Testing the generalizability and effectiveness of deep learning models among clinics: sperm detection as a pilot study.

BACKGROUND: Deep learning has been increasingly investigated for assisting clinical in vitro fertilization (IVF). The first technical step in many tasks is to visually detect and locate sperm, oocytes, and embryos in images. For clinical deployment of such deep learning models, different clinics use different image acquisition hardware and different sample preprocessing protocols, raising the concern over whether the reported accuracy of a deep learning model by one clinic could be reproduced in another clinic. Here we aim to investigate the effect of each imaging factor on the generalizability of object detection models, using sperm analysis as a pilot example. METHODS: Ablation studies were performed using state-of-the-art models for detecting human sperm to quantitatively assess how model precision (false-positive detection) and recall (missed detection) were affected by imaging magnification, imaging mode, and sample preprocessing protocols. The results led to the hypothesis that the richness of image acquisition conditions in a training dataset deterministically affects model generalizability. The hypothesis was tested by first enriching the training dataset with a wide range of imaging conditions, then validated through internal blind tests on new samples and external multi-center clinical validations. RESULTS: Ablation experiments revealed that removing subsets of data from the training dataset significantly reduced model precision. Removing raw sample images from the training dataset caused the largest drop in model precision, whereas removing 20x images caused the largest drop in model recall. by incorporating different imaging and sample preprocessing conditions into a rich training dataset, the model achieved an intraclass correlation coefficient (ICC) of 0.97 (95% CI: 0.94-0.99) for precision, and an ICC of 0.97 (95% CI: 0.93-0.99) for recall. Multi-center clinical validation showed no significant differences in model precision or recall across different clinics and applications. CONCLUSIONS: The results validated the hypothesis that the richness of data in the training dataset is a key factor impacting model generalizability. These findings highlight the importance of diversity in a training dataset for model evaluation and suggest that future deep learning models in andrology and reproductive medicine should incorporate comprehensive feature sets for enhanced generalizability across clinics.

Role of the RIP3-PGAM5-Drp1 pathway in aluminum-induced PC12 cells necroptosis.

Epidemiological studies from diverse global regions suggest a correlation between the accumulation of aluminum in the brain and the onset of various neurodegenerative diseases, including Alzheimer's disease, of which, neuronal cells death happen. Our previous research has found the potential of aluminum to induce neuronal cell death. A comprehensive exploration of the regulatory pathways influenced by aluminum in neuronal cell death could contribute to the development of strategies aimed at preventing the detrimental impact of aluminum on neuronal cells. This study is dedicated to exploring the impact of aluminum on mitochondrial homeostasis through the RIP3-PGAM5-Drp1 pathway, with a specific focus on its potential role in necroptosis. We observed that the inhibition of RIP3 function and the reduction in PGAM5 protein expression both mitigate aluminum-induced necroptosis in PC12 cells and enhance mitochondrial function. However, the inhibition of PGAM5 protein expression does not exert an impact on the expression of RIP3 and MLKL proteins. In summary, our study posits that aluminum can induce necroptosis in PC12 cells through the RIP3-PGAM5-Drp1 pathway.

Prognostic value of fibrinogen-to-albumin ratio combined with coronary calcification score in patients with suspected coronary artery disease.

OBJECTIVE: The aim of this work was to evaluate the predictive value of FAR combined with CACS for MACCEs. BACKGROUND: The fibrinogen-albumin-ratio (FAR), a novel biomarker of inflammation, is associated with the severity of coronary artery disease (CAD). Coronary calcification score (CACS) is associated with the severity of coronary stenosis and is closely related to the prognosis of CAD patients. What is the prognostic value of FAR in patients with chest pain, which has not been reported. This study aims to evaluate the relationship between CACS and FAR and their impact on prognosis in patients with suspected CAD. METHODS: We used information from 12,904 individuals who had coronary computed tomography angiography (CTA) for chest pain and tracked down any significant adverse cardiac and cerebrovascular events (MACCEs). The following formula was used to calculate FAR: fibrinogen (g/L)/albumin (g/L). Patients were separated into groups with greater levels of FAR (FAR-H) and lower levels of FAR (FAR-L) in accordance with the ideal cut-off value of FAR for MACCEs prediction. In addition, patients were divided into three groups based on their CACS scores (CACS ≤ 100, 100 < CACS ≤ 400, and CACS > 400). RESULTS: 4946 patients [62(55-71) years, 64.4% male] were ultimately enrolled in the present study. During follow-up, a total of 234 cases (4.7%) of MACCEs were documented. Linear regression analysis results showed that CACS (R2 = 0.004, Standard ß = 0.066, P < 0.001) was positively associated with FAR in patients with chest pain.Compared to ones with FAR-L, FAR-H had an increased risk for MACCEs (adjusted HR 1.371(1.053-1.786) P = 0.019). Multivariate Cox regression showed that age (adjusted HR 1.015 95% CI 1.001-1.028;p = 0.03), FAR (adjusted HR 1.355 95% CI 1.042-1.763;p = 0.023),FBG (adjusted HR 1.043 95% CI 1.006-1.083;p = 0.024) and CACS (adjusted HR 1.470 95% CI 1.250-1.727;p < 0.001) were the independent risk factors for MACCEs. The FAR and CACS significantly improved MACCEs risk stratification, contributing to substantial net reclassification improvement ( NRI 0.122, 95% CI 0.054-0.198, P < 0.001) and integrated discrimination improvement(IDI 0.011, 95% CI 0.006-0.017, P < 0.001). CONCLUSION: FAR was an independent risk factor for MACCEs. The results showed that CACS was positively associated with FAR in patients with suspected CAD. A higher level of FAR and heavier coronary calcification burden was associated with worse outcomes among patients with suspected CAD. FAR and CACS improved the risk identification of patients with suspected CAD, leading to a significant reclassification of MACCEs.

Staining-free, Automated Sperm Analysis for In Vitro Fertilization Lab Use.

PURPOSE: Computer-aided sperm analysis is typically used in andrology labs, not in in vitro fertilization labs, which requires staining for sperm morphology measurement. In in vitro fertilization labs, sperm analysis still relies on manual observation and suffers from subjectivity and inconsistency. We developed a system for automated measurement of sperm concentration, motility, and morphology without the need for sperm staining. The reproducibility and reliability of the system were evaluated. MATERIALS AND METHODS: Thirty-five fresh semen and 25 washed samples were obtained from male partners attending for fertility investigations. Sperm concentration, motility, and morphology were automatically measured simultaneously, leveraging robust sperm tracking for concentration and motility measurement and low contrast image segmentation for morphology measurement of live sperm. Reproducibility of sperm measurements was evaluated by intraclass correlation coefficients. Reliability of sperm measurement was evaluated by Passing and Bablok regression analysis and Bland-Altman analysis. RESULTS: Automated measurement of concentration, motility, and morphology had intraclass correlation coefficients higher than 0.97. The regression and Bland-Altman analysis indicated that automated measurement and off-line manual benchmarking with zoomed-in images were interchangeable. Further analysis on semen and washed samples and the measurement on progressive and nonprogressive motility also showed high reproducibility and reliability. CONCLUSIONS: Automated sperm analysis revealed high reproducibility and reliability. The system is designed for routine use in in vitro fertilization labs to perform quantitative sperm analysis on live samples.

Myeloid cell-targeted miR-146a mimic inhibits NF-κB-driven inflammation and leukemia progression in vivo.

NF-κB is a key regulator of inflammation and cancer progression, with an important role in leukemogenesis. Despite its therapeutic potential, targeting NF-κB using pharmacologic inhibitors has proven challenging. Here, we describe a myeloid cell-selective NF-κB inhibitor using an miR-146a mimic oligonucleotide conjugated to a scavenger receptor/Toll-like receptor 9 agonist (C-miR146a). Unlike an unconjugated miR146a, C-miR146a was rapidly internalized and delivered to the cytoplasm of target myeloid cells and leukemic cells. C-miR146a reduced expression of classic miR-146a targets (IRAK1 and TRAF6), thereby blocking activation of NF-κB in target cells. IV injections of C-miR146a mimic to miR-146a-deficient mice prevented excessive NF-κB activation in myeloid cells, and thus alleviated myeloproliferation and mice hypersensitivity to bacterial challenge. Importantly, C-miR146a showed efficacy in dampening severe inflammation in clinically relevant models of chimeric antigen receptor (CAR) T-cell-induced cytokine release syndrome. Systemic administration of C-miR146a oligonucleotide alleviated human monocyte-dependent release of IL-1 and IL-6 in a xenotransplanted B-cell lymphoma model without affecting CD19-specific CAR T-cell antitumor activity. Beyond anti-inflammatory functions, miR-146a is a known tumor suppressor commonly deleted or expressed at reduced levels in human myeloid leukemia. Using The Cancer Genome Atlas acute myeloid leukemia data set, we found an inverse correlation of miR-146a levels with NF-κB-related genes and with patient survival. Correspondingly, C-miR146a induced cytotoxic effects in human MDSL, HL-60, and MV4-11 leukemia cells in vitro. The repeated IV administration of C-miR146a inhibited expression of NF-κB target genes and thereby thwarted progression of disseminated HL-60 leukemia. Our results show the potential of using myeloid cell-targeted miR-146a mimics for the treatment of inflammatory and myeloproliferative disorders.

Targeted In Vivo Delivery of NF-κB Decoy Inhibitor Augments Sensitivity of B Cell Lymphoma to Therapy.

Despite recent advances, non-Hodgkin's B cell lymphoma patients often relapse or remain refractory to therapy. Therapeutic resistance is often associated with survival signaling via nuclear factor κB (NF-κB) transcription factor, an attractive but undruggable molecular target. In this study, we describe a bipartite inhibitor comprising a NF-κB-specific decoy DNA tethered to a CpG oligodeoxynucleotide (ODN) targeting Toll-like receptor-9-expressing B cell lymphoma cells. The Bc-NFκBdODN showed efficient uptake by human diffuse large B cell (U2932, OCI-Ly3), Burkitt (RaJi), and mantle cell (Jeko1) lymphomas, respectively. We confirmed that Bc-NFκBdODN inhibited NF-κB nuclear translocation and DNA binding, resulting in CCND2 and MYC downregulation. Bc-NFκBdODN enhanced radiosensitivity of lymphoma cells in vitro. In xenotransplanted human lymphoma, local injections of Bc-NFκBdODN reduced NF-κB activity in whole tumors. When combined with a local 3-Gy dose of radiation, Bc-NFκBdODN effectively arrested OCI-Ly3 lymphoma progression. In immunocompetent mice, intratumoral injections of Bc-NFκBdODN suppressed growth of directly treated and distant A20 lymphomas, as a result of systemic CD8 T cell-dependent immune responses. Finally, systemic administration of Bc-NFκBdODN to mice bearing disseminated A20 lymphoma induced complete regression and extended survival of most of the treated mice. Our results underscore clinical relevance of this strategy as monotherapy and in support of radiation therapy to benefit patients with resistant or relapsed B cell lymphoma.

Immunization of Vγ2Vδ2 T cells programs sustained effector memory responses that control tuberculosis in nonhuman primates.

Tuberculosis (TB) remains a leading killer among infectious diseases, and a better TB vaccine is urgently needed. The critical components and mechanisms of vaccine-induced protection against Mycobacterium tuberculosis (Mtb) remain incompletely defined. Our previous studies demonstrate that Vγ2Vδ2 T cells specific for (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBPP) phosphoantigen are unique in primates as multifunctional effectors of immune protection against TB infection. Here, we selectively immunized Vγ2Vδ2 T cells and assessed the effect on infection in a rhesus TB model. A single respiratory vaccination of macaques with an HMBPP-producing attenuated Listeria monocytogenes (Lm ΔactA prfA*) caused prolonged expansion of HMBPP-specific Vγ2Vδ2 T cells in circulating and pulmonary compartments. This did not occur in animals similarly immunized with an Lm ΔgcpE strain, which did not produce HMBPP. Lm ΔactA prfA* vaccination elicited increases in Th1-like Vγ2Vδ2 T cells in the airway, and induced containment of TB infection after pulmonary challenge. The selective immunization of Vγ2Vδ2 T cells reduced lung pathology and mycobacterial dissemination to extrapulmonary organs. Vaccine effects coincided with the fast-acting memory-like response of Th1-like Vγ2Vδ2 T cells and tissue-resident Vγ2Vδ2 effector T cells that produced both IFN-γ and perforin and inhibited intracellular Mtb growth. Furthermore, selective immunization of Vγ2Vδ2 T cells enabled CD4+ and CD8+ T cells to mount earlier pulmonary Th1 responses to TB challenge. Our findings show that selective immunization of Vγ2Vδ2 T cells can elicit fast-acting and durable memory-like responses that amplify responses of other T cell subsets, and provide an approach to creating more effective TB vaccines.

DNA-methylation-mediated activating of lncRNA SNHG12 promotes temozolomide resistance in glioblastoma.

BACKGROUND: Accumulating evidence shows that long noncoding RNAs (lncRNAs) are important regulator molecules involved in diverse biological processes. Acquired drug resistance is a major challenge in the clinical treatment of glioblastoma (GBM), and lncRNAs have been shown to play a role in chemotherapy resistance. However, the underlying mechanisms by which lncRNA mediates TMZ resistance in GBM remain poorly characterized. METHODS: Quantitative reverse transcription PCR (qRT-PCR) and fluorescence in situ hybridization assays were used to detect small nucleolar RNA host gene 12 (SNHG12) levels in TMZ-sensitive and TMZ-resistant GBM cells and tissues. The effects of SNHG12 on TMZ resistance were investigated through in vitro assays (western blots, colony formation assays, flow cytometry assays, and TUNEL assays). The mechanism mediating the high expression of SNHG12 in TMZ-resistant cells and its relationships with miR-129-5p, mitogen-activated protein kinase 1 (MAPK1), and E2F transcription factor 7 (E2F7) were determined by bioinformatic analysis, bisulfite amplicon sequencing, methylation-specific PCR, dual luciferase reporter assays, chromatin immunoprecipitation assays, RNA immunoprecipitation assays, immunofluorescence, qRT-PCR, and western blot. For in vivo experiments, an intracranial xenograft tumor mouse model was used to investigate SNHG12 function. RESULTS: SNHG12 was upregulated in TMZ-resistant cells and tissues. Overexpression of SNHG12 led to the development of acquired TMZ resistance, while knockdown of SNHG12 restored TMZ sensitivity. An abnormally low level of DNA methylation was detected within the promoter region of SNHG12, and loss of DNA methylation made this region more accessible to the Sp1 transcription factor (SP1); this indicated that methylation and SP1 work together to regulate SNHG12 expression. In the cytoplasm, SNHG12 served as a sponge for miR-129-5p, leading to upregulation of MAPK1 and E2F7 and endowing the GBM cells with TMZ resistance. Disinhibition of MAPK1 regulated TMZ-induced cell apoptosis and the G1/S cell cycle transition by activating the MAPK/ERK pathway, while E2F7 dysregulation was primarily associated with G1/S cell cycle transition. Clinically, SNHG12 overexpression was associated with poor survival of GBM patients undergoing TMZ treatment. CONCLUSION: Our results suggest that SNHG12 could serve as a promising therapeutic target to surmount TMZ resistance, thereby improving the clinical efficacy of TMZ chemotherapy.

Adoptive Transfer of Phosphoantigen-Specific γδ T Cell Subset Attenuates Mycobacterium tuberculosis Infection in Nonhuman Primates.

The dominant Vγ2Vδ2 T cell subset recognizes phosphoantigen and exists only in humans and nonhuman primates. Despite the discovery of γδ T cells >30 y ago, a proof-of-concept study has not been done to prove the principle that the Vγ2Vδ2 T cell subset is protective against Mycobacterium tuberculosis and other infections. In this study, we used an adoptive cell-transfer strategy to define the protective role of Vγ2Vδ2 T cells in a primate tuberculosis (TB) model. Vγ2Vδ2 T cells for adoptive transfer displayed central/effector memory and mounted effector functions, including the production of anti-M. tuberculosis cytokines and inhibition of intracellular mycobacteria. They also expressed CXCR3/CCR5/LFA-1 trafficking/tissue-resident phenotypes and consistently trafficked to the airway, where they remained detectable from 6 h through 7 d after adoptive transfer. Interestingly, the test group of macaques receiving transfer of Vγ2Vδ2 T cells at weeks 1 and 3 after high-dose (500 CFU) M. tuberculosis infection exhibited significantly lower levels of M. tuberculosis infection burdens in lung lobes and extrapulmonary organs than did the control groups receiving PBLs or saline. Consistently, adoptive transfer of Vγ2Vδ2 T cells attenuated TB pathology and contained lesions primarily in the infection site of the right caudal lung lobe, with no or reduced TB dissemination to other lobes, spleen, or liver/kidney; in contrast, the controls showed widespread TB dissemination. The proof-of-concept finding supports the view that the dominant Vγ2Vδ2 T cell subset may be included in the rational design of a TB vaccine or host-directed therapy.

B Cell Lymphoma Immunotherapy Using TLR9-Targeted Oligonucleotide STAT3 Inhibitors.

Growing evidence links the aggressiveness of non-Hodgkin's lymphoma, especially the activated B cell-like type diffuse large B cell lymphomas (ABC-DLBCLs) to Toll-like receptor 9 (TLR9)/MyD88 and STAT3 transcription factor signaling. Here, we describe a dual-function molecule consisting of a clinically relevant TLR9 agonist (CpG7909) and a STAT3 inhibitor in the form of a high-affinity decoy oligodeoxynucleotide (dODN). The CpG-STAT3dODN blocked STAT3 DNA binding and activity, thus reducing expression of downstream target genes, such as MYC and BCL2L1, in human and mouse lymphoma cells. We further demonstrated that injections (i.v.) of CpG-STAT3dODN inhibited growth of human OCI-Ly3 lymphoma in immunodeficient mice. Moreover, systemic CpG-STAT3dODN administration induced complete regression of the syngeneic A20 lymphoma, resulting in long-term survival of immunocompetent mice. Both TLR9 stimulation and concurrent STAT3 inhibition were critical for immune-mediated therapeutic effects, since neither CpG7909 alone nor CpG7909 co-injected with unconjugated STAT3dODN extended mouse survival. The CpG-STAT3dODN induced expression of genes critical to antigen-processing/presentation and Th1 cell activation while suppressing survival signaling. These effects resulted in the generation of lymphoma cell-specific CD8/CD4-dependent T cell immunity protecting mice from tumor rechallenge. Our results suggest that CpG-STAT3dODN as a systemic/local monotherapy or in combination with PD1 blockade can provide an opportunity for treating patients with B cell NHL.

Comparative Analysis of Transcriptome Responses to Cold Stress in Galeruca daurica (Coleoptera: Chrysomelidae).

Galeruca daurica (Joannis) has become a new insect pest in the Inner Mongolia grasslands since 2009, and its larvae and eggs have strong cold tolerance. To get a deeper insight into its molecular mechanisms of cold stress responses, we performed de novo transcriptome assembly for G. daurica by RNA-Seq and compared the transcriptomes of its larvae exposed to five different temperature treatments (-10, -5, 0, 5, and 25°C for 1 h and then recovered at 25°C for 1 h), respectively. Compared with the control (25°C), the numbers of differentially expressed genes (DEGs) decreased from 1,821 to 882, with the temperature declining from 5 to -10°C. Moreover, we obtained 323 coregulated DEGs under different low temperatures. Under four low temperatures (-10, -5, 0, and 5°C), a large number of genes were commonly upregulated during recovery from cold stresses, including those related to cuticle protein, followed by cytochrome P450, clock protein, fatty acid synthase, and fatty acyl-CoA reductase; meanwhile, lots of genes encoding cuticle protein, RNA replication protein, RNA-directed DNA polymerase, and glucose dehydrogenase were commonly downregulated. Our findings provide important clues for further investigations of key genes and molecular mechanisms involved in the adaptation of G. daurica to harsh environments.

Characterizing Inner Pressure and Stiffness of Trophoblast and Inner Cell Mass of Blastocysts.

It has long been recognized that mechanical forces underlie mammalian embryonic shape changes. Before gastrulation, the blastocyst embryo undergoes significant shape changes, namely, the blastocyst cavity emerges and expands, and the inner cell mass (ICM) forms and changes in shape. The embryo's inner pressure has been hypothesized to be the driving mechanical input that causes the expansion of the blastocyst cavity and the shape changes of the ICM. However, how the inner pressure and the mechanics of the trophoblast and the ICM change during development is unknown because of the lack of a suitable tool for quantitative characterization. This work presents a laser-assisted magnetic tweezer technique for measuring the inner pressure and Young's modulus of the trophoblast and ICM of the blastocyst-stage mouse embryo. The results quantitatively showed that the inner pressure and Young's modulus of the trophoblast and ICM all increase during progression of mouse blastocysts, providing useful data for understanding how mechanical factors are physiologically integrated with other cues to direct embryo development.

H19 Functions as a Competing Endogenous RNA to Regulate EMT by Sponging miR-130a-3p in Glioma.

BACKGROUND/AIMS: Glioma is one of the most devasting tumors and confers dismal prognosis. Long noncoding RNAs(lncRNAs) have emerged as important regulators in various tumors including glioma. A classic lncRNA-H19, which is found to be highly expressed in human glioma tissues and cell lines, and is associated with tumor progression thus predicating clinical outcomes in glioma patients. However, the overall biological functions and their mechanism of H19 in glioma are not fully understood. METHODS: Firstly, we analyzed H19 alterations in different grades of glioma tissues through an analysis of 5 sequencing datasets and qRT-PCR was performed to confirm the results. Next, we evaluated the effect of H19 on glioma cells migration, invasion and EMT process. Luciferase assays and RIP assays were employed to figure out the correlation of H19 and SOX4. RESULTS: H19 was overexpressed in glioma tissues. Down-regulation of H19 led to the inhibition of migration, invasion and EMT process with a reduction in N-cadherin and Vimentin. H19 and SOX4 are both direct target of miR-130a-3p. H19 could compete with SOX4 via sponging miR-130a-3p. CONCLUSION: Taken together, these results provide a possible function of H19 as an oncogene in glioma tissues and provide a potential new therapeutic strategy for human glioma.

FOXO1 Inhibits Tumor Cell Migration via Regulating Cell Surface Morphology in Non-Small Cell Lung Cancer Cells.

BACKGROUND/AIMS: Cell surface morphology plays pivotal roles in malignant progression and epithelial-mesenchymal transition (EMT). Previous research demonstrated that microvilli play a key role in cell migration of non-small cell lung cancer (NSCLC). In this study, we report that Forkhead box class O1 (FOXO1) is downregulated in human NSCLC and that silencing of FOXO1 is associated with the invasive stage of tumor progression. METHODS: The cell proliferation, migration, and invasion were characterized in vitro, and we tested the expression of the Epithelial-mesenchymal transition (EMT) marker by immunofluorescence staining and also identified the effect of FOXO1 on the microvilli by scanning electron microscopy (SEM). RESULTS: Functional analyses revealed that silencing of FOXO1 resulted in an increase in NSCLC cell proliferation, migration, and invasion; whereas overexpression of FOXO1 significantly inhibited the migration and invasive capability of NSCLC cells in vitro. Furthermore, cell morphology imaging showed that FOXO1 maintained the characteristics of epithelial cells. Immunofluorescence staining and western blotting showed that the E-cadherin level was elevated and Vimentin was reduced by FOXO1 overexpression. Conversely, the E-cadherin level was reduced and Vimentin was elevated in cells silenced for FOXO1. Furthermore, scanning electron microscopy (SEM) showed that FOXO1 overexpression increased the length of the microvilli on the cell surface, whereas FOXO1 silencing significantly reduced their length. CONCLUSIONS: FOXO1 is involved in human lung carcinogenesis and may serve as a potential therapeutic target in the migration of human lung cancer.

Synthesis and Characterization of Electron-Deficient Asymmetrically Substituted Diarylindenotetracenes.

Electron-deficient asymmetrically substituted diarylindenotetracenes were prepared via a series of Friedel-Crafts acylations, aryl-aryl cross-couplings, and an intramolecular oxidative cyclization to form the indene ring. Single-crystal X-ray experiments showed good π-π overlap with π-π distances ranging from 3.26 to 3.76 Å. Both thermogravimetric analysis and differential scanning calorimetry indicated that asymmetrically substituted indenotetracenes (ASIs) are stable at elevated temperatures. From cyclic voltammetry experiments, HOMO/LUMO energy levels of ASI derivatives were determined to be near -5.4/-4.0 eV. UV/visible absorption spectra showed strong absorption of light between 400 and 650 nm with molar attenuation coefficients from 104 to 105 M-1 cm-1. ASIs were also found to have very low fluorescence quantum yields, less than 4%. Using the solid-state packing determined from the single-crystal X-ray experiments, computational modeling indicated that ASI molecules should favor electron transport.

Interaction network analysis revealed biomarkers in myocardial infarction.

Myocardial infarction (MI) is a serious heart disease. The cardiac cells of patients with MI will die due to lack of blood for a long time. In this study, we aimed to find new targets for MI diagnosis and therapy. We downloaded GSE22229 including 12 blood samples from healthy persons and GSE29111 from Gene Expression Omnibus including 36 blood samples from MI patients. Then we identified differentially expressed genes (DEGs) in patients with MI compared to normal controls with p value < 0.05 and |logFC| > 1. Furthermore, interaction network and sub-network of these of these DEGs were constructed by NetBox. Linker genes were screened in the Global Network database. The degree of linker genes were calculated by igraph package in R language. Gene ontology and kyoto encyclopedia of genes and genomes pathway analysis were performed for DEGs and network modules. A total of 246 DEGs were identified in MI, which were enriched in the immune response. In the interaction network, LCK, CD247, CD3D, FYN, HLA-DRA, IL2, CD8A CD3E, CD4, CD3G had high degree, among which CD3E, CD4, CD3G were DEGs while others were linker genes screened from Global Network database. Genes in the sub-network were also enriched in the immune response pathway. The genes with high degree may be biomarkers for MI diagnosis and therapy.

LNC000152 Mediates Aluminum-Induced Proliferation of Reactive Astrocytes.

Aluminum is a metal element with significant neurotoxicity, and there is a substantial correlation between aluminum exposure and cognitive dysfunction. Glial fibrillary acidic protein (GFAP) is widely used as a marker of reactive astrocyte proliferation in response to pathological injury of the central nervous system. Studies of various neurodegenerative diseases have confirmed that the expression changes in GFAP are associated with nerve injury. We investigated the role of LNC000152 in the aluminum-induced reactive proliferation of astrocytes. By establishing two aluminum-exposed cell models of rat primary astrocytes and CTX-TNA2 cell lines, we examined the expression of LNC000152 and GFAP and detected cell proliferation with EdU and cell cycle changes with flow cytometry. The role of aluminum in promoting glial cell proliferation was verified; the expression levels of LNC000152 and GFAP increased with the concentration of aluminum exposure. Intervention of LNC000152 expression by siRNA technology revealed that LNC000152 affected glial cell responsive proliferation by influencing GFAP expression. These results suggest that LNC000152 plays a role in the reactive proliferation of astrocytes induced by aluminum.

Wheat peptides inhibit the activation of MAPK and NF-κB inflammatory pathways and maintain epithelial barrier integrity in NSAID-induced intestinal epithelial injury.

The use of non-steroidal anti-inflammatory drugs (NSAIDs) has negative effects on the gastrointestinal tract, but the proton pump inhibitors currently in use only protect against gastrointestinal disease and may even make NSAID-induced enteropathy worse. Therefore, new approaches to treating enteropathy are required. This study aimed to investigate the protective effect of wheat peptides (WPs) against NSAID-induced intestinal damage in mice and their mechanism. Here, an in vivo mouse model was built to investigate the protective and reparative effects of different concentrations of WPs on NSAID-induced intestinal injury. WPs ameliorated NSAID-induced weight loss and small intestinal tissue damage in mice. WP treatment inhibited NSAID-induced injury leading to increased levels of oxidative stress and expression levels of inflammatory factors. WPs protected and repaired the integrity and permeability injury of the intestinal tight junction induced by NSAIDs. An in vitro Caco-2 cell model was built with lipopolysaccharide (LPS). WP pretreatment inhibited LPS-induced changes in the Caco-2 cell permeability and elevated the levels of oxidative stress. WPs inhibited LPS-induced phosphorylation of NF-κB p65 and mitogen-activated protein kinase (MAPK) signaling pathways and reduced the expression of inflammatory factors. In addition, WPs increased tight junction protein expression, which contributed to improved intestinal epithelial dysfunction. Our results suggest that WPs can ameliorate NSAID-induced impairment of intestinal barrier functional integrity by improving intestinal oxidative stress levels and reducing inflammatory factor expression through inhibition of NF-κB p65 and MAPK signaling pathway activation. WPs can therefore be used as potential dietary supplements to reduce NSAID-induced injury of the intestine.

Correction: Wheat peptides inhibit the activation of MAPK and NF-κB inflammatory pathways and maintain epithelial barrier integrity in NSAID-induced intestinal epithelial injury.

Correction for 'Wheat peptides inhibit the activation of MAPK and NF-κB inflammatory pathways and maintain epithelial barrier integrity in NSAID-induced intestinal epithelial injury' by Zhiyuan Feng et al., Food Funct., 2024, https://doi.org/10.1039/D3FO03954D.

100 days of Adolescence: Elucidating Externalizing Behaviors Through the Daily Assessment of Inhibitory Control.

Inhibitory control is a transdiagnostic risk factor for externalizing behaviors, particularly during adolescence. Despite advances in understanding links between inhibitory control and externalizing behaviors across youth on average, significant questions remain about how these links play out in the day-to-day lives of individual adolescents. The goals of the current study were to: (1) validate a novel 100-occasion measure of inhibitory control; (2) assess links between day-to-day fluctuations in inhibitory control and individual differences in externalizing behaviors; and (3) illustrate the potential of intensive longitudinal studies for person-specific analyses of adolescent externalizing behaviors. Participants were 106 youth (57.5% female, Mage = 13.34 years; SDage = 1.92) who completed a virtual baseline session followed by 100 daily surveys, including an adapted Stroop Color Word task designed to assess inhibitory control. Results suggested that the novel task was generally reliable and valid, and that inhibitory control fluctuated across days in ways that were meaningfully associated with individual differences in baseline impulsive behaviors. Results of illustrative personalized analyses suggested that inhibitory control had more influence in the daily networks of adolescents who used substances during the 100 days than in a matched set of adolescents who did not. This work marks a path forward in intensive longitudinal research by validating a novel inhibitory control measure, revealing that daily fluctuations in inhibitory control may be a unique construct broadly relevant to adolescent externalizing problems, and at the same time, highlighting that links between daily inhibitory control and impulsive behaviors are adolescent-specific.