14-3-3η lacking the C-terminal helix (αI) and tail. The cleaved form of 14-3-3η (sub-14-3-3η) could strongly interact with MDA5 but could not support MDA5-dependent type I IFN induction, indicating the opposite functions between the full-length 14-3-3η and sub-14-3-3η. During human coronavirus or enterovirus infections, the accumulation of sub-14-3-3η was observed along with the activation of Caspase-3, suggesting that RNA viruses may antagonize 14-3-3η by promoting the formation of sub-14-3-3η to impair antiviral innate immunity. In conclusion, sub-14-3-3η, which could not promote MDA5 activation, may serve as a negative feedback to return to homeostasis to prevent excessive type I IFN production and unnecessary inflammation.
Subject(s)
14-3-3 Proteins , Caspase 3 , Interferon-Induced Helicase, IFIH1 , 14-3-3 Proteins/metabolism , Humans , Interferon-Induced Helicase, IFIH1/metabolism , Interferon-Induced Helicase, IFIH1/genetics , Caspase 3/metabolism , Immunity, Innate , HEK293 Cells , Animals , Signal Transduction , Interferon Type I/metabolismABSTRACT
Background: Stress hyperglycemia ratio (SHR) has shown a predominant correlation with transient adverse events in critically ill patients. However, there remains a gap in comprehensive research regarding the association between SHR and mortality among patients experiencing cardiac arrest and admitted to the intensive care unit (ICU). Methods: A total of 535 patients with their initial ICU admission suffered cardiac arrest, according to the American Medical Information Mart for Intensive Care (MIMIC)-IV database. Patients were stratified into four categories based on quantiles of SHR. Multivariable Cox regression models were used to evaluate the association SHR and mortality. The association between SHR and mortality was assessed using multivariable Cox regression models. Subgroup analyses were conducted to determine whether SHR influenced ICU, 1-year, and long-term all-cause mortality in subgroups stratified according to diabetes status. Results: Patients with higher SHR, when compared to the reference quartile 1 group, exhibited a greater risk of ICU mortality (adjusted hazard ratio [aHR] = 3.029; 95% CI: 1.802-5.090), 1-year mortality (aHR = 3.057; 95% CI: 1.885-4.958), and long-term mortality (aHR = 3.183; 95% CI: 2.020-5.015). This association was particularly noteworthy among patients without diabetes, as indicated by subgroup analysis. Conclusion: Elevated SHR was notably associated with heightened risks of ICU, 1-year, and long-term all-cause mortality among cardiac arrest patients. These findings underscore the importance of considering SHR as a potential prognostic factor in the critical care management of cardiac arrest patients, warranting further investigation and clinical attention.